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
• TMPs tissue inhibitors of metallopro tease
• MMP-13 matrix metalloprotease-13 is a collagenase-type MMP which constitutes the predominant collagenase observed during osteoarthritis, in the course of which pathology the chondrocyte directs the destruction of cartilage.
• MMP inhibitors are known. Most of these MMP-inhibitors are not selective for a single MMP, such as those described by Montana and Baxter (2000) or by Clark et al. (2000).
• the applicant has identified novel thiazine and oxazine derivatives 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, mono(C ⁇ -C 6 )alkylamino, di(C ⁇ -C 6 )alkylamino, hydroxy, (C ⁇ -C 6 )alkoxy, and halogen, it being understood that not more than two of the groups X ⁇ , X 2 and X 3 simultaneously represent a nitrogen atom,
• Gi 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 ⁇ -C 6 )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 -C jRs 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,
• hydrocarbon chain Z 2 optionally contains one or two isolated or conjugated multiple bonds
• one of said -CR R]o 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 ⁇ -C 6 )alkyl, and carbonyl,
• ⁇ / 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,
• - X 4 represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen, and nitrogen substituted by a hydrogen 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 ⁇ , R12 and R i3 which may be identical or different independently of each other, are selected from hydrogen and (C 1 -C 6 )alkyl,
• R ⁇ 5 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,-C 6 )alkyl,
• R 2 which may be identical or different independently of each other, is (are) selected from (C ⁇ -C 6 )alkyl, halogen, -CN, -NO 2 , -SCF 3 , -CF 3 , -OCF 3 , -NR 7 R 8 , -OR 7 ,
• X represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen, and nitrogen substituted by hydrogen or (C ⁇ -C 6 )alkyl,
• - k is an integer from 0 to 3 inclusive
• L 5 - R 7 and R 8 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, sulphur optionally substituted by one or two oxygen, and nitrogen substituted by hydrogen or (C C 6 )alkyl,
• JO - R ⁇ 8 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 ⁇ -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- 1 ,3-benzothiazine)-benzoate, 6-phenylthio-2,4-dioxo-3,4-dihydro-2H-l ,3-benzothiazine, 6- benzylsulphonyl-2,4-dioxo-3,4-dihydro-2H-l ,3
• the invention relates to compounds of formula (I) wherein : • Gi represents a sulphur atom,
• G 2 represents a group of formula (i/a):
• Yj represents an oxygen atom
• Y 2 represents a group -NH, • X ⁇ , X2, X , n, Zj, A, Re m and R2 are as defined in formula (I).
• 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 :
• n represents an integer from 1 to 6 inclusive
• Xi, X 2 , X 3 , Zi, A, R ⁇ ; m and R2 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, Ri, m and R 2 are as defined in formula (I).
• substituent Ri that is preferred according to the invention is the group of formula (i b):
• Z2 represents a group -CR R ⁇ 0 in which R 9 and Rio 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 Ri 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 1; X 2 , and X represent each a group -CR 3 in which R represents a hydrogen atom.
• X ⁇ represents a group -CR 3 in which R 3 represents a hydrogen atom
• X 2 represents a nitrogen atom
• 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 Zi represents -CR 4 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 phenyl group , m is equal to zero or one, and R 2 represents a (C]-C 6 )alkoxy group or a hydrogen atom.
• preferred compounds of the invention are compounds of formula (I) wherein A represents a pyridyl group, m is equal to zero or one, and R 2 represents a (C ⁇ -C 6 )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) : - 3-benzyl-2,4-dioxo-3,4-dihydro-2H-benzo[e][l,3]thiazine-6-carboxylic acid 4-methoxy benzylamide;
• 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.
• a disease selected from arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases, age-related degeneration and cancers.
• a preferred method of treatment according to this invention is treatment of disease selected from arthritis, osteoarthritis and rheumatoid arthritis.
• - a (C ⁇ -C ⁇ )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 ethyn
• - a (C ⁇ -C 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).
• a review of the pharmaceutically acceptable salts will be found in J. Pharm.
• 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): in which Xj, X 2 , X 3 , 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 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): in which G ⁇ has the same definitions as the compound of formula (I),
• 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 3 , 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 is hydrogen or (C ⁇ -C 6 )alkyl
• R" is hydrogen or (C ⁇ -C 6 )alkyl
• compounds of the invention that are present in the form of a mixture of diastereoisomers are isolated in a pure form by using conventional separation techniques such as chromatography.
• compounds of formula (I) of the present invention are matrix metalloprotease inhibitors, and more particularly inhibitors of the enzyme MMP-13.
• the use of the compounds of the present invention may be recommended for the treatment of any pathology in which destruction of extracellular matrix tissue occurs, and most particularly pathologies such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease, age-related macular degeneration and cancers.
• pathologies such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease, age-related macular degeneration and cancers.
• the present invention also relates to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), an isomer thereof, a N-oxide thereof, or an addition salt thereof with a pharmaceutically-acceptable acid or base, alone or in combination with one or more pharmaceutically-acceptable, inert, non-toxic excipients or carriers.
• compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, intravaginal, rectal, nasal, perlingual, buccal, ocular or respiratory administration.
• compositions according to the invention for parenteral injections especially include aqueous and non-aqueous sterile solutions, dispersions, suspension and emulsions, and also sterile powders for reconstituting injectable solutions or dispersions.
• 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.
• compositions mentioned hereinbefore illustrate the invention but do 5 not limit it in any way.
• inert, non-toxic excipients or carriers there may be mentioned, by way of non-limiting example, diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, swelling agents, disintegrating agents, retardants, lubricants, absorbents, suspending agents, colorants, aromatizing agents etc...
• the useful dosage varies according to the age and weight of the patient, the administration route, the pharmaceutical composition used, the nature and severity of the disorder and the administration of any associated treatments.
• the dosage ranges from 2 mg to 1 g per day in one or more administrations.
• the compositions are prepared by methods that are common to those skilled in the art and generally comprise 0.5% to 60% by weight of active
• 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 '.0 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
• 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 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 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 test described above for the inhibition of MMP-13 was also adapted and used to determine the ability of the compounds of formula (I) to inhibit the matrix metalloproteases MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12 and MMP-14.
• the results obtained show that the compounds according to the invention generally have IC 50 values for MMP-13 which are about 100 times lower than the IC 50 values for the same compounds with respect to the other matrix metalloproteases tested.
• the IC 50 values on MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP- 12 and MMP- 14 for the compound of Example 1 are respectively 30 ⁇ M, lOO ⁇ M, 18 ⁇ M, 30 ⁇ M, lOO ⁇ M, lOO ⁇ M, and lOO ⁇ M.

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• 2003
  • 2003-06-24 EP EP03760686A patent/EP1539176A1/de not_active Withdrawn

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