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WO2004000321A1 - Derives de thiazine et d'oxazine en tant qu'inhibiteurs de mmp-13 pour traiter l'arthrite - Google Patents

Derives de thiazine et d'oxazine en tant qu'inhibiteurs de mmp-13 pour traiter l'arthrite Download PDF

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WO2004000321A1
WO2004000321A1 PCT/EP2002/008062 EP0208062W WO2004000321A1 WO 2004000321 A1 WO2004000321 A1 WO 2004000321A1 EP 0208062 W EP0208062 W EP 0208062W WO 2004000321 A1 WO2004000321 A1 WO 2004000321A1
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formula
compound
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alkyl
oxygen
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Bernard Gaudilliere
Henry Jacobelli
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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Priority to AU2002333256A priority Critical patent/AU2002333256A1/en
Priority to PCT/EP2002/008062 priority patent/WO2004000321A1/fr
Priority to CA002491210A priority patent/CA2491210A1/fr
Priority to US10/602,160 priority patent/US20040006077A1/en
Priority to JP2004514844A priority patent/JP2005538965A/ja
Priority to EP03760686A priority patent/EP1539176A1/fr
Priority to BR0312107-0A priority patent/BR0312107A/pt
Priority to PCT/EP2003/006601 priority patent/WO2004000322A1/fr
Priority to MXPA05000004A priority patent/MXPA05000004A/es
Priority to AU2003246574A priority patent/AU2003246574A1/en
Publication of WO2004000321A1 publication Critical patent/WO2004000321A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
    • C07D265/26—Two oxygen atoms, e.g. isatoic anhydride
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to novel thiazine and oxazine derivatives which are useful for preparing medicinal products for treating complaints involving a therapy with a matrix metalloprotease-13 (MMP-13) inhibitor.
  • MMP-13 matrix metalloprotease-13
  • These medicinal products are useful in particular for treating certain inflammatory conditions such as rheumatoid arthritis or osteoarthritis, as well as certain proliferative conditions such as cancers.
  • MMPs Matrix metalloproteases
  • TLMPs tissue inhibitors of metalloprotease
  • MMP-13 matrix metalloprotease-13 is a collagenase-type MMP which constitutes the predominant collagenase observed during osteoarthritis, in the course of which pathology the chondrocyte directs the destruction of cartilage.
  • MMP inhibitors are known. Most of these MMP-inhibitors are not selective for a single MMP, such as those described by Montana and Baxter (2000) or by Clark et al. (2000).
  • the applicant has identified novel thiazine and oxazine derivatives that are matrix metalloprotease inhibitors, and more specifically compounds that are selective MMP-13 inhibitors.
  • X ⁇ , 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 ⁇ alkyl, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, hydroxy, ( -C 6 )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 an oxygen atom or a group S(O) p in which p represents an integer from 0 to 2 inclusive,
  • Yi represents a group selected from oxygen, sulphur, -NH and -N(C ⁇ -C 6 )alkyl
  • Y 2 represents a group selected from oxygen, sulphur, -NH and -N ⁇ -C ⁇ alkyl
  • n represents an integer from 0 to 6 inclusive
  • hydrocarbon chain Z 1 optionally contains one to two isolated or conjugated multiple bonds
  • one of said -CR4R 5 may be replaced with a group selected from oxygen, S(O) r in which r represents an integer from 0 to 2 inclusive, -NH and -N(C ⁇ -C 6 )alkyl,
  • A represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being a 5- or 6-membered monocycle, or bicycle itself composed of two 5- or 6-membered monocycles
  • R ⁇ represents a group selected from :
  • hydrocarbon chain Z 2 optionally contains one or two isolated or conjugated multiple bonds
  • one of said -CR 9 R 10 may be replaced with a group selected from oxygen, S(O) u in which u is an integer from 0 to 2 inclusive, -NH, -N(C 1 -C 6 )alkyl, and carbonyl,
  • ⁇ S B represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being a 5- or 6-membered monocycle, or bicycle itself composed of two 5- or 6-membered monocycles,
  • the group(s) G 3 which may be identical or different independently of each other, is (are) selected from (CrC 6 )alkyl, halogen, CN, NO 2 , CF 3 , OCF 3 , -(CH 2 ) k NR ⁇ R ⁇ 2 , -N(R ⁇ )SO 2 R 12 , -N(SO 2 R u ) 2 , -OR u , -S(O) kl R lb -SO 2 -N(R ⁇ )-(CH 2 ) ⁇ ⁇ -NR 12 R 13 , -(CH 2 ) k SO 2 NR ⁇ R 12 ,
  • - represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen, and nitrogen substituted by a hydrogen or a (C 1 -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 ⁇ , R 12 and R 13 which may be identical or different independently of each other, are selected from hydrogen and (CrC ⁇ alkyl,
  • R 15 represents a (C 3 -C 6 )cycloalkyl group
  • - X 5 represents a group selected from a single bond, -CH 2 -, oxygen, sulphur optionally substituted by one or two oxygen, and nitrogen substituted by hydrogen or (C 1 -C 6 )alkyl,
  • X 7 represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen, and nitrogen substituted by hydrogen or (C 1 -C 6 )alkyl,
  • - k is an integer from 0 to 3 inclusive
  • R 7 and R 8 which may be identical or different independently of each other, are selected from hydrogen and (CpC 6 )alkyl,
  • X 8 represents a group selected from single bond, -CH 2 -, oxygen, sulphur optionally substituted by one or two oxygen, and nitrogen substituted by hydrogen or (d-C 6 )alkyl,
  • R 18 represents a group selected from phenyl, a 5- or 6-membered monocyclic, heteroaryl, and a 5- or 6-membered monocyclic cycloalkyl, each of these groups being optionally substituted by one or more groups, which may be identical or different independently of each other, selected from (C 1 -C 6 )alkyl, halogen, hydroxy and amino, and optionally, their racemic forms, isomers, N-oxides, and pharmaceutically acceptable salts, and with the proviso that the compound of formula (I) is not 6-(2,4-dioxo-3,4-dihydro-2H- l,3-benzothiazine)-benzoate, 6-benzophenone-2,4-dioxo-3,4-dihydro-2H-l,3- benzothiazine and 6-(2,4-dihydroxy)-benzophenone-2,4-dioxo-3,4-dihydro-2H-l,3- benzo
  • the invention relates to compounds of formula (I) wherein :
  • Y in which the carbon atom with the number 1 is attached to the bicycle of the compound of formula (I), Y ⁇ represents an oxygen atom, and Y 2 represents a group -NH,
  • the invention relates to compounds of formula (I) wherein :
  • G 2 represents a group of formula (i/a):
  • the invention relates to compounds of formula (I) wherein : • G t represents a sulphur atom,
  • G 2 represents a carbon-carbon triple bond
  • n represents an integer from 1 to 6 inclusive
  • X ls X 2 , X 3 , Zi, A, R 1; m and R 2 are as defined in formula (I).
  • the invention relates to compounds of formula (I) wherein :
  • n represents an integer from 1 to 6 inclusive
  • Xi, X 2 , X 3 , Zi, A, R ; m and R are as defined in formula (I).
  • Z 2 represents a group -CR 9 R 10 in which R 9 and R 10 represents each a hydrogen atom, s is equal to one, and B, G 3 , and t are as defined in the compound of formula (I).
  • substituent Rj that is preferred according to the invention is the group of formula (i/b):
  • B represents a phenyl group
  • t is equal to 0 or 1
  • Preferred compounds of the invention are compounds of formula (I) wherein X represents a group -CR in which R 3 represents a hydrogen atom, X 2 represents a nitrogen atom or a group -CR in which R represents a hydrogen atom, and X 3 represents a group -CR 3 in which R 3 represents a hydrogen atom.
  • preferred compounds of the invention are those compounds of formula (I) wherein Z ⁇ represents -CR R 5 in which t and R 5 represent each a hydrogen atom, and n is equal to one.
  • Especially preferred compounds of the invention are compounds of formula (I) wherein A represents a group selected from phenyl and pyridyl, m is equal to zero or one, and R 2 represents a ( -C ⁇ alkoxy group or a hydrogen atom.
  • Another especially preferred compounds of the invention are compound of formula (I) wherein A represents an imidazolyl group.
  • the invention relates to the following compounds of formula (I) :
  • optical isomers, the N-oxides, as well as the addition salts with a pharmaceutically- acceptable acid or base, of the preferred compounds form an integral part of the invention.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient an effective amount of a compound of formula (I) together with one or more pharmaceutically-acceptable excipients or carriers.
  • Another embodiment of the invention concerns the use of the compound of formula (I) for the preparation of a medicinal product intended for treating a disease involving therapy by inhibition of matrix metalloprotease, and more particularly of type- 13 matrix metalloprotease.
  • the invention also relates to a method for treating a living body afflicted with a disease involving a therapy by inhibition of matrix metalloprotease, and more particularly of type- 13 matrix metalloprotease, the said method comprising the administration of an effective amount of a compound of formula (I) to a patient in need thereof.
  • a preferred method of treatment according to this invention is treatment of a disease selected from arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases, age-related degeneration and cancers.
  • a disease selected from arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases, age-related degeneration and cancers.
  • a preferred method of treatment according to this invention is treatment of disease selected from arthritis, osteoarthritis and rheumatoid arthritis.
  • - a (C 1 -C 6 )alkyl group denotes a linear or branched group containing from 1 to 6 carbon atoms ;
  • example of such groups, without implying any limitation are methyl, ethyl, propyl, isopropyl, tert-butyl, neopentyl, hexyl, - a (C 2 -C 6 )alkenyl group denotes a linear or branched group containing from 2 to 6 carbon atoms, and one or more double bonds ; examples of such groups without implying any limitation are vinyl, allyl, 3-buten-l-yl, 2-methyl-buten-l-yl, hexenyl,
  • - a (C 2 -C 6 )alkynyl group denotes a linear or branched group containing from 2 to 6 carbon atoms, and one or more triple bonds ; examples of such groups without implying any limitation are ethynyl, propynyl, 3-butyn-l-yl, 2-methyl-butyn-l-yl, hexynyl, - a (C 1 -C 6 )alkoxy group means the alkyl group as mentioned above bound through an oxygen atom ; examples of such compounds without implying any limitation are methoxy, ethoxy, n-propyloxy, tert-butyloxy,
  • a mono(C 1 -C 6 )alkylamino denotes a amino group substituted by one (d-C ⁇ alkyl group as defined hereinbefore ;
  • example of such groups, without implying any limitation are methyl amino, isobutyl amino, ethylamino, a di(C 1 -C 6 )alkylamino denotes a amino group substituted by two (C 1 -C 6 )alkyl groups as defined hereinbefore, each alkyl group being identical or different ;
  • 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, naph
  • a cycloalkyl group denotes a monocyclic or bicyclic system containing from 3 to 10 carbon atoms, this system being saturated or partially unsaturated but without aromatic character ; examples of such groups without implying any limitation are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, adamantyl, decalinyl, norbornyl, a heterocycloalkyl group denotes a cycloalkyl group as defined hereinbefore in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms selected from oxygen, sulfur, and nitrogen,
  • a bicycle denotes two fused-monocycle or two bridged-monocycle
  • a trihalogeno(C -C 6 )alkyl group denotes an alkyl group as defined above which contains a trihalogeno group
  • examples of such groups without implying any limitation are trifluoromethyl, 2,2,2-trifluoroethyl
  • a (CrC 7 )acyl group denotes an alkyl group or an 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).
  • Pharmaceutically acceptable acids mean non-toxic mineral or organic acids. Among those there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, nitric acid, citric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, benzoic acid, toluenesulfonic acid, etc...
  • Pharmaceutically acceptable bases mean non-toxic mineral or organic bases. Among those, there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, tert-butylamine, dibenzylethylenediamine, piperidine, pyrrolidine, benzylamine, quaternary ammonium hydroxides etc...
  • the invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (II):
  • compounds of formula (I/a) 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 another process for the preparation of specific compounds of formula (I/a), which are a particular case of compounds of formula (I), which uses as starting material a compound of formula (11/ A):
  • compounds of formula (I/c) 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 (II):
  • X 2 , X , and Gi have the same definitions as the compound of formula (I), and X represents a leaving group selected from halogen, triflate, mesyslate, tosylate and SO 2 alkyl,
  • compounds of formula (I/b) 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.
  • R 7 is hydrogen or (C ⁇ -C 6 )alkyl
  • R" is hydrogen or (CrC 6 )alkyl
  • Ri, R 2 , Gi, Xi, X 2 , X 3 , A, Y 1 ⁇ Zi, n and m have the same meaning as that defined for 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.
  • compounds of formula (I) of the present invention are matrix metalloprotease inhibitors, and more particularly inhibitors of the enzyme MMP-13.
  • their use is recommended for the treatment of diseases or complaints involving a therapy by MMP-13 inhibition.
  • the use of the compounds of the present invention may be recommended for the treatment of any pathology in which destruction of extracellular matrix tissue occurs, and most particularly pathologies such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease, age-related macular degeneration and cancers.
  • the present invention also relates to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), an isomer thereof, a N-oxide thereof, or an addition salt thereof with a pharmaceutically-acceptable acid or base, alone or in combination with one or more pharmaceutically-acceptable, inert, non-toxic excipients or carriers.
  • compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, intravaginal, rectal, nasal, perlingual, buccal, ocular or respiratory administration.
  • compositions according to the invention for parenteral injections especially include aqueous and non-aqueous sterile solutions, dispersions, suspension and emulsions, and also sterile powders for reconstituting injectable solutions or dispersions.
  • compositions according to the invention for oral administration in solid form especially include tablets or dragees, sublingual tablets, sachets, gelatin capsules and granules, for oral, nasal, buccal or ocular administration in liquid form, especially include emulsions, solutions, suspensions, drop, syrups and aerosols.
  • compositions for rectal or vaginal administration are preferably suppositories, and those for per- or trans-cutaneous administration especially include powders, aerosols, creams, ointment, gels and patches.
  • the pharmaceutical compositions mentioned hereinbefore illustrate the invention but do not limit it in any way.
  • inert, non-toxic excipients or carriers there may be mentioned, by way of non-limiting example, diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, swelling agents, disintegrating agents, retardants, lubricants, absorbents, suspending agents, colorants, aromatizing agents etc...
  • the useful dosage varies according to the age and weight of the patient, the administration route, the phannaceutical 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.
  • aluminium chloride (5.51 g, 41.3 mmol) was added in portions to a suspension of 3-benzyl-6-bromo-3,4-dihydro-benzothiazine-2,4-dione (intermediate A ; 2.4 g, 6.89 mmol) in benzene (50 ml) and the mixture obtained was heated at 50°C under stirring for 2 hours.
  • the mixture obtained was heated to 50°C under nitrogen atmosphere and maintained under stirring for 3 hours. After cooling, the solvent was removed under reduced pressure and the semi-solid residue obtained was stirred in a mixture of water and dichloromethane for 25 minutes.
  • the solid insoluble in the 2 phases was isolated by filtration, washed with CH 2 C1 2 and dried under vacuum to afford a first portion (0.16 g) of the entitled compound.
  • the organic phase was separated, washed with brine, dried over Na 2 SO 4 and evaporated to give an additional portion (0.23 g) of the desired compound
  • Example 4 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 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.
  • IC 50 value is the concentration of inhibitor for which an inhibition of 50% of the activity of the matrix metalloprotease under consideration is observed.
  • concentrations of the inhibitory compound present in a 2.0% DMSO solution and 2.5 nM of the catalytic domain of human MMP-13 are added to the test samples.
  • concentrations of inhibitors present in the test samples range from 100 ⁇ M to 0.5 nM.
  • the measurement of the proteolysis of the substrate peptide is monitored by measuring the absorbance at 405 nm using a spectrophotometer for reading microplates, at the laboratory temperature, the measurements being carried out continuously for 10 to 15 minutes.
  • the IC 50 values are calculated from a curve in which the percentage of the catalytic activity relative to the control is represented on the X-axis and the concentration of inhibitor is represented on the Y-axis.
  • the IC 50 values on MMP-13 of the compounds of Examples 1 to 3 are all below 0.1 ⁇ M.
  • IC 50 values for MMP-13 which are about 100 times lower than the IC 50 values for the same compounds with respect to the other matrix metalloproteases tested.

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  • Pain & Pain Management (AREA)
  • Vascular Medicine (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne un composé de formule (I) dans laquelle: X1, X2 et X3 représentent azote ou -CR3 où R3 représente hydrogène, alkyle, amino, alkylamino, dialkylamino, hydroxy, alcoxy, ou halogène; G1 représente oxygène ou S(O)p où p vaut de 0 à 2; G2 représente une triple liaison carbone-carbone, C=O, C=S, S(O)q où q vaut de 0 à 2, ou un groupe de formule (i/a) dans laquelle Y1 et Y2 ont les correspondances indiquées dans la description; n vaut de 0 à 6; Z1 représente CR4R5 où R4 et R5 ont les correspondances indiquées dans la description; A représente aryle, hétéroaryle, cycloalkyle, ou hétérocycloalkyle à un ou deux cycles à 5 ou 6 éléments; R1 représente hydrogène, alkyle, alcényle, alcinyle, (ces groupes peuvent éventuellement être substitués comme indiqué dans la description) ou un groupe de formule (i/b) dans laquelle s, Z2, B, t et G3 ont les correspondances indiquées dans la description. Ce composé et éventuellement ses isomères optiques, N-oxydes, et sels d'addition avec un acide ou une base pharmaceutiquement acceptable, ainsi que des produits pharmaceutiques les contenant peuvent être utilisés comme inhibiteurs spécifiques de la métalloprotéase matricielle de type 13, pour traiter entre autres l'arthrite et le cancer.
PCT/EP2002/008062 2002-06-25 2002-06-25 Derives de thiazine et d'oxazine en tant qu'inhibiteurs de mmp-13 pour traiter l'arthrite Ceased WO2004000321A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
AU2002333256A AU2002333256A1 (en) 2002-06-25 2002-06-25 Thiazine and oxazine derivatives as mmp-13 inhibitors for treating arthritis
PCT/EP2002/008062 WO2004000321A1 (fr) 2002-06-25 2002-06-25 Derives de thiazine et d'oxazine en tant qu'inhibiteurs de mmp-13 pour traiter l'arthrite
CA002491210A CA2491210A1 (fr) 2002-06-25 2003-06-24 Derives de thiazine et d'oxazine utilises en tant qu'inhibiteurs mmp-13 pour traiter l'arthrite
US10/602,160 US20040006077A1 (en) 2002-06-25 2003-06-24 Thiazine and oxazine derivatives as MMP-13 inhibitors
JP2004514844A JP2005538965A (ja) 2002-06-25 2003-06-24 関節炎を治療するためのｍｍｐ−１３阻害剤としてのチアジン及びオキサジン誘導体
EP03760686A EP1539176A1 (fr) 2002-06-25 2003-06-24 Derives de thiazine et d'oxazine utilises en tant qu'inhibiteurs mmp-13 pour traiter l'arthrite
BR0312107-0A BR0312107A (pt) 2002-06-25 2003-06-24 Derivados de tiazina e de oxazina como inibidores de mmp-13 para o tratamento da artrite
PCT/EP2003/006601 WO2004000322A1 (fr) 2002-06-25 2003-06-24 Derives de thiazine et d'oxazine utilises en tant qu'inhibiteurs mmp-13 pour traiter l'arthrite
MXPA05000004A MXPA05000004A (es) 2002-06-25 2003-06-24 Derivados de triazina y oxazina como inhibidores de la metaloproteasa-13 de matriz para tratar artritis.
AU2003246574A AU2003246574A1 (en) 2002-06-25 2003-06-24 Thiazine and oxazine derivatives as mmp-13 inhibitors for treating arthritis

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2002/008062 WO2004000321A1 (fr) 2002-06-25 2002-06-25 Derives de thiazine et d'oxazine en tant qu'inhibiteurs de mmp-13 pour traiter l'arthrite

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PCT/EP2003/006601 Ceased WO2004000322A1 (fr) 2002-06-25 2003-06-24 Derives de thiazine et d'oxazine utilises en tant qu'inhibiteurs mmp-13 pour traiter l'arthrite

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JP (1) JP2005538965A (fr)
AU (2) AU2002333256A1 (fr)
BR (1) BR0312107A (fr)
CA (1) CA2491210A1 (fr)
MX (1) MXPA05000004A (fr)
WO (2) WO2004000321A1 (fr)

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US6962922B2 (en) 2001-10-12 2005-11-08 Warner-Lambert Company Llc Alkynylated quinazoline compounds
US6894057B2 (en) 2002-03-08 2005-05-17 Warner-Lambert Company Oxo-azabicyclic compounds
AU2003253150A1 (en) 2002-08-13 2004-02-25 Warner-Lambert Company Llc Chromone derivatives as matrix metalloproteinase inhibitors
BR0313385A (pt) 2002-08-13 2005-06-14 Warner Lambert Co Derivados de pirimidina-2,4-diona como inibidores de metaloproteinase da matriz
EP1539709A1 (fr) 2002-08-13 2005-06-15 Warner-Lambert Company LLC Derives d'azaisoquinoline utilises comme inhibiteurs de metalloproteases matricielles
WO2004014892A1 (fr) 2002-08-13 2004-02-19 Warner-Lambert Company Llc Derives monocycliques en tant qu'inhibiteurs de metalloproteinases matricielles
WO2004014909A1 (fr) 2002-08-13 2004-02-19 Warner-Lambert Company Llc Derives fusionnes de la tetrahydropyridine inhibiteurs de la metalloprotease matricielle
AU2003249540A1 (en) 2002-08-13 2004-02-25 Warner-Lambert Company Llc Fused bicyclic metalloproteinase inhibitors
PA8578101A1 (es) 2002-08-13 2004-05-07 Warner Lambert Co Derivados de heterobiarilo como inhibidores de metaloproteinasa de la matriz
AU2003250470A1 (en) 2002-08-13 2004-02-25 Warner-Lambert Company Llc Pyrimidinone fused bicyclic metalloproteinase inhibitors

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CN112159347B (zh) * 2020-10-27 2022-06-07 常州工程职业技术学院 吡考他胺的制备方法

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BR0312107A (pt) 2005-03-29
AU2002333256A1 (en) 2004-01-06
AU2003246574A1 (en) 2004-01-06
JP2005538965A (ja) 2005-12-22
WO2004000322A1 (fr) 2003-12-31
MXPA05000004A (es) 2005-04-08
CA2491210A1 (fr) 2003-12-31

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