WO2003076416A1 - Oxo azabicyclic compounds - Google Patents
Oxo azabicyclic compounds Download PDFInfo
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- WO2003076416A1 WO2003076416A1 PCT/EP2002/003240 EP0203240W WO03076416A1 WO 2003076416 A1 WO2003076416 A1 WO 2003076416A1 EP 0203240 W EP0203240 W EP 0203240W WO 03076416 A1 WO03076416 A1 WO 03076416A1
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- 0 C*C(C)*C(*)=*C(C(C)=O)=C(C)N Chemical compound C*C(C)*C(*)=*C(C(C)=O)=C(C)N 0.000 description 9
- CREMAOVCPZRLIR-UHFFFAOYSA-N CN(CN1Cc(cc2)ccc2OC)c(ccc(C(NCc(cc2)ccc2OC)=O)c2)c2C1=O Chemical compound CN(CN1Cc(cc2)ccc2OC)c(ccc(C(NCc(cc2)ccc2OC)=O)c2)c2C1=O CREMAOVCPZRLIR-UHFFFAOYSA-N 0.000 description 1
- XAHHWERESZSTEA-UHFFFAOYSA-N COC(c(nc1)cc2c1N=CN(Cc1cccc(F)c1)C2=O)=O Chemical compound COC(c(nc1)cc2c1N=CN(Cc1cccc(F)c1)C2=O)=O XAHHWERESZSTEA-UHFFFAOYSA-N 0.000 description 1
- DOADCMDDDNIBIH-UHFFFAOYSA-N COc1ccc(CNC(c(cc2)cc3c2N=CN(Cc(cc2)ccc2OC)C3=O)=O)cc1 Chemical compound COc1ccc(CNC(c(cc2)cc3c2N=CN(Cc(cc2)ccc2OC)C3=O)=O)cc1 DOADCMDDDNIBIH-UHFFFAOYSA-N 0.000 description 1
- QPJVIYCYTOLCRY-UHFFFAOYSA-N COc1ccc(CNC(c(cc23)ccc2NCN(Cc(cc2)ccc2C(O)=O)C3=O)=O)cc1 Chemical compound COc1ccc(CNC(c(cc23)ccc2NCN(Cc(cc2)ccc2C(O)=O)C3=O)=O)cc1 QPJVIYCYTOLCRY-UHFFFAOYSA-N 0.000 description 1
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to novel oxo azabicyclic compounds which are useful for preparing medicinal products for treating complaints involving a therapy with a matrix metalloprotease-13 (MMP-13) inhibitor.
- MMP-13 matrix metalloprotease-13
- These medicinal products are useful in particular for treating certain mflammatory conditions such as rheumatoid arthritis or osteoarthritis, as well as certain proliferative conditions such as cancers.
- MMPs Matrix metalloproteases
- TMPs tissue inhibitors of metalloprotease
- MMP-13 matrix metalloprotease-13 is a collagenase-type MMP which constitutes the predominant collagenase observed during osteoarthritis, in the course of which pathology the chondrocyte directs the destruction of cartilage.
- MMP inhibitors in order to prevent and/or correct the imbalance in the renewal of extracellular matrix tissue, such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases (COPD), age-related macular degeneration (ARMD) and cancer.
- MMP-inhibitor compounds are known. Most of these MMP-inhibitors are not selective for a single MMP, such as those described by Montana and Baxter (2000) or by Clark et al. (2000).
- the compounds of the present application are novel and represent powerful inhibitors of MMP-13. They are consequently of use in the treatment of rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases (COPDs), age-related degeneration (ARMD) and cancer.
- the applicant has identified novel oxo azabicyclic compounds that are matrix metalloprotease inhibitors, and more specifically compounds that are selective MMP-13 inhibitors.
- Xi, X 2 , and X 3 independently of each other, represent a nitrogen atom or a group -CR 3 in which R 3 represents a group selected from hydrogen, (C ⁇ -C 6 )alkyl, amino, rnono ⁇ - C 6 )all-ylamino, d ⁇ -C ⁇ alkylamino, hydroxy, ( -C ⁇ alkoxy, and halogen, with the proviso that not more than two of the groups Xi, X 2 and X 3 simultaneously represent a nitrogen atom,
- G ⁇ represents a group selected from those of formulae (i/a) and (i/b):
- R 5 identical or different, independently of each other, represent a group selected from hydrogen, (d-C ⁇ alkyl, aryl, aryl(C ⁇ -C 6 )alkyl, cycloalkyl, cycloalkyl(C 1 -C 6 )alkyl, heteroaryl, heteroary ⁇ CrC ⁇ alkyl, heterocycloalkyl, and heterocycloalky ⁇ -C ⁇ alkyl,
- - Re represents a group selected from :
- ⁇ S hydrogen, trifluoromethyl, OR 7 , NR 7 Rs, in which R 7 and Rs, identical or different independently of each other, represent hydrogen or (C ⁇ -C 6 )alkyl, ⁇ (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, aryl(C ⁇ -C 6 )alkyl, cycloalkyl(C ⁇ -C 6 )alkyl, heteroaryl, heteroaryl(C ⁇ -C 6 )alkyl, heterocycloalkyl, and heterocycloalkyl(C ⁇ -C 6 )alkyl, these groups being optionally substituted by one or more groups, which may be identical or different independently of each other, selected from halogen, amino, mono(C ⁇ -C 6 )alkylamino, d ⁇ -C ⁇ alkylamino, each alkyl moiety being identical or different independently of each other, cyano,
- Yi represents a group selected from oxygen, sulphur, -NH and -N(C ⁇ -C6)alkyl
- Y 2 represents a group selected from oxygen, sulphur, -NH and -N(C 1 -Ce)alkyl
- n represents an integer from 0 to 6 inclusive
- hydrocarbon chain Z ⁇ optionally contains one to two isolated or conjugated multiple bonds
- one of said -CR9R10 may optionally be replaced with a group selected from oxygen, S(O) nl in which nl is as defined hereinbefore, -NH and -N(C C 6 )alkyl,
- A represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle,
- Ri represents a group selected from :
- hydrocarbon chain Z 2 optionally contains one or two isolated or conjugated multiple bonds
- one of said -CR ⁇ R 12 may optionally be replaced with a group selected from oxygen, S(O) n ⁇ in which nl is as defined hereinbefore, -NH, -N(C ⁇ -C 6 )alkyl, and carbonyl,
- V B represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle,
- V q is an integer from 0 to 7 inclusive
- - X 4 represents a group selected from oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by a hydrogen atom or a (C ⁇ -C 6 )alkyl group,
- - k is an integer from 0 to 3 inclusive
- - kl is an integer from 0 to 2 inclusive
- - k2 is an integer from 1 to 4 inclusive
- R 13 , R 1 and R ⁇ 5 which may be identical or different independently of each other, are selected from hydrogen and (d-C6)alkyl,
- Ri 6 represents a group selected from (d-C 6 )alkyl, -R 19 -NR 13 R 14 , in which R 19 represents a linear or branched (d-C 6 )alkylene group, and R ⁇ , R ⁇ 4 and R 15 are as defined hereinbefore,
- R 17 represents a (C 3 -C 6 )cycloalkyl group
- - X 5 represents a group selected from single bond, -CH 2 -, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (d-C 6 )alkyl group,
- - X 7 represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen atoms, and nitrogen substituted by hydrogen or (C 1 -C 6 )alkyl,
- - k is an integer from 0 to 3 inclusive
- R 7 and Rs which may be identical or different independently of each other, are selected from hydrogen and (d-C 6 )alkyl,
- - X 8 represents a group selected from single bond, -CH 2 -, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (d-C 6 )alkyl group,
- R 2 o represents 5- or 6-menbered monocycle aryl, heteroaryl, cycloalkyl, or heterocycloalkyl which is optionally substituted by one or more groups, which may be identical or different, selected from (C ⁇ -C 6 )alkyl, halogen, hydroxy and amino, and when the ring is heterocyclic, it comprises from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur,
- the invention relates to compounds of formula (I) wherein :
- the invention relates to compounds of formula (I) wherein :
- n represents an integer from 1 to 6 inclusive
- the invention relates to compounds of formula (I) wherein :
- A represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle,
- the invention relates to compounds of formula (I) wherein :
- Ri represents a hydrogen atom or a group of formula (i/d) :
- - X 4 represents a group selected from oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by a hydrogen atom or a (d-C 6 )alkyl group,
- - k is an integer from 0 to 3 inclusive
- - kl is an integer from 1 to 2 inclusive
- - k2 is an integer from 1 to 4 inclusive
- R13, R 14 and R 15 which may be identical or different independently of each other, are selected from hydrogen and (C ⁇ -C 6 )alkyl
- - R 16 represents a group selected from (d-C 6 )alkyl, -R ⁇ 9 -NR 13 R 14 , in which R 19 represents a linear or branched (d-C 6 )alkylene group, and R 13 , R ⁇ 4 and R 15 are as defined hereinbefore
- - R 17 represents a (C -C 6 )cycloalkyl group
- - X 5 represents a group selected from single bond, -CH 2 -, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (C ⁇ -C 6 )alkyl group,
- R ⁇ 8 represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl, these groups being 5- or 6-membered monocycle or bicycle composed of two 5- or
- substituent Rt that is preferred according to the invention is the group of formula (i/d):
- Z 2 represents a group -CR ⁇ R 12 in which Rn and R ⁇ 2 represents each a hydrogen atom.
- p, B, G 3 and q are as defined in the compound of formula (I).
- substituent Ri that is preferred according to the invention is the group of formula (i/d):
- substituent Ri that is preferred according to the invention is the group of formula (i/d) :
- B represents a phenyl group
- q is equal to 0 or 1
- the invention relates also to the compounds of formula (I) wherein Gi represents a group of formula (i/a) in which 1- represents a hydrogen atom or a methyl group, or a group of formula (i/b) in which and R , identical, represent each a hydrogen atom or a methyl group, and Re represents a hydrogen atom or a methyl group, and X ls X 2 , X 3 , G 2 , Z 1 ⁇ n, m and R 2 are as defined in formula (I).
- Preferred compounds of the invention are compounds of formula (I) wherein Xi represents a group -CR 3 in which R 3 represents a hydrogen atom, X 2 represents a nitrogen atom or a group -CR 3 in which R 3 represents a hydrogen atom, and X 3 represents a group -CR 3 in which R 3 represents a hydrogen atom.
- Other preferred compounds of the invention are compounds wherein G 2 represents a carbon-carbon triple bond or a group of formula (i/c) in which Y ⁇ represents an oxygen atom, and Y 2 represents a group -NH.
- Still more preferred compounds of the invention are those compounds of formula (I) wherein Zi represents -CR9R 1 0 in which R 9 and Rio represent each a hydrogen atom, and n is one.
- Especially preferred compounds of the invention are compounds wherein A represents a group selected from phenyl and pyridyl, m is zero or one, and R 2 represents a (C ⁇ -C 6 )alkoxy group or a hydrogen atom.
- the invention relates to the following compounds of formula (I) :
- optical isomers, the N-oxides, as well as the addition salts with a pharmaceutically- acceptable acid or base, of the preferred compounds form an integral part of the invention.
- the invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising as active ingredient an effective amount of a compound of formula (I) together with one or more pharmaceutically-acceptable excipients or carriers.
- Another embodiment of the invention concerns the use of the compound of formula (I) for the preparation of a medicinal product intended for treating a disease involving therapy by inhibition of matrix metalloprotease, and more particularly of type- 13 matrix metalloprotease.
- the invention also relates to a method for treating a living body afflicted with a disease involving a therapy by inhibition of matrix metalloprotease, and more particularly of type- 13 matrix metalloprotease, the said method comprising the administration of an effective amount of a compound of formula (I) to a patient in need thereof.
- a preferred method of treatment according to this invention is treatment of a disease selected from arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases, age-related degeneration and cancers.
- a disease selected from arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases, age-related degeneration and cancers.
- a preferred method of treatment according to this invention is treatment of disease selected from arthritis, osteoarthritis and rheumatoid arthritis.
- a (d-C6)alkyl group denotes a linear or branched group containing from 1 to 6 carbon atoms ; example of such groups, without implying any limitation are methyl, ethyl, propyl, isopropyl, tert-butyl, neopentyl, hexyl,
- - a (C 2 -C 6 )alkenyl group denotes a linear or branched group containing from 2 to 6 carbon atoms, and one or more double bonds ; examples of such groups without implying any limitation are vinyl, allyl, 3-buten-l-yl, 2-methyl-buten-l-yl, hexenyl, - a (C 2 -C )alkynyl group denotes a linear or branched group containing from 2 to 6 carbon atoms, and one or more triple bonds ; examples of such groups without implying any limitation are ethynyl, propynyl, 3-butyn-l-yl, 2-methyl-butyn-l-yl, hexynyl,
- - a (d-C6)alkoxy group means the alkyl group as mentioned above bound through an oxygen atom ; examples of such compounds without implying any limitation are methoxy, ethoxy, n-propyloxy, tert-butyloxy,
- - a mono(C ⁇ -C 6 )alkylamino denotes a amino group substituted by one (C ⁇ -C 6 )alkyl group as defined hereinbefore ;
- example of such groups, without implying any limitation are methyl amino, isobutyl amino, ethylamino, - a di(C ⁇ -C 6 )alkylamino denotes a amino group substituted by two (d-C ⁇ alkyl groups as defined hereinbefore, each alkyl group being identical or different ; example of such groups, without implying any limitation are dimethylamino, diethylamino,
- an aryl group denotes an aromatic monocyclic or bicyclic system containing from 5 to 10 carbon atoms, and in the case of a bicyclic system, one of the ring of which is aromatic in character, and the other ring of which may be aromatic or partially hydrogenated ; examples of such groups without implying any limitation are, phenyl, naphthyl, indenyl, benzocyclobutenyl,
- a heteroaryl group denotes an aryl group as described above in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen ; examples of such groups without implying any limitation are furyl, thienyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, quinolyl, isoquinolyl, benzodioxolyl, benzodioxinyl, benzo[l,2,5]thiadiazolyl, benzo[l,2,5]oxadiazolyl,
- a cycloalkyl group denotes a monocyclic or bicyclic system containing from 3 to 10 carbon atoms, this system being saturated or partially unsaturated but without aromatic character ; examples of such groups without implying any limitation are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, adamantyl, decalinyl, norbornyl,
- heterocycloalkyl group denotes a cycloalkyl group as defined hereinbefore in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms selected from oxygen, sulfur, and nitrogen,
- a bicycle denotes two fused-monocycle and, - a trihalogeno(C 1 -C6)alkyl group denotes an alkyl group as defined above which contains a trihalogeno group ; examples of such groups without implying any limitation are trifluoromethyl, 2,2,2-trifluoroethyl,
- - a (C ⁇ -C 7 )acyl group denotes an alkyl group or a aryl group as defined above bound through a carbonyl group ; examples of such groups without implying any limitation are acetyl, ethylcarbonyl, benzoyl,
- a multiple bond denotes double bond or triple bond
- a halogen atom means fluoro, chloro, bromo or iodo
- the invention also relates to the pharmaceutically acceptable salts of the compounds of formula (I).
- a review of the pharmaceutically acceptable salts will be found in J. Pharm. Sci., 1977, 66, 1-19.
- Pharmaceutically acceptable acids mean non-toxic salts derived from mineral or organic acids. Among those there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, nitric acid, citric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, benzoic acid, toluenesulfonic acid, etc...
- Pharmaceutically acceptable bases mean non-toxic salts derived from mineral or organic bases.
- the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (H):
- compounds of formulae (I/a), (I/b), (I/c) and (I/d) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into ⁇ -oxide thereof.
- the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (X):
- compounds of formula (I e) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
- An alternative way to obtain the compound of formula (XD-I/a) from compound of formula (XI) is described in the following scheme 1:
- compound of formula (XI) is treated with an aqueous solution of ammonium hydroxide to yield compound of formula (XVa) which is reacted with triethyl orthoformate in the presence of a catalytic amount of acid like r ⁇ -toluene sulfonic acid (PTSA).
- PTSA r ⁇ -toluene sulfonic acid
- the 3H-quinazolin-4-one (Xl/b) obtained is condensed in basic medium to a compound of formula Ri- ⁇ al, in which Ri is as defined in the compound of formula (I) and Hal represents a halogen, to yield the compound of formula (XHI/a),
- the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (Xi ⁇ /e) :
- the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (XHI/e) :
- compounds of formula (I/f) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
- the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (XLX) : in which Hal represents a halogen atom,
- compounds of formula (I/g) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
- the compounds of the invention that are present in the form of a mixture of diastereoisomers are isolated in a pure form by using conventional separation techniques such as chromatography.
- compounds of formula (I) of the present invention are matrix metalloprotease inhibitors, and more particularly inhibitors of the enzyme MMP- 13.
- the use of the compounds of the present invention may be recommended for the treatment of any pathology in which destruction of extracellular matrix tissue occurs, and most particularly pathologies such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease, age-related macular degeneration and cancers.
- pathologies such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease, age-related macular degeneration and cancers.
- the present invention also relates to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), an isomer thereof, aN-oxide thereof, or an addition salt thereof with a pharmaceutically-acceptable acid or base, alone or in combination with one or more pharmaceutically-acceptable, inert, non-toxic excipients or carriers.
- compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, intravaginal, rectal, nasal, perlingual, buccal, ocular or respiratory administration.
- compositions according to the invention for parenteral injections especially include aqueous and non-aqueous sterile solutions, dispersions, suspension and emulsions, and also sterile powders for reconstituting injectable solutions or dispersions.
- compositions according to the invention for oral administration in solid form especially include tablets or dragees, sublingual tablets, sachets, gelatin capsules and granules, for oral, nasal, buccal or ocular administration in liquid form, especially include emulsions, solutions, suspensions, drop, syrups and aerosols.
- compositions for rectal or vaginal administration are preferably suppositories, and those for per- or trans-cutaneous administration especially include powders, aerosols, creams, ointment, gels and patches.
- compositions mentioned hereinbefore illustrate the invention but do not limit it in any way.
- inert, non-toxic excipients or carriers there may be mentioned, by way of non-limiting example, diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, swelling agents, disintegrating agents, retardants, lubricants, absorbents, suspending agents, colourants, aromatizing agents etc...
- the useful dosage varies according to the age and weight of the patient, the administration route, the pharmaceutical composition used, the nature and severity of the disorder and the administration of any associated treatments.
- the dosage ranges from 2 mg to 1 g per day in one or more administrations.
- the compositions are prepared by methods that are common to those skilled in the art and generally comprise 0.5% to 60% by weight of active principle (compound of formula (I)) and 40% to 99.5% by weight of pharmaceutically acceptable excipients or carriers.
- the starting materials used are products that are known or that are prepared according to known operating procedures.
- the various preparations yield synthetic intermediates that are useful in preparation of the compounds of the invention. Some of these intermediates are new compounds.
- TOTU O-(ethoxycarbonyl)cyanomethylamino]-N-N-N'-N'-tetramethyl uronium fluoroborate
- DIPEA dusopropylethylamine
- Step 1 4-Amino-isophthalic acid
- Step 2 4-Amino-3-[(4-methoxy)-benzylcarbamoyl]-phenyl-l-carboxylic acid 4-methoxy- benzylamide
- Step 2 6-Amino-N-(4-methoxy-benzyl)-isophthalamic acid
- Step 3 Methyl 4- ⁇ [2-Amino-5-(4-methoxy-benzylcarbamoyl)-benzoylamino]-methyl ⁇ - benzoate
- the desired compound is obtained according to the procedure described in the Step 1 of Preparation 2 using as starting material the compound obtained in the preceding step 2 and as reactant the methyl 4-(aminomethyl)benzoate hydrochloride. It is purified by chromatography over silica gel using a mixture of dichloromethane/ether as eluant.
- Step 1 6-iodo-lH-henzo[a][l,3]oxazine ⁇ 2,4-dione
- Step 3 3-(4-fluorobenzyl)-6-iodo-3H-quinazotin-4-one
- Step 2 Methyl 4-(6-Iodo-4-oxo-4H-quinazolin-3-ylmethyl)-benzoate
- Step 1 6-Iodo-lH-pyrido[3,4-d][l,3]oxazine-2,4-dione
- 2-amino-5-iodo-isonicotinic acid (18.0 mmol) in H2O (20 ml) and concentrated HC1 (5 ml) is added dioxane (50 ml) until a clear solution is obtained.
- Neat diphosgene (5.95 g, 30.0 mmol) is added dropwise (with cooling at times so that the solution does not boil) until a precipitate formed.
- H2O 100 ml
- the filter cake is dried in vacuo to give the desired compound.
- Step 3 3-(4-Fluoro-benzyl)-6-iodo-3H-pyrido[3,4-d]pyrimidin-4-one
- Step 2 To a solution of the compound obtained in Step 2 (7.27 mmol) in triethyl orthoformate is added a catalytic amount of ⁇ r -toluenesulfonic acid. The solution is refluxed for 5 hours, and cooled to room temperature. After removal of all volatiles in vacuo, the residue is purified using flash chromatography on silica gel to give the desired compound.
- Step 1 Methyl 4- ⁇ [(5-Amino-2-iodo-pyridine-4-carbonyl)-amino]-methyl ⁇ -benzoate
- Step 2 Methyl 4-(6-Iodo-4-oxo-4H-pyrido[3,4-d]pyrimidin-3-ylmethyl)-benzoate
- Step 2 To a solution of the compound obtained in Step 1 (4.84 mmol) in triethyl orthoformate is added a catalytic amount of TsOH. The solution is refluxed for 5 hours, and cooled to room temperature. After removal of all volatile solvents in vacuo, the residue is purified using flash chromatography on silica gel to give the desired compound.
- the compound is obtained according to the procedure described in Preparation 7 but using in step 1 the compound obtained in Preparation 3 in which 4-(pyrrolidine-l-sulfonyl)- benzylamine is used in place of 4-fluorobenzylamine in the Step 2.
- the compound is obtained according to the procedure described in the second step of Example 3 using as substrate the compound obtained in the Example 5.
- Step 1 4-(6-Iodo-4-oxo-4H-quinazolin-3-ylmethyl)-benzoic acid
- Step 2 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid
- Example 13 4-[6-(3-phenyI-prop-l-ynyI)-4-oxo-4H-pyrido[3 5 4-dlpyrimidin- 3-ylmethyl]-benzoic acid
- Step 1 4-(6-Iodo-4-oxo-4H-pyrido[3,4--t pyrimidin-3-ylmethyl)-benzoic acid
- Example 1 4-Oxo-3-[4-(pyrrolidine-l-sulfonyl)-benzyll-3,4-dihydro-quinazoline- 6-carboxylic acid 4-methoxy-benzylamide
- the compound is obtained according to the procedure described in Example 14 using as substrate the compound obtained in Preparation 9 and 4-methoxybenzylamine.
- Example 17 4-[6-(3-Methoxy-benzylcarbamoyl)-4-oxo-4H-quinazoiin-3-ylmethylI- benzoic acid.
- the desired product is obtained by following the procedure of Example 14, except 4- flurobenzylamine in step 2 of the preparation 3 is replaced by tert-butyl 3-aminomethyl- benzoate, and at the end stirring the collected residue in an excess amount of trifluoroacetic acid for 30 minutes at room temperature. After removing the volatiles in vacuum, the residue is filtered to furnish the desired product as an off white solid.
- Example 18 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazoline-3-ylmethyll- benzoic acid
- Step 1 tert-Butyl 4-[4-oxo-6-(3 -phenyl-prop- 1 -ynyl)-4H-quinazoline-3 -ylmethyl] - benzoate
- Step 2 4-[4-oxo-6-(3 -phenyl-prop- 1 -ynyl)-4H-quinazoline-3 -ylmethyl] -benzoic acid
- the product is obtained by following the procedure of Example 18, the only difference is that 3 -phenyl- 1-propyne used in Step 1 is replaced by l-methoxy-4-prop-2-ynyl-benzene.
- the product is obtained as a white solid.
- Example 18 0.1 g (0.254 mmol) of the compound of Example 18 is suspended in 50 ml of dichloromethane. 35.4 mg of oxalyl chloride (0.279 mmol) is added, followed by 1 drop of DMF. The reaction is refluxed under nitrogen for 2 hours, and stirred at room temperature for an additional 12 hours. Then an excess amount of 0.5 M ammonia in dioxane is added. The reaction is stirred at room temperature for 1 hour. The solvent is then removed in vacuum and the residue is washed with 1:1 water:methanol to yield 70 mg of an off-white powder as the desired product.
- Step 2 Methyl 3-(3-fluorobenzyl)-4-oxo-3,4-dihydro-pyrido[3,4- ]pyrimidine-6- carboxylate
- Step 1 The compound obtained in the preceding Step 1 (3.0 g, 1.07 mmol), is dissolved in 50 ml of methanol, with an excess amount of triethylamine, and a catalytic amount of Pd(dppf)Cl 2 .
- the reaction solution is poured into an autoclave and heated at 100°C for 4 hours under the carbon monoxide atmosphere.
- the reaction is cooled to room temperature and filtered.
- the filtrate is concentrated in vacuum and the residue is purified on a silica gel column using 1 : 1 Hex:EtOAc to yield the desired product as a white solid (100%).
- Step 3 3-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide
- Example 25 4-[4-Oxo-6-(3-phenyl-propa-l,2-dienyl)-4H-quinazolin-3-ylmethyll- benzoic acid
- the inhibitory activity of the compounds of formula (I) according to the invention with respect to matrix metalloprotease-13 is evaluated by testing the ability of the compounds of the invention to inhibit the proteolysis of a peptide substrate with MMP- 13.
- the peptide substrate used in the test is the following peptide: Ac-Pro-Leu-Gly-thioester-
- the inhibitory activity of a compound of formula (I) according to the invention is expressed as the IC 50 value, which is the concentration of inhibitor for which an inhibition of 50% of the activity of the matrix metalloprotease under consideration is observed.
- reaction medium of 100 ⁇ l volume is prepared, containing: 50 mM of HEPES buffer, 10 mM of CaCl 2 and 1 mM of 5,5'-dithiobis-(2-nitrobenzoic acid)
- the concentrations of inhibitors present in the test samples range from 100 ⁇ M to 0.5 nM.
- the measurement of the proteolysis of the substrate peptide is monitored by measuring the absorbence at 405 nm using a spectrophotometer for reading microplates, at the laboratory temperature, the measurements being carried out continuously for 10 to 15 minutes.
- the IC 5 0 values are calculated from a curve in which the percentage of the catalytic activity relative to the control is represented on the X-axis and the concentration of inhibitor is represented on the Y-axis.
- the IC 5 0 values on MMP-13 of the compounds of Examples 1 to 10 are all below 1 ⁇ M.
- the test described above for the inhibition of MMP-13 was also adapted and used to determine the ability of the compounds of formula (I) to inhibit the matrix metalloproteases MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12 and MMP-14.
- the results obtained show that the compounds according to the invention generally have IC50 values for MMP-13 which are about 100 times lower than the IC 5 o values for the same compounds with respect to the other matrix metalloproteases tested.
Abstract
A compound selected from those of formula (I): 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): formula (II) 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)nt in which n1 represents an integer from 0 to 2 inclusive, or a group of formula (i/c): formula (III) 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): formula (IV) 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 mflammatory conditions such as rheumatoid arthritis or osteoarthritis, as well as certain proliferative conditions such as cancers.
TECHNOLOGICAL BACKGROUND OF THE INVENTION
Matrix metalloproteases (MMPs) are enzymes which are involved in the renewal of extracellular matrix tissue, such as cartilage, tendons and joints. MMPs bring about the destruction of the extracellular matrix tissue, which is compensated for, in a non- pathological physiological state, by its simultaneous regeneration.
Under normal physiological conditions, the activity of these extremely aggressive peptidases is controlled by specialized proteins which inhibit MMPs, such as the tissue inhibitors of metalloprotease (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 -mtifungic 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:
• Xi, X2, and X3, independently of each other, represent a nitrogen atom or a group -CR3 in which R3 represents a group selected from hydrogen, (Cι-C6)alkyl, amino, rnono^- C6)all-ylamino, d^ -C^alkylamino, hydroxy, ( -C^alkoxy, and halogen, with the proviso that not more than two of the groups Xi, X2 and X3 simultaneously represent a nitrogen atom,
• G\ 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, i and R5, identical or different, independently of each other, represent a group selected from hydrogen, (d-C^alkyl, aryl, aryl(Cι-C6)alkyl, cycloalkyl, cycloalkyl(C1-C6)alkyl, heteroaryl, heteroary^CrC^alkyl, heterocycloalkyl, and heterocycloalky^ -C^alkyl,
- Re represents a group selected from :
■S hydrogen, trifluoromethyl, OR7, NR7Rs, in which R7 and Rs, identical or different independently of each other, represent hydrogen or (Cι-C6)alkyl, ✓ (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(Cι-C6)alkyl, cycloalkyl(Cι-C6)alkyl, heteroaryl, heteroaryl(Cι-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, d^ -C^alkylamino, each alkyl moiety being identical or different independently of each other, cyano,
trihalogeno^r 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-, C=O, C=S, S(O)nl in which nl represents an integer from 0 to 2 inclusive, and a group of formula (i/c):
• n represents an integer from 0 to 6 inclusive,
• Zi represents -CR9Rlυ) wherein R9 and Rto, identical or different independently of each other, represent a group selected from hydrogen,
halogen, -OR7, -SR7, and -C(=O)OR7, in which R7 is as defined hereinbefore, amino, mono^-C^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 -CR9R10 may optionally be replaced with a group selected from oxygen, S(O)nl in which nl is as defined hereinbefore, -NH and -N(C 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-C6)alkyl, (C2-C6)alkenyl, (C -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(d-C6)alkyl, cycloalkyl, -C(=O)NR7R8, -C(=O)OR8, OR8) SRs, 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,
S Z2 represents -CRnR12 wherein Rπ and R12, 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 -CRπR12 may optionally be replaced with a group selected from oxygen, S(O)nι in which nl is as defined hereinbefore, -NH, -N(Cι-C6)alkyl, and carbonyl,
V B represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- membered monocycle,
V q is an integer from 0 to 7 inclusive,
the group(s) G3, which may be identical or different independently of each other, is (are) selected from (Cι-C6)alkyl, halogen, CN, NO2, CF3, OCF3, -(CH2)kNR13Rι4,
-N(Rι3)C(=O)OR14, -N(Rι3)SO2R14, -N(SO2R13)2, -OR13, -S(O)klR13, -SO2-N(R13)-(CH2)k2-NRι4Ri5, -(CH2)kSO2NR13R14,
-X4(CH2)kC(-O)OR13, -(CH2)kC(=O)OR13, -C(=O)O-(CH2)k2-NR13R14,
-R17-C(=O)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,
- R13, R1 and Rι5, which may be identical or different independently of each other, are selected from hydrogen and (d-C6)alkyl,
- Ri6 represents a group selected from (d-C6)alkyl, -R19-NR13R14,
in which R19 represents a linear or branched (d-C6)alkylene group, and Rι , Rι4 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,
- R18 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 (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 (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, - SRs, -SORs, -SO2R8, -(CH2)kSO2NR7R8, -X7(CH2)kC(=O)OR8, -(CH2)kC(=O)OR8, -X7(CH2)kC(=O)NR7R8, -(CH2)kC(=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 (C1-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 (d-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 (d-C6)alkyl group,
- R2o 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 :
• G 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/c) Y. 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 Y represents a group selected from oxygen, sulphur, -NH and -N(Cι-C6)alkyl,
• Xi, X2, X3, Gi, n, Zi, A, Ri, 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, X3, Gi, Zi, A, R1; 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, X3, 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,
• Z\ is absent,
• A represents a phenyl group,
• Ri represents a hydrogen atom or a group of formula (i/d) :
V in which p is an integer from 0 to 8 inclusive, Z2 represents -CRnRι2 wherein Rn and Rι2, 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 (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 -CR11R12 may optionally be replaced with a group selected from oxygen, S(O)nι in which nl is as defined hereinbefore, -NH, -N(Cι-C6)alkyl, and carbonyl, X 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(RB)SO2Rι4, -N(SO2R13)2, -S(O)kιR13, -SO2-N(Rι3)-(CH2)k2-NR14Ri5, -(CH2)kSO2NR13Rι4, -X4(CH2)kC(=O)ORι3, -(CH2)kC(=O)OR13, -C(=O)O-(CH2)k2-NR13Rι ,
-R17-C(=O)OR13, -X5-R18, -C(=O)-R19-NRι3R14 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 (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 R15. which may be identical or different independently of each other, are selected from hydrogen and (Cι-C6)alkyl,
- R16 represents a group selected from (d-C6)alkyl, -Rι9-NR13R14,
in which R19 represents a linear or branched (d-C6)alkylene group, and R13, Rι4 and R15 are as defined hereinbefore, - R17 represents a (C -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 (Cι-C6)alkyl group,
Rι8 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 (d-C6)alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and -C(=O)OR7 wherein R7 represents hydrogen or (Cι-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 (Cι-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 (d-C6)alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and -C(=O)OR7 wherein R7 represents hydrogen or (d-C6)alkyl, • and Xi, X2, X3, Gls 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):
More particularly, the substituent Rt that is preferred according to the invention is the group of formula (i/d):
More particularly, the substituent Ri that is preferred according to the invention is the group of formula (i/d):
More particularly, the substituent Ri that is preferred according to the invention is the group of formula (i/d) :
The invention relates also to the compounds of formula (I) wherein Gi represents a group of formula (i/a) in which 1- represents a hydrogen atom or a methyl group, or a group of formula (i/b) in which and R , identical, represent each a hydrogen atom or a methyl group, and Re represents a hydrogen atom or a methyl group, and Xls X2, X3, G2, Z1} 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 Yι represents an oxygen atom, and Y2 represents a group -NH.
Still more preferred compounds of the invention are those compounds of formula (I) wherein Zi represents -CR9R10 in which R9 and Rio represent each a hydrogen atom, and n is one.
Especially preferred compounds of the invention are compounds wherein A represents a group selected from phenyl and pyridyl, m is zero or one, and 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)-l-methyl-4-oxo-l,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide
3-(4-methoxy-benzyl)-l,2,2-trimethyl-4-oxo-l,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)-l-methyl-4-oxo-l,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- yrrolidme-l-sulfonyl)-benzyl]-3,4-dihydro-quinazohne-6-carboxylic acid 4-methoxy-benzylamide
- 4-[6-(3-memoxy-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-mhydro-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.
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-l-ynyl)-3H-pyrido[354-- lpyrimidin-4-one, - methyl 4-[6-(3-phenyl-prop-l-ynyl)-4-oxo-4H-pyrido[3,4--i]pyrimidin-3-yhnethyl]- benzoate,
- 4-[6-(3-phenyl-prop-l-ynyl)-4-oxo-4H-pyrido[3,4-J]pyrimidin-3-ylmethyl]-benzoic acid,
- 4- [4-oxo-6-(3 -phenyl-prop- 1 -ynyl)-4Η-quinazoline-3 -ylmethyl] -benzoic acid, - 4- {6-[3 -(4-methoxy-phenyl)-prop- 1 -ynyl] -4-oxo-4H-quinazoline-3 -ylmethyl} -benzoic acid,
- 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazoline-3-ylmethyl]-benzamide
- and 3 -[(3 , 5 -difluoro-4-hydroxy)-benzyl] -6-(3 -phenyl-prop- 1 -ynyl)-3H-quinazolin-4- one.
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 (d-C6)alkyl group denotes a linear or branched group containing from 1 to 6 carbon atoms ; example of such groups, without implying any limitation are methyl, ethyl, propyl, isopropyl, tert-butyl, neopentyl, hexyl,
- a (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-C )alkynyl group denotes a linear or branched group containing from 2 to 6 carbon atoms, and one or more triple bonds ; examples of such groups without implying any limitation are ethynyl, propynyl, 3-butyn-l-yl, 2-methyl-butyn-l-yl, hexynyl,
- a (d-C6)alkoxy group means the alkyl group as mentioned above bound through an oxygen atom ; examples of such compounds without implying any limitation are methoxy, ethoxy, n-propyloxy, tert-butyloxy,
- a mono(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 (d-C^alkyl groups as defined hereinbefore, each alkyl group being identical or different ; example of such groups, without implying any limitation are dimethylamino, diethylamino,
- an aryl group denotes an aromatic monocyclic or bicyclic system containing from 5 to 10 carbon atoms, and in the case of a bicyclic system, one of the ring of which is aromatic in character, and the other ring of which may be aromatic or partially hydrogenated ; examples of such groups without implying any limitation are, phenyl, naphthyl, indenyl, benzocyclobutenyl,
- a heteroaryl group denotes an aryl group as described above in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen ; examples of such groups without implying any limitation are furyl, thienyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, quinolyl, isoquinolyl, benzodioxolyl, benzodioxinyl, benzo[l,2,5]thiadiazolyl, benzo[l,2,5]oxadiazolyl,
- a cycloalkyl group denotes a monocyclic or bicyclic system containing from 3 to 10 carbon atoms, this system being saturated or partially unsaturated but without aromatic character ; examples of such groups without implying any limitation are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, adamantyl, decalinyl, norbornyl,
- 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(C1-C6)alkyl group denotes an alkyl group as defined above which contains a trihalogeno group ; examples of such groups without implying any limitation are trifluoromethyl, 2,2,2-trifluoroethyl,
- a (Cι-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 (H):
compound of formula (II) which is treated with a compound of formula (US):
by activating the acid function with an activator, in the presence of dusopropylethylamine and a solvent, to yield the compound of formula (IV) :
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 Ri-NH2 in which Ri is as defined in the compound of formula (I),
to yield the compound of formula (V) :
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, X , X3, Yl5 Y2, Zl5 R2, Ri, A, n and m are as defined hereinbefore,
• or under heating condition in the presence of acid, with a compound of formula (NI):
• or with a compound of formula (Nil) in basic condition:
R< Rs W
O in which J 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):
Re-Hal CVUI) 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):
compounds of formulae (I/a), (I/b), (I/c) and (I/d) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into Ν-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):
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):
which compound of formula (XII) is treated: • either with triethyl orthoformate under heating condition, to yield the compound of formula (XHI/a) :
• or under heating condition in the presence of an acid, with a compound of formula (NI):
• or with a compound of formula (Nil) in basic conditions:
to yield the compound of formula (XIII/c)
which compound of formula (XIII/c) is optionally treated with a hydride, in the presence of a compound of formula (Vπi):
Rθ-Hal (NIII) in which Re has the same definition as the compound of formula (I), and Hal is a halogen atom, to yield the compound of formula (Xπi/d), which is a particular case of the compound of formula (I):
all compounds of formulae (Xm/a), (XTTI/b), (XIII c) and (Xffl/d) constitute the compound of formula (XIQ/e):
compound of formula (Xffl/e) which is treated under conditions of palladium-catalyzed alkynylation with a compound of formula (XIV):
to yield the compound of formula (Ve), which is a particular case of the compound of formula (I):
Scheme 1
Wherein Xi, X , X3, 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 (XVa) which is reacted with triethyl orthoformate in the presence of a catalytic amount of acid like rα-toluene sulfonic acid (PTSA). The 3H-quinazolin-4-one (Xl/b) obtained is condensed in basic medium to a compound of formula Ri-Ηal, in which Ri is as defined in the compound of formula (I) and Hal represents a halogen, to yield the compound of formula (XHI/a),
The invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (Xiπ/e) :
to yield the compound of formula (Ve), which is a particular case of 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 (XHI/e) :
compound of formula (XHI/e) 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 (XNI):
compound of formula (XVI) which is hydrolysed under basic medium to yield the compound of formula (XVII):
compound of formula (XVII) which is condensed under basic medium in the presence of a Mukayama reagent, on the compound of formula (XVHI):
to yield the compound of formula (I/f), which is a particular case of 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 (XLX) :
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):
compound of formula (XX) which is treated in basic medium with a compound of formula Ri-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):
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):
to yield the compound of formula (I g), which is a particular case of the compound of formula (I):
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, aN-oxide thereof, or an addition salt thereof with a pharmaceutically-acceptable acid or base, alone or in combination with one or more pharmaceutically-acceptable, inert, non-toxic excipients or carriers.
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'-tetramethyl uronium fluoroborate,
- DIPEA means dusopropylethylamine.
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 st red 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 (DMSO-έfc) 1H δ (ppm ) : 6.80 (d,lH); 6.80-7.80 (bs); 7.80 (dcLlH); 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 2.1 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 (DMSO-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) ; 8J5 (t,lH)
Preparation 2 : Methyl 4-{[2-Amino-5-(4-methoxy-benzyIcarbamoyl)-benzoylamino]- methylj-benzoate
Step 1 : Methyl 6-Amino-N-(4-methoxy-benzyl)-isophthalate
6.56 g (20 mmol) of TOTU and 2.6 ml (2J4 g, 20 mmol) of 4- methoxybenzylamine are added to a stirred solution of 4.2 g (18.1 mmol) of 4-amino-3-methylcarboxylate-l -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 (^6^=62%) of the desired compound are isolated. TLC : CH2Cl2/MeOH 90/10 Rf = 0.80
N.M.R (OMSO-dβ) 1H 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,lH). PURITY : HPLC = 98.5%
Step 2 : 6-Amino-N-(4-methoxy-benzyl)-isophthalamic acid
0.3 g (7 mmol) of LiOH, H ■2tO is adxded to a stirred soluxtion 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-ck) 1H δ (ppm) : 3J0 (s,3H) ; 4.35 (d,2H) ; 6J5 (d,lH) ; 6.85 (d,2H) ; 7.20 (d,2H) ; 7J5 (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-d6) 1H 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-quinazolin-4-one
Step 1 : 6-iodo-lH-henzo[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 (DMSO-- ) 1H δ (ppm) : 6.93 (d, J= 8.6 Hz, 1H), 8.00 (dd, J = 8.6, 2.0 Hz, 1H), 8.10 (d, j= 2.0 Hz, 1H), 11.8 (s, 1H);
MS (APCD, 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 (CO2), 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-- ) 1H 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,j = 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-quinazotin-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--itf) 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 CH2C12 and H2O. After separation, the organic layer is washed with H2O three times to remove DMF. It is then washed with brine, dried (Na SO4), filtered and concentrated in vacuo to give the desired amide as a brown solid (2.0 g, quantitative). N.M.R (DMSO-ct ) 1H δ (ppm) : 3.31 (s, 3H), 4.36 (d, J= 5.9 Hz, 2H), 6.55 (d, J= 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) 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-pyrido[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
Step 3 : 3-(4-Fluoro-benzyl)-6-iodo-3H-pyrido[3,4-d]pyrimidin-4-one
Preparation 6 : Methyl 4-(6-Iodo-4-oxo-4/-^pyrido[3,4-./]pyrimidin-3-ylmethyl)- benzoate
Step 1 : Methyl 4-{[(5-Amino-2-iodo-pyridine-4-carbonyl)-amino]-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 (Na2SO_ι), 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-FIuoro-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
Preparation 8 : 3-(4-MethanesuIfonyl-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-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-(pyrrolidine-l-sulfonyl)- benzylamine is used in place of 4-fluorobenzylamine in the Step 2.
Preparation 10 : fert-butyl 4-(6-iodo-4-oxo-4H-quinazolin-3-ylmethyl)-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-- ) 1H δ (ppm) : 6.50 (d, J= 8.8Hz, IH), 6.68 (s, 2H), 7.12 (s, IH), 7.33 (dd, Ji = 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 (DMSO--?«j) 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
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, Ji = 6.6Hz, J2 = 3.1Hz, 2H), 8.01 (dd, Ji = 6.5Hz, J2 = 2.1Hz, IH), 8.07 (s, IH), 8.64 (d, J= 1.8Hz, IH)
Example 1 : 3-(4-Metb.oxy-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxyHc acid 4-methoxy-benzylamide
N.M.R (DMSO-- ) 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) ; 7J5 (d,lH) ; 8.25 (d,lH) ; 8.65 (s,lH) ; 8J0 (s,lH) ; 9.25 (t,lH)
IR : 3282, 1661, 1606, 1513, 1248, 1032, 841 cm"1 MP = 169°C PURITY : HPLC = 96.7%
Example : 3-(4-Metb.oxy-benzyl)-2-methyl-4-oxo-3,4-dib.ydro-quinazoHne-6- carboxylic acid 4-methoxy-benzylamide, 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 recrystalhzed from acetonitrile to yield the desired compound. TLC : CH2Cl2/MeOH 90/10 Rf = 0.56
N.M.R (DMSO-d6) 1H 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).
IR : 3282, 1702, 1648, 1634, 1547, 1512, 1250, 1178 , 1035, 793 cm"1
MP = 208°C
PURITY : HPLC = 98.9%
Example 3 : 3-(4-Methoxy-benzyl)-l-methyl-4-oxo-1^2;,3,4-tetrahydrQ-quinazoπne- 6-carboxylic acid 4-metnoxy-benzylajmide
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 (DMSO-de) 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-MethQxy-benzyl)-l,2,2-trimethyl-4-oxo-l,2,3,4-tetrahydro- quinazoline-6-carboxylic acid 4-methoxy-benzylamide
N.M.R (DMSO- ) 1H δ (ppm) : 1.40 (s,6H) ; 2.90 (s,3H) ; 3J5 (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-Metlιoxy-benzyIcarbamoyl)-4-oxo-l,4-dihydro^2Jιf-quinazolin-' 3-yImethyl]-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-dβ) 1H δ (ppm) : 3 JO (s,3H) ; 4.35 (d,2H) ;4.60 (s,2H); 4J0 (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-raethyl-4-oxo-l,4- dihydro-2JET-quinazolin-3-ylmethyll-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 /l 0 Rf = 0.70
N.M.R (DMSO--ftf) 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 Ϊ 4-I6-(4-Methoxy-benzylcarbamoyl)-l-methyI-4-oxo-ls4-dihydro-2BT- quinazolin-3-ylmethyll-benzoic acid
Preparation 5 using as substrate the compound of Example 6.
TLC : CH2Cl2/MeOH 90/10 Rf = 0.35
N.M.R (DMSO-- ) 1H δ (ppm) : 2.85 (s,3H) ; 3J0 (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-ynyI)-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 n-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 ϊ Methyl 4-[4-Oxo-6-(3-phenyl-prop-l-ynyI)-4H-quinazolin-3-y!methyI] -benzoate
N.M.R (CDCI3) 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-phenyI-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 Preparation 4 (2.25 g, 5.36 mmol) in 10% Η2O 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 (DMSO-έfc) 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
N.M.R (DMSO-d6) 1H 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, Ji=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-ynyl)-3H-pyrido[3,4-d] pyrιmidin-4-one
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 n-BuLi to the -78°C solution of benzylacetylene, followed by quenching with tributyltin chloride) is added catalytic amount of PdCl2(Ph.3P)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-phenyI-prop-l-ynyI)-4-oxo-4H-pyrido[354-dlpyrimidin- 3-ylmethyl]-benzoic acid
Step 1: 4-(6-Iodo-4-oxo-4H-pyrido[3,4--t 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 (MgSO-i) 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-l-ynyl)-4-oxo-4H-pyrido[3,4--^ρyrimidin-3-yhnethyl]- benzoic acid
To a solution of the compound obtained in Step 1 (0.739 mmol) in 6.5 ml of DMF, is added dusopropylethylamine (0.381 g, 2.96 mmol), Cul (catalytic amount), 3-phenyl-
1-propyne (0.120 g, 1.03 mmol), and Pd(PPh3)2θ2 (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-benzyI)-4-oxo-3,4-dihydro-quinazoline-6-carboxyIic acid 3-methoxy-benzyIamide
Example 15 : 3-(4-MethanesιUfonyl-benzyl-4-oxo-3,4-dihydro-quinazoIine-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-d6) 1H 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, IH), 9.15 (s, IH).
Example 1 : 4-Oxo-3-[4-(pyrrolidine-l-sulfonyl)-benzyll-3,4-dihydro-quinazoline- 6-carboxylic acid 4-methoxy-benzylamide
The compound is obtained according to the procedure described in Example 14 using as substrate the compound obtained in Preparation 9 and 4-methoxybenzylamine. MS(APCI), M/z 533.2 (M+l) N.M.R (DMSO- 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-quinazoiin-3-ylmethylI- benzoic acid.
The desired product is obtained by following the procedure of Example 14, except 4- flurobenzylamine in step 2 of the preparation 3 is replaced by tert-butyl 3-aminomethyl- benzoate, and at the end stirring the collected residue in an excess amount of trifluoroacetic
acid for 30 minutes at room temperature. After removing the volatiles in vacuum, the residue is filtered to furnish the desired product as an off white solid. N.M.R (DMSO-- ) 1H 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-ylmethyll- benzoic acid
Step 1 : tert-Butyl 4-[4-oxo-6-(3 -phenyl-prop- 1 -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 dusopropylethylamine, catalytic amount of copper(I) iodide, 3.01 g (25.9 mmol) 3-phenyl-l-propyne and catalytic amount of Pd(PPh )2Cl 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-^) 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, Ji = 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- 1 -ynyl)-4H-quinazoline-3 -ylmethyl] -benzoic acid
N.M.R (DMSO-rftf) 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, Ji = 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- ylraethyl}-benzoic acid
The product is obtained by following the procedure of Example 18, the only difference is that 3 -phenyl- 1-propyne used in Step 1 is replaced by l-methoxy-4-prop-2-ynyl-benzene. The product is obtained as a white solid.
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, Ji = 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-ylmethyll- 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 (M1!).
N.M.R (DMSO-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-FIuoro-benzyl)-4-oxo-3»4-dihydro-quinazoline-6-carboxylic acid (2-methoxy-pyridm-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 CHC13 (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- tf) 1H δ (ppm) : 9.40 (t, J= 5.9 Hz, IH), 8J0 (s, IH), 8.69 (s, IH), 8.28 (dd, IH), 8.07 (d, J= 5.4 Hz, IH), 7J7 (d, J= 8.3 Hz, IH), 7.44 (m, IH), 7.19 (t, J= 8.7 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)-benzyll-6-(3-phenyl-prop-l-ynyl)-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 + 1).
N.M.R (DMSO-^) 1H 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]pyriraidine-6- carboxylic acid 3-methoxy-benzylamide
Step 1: 6-Chloro-3-(3-fluoro-benzyl)-3H-pyrido[3,4-d]pyrimidin-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 CH2C1 , the organic layer is washed with H2O and brine, dried (Na SO4) 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-dihydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide
N.M.R (CDCI3) 1H δ (ppm) : 9.40 (t, IH), 9.09 (s, IH), 8.76 (s, IH), 8.54 (s, IH), 6.7-7.4 (m, 1 IH), 5.22 (s, 2H), 4.45 (d, J= 6.6 Hz, IH), 3.67 (s, 3H)
Example 24 : 3-(3-Fluoro-benzyl)-4-oxo-354-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-methoxyberιzylamine. MS (APCI), M/z 419.1 (M + 1).
N.M.R (CDCl) 1H 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-quinazolin-3-ylmethyll- 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 HCl 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-- ) 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, Ji = 8.5Hz, J2= lJHz, IH), 7.87 (d, J= 8.1Hz, 2H), 8.07 (s, IH), 8.53(s, IH).
Examples 26 to 58 :
These compounds are obtained according to the procedure described in the Preparation 5 and Example 8 using the corresponding substrates and reagents.
- 4-{6-[3-(4-Methoxy-ρhenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-ylmethyl}-benzoic acid,
- 3-(4-Methanesulfonyl-benzyl)-6-[3-(4-methoxy-phenyl)-prop-l-ynyl]-3H-quinazolin- 4-one, - 4-{6-[3-(3-Methoxy-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-ylmethyl}-benzoic acid,
- 3-(4-Methanesulfonyl-benzyl)-6-[3-(3-methoxy-phenyl)-prop-l-ynyl]-3H-quinazolin- 4-one,
- 4-[4-oxo-6-(3-pyridin-4-yl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid, - 3-(4-Methanesulfonyl-benzyl)-6-(3-pyridin-4-yl-prop-l-ynyl)-3H-quinazolin-4-one
- 4-[4-oxo-6-(3-pyridin-3-yl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid,
- 3-(4-Methanesulfonyl-benzyl)-6-(3-pyridin-3-yl-prop-l-ynyl)-3H-quinazolin-4-one,
- 4- {6-[3-(4-fluro-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid,
- 6-[3-(4-Fluro-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H-quinazolin-4- one,
- 4- {6-[3 -(3-fluro-phenyl)-prop- 1 -ynyl]-4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid,
- 6-[3-(3-Fluro-phenyl)-ρrop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H-quinazolin-4- one,
- 4-{6-[3-(4-chloro-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-yhnethyl}-benzoic acid,
- 6-[3-(4-Chloro-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H-quinazolin-4- one,
- 4-{6-[3-(3-chloro-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-yhnethyl}-benzoic acid, - 6-[3-(3-Chloro-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H-quinazolin-4- one,
- 4-{6-[3-(4-bromo-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-ylmethyl}-benzoic acid,
- 6- [3 -(4-bromo-phenyl)-prop- 1 -ynyl] -3 -(4-methanesulfonyl-benzyl)-3H-quinazolin-4- one,
- 4-{6-[3-(3-bromo-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-ylmethyl}-benzoic acid,
- 6-[3-(3-bromo-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H-quinazolin-4- one,
- 4- {6-[3-(4-nitro-phenyl)-ρrop-l -ynyl]-4-oxo-4H-quinazolin-3 -ylmethyl} -benzoic acid,
- 3-(4-Methanesulfonyl-benzyl)-6-[3-(4-nitro-phenyl)-prop-l-ynyl]-3H-quinazolin-4- one,
- 4- {6-[3-(2-methoxy-pyridin-4-yl)-prop-l -ynyl]-4-oxo-4H-quinazolin-3-yhnethyl} - benzoic acid,
3-(4-Methanesulfonyl-benzyl)-6-[3-(2-methoxy-pyridin-4-yl)-prop- 1 -ynyl]-3H- quinazolin-4-one, - 4- {6-[3 -(4-methylsulfanyl-ρhenyl)-prop- 1 -ynyl] -4-oxo-4H-quinazolin-3 -ylmethyl} - benzoic acid.
3-(4-Methanesulfonyl-benzyl)-6-[3-(4-methylsulfanyl-phenyl)-prop-l-ynyl]-3H- quinazolin-4-one
- 4- { 6-[3 -(3 -methylsulfanyl-phenyl)-prop- 1 -ynyl] -4-oxo-4H-quinazolin-3-ylmethyl} - benzoic acid
- 3 -(4-Methanesulfonyl-benzyl)-6- [3 -(3-methylsulfanyl-phenyl)-prop- 1 -ynyl] -3H- quinazolin-4-one
- 4-[4-oxo-6-(3-j->-tolyl-prop-l-ynyl)-4H-quinazolin-3-yhnethyl]-benzoic acid
- 3 -(4-Methanesulfonyl-benzyl)-6-(3 -p-tolyl-prop- 1 -ynyl)-3H-quinazolin-4-one - 4-[4-oxo-6-(3-m-tolyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid
- and 3-(4-Methanesulfonyl-benzyl)-6-(3-m-tolyl-prop-l-ynyl)-3H-quinazolin-4-one
Examples 59 to 81 :
These compounds are obtained according to the procedure described in the Preparation 6 and Example 11 using the corresponding substrates and reagents.
- 4- {6-[3-(4-methoxy-phenyl)-prop-l-ynyl]-4-oxo-4Η-pyrido[3,4--^pyrimidin-3- ylmethyl} -benzoic acid,
- 3-(4-methanesulfonyl-benzyl)-6-[3-(4-methoxyl-phenyl)-prop-l-ynyl]-3H-pyrido [3 ,4--i]pyrimidin-4-one,
- 4-{6-[3-(3-methoxy-phenyl)-prop-l-ynyl]-4-oxo-4H-pyrido[3,4--^pyrimidin-3- ylmethyl} -benzoic acid,
- 3-(4-Methanesulfonyl-benzyl)-6-[3-(3-methoxyl-phenyl)-prop-l-ynyl]-3H-pyrido [3 ,4- ]pyrimidin-4-one, - 4-[4-oxo-6-(3-pyridin-4-yl-prop-l-ynyl)-4H-pyrido[3,4--^pyrimidin-3-ylmethyl]- benzoic acid,
- 3-(4-Methanesulfonyl-benzyl)-6-(3-pyridin-4-yl-prop-l-ynyl)-3H-pyrido[3,4-- ] pyrimidin-4-one,
- 4-[4-oxo-6-(3-pyridin-3 -yl-prop- 1 -ynyl)-4H-pyrido [3 ,4-- ]pyrimidin-3 -ylmethyl] - benzoic acid,
- 3-(4-Methanesulfonyl-benzyl)-6-(3 -pyridin-3 -yl-prop- 1 -ynyl)-3H-pyrido [3 ,4- ]pyrimidin-4-one,
- 4-{6-[3-(4-fluro-phenyl)-prop-l-ynyl]-4-oxo-4H-pyrido[3,4--f]pyrimidin-3-ylmethyl}- benzoic acid, - 6-[3-(4-Fluro-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H-pyrido[3,4-
-f]pyrimidin-4-one,
- 4- {6-[3 -(3 -fluro-phenyl)-prop- 1 -ynyl] -4-oxo-4H-pyrido[3 ,4-c lpyrimidin-3 -ylmethyl} - benzoic acid,
- 6-[3 -(3 -Fluro-phenyl)-prop- 1 -ynyl] -3 -(4-methanesulfonyl-benzyl)-3H-pyrido [3 ,4- c/]pyrirnidin-4-one,
- 4-{6-[3-(4-chloro-phenyl)-prop-l-ynyl]-4-oxo-4H-pyrido[3,4--i]pyrimidin-3- ylmethyl} -benzoic acid,
- 6-[3 -(4-Chloro-phenyl)-prop- 1 -ynyl] -3 -(4-methanesulfonyl-benzyl)-3H-pyrido [3 ,4- rf]pyrimidin-4-one, - 4-{6-[3-(3-chloro-phenyl)-prop-l-ynyl]-4-oxo-4H-pyrido[3,4-- ]pyrimidin-3- ylmethyl} -benzoic acid,
- 6-[3-(3-Chloro-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H-pyrido[3,4- -f|pyrimidin-4-one,
- 4-{6-[3-(4-bromo-phenyl)-prop-l-ynyl]-4-oxo-4H-pyrido[3,4--flpyrimidin-3- ylmethyl} -benzoic acid,
- 6-[3-(4-Bromo-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H-pyrido[3,4- -i]pyrimidin-4-one,
- 4-{6-[3-(3-bromo-phenyl)-prop-l-ynyl]-4-oxo-4H-pyrido[3,4--f]pyrimidin-3- ylmethyl} -benzoic acid,
- 6-[3 -(3 -Bromo-phenyl)-prop- 1 -ynyl] -3 -(4-methanesulfonyl-benzyl)-3H-pyrido [3 ,4- cTJpyrimidin-4-one, - 4- {6-[3 -(4-nitro-phenyl)-prop- 1 -ynyl] -4-oxo-4H-pyrido [3 ,4-- ]pyrimidin-3 -ylmethyl} - benzoic acid,
- 3 -(4-Methanesulfonyl-benzyl)-6-[3-(4-nitro-phenyl)-prop- 1 -ynyl)-3H-pyrido[3 ,4- -f]pyrimidin-4-one,
- 4- {6- [3 -(2-methoxy-pyridin-4yl)-prop- 1 -ynyl]-4-oxo-4H-pyrido [3 ,4-- ]pyrimidin-3 - ylmethyl} -benzoic acid,
- 3 -(4-Methanesulfonyl-benzyl)-6- [3 -(2-methoxy-pyridin-4-yl)-prop- 1 -ynyl)-3H- pyrido [3 ,4-- ]pyrimidin-4-one,
- 4- {6-[3-(4-methylsulfanyl-phenyl)-prop-l-ynyl]-4-oxo-4H-pyrido[3,4--i]pyrimidin-3- ylmethyl} -benzoic acid, - 3-(4-Methanesu lfonyl-benzyl)-6-[3-(4-methylsulfanyl-phenyl)-prop-l-ynyl)-3H- pyrido[3 ,4--i]pyrimidin-4-one,
- 4- {6-[3 -(3 -methylsulfanyl-phenyl)-prop- 1 -ynyl] -4-oxo-4H-pyrido [3 ,4--φyrimidin-3- ylmethyl} -benzoic acid,
- 3-(4-Methanesulfonyl-benzyl)-6-[3-(3-methylsulfanyl-phenyl)-prop-l-ynyl)-3H- pyrido[3,4--φyrimidin-4-one,
- 4- [4-oxo-6-(3- ?-tolyl-prop- 1 -ynyl)-4H-pyrido [3 ,4--i]pyrimidin-3 -ylmethyl] -benzoic acid,
- 3-(4-Meth- esulfonyl-benzyl)-6-(3-j!?-tolyl-prop-l-ynyl)-3H-pyrido[3,4--t pyrimidin-4- one, - 4-[4-oxo-6-(3-m-tolyl-prop-l-ynyl)-4H-pyrido[3,4-c?]pyrimidin-3-yhnethyl]-benzoic acid,
- and 3 -(4-Methanesulfonyl-benzyl)-6-(3 -m-tolyl-prop- 1 -ynyl)-3H-pyrido [3 ,4- cQpyrimidin-4-one.
PHARMACOLOGICAL STUDIES OF COMPOUNDS OF THE INVENTION
Example 83 : Evaluation of the in vitro activity of the MMP-13 inhibitor compounds according to the invention-
The inhibitory activity of the compounds of formula (I) according to the invention with respect to matrix metalloprotease-13 is evaluated by testing the ability of the compounds of the invention to inhibit the proteolysis of a peptide substrate with MMP- 13.
The peptide substrate used in the test is the following peptide: Ac-Pro-Leu-Gly-thioester-
Leu-Leu-Gly-OEt.
The inhibitory activity of a compound of formula (I) according to the invention is expressed as the IC50 value, which is the concentration of inhibitor for which an inhibition of 50% of the activity of the matrix metalloprotease under consideration is observed.
To carry out this test, a reaction medium of 100 μl volume is prepared, containing: 50 mM of HEPES buffer, 10 mM of CaCl2 and 1 mM of 5,5'-dithiobis-(2-nitrobenzoic acid)
(DTNB), and 100 μM of substrate, the pH being adjusted to 7.0.
Increasing concentrations of the inhibitory compound present in a 2.0% DMSO solution and 2.5 nM of the catalytic domain of human MMP-13 are added to the test samples.
The concentrations of inhibitors present in the test samples range from 100 μM to 0.5 nM.
The measurement of the proteolysis of the substrate peptide is monitored by measuring the absorbence at 405 nm using a spectrophotometer for reading microplates, at the laboratory temperature, the measurements being carried out continuously for 10 to 15 minutes. The IC50 values are calculated from a curve in which the percentage of the catalytic activity relative to the control is represented on the X-axis and the concentration of inhibitor is represented on the Y-axis.
The IC50 values on MMP-13 of the compounds of Examples 1 to 10 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 IC5o values for the same compounds with respect to the other matrix metalloproteases tested.
Claims
1 - A compound selected from those of formula (I)
• 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-Ri in the ring,
P^ and R5, identical or different, independently of each other, represent a group selected from hydrogen, (Ci-C6)alkyl, aryl, aryl(Cι-C6)alkyl, cycloalkyl, cycloalkyl(Cι-C6)alkyl, heteroaryl, heteroaryl(d-C6)alkyl, heterocycloalkyl, and heterocycloalkyl(C i -C6)alkyl,
- Re represents a group selected from :
■S hydrogen, trifluoromethyl, OR7, NR7Rs, in which R7 and Rs, identical or different independently of each other, represent hydrogen or (Cι-C6)alkyl, (Cι-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(Cι-C6)alkyl, cycloalkyl(Cι-C6)alkyl, heteroaryl, heteroaryl(Ci-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(Ci-C6)alkylamino, di(Cι-C6)alkylamino, each alkyl moiety being identical or different independently of each other, cyano, trihalogeno(Ci-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-, C=O, C=S, S(O)ni in which nl represents an integer from 0 to 2 inclusive, and a group of formula (i/c):
• n represents an integer from 0 to 6 inclusive,
• Zi represents -CR9Rιo, wherein R9 and Rio, identical or different independently of each other, represent a group selected from hydrogen, (d-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(Ci-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 -CR Rιo 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,
- (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(C1-C6)alkyl, cycloalkyl, -C(=O)NR7R8, -C(=O)OR8, ORs, SRs, 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,
X Z2 represents -CRnR12 wherein Rn and Rι2, identical or different independently of each other, represent a group selected from hydrogen, (Ci-C6)alkyl, phenyl, trihalogeno(Ci-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 Z optionally contains one or two isolated or conjugated multiple bonds,
- andor wherein n is greater than or equal to 2, one of said -CRπRπ may optionally be replaced with a group selected from oxygen, S(O)nι in which nl is as defined hereinbefore, -NH, -N(Cι-C6)alkyl, and carbonyl,
■S 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,
■S the group(s) G3, which may be identical or different independently of each other, is (are) selected from (Ci-C6)alkyl, halogen, CN, NO2, CF3, OCF3, -(CH2)kNRι3R14, -N(Rι3)C(=O)R14, -N(R13)C(=O)ORι4, -N(R13)SO2R14, -N(SO2R13)2, -OR13, -S(O)kιR13, -SO2-N(Ri3)-(CH2)k2-NR14Ri5, -(CH2)kSO2NR13R14, -X4(CH2)kC(=O)ORi3, -(CH2)kC(=O)OR13, -C(=O)O-(CH2)k2-NR13Rι4,
-Rι7-C(=O)OR13, -X5-R18, and -C(=O)-Rι9-NRι3R14 in wliich :
- 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 (Ci-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,
- Ri3, R14 and R15, wliich may be identical or different independently of each other, are selected from hydrogen and (Cι-C6)alkyl,
- Ri6 represents a group selected from (Cι-C6)alkyl, -R19-NRi3Rι4,
in which Rι9 represents a linear or branched (Cι-C6)alkylene group, and R13, Rι4 and Rι5 are as defined hereinbefore,
- Rι7 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 (Cι-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 (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 (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 (C 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)kC(=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 (Cι-C6)alkyl,
- k is an integer from 0 to 3 inclusive,
- R7 and R8, 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,
- R2o 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)nl in which nl represents an integer from 0 to 2 inclusive, or a group of formula (i/c):
• Xi, X2, X3, Gi, n, 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.
3- A compound according to Claim 1 characterized in that:
• G represents a carbon-carbon triple bond,
• n represents an integer from 1 to 6 inclusive,
• Xi, X , 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,
• Xls X2, X3, Gi, 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.
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, • Ri represents a hydrogen atom or a group of formula (i/d) :
•f in which p is an integer from 0 to 8 inclusive,
■f Z2 represents -CRnR12 wherein Rn and R12, identical or different independently of each other, represent a group selected from hydrogen, (Ci-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 -CRnRι2 may optionally be replaced with a group selected from oxygen, S(O)nι in which nl is as defined hereinbefore, -NH, -N(Cι-C6)alkyl, and carbonyl, ■S B represents a phenyl group, S 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)kNRι3Rι , -N(Rι3)C(=O)ORι4, -N(Rι3)SO2Rι4, -N(SO2Ri3)2, -S(O)klR13, -SO2-N(Rι3)-(CH2)k2-NR14Ri5, -(CH2)kSO2NR13Ri4, -X4(CH2)kC(=O)OR13, -(CH2)kC(=O)ORι3, -C(=O)O-(CH2)k2-NR13Rι ,
-Rι7-C(=O)ORi3, -X5-Rιs, -C(=O)-Rι9-NRι3Rι 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 (Cι-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 R15, which may be identical or different independently of each other, are selected from hydrogen and (Cι-C6)alkyl, - Riδ represents a group selected from (d-C6)alkyl, -Rι9-NRι3Ri4,
in which R19 represents a linear or branched (Cι-C6)alkylene group, and R13, Rι4 and Rι5 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 (Cι-C6)alkyl group,
- Ris 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
(Ci-C6)alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and -C(=O)OR7 wherein R7 represents hydrogen or (Cι-C6)alkyl,
- X6 represents a group selected from -CH -, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (Cι-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 (Cι-C6)alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and -C(=O)OR7 wherein R7 represents hydrogen or (Ci-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 -CR11R12 in which Ri 1 and R12 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)iciRi3 and (CH2) C(=O)ORι3 in which R13 represents an hydrogen atom or a (Ci- C6)alkyl group, k is zero, and ki 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 R-t 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 R$ 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 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, 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 Yi 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 Zi represents -CR9Rιo 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 accordmg 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 (d-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, hydrochlorid
- 3-(4-methoxy-benzyl)-l-methyl-4-oxo-l,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide
- 3-(4-methoxy-benzyl)-l ,2,2-trimethyl-4-oxo-l ,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-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-berιzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrirnidine-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-yhnethyl]-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--f]pyrimidin-4-one,
- methyl 4-[6-(3 -phenyl-prop- 1 -ynyl)-4-oxo-4H-pyrido [3 ,4- ]pyrimidin-3 -ylmethyl] - benzoate, - 4-[6-(3-phenyl-ρrop-l-ynyl)-4-oxo-4H-pyrido[3,4- ]pyrimidin-3-ylmethyl]-benzoic acid,
- 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4Η-quinazoline-3-ylmethyl]-benzoic acid,
- 4-{6-[3-(4-methoxy-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazoline-3-ylmethyl}-benzoic acid, - 4-[4-oxo-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.
17- A process for the preparation of compounds according to claim 1 which uses as starting material a compound of formula (II):
compound of formula (II) which is treated with a compound of formula (nt):
compound of formula (IN) 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 Rι-ΝH2 in which Ri is as defined in the compound of formula (I), to yield the compound of formula (V) :
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):
or under heating condition in the presence of acid, with a compound of formula (VI):
• or with a compound of formula (Nil) in basic condition:
B, R' (vπ)
O in which R 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):
which compound of formula (I/c) is optionally treated with a hydride, in the presence of a compound of formula (NIII): Re-Hal (NIII) in which R^ 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, Yi, Y2, Zi, R2, Ri, R4, R5, Re, A, n and m are as defined hereinbefore,
compounds of formulae (I a), (I b), (I/c) and (I/d) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
18- A process for the preparation of compounds according to claim 1 which uses as starting material a compound of formula (X) :
which compound of formula (XII) is treated:
• either with triethyl orthoformate under heating condition, to yield the compound of formula (XlH/a) :
• or under heating conditions in the presence of an acid, with a compound of formula (VI):
• or with a compound of formula (Nil) in basic conditions:
R- .R,
(Nπ) o in which i and R5 have the same defimtion as the compound of formula (I),
to yield the compound of formula (XIU/c) :
which compound of formula (XHI/c) is optionally treated with a hydride, in the presence of a compound of formula (NIII):
Re-Hal (Nπi) in which Re has the same definition as the compound of formula (I), and Hal is a halogen atom, to yield the compound of formula (XIH/d), which is a particular case of the compound of formula (I):
all compounds of formulae (XlH/a), (XIH/b), (Xffl/c) and (XIH/d) constitute the compound of formula (Xffl/e):
compound of formula (XHVe) which is treated under conditions of palladium-catalyzed alkynylation with a compound of formula (XIV):
to yield the compound of formula (Ve), which is a particular case of the compound of formula (I):
19- A process for the preparation of compounds according to claim 1 wherein it is used as starting material a compound of formula (Xiπ/e)
to yield the compound of formula (I/e), which is a particular case of the compound of formula (I):
20 - A process for the preparation of compounds according to claim 1, which uses as starting material a compound of formula (XHI/e) :
compound of formula (Xffl/e) 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):
compound of formula (XVI) which is hydrolyzed under basic medium to yield the compound of formula (XVII):
compound of formula (XNII) which is condensed under basic medium in the presence of a Mukayama reagent, on the compound of formula (XNDT):
to yield the compound of formula (I/f), which is a particular case of 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 (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):
compound of formula (XX) which is treated in basic medium with a compound of formula Ri-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):
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 (XXH):
(^-©^^^ΝH, (X ΠD in which Zi, R2, A, n and m have the same definitions as the compound of formula (I),
to yield the compound of formula (I/g), which is a particular case of the compound of formula (I):
22- 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.
23- 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.
24- 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.
25- A pharmaceutical composition useful in the method of Claim 22 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.
26- A pharmaceutical composition useful in the method of Claim 22 comprising as active ingredient an effective amount of a compound as claimed in claim 15, together with one or more pharmaceutically-acceptable excipients or carriers.
27- A pharmaceutical composition useful in the method of Claim 22 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- 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.
29- Use according to Claim 28, 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.
30- Use according to Claim 29, characterized in that the disease is arthritis.
31- Use according to Claim 29, characterized in that the disease is osteoarthritis.
32- Use according to Claim 29, characterized in that the disease is rheumatoid arthritis.
Priority Applications (29)
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| MXPA04008681A MXPA04008681A (en) | 2002-03-08 | 2003-03-06 | Oxo-azabicyclic compounds. |
| JP2003574636A JP2005526070A (en) | 2002-03-08 | 2003-03-06 | Oxo-azabicyclic compounds |
| UY27700A UY27700A1 (en) | 2002-03-08 | 2003-03-06 | OXO COMPOUNDS - AZABYCLES. |
| PL03372622A PL372622A1 (en) | 2002-03-08 | 2003-03-06 | Oxo-azabicyclic compounds |
| CNA038048752A CN1738806A (en) | 2002-03-08 | 2003-03-06 | Oxo-azabicyclic compounds |
| CA002478706A CA2478706A1 (en) | 2002-03-08 | 2003-03-06 | Oxo-azabicyclic compounds |
| BR0308280-6A BR0308280A (en) | 2002-03-08 | 2003-03-06 | Oxo-azabicyclic compounds |
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| IL16381803A IL163818A0 (en) | 2002-03-08 | 2003-03-06 | Oxo-azabicyclic compounds |
| AU2003212307A AU2003212307A1 (en) | 2002-03-08 | 2003-03-06 | Oxo-azabicyclic compounds |
| KR10-2004-7013994A KR20040095270A (en) | 2002-03-08 | 2003-03-06 | Oxo-Azabicyclic Compounds |
| PE2003000218A PE20031018A1 (en) | 2002-03-08 | 2003-03-06 | OXO-AZABYCLIC COMPOUNDS |
| PCT/EP2003/002277 WO2003076417A2 (en) | 2002-03-08 | 2003-03-06 | Oxo-azabicyclic compounds |
| ARP030100749A AR039562A1 (en) | 2002-03-08 | 2003-03-06 | OXO-AZABICICLIC COMPOUNDS |
| US10/384,115 US6894057B2 (en) | 2002-03-08 | 2003-03-07 | Oxo-azabicyclic compounds |
| US10/417,073 US6747147B2 (en) | 2002-03-08 | 2003-04-16 | Oxo-azabicyclic compounds |
| IS7414A IS7414A (en) | 2002-03-08 | 2004-08-19 | Oxo-azabicyclic compounds |
| CO04082792A CO5601020A2 (en) | 2002-03-08 | 2004-08-25 | OX-AZABICICLIC COMPOUNDS |
| MA27842A MA27183A1 (en) | 2002-03-08 | 2004-08-31 | OXO-AZABICYCLIC COMPOUNDS |
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| EC2004005278A ECSP045278A (en) | 2002-03-08 | 2004-09-03 | OXO-AZABYCLIC COMPOUNDS |
| NO20044041A NO20044041L (en) | 2002-03-08 | 2004-09-24 | Oxo-azabicyclic compounds |
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| JP (1) | JP2005526070A (en) |
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| RU2009112397A (en) | 2006-10-05 | 2010-10-10 | Си Ви ТЕРАПЬЮТИКС, ИНК (US) | BICYCLIC NITROGEN-CONTAINING HETEROCYCLIC COMPOUNDS FOR USE AS STEAROIL COA DESATURASES INHIBITORS |
| CN103524431B (en) * | 2013-09-24 | 2016-01-13 | 西安交通大学 | 3-benzyl-4-quianzolinones and synthetic method thereof and application |
| 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 |
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| WO1998026664A1 (en) * | 1996-12-17 | 1998-06-25 | E.I. Du Pont De Nemours And Company | Fungicidal quinazolinones |
| WO2002064080A2 (en) * | 2001-02-14 | 2002-08-22 | Warner-Lambert Company Lcc | Matrix metalloproteinase inhibitors |
| WO2002064572A1 (en) * | 2001-02-14 | 2002-08-22 | Warner-Lambert Company Llc | Quinazolines as mmp-13 inhibitors |
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2002
- 2002-03-08 AU AU2002249275A patent/AU2002249275A1/en not_active Abandoned
- 2002-03-08 WO PCT/EP2002/003240 patent/WO2003076416A1/en not_active Application Discontinuation
-
2003
- 2003-03-04 SV SV2003001495A patent/SV2003001495A/en not_active Application Discontinuation
- 2003-03-06 UY UY27700A patent/UY27700A1/en not_active Application Discontinuation
- 2003-03-06 WO PCT/EP2003/002277 patent/WO2003076417A2/en not_active Application Discontinuation
- 2003-03-06 MX MXPA04008681A patent/MXPA04008681A/en unknown
- 2003-03-06 CA CA002478706A patent/CA2478706A1/en not_active Abandoned
- 2003-03-06 PE PE2003000218A patent/PE20031018A1/en not_active Application Discontinuation
- 2003-03-06 EP EP03708181A patent/EP1492775A2/en not_active Withdrawn
- 2003-03-06 KR KR10-2004-7013994A patent/KR20040095270A/en not_active Application Discontinuation
- 2003-03-06 PA PA20038568501A patent/PA8568501A1/en unknown
- 2003-03-06 CN CNA038048752A patent/CN1738806A/en active Pending
- 2003-03-06 AR ARP030100749A patent/AR039562A1/en not_active Application Discontinuation
- 2003-03-06 AP APAP/P/2004/003125A patent/AP2004003125A0/en unknown
- 2003-03-06 IL IL16381803A patent/IL163818A0/en unknown
- 2003-03-06 EA EA200401053A patent/EA200401053A1/en unknown
- 2003-03-06 OA OA1200400234A patent/OA12782A/en unknown
- 2003-03-06 JP JP2003574636A patent/JP2005526070A/en not_active Withdrawn
- 2003-03-06 PL PL03372622A patent/PL372622A1/en not_active Application Discontinuation
- 2003-03-06 BR BR0308280-6A patent/BR0308280A/en not_active IP Right Cessation
- 2003-03-06 AU AU2003212307A patent/AU2003212307A1/en not_active Abandoned
-
2004
- 2004-08-19 IS IS7414A patent/IS7414A/en unknown
- 2004-08-25 CO CO04082792A patent/CO5601020A2/en not_active Application Discontinuation
- 2004-08-31 MA MA27842A patent/MA27183A1/en unknown
- 2004-09-03 EC EC2004005278A patent/ECSP045278A/en unknown
- 2004-09-03 TN TNP2004000169A patent/TNSN04169A1/en unknown
- 2004-09-24 NO NO20044041A patent/NO20044041L/en not_active Application Discontinuation
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| WO1998026664A1 (en) * | 1996-12-17 | 1998-06-25 | E.I. Du Pont De Nemours And Company | Fungicidal quinazolinones |
| WO2002064080A2 (en) * | 2001-02-14 | 2002-08-22 | Warner-Lambert Company Lcc | Matrix metalloproteinase inhibitors |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004014384A2 (en) * | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | Cyclic compounds containing zinc binding groups as matrix metalloproteinase inhibitors |
| WO2004014384A3 (en) * | 2002-08-13 | 2004-07-22 | Warner Lambert Co | Cyclic compounds containing zinc binding groups as matrix 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 |
| JP4848286B2 (en) * | 2004-04-30 | 2011-12-28 | 武田薬品工業株式会社 | Heterocyclic amide compounds and their use as MMP-13 inhibitors |
| WO2005123696A1 (en) * | 2004-06-15 | 2005-12-29 | Astrazeneca Ab | Substituted quinazolones as anti-cancer agents |
| WO2012052451A1 (en) | 2010-10-18 | 2012-04-26 | Merz Pharma Gmbh & Co. Kgaa | Metabotropic glutamate receptor modulators |
| WO2015144803A1 (en) | 2014-03-26 | 2015-10-01 | Astex Therapeutics Ltd | Quinoxaline derivatives useful as fgfr kinase modulators |
| WO2017050864A1 (en) | 2015-09-23 | 2017-03-30 | Janssen Pharmaceutica Nv | New compounds |
| US11155555B2 (en) | 2015-09-23 | 2021-10-26 | Janssen Pharmaceutica Nv | Compounds |
| US11542247B2 (en) | 2015-09-23 | 2023-01-03 | Janssen Pharmaceutica Nv | Bi-heteroaryl substitute 1,4-benzodiazepines and uses thereof for the treatment of cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| PA8568501A1 (en) | 2003-12-19 |
| EP1492775A2 (en) | 2005-01-05 |
| WO2003076417A2 (en) | 2003-09-18 |
| WO2003076417A3 (en) | 2003-11-13 |
| AU2003212307A1 (en) | 2003-09-22 |
| IS7414A (en) | 2004-08-19 |
| EA200401053A1 (en) | 2005-04-28 |
| JP2005526070A (en) | 2005-09-02 |
| MXPA04008681A (en) | 2004-12-06 |
| TNSN04169A1 (en) | 2007-03-12 |
| CO5601020A2 (en) | 2006-01-31 |
| KR20040095270A (en) | 2004-11-12 |
| UY27700A1 (en) | 2003-10-31 |
| CN1738806A (en) | 2006-02-22 |
| NO20044041L (en) | 2004-10-07 |
| ECSP045278A (en) | 2004-10-26 |
| SV2003001495A (en) | 2003-11-04 |
| PE20031018A1 (en) | 2004-01-09 |
| MA27183A1 (en) | 2005-01-03 |
| IL163818A0 (en) | 2005-12-18 |
| AU2002249275A1 (en) | 2003-09-22 |
| BR0308280A (en) | 2004-12-28 |
| PL372622A1 (en) | 2005-07-25 |
| AR039562A1 (en) | 2005-02-23 |
| AP2004003125A0 (en) | 2004-09-30 |
| CA2478706A1 (en) | 2003-09-18 |
| OA12782A (en) | 2006-07-10 |
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