MXPA00006424A - Metalloprotease inhibitors, process for their preparation and pharmaceutical compositions containing them - Google Patents
Metalloprotease inhibitors, process for their preparation and pharmaceutical compositions containing themInfo
- Publication number
- MXPA00006424A MXPA00006424A MXPA/A/2000/006424A MXPA00006424A MXPA00006424A MX PA00006424 A MXPA00006424 A MX PA00006424A MX PA00006424 A MXPA00006424 A MX PA00006424A MX PA00006424 A MXPA00006424 A MX PA00006424A
- Authority
- MX
- Mexico
- Prior art keywords
- formula
- group
- compounds
- preparation
- compound
- Prior art date
Links
- 239000003475 metalloproteinase inhibitor Substances 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 title claims description 110
- 238000002360 preparation method Methods 0.000 title claims description 100
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
- 239000002253 acid Substances 0.000 claims abstract description 56
- 238000007792 addition Methods 0.000 claims abstract description 18
- 239000011780 sodium chloride Substances 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims abstract description 9
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 claims abstract description 5
- 229910052736 halogen Chemical group 0.000 claims abstract description 5
- 150000002367 halogens Chemical group 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 36
- -1 1, 3, 4-triazol-1-yl Chemical group 0.000 claims description 29
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 29
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 29
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 23
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000004434 sulfur atoms Chemical group 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
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- 125000005842 heteroatoms Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N oxygen atom Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 125000004385 trihaloalkyl group Chemical group 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 3
- 125000004952 trihaloalkoxy group Chemical group 0.000 claims description 3
- 125000006267 biphenyl group Chemical group 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 150000002366 halogen compounds Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000003000 nontoxic Effects 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
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- 125000003277 amino group Chemical group 0.000 claims 1
- 125000004429 atoms Chemical group 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000000546 pharmaceutic aid Substances 0.000 claims 1
- 239000005864 Sulphur Chemical group 0.000 abstract 1
- 239000000047 product Substances 0.000 description 169
- 159000000000 sodium salts Chemical class 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 24
- 238000004452 microanalysis Methods 0.000 description 17
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- 230000015556 catabolic process Effects 0.000 description 10
- 230000004059 degradation Effects 0.000 description 10
- 238000006731 degradation reaction Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 125000000471 iminomethylidene group Chemical group [H]N=C=* 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
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- 230000002401 inhibitory effect Effects 0.000 description 6
- PKJBWOWQJHHAHG-UHFFFAOYSA-N 1-bromo-4-phenylbenzene Chemical group C1=CC(Br)=CC=C1C1=CC=CC=C1 PKJBWOWQJHHAHG-UHFFFAOYSA-N 0.000 description 5
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- 101700084657 MMP13 Proteins 0.000 description 5
- 102000005741 Metalloproteases Human genes 0.000 description 5
- 108010006035 Metalloproteases Proteins 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
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- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 4
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 4
- 229940110715 ENZYMES FOR TREATMENT OF WOUNDS AND ULCERS Drugs 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 102100004962 MMP13 Human genes 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 230000035492 administration Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- YXVFYQXJAXKLAK-UHFFFAOYSA-N biphenyl-4-ol Chemical group C1=CC(O)=CC=C1C1=CC=CC=C1 YXVFYQXJAXKLAK-UHFFFAOYSA-N 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000002255 enzymatic Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 3
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- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
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- 102100014897 MMP8 Human genes 0.000 description 3
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Abstract
A compound selected from those of the formula (I):wherein:R1 represents hydrogen or halogen, or alkyl or alkoxy,R2 represents hydroxy, alkoxy or -NHOH,Ar1 represents phenylene or biphenylene,X represents oxygen or sulphur, NR, -C=C- or a bond,R represents hydrogen or alkyl,n is an integer from 0 to 6 inclusive,Ar2 represents any one of the groups as defined in the description,its isomers and addition salts thereof with a pharmaceutically-acceptable acid or base, and medicinal products containing the same which are useful as metalloprotease inhibitors
Description
NEW METALOPROTEASE INHIBITORS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT THE
THEY CONTAIN
DESCRIPTION OF THE INVENTION The present invention is drafted to new metalloprotease inhibitors, to a process for their preparation, and to pharmaceutical compositions containing them. In the physiological state, the synthesis of connective tissues is in dynamic equilibrium with the degradation of the extra-detached matrix. This degradation is due to zinc proteases (metalloproteases) secreted by the cells of the existing matrix: they are, without implying any limitation, collagenases (MMP-1, MMP-8, MMP-13), gelatinases or collagenase type IV (MMP) -2, MMP-9) and is tromethos inas (MMP-3). In the normal state, these catabolic enzymes are regulated in terms of their synthesis and their secretion, and in terms of their extracellular enzymatic activity, by natural inhibitors, such as a2-raacroglobulin or the TIMPs (Tissue Inhibitors of MetalloProteinases), which form inactive complexes with metalloproteinases. A common factor in the pathologies in which these enzymes are involved is an imbalance between the activity of the activated enzymes and that of their natural inhibitors, the consequence of which is an excessive degradation of theses. The uncontrolled and accelerated degradation of the membranes by resorption of the extracellular matrix catalyzed by the metalloproteases is a common parameter to a number of pathological conditions, such as rheumatoid arthritis, osteoarthritis, tumor invasion and growth, including malignant spread and formation of metastasis, ulcerations, arteriosclerosis, etc. BB94, a metalloprotease inhibitor, has recently exhibited anti-tumor activity in clinical use, where it has been shown to be active against ovarian cancers (Becker et al., DDT 1996, 1_ (1) 16). Therefore, it can be expected that a meta-protease inhibitor will restore the equilibrium between protease and inhibitor, and thus modify favorably the development of these pathogens. A certain number of metalloprotease inhibitors has been described in the literature. More specifically, two compounds described in patent specifications WO 95/35275, WO 95/35276, EP 606 046, WO 96/00214 and EP 803 505 should be mentioned. The compounds of the present invention are not only new, but also they have also proven to be more powerful metalloprotease inhibitors than those described in the literature, thus making them potentially useful in the treatment of cancer, rheumatoid diseases, such as osteoarthritis and rheumatoid arthritis, arteriosclerosis, etc. More specifically, the present invention relates to compounds of formula (I):
wherein: Ri represents a hydrogen or halogen atom, or an alkyl group of 1 to 6 straight or branched carbon atoms, or straight or branched alkoxy of 1 to 6 carbon atoms, R2 represents a hydroxy group, alkoxy of 1 to 6 straight or branched carbon atoms, or -NHOH, ARi represents a phenylene or biphenylene group, X represents an oxygen or sulfur atom, a group NR, a group -C = C-, or a bond, R represents a carbon atom, hydrogen or a straight or branched alkyl group of 1 to 6 carbon atoms, n is an integer from 0 to 6 inclusive, AR2 represents: a phenyl group substituted by a heteroaryl group, a biphenyl group substituted by a heteroaryl group, - a group pyridinyl substituted by a heteroaryl group, or heterocyclic group, its isomers and addition salts thereof with a pharmaceutically acceptable acid or base, it being understood that: "heteroaryl group" is understood to mean a mono-cyclic aromatic group or aromatic group bi-cyclic co where at least one cycle is aromatic, containing one, two or three identical or different heteroatoms, selected from nitrogen, oxygen and sulfur, optionally substituted by one or more identical or different groups selected from halogen, to 6 carbon atoms dineai or branched, akoxy of 1 to 6 carbon atoms straight or branched, trihalo-alkyl of
1 to 6 straight or branched carbon atoms, trihalo-adkoxy of 1 to 6 straight or branched carbon atoms, and hydroxy, - "heterocyclic group" is understood to mean a non-aromatic, mono- or bi-cyclic group saturated or partially saturated containing one, two or three identical or different heteroatoms, selected from nitrogen, oxygen and sulfur, optionally substituted by one or more identical or different groups selected from halogen, alkyl of 1 to 6 carbon atoms straight or branched, alkoxy of 1 to 6 straight or branched carbon atoms, trihalo-alkyl of 1 to 6 straight or branched carbon atoms, trihalo-alkoxy of 1 to 6 straight or branched carbon atoms, and hydroxy, Among pharmaceutically acceptable acids may be mentioned, without imply some limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid co, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulfonic acid, camphoric acid, oxalic acid, etc. Among the pharmaceutically acceptable bases can be mentioned, without implying any limitation, the sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc. The preferred heteroaryl groups are the imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidyl, triazolyl, pyrazolyl and benzimidazolyl groups. Preferred heterocyclyl groups are pyrrolidinyl, morpholino, piperidino, imidazolidinyl, thiazolidinyl, oxazolidinyl, piperazinyl, isoindolyl, 2,3-dihydroisoindolyl and cyclopenta [c] pyrrolidinyl groups. Preferred compounds of the invention are the compounds of formula (I) wherein X represents an oxygen atom or a sulfur atom. The preferred Ri group is the hydrogen atom. The preferred R2 group is the -NHOH group. When Arx represents a phenylene group, n is more especially zero. When Ar! represents a phenylene group, Ar2 preferably represents a phenyl group substituted by a heteroaryl group, the heteroaryl group is preferably an imidazolyl, triazolyl or pyridinyl group. More especially, the preferred compounds of the invention are the compounds of formula (I) wherein Ari represents a phenylene group, X represents an oxygen or sulfur atom, n is zero, and Ar2 represents a phenyl group substituted by a heteroaryl group selected of imidazolyl, triazolyl and pyridinyl. When Ari represents a biphenylene group, Ar 2 preferably represents a heterocyclic group. The configuration of the 4,5,6,7-tetrahydrofuro [2,3-c] pyridine ring is preferably (5R). The preferred compounds of the invention are: 6-. { 4- [4- (imidazol-1-yl) phenoxy] benzenesulfonyl} -4, 5, 6, 7-tetrahydrofuro. [2, 3-c] piridin- (5R) - (N-hydroxy) carboxamide, and their corresponding addition salts, -6. { 4 '- [2- (pyrrolidin-1-yl) ethoxy] biphenyl-4-sulfonyl} -4, 5, 6, 7-tetrahydro furo [2, 3-c] pyridin- (5R) - (N-hydroxy) -carboxamide, and their corresponding addition salts, 6-. { 4- [4- (1, 3,4-triazol-1-yl) phenoxy] benzenesulfonyl} 4, 5, 6,7-tetrahydrofuro [2,3-c] pyridin- (5R) - (N-hydroxy) -carboxamide, and their corresponding addition salts, 6-. { 4- [4- (pyridin-4-yl) phenoxy] benzenesulfonyl} 4, 5, 6, 7-tetrahydro furo [2, 3-c] pyridine- (5R) - (N-hydroxy) -carboxamide, and their corresponding addition salts, 6-. { 4- [(4- (1, 3, 4-triazol-1-yl) phenylthiojbenzenesulfonyl] -4, 5, 6, 7-tetrahydro furo [2, 3-c] pyridine- (5R) - (N- hydroxy) -carboxamide, and their corresponding addition salts The invention also relates to a process for the preparation of compounds of formula (I), characterized in that a compound of formula (II), in racemic form, is used as the starting material. or in the form of a specific isomer:
Where Ri is as defined for formula (I), and R 'represents a hydrogen atom or an alkyl group of 1 to 6 straight or branched carbon atoms, the amine function of which is substituted by a halogen compound of Formula (III):
ClS02-Ar? -X- (CH2) "-Ar2 (III
Where Arj., X, n and Ar2 are as defined for formula (I), to provide: when R 'represents a hydrogen atom, a compound of formula (I / a), a particular case of the compounds of formula (I):
wherein Ri, Arx, X, n and Ar2 are as defined above, - or, when R 'represents a group (R ") alkyl of 1 to 6 straight or branched carbon atoms, a compound of formula (I / ai), a particular case of the compounds of formula (I):
wherein Ri, ri, X, n, Ar2 and R "are as defined in the foregoing, which can be subjected to the action of an acid, to provide a compound of formula (I / a) described in the above, * the compound of formula (I / a): is subjected, if desired, to the action of an O-substituted hydroxylamine, to provide, after deprotection of the hydroxylamine function, a compound of formula (I / b):
wherein Ri, Ari, X, n and Ar2 are as defined above, * the compounds of formulas (I / a), (I / ai) and (I / b) constitute the totality of the compounds of formula
(I), which are purified, if necessary, according to a conventional purification technique, are separated, when appropriate, into their isomers according to a conventional separation technique, and are converted, if desired, to its addition salts with a pharmaceutically acceptable acid or base. The compounds of formulas (II) and (III) are either commercial products, or are obtained according to known procedures. The invention also relates to pharmaceutical compositions comprising as active ingredient a compound of formula (I) with one or more suitable inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention, those which are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or lozenges, sublingual tablets, gelatin capsules, lozenge-shaped pastilles, suppositories, can be mentioned more especially. creams, ointments, dermal gels, injectable preparations, ingestible suspensions, etc. The dosage used can be adapted to the nature and gives severity of the disorder, the route of administration and according to the age and weight of the patient, and may vary from 0.01 to 2 g per day, in one or more administrations. The following Examples illustrate the invention, but do not limit it in any way. The starting materials used are known compounds, or they are prepared according to known procedures. The Preparations provide synthetic intermediates for use in the preparation of the compounds of the invention. The structures of the compounds described in the Examples and Preparations were determined according to the usual spectrophotometric techniques (Infra Red, NMR, mass spectrometry, etc.).
PREPARATION A: 4- [4- (imidazol-1-yl) phenoxy] benzenesulfonic acid chloride Step A: 4- [4- (imidazol-1-yl) phenoxy] -benzenesulfonic acid 137 mmoles of 1- (4 -phenoxy-phenyl) imidazole in 250 ml of chloroform. 190 mmoles of chlorosulfonic acid were then added dropwise. The whole was left at 45 ° C overnight. After cooling and removal of the solvent by evaporation, the resulting oil was dissolved in diethyl ether. The resulting solid was separated by filtration and dried to provide the expected product. Melting point: 80 ° C
Step B: 4- [4- (Imidazol-1-yl) phenoxy Ibencenesulfonic acid chloride 80 mmoles of the product described in the preceding Step and 90 mmoles of PCI5 were placed in 100 ml of P0C13. The suspension was heated to reflux for 3 hours. After cooling, the oily residue was washed with ether, and then dissolved in acetonitrile. The resulting precipitate was separated by filtration, and washed with isopropyl ether to provide the title compound.
Melting point: 170 ° C
PREPARATION B: Chloride of '- [2-pyrrolidin-1-yl] ethoxy] -bifeni-1-4 -sulonic acid chloride Step A: 1- [2- (Biphenyloxy) ethyl] pyrrolidine 1.76 moles of 4-hydroxybiphenyl were placed, 2.29 moles of 1- (2-chloroethyl) pyrrolidine and 5.3 moles of potassium carbonate in 2.5 liters of dimethylformamide. The whole was heated to 50 ° C overnight. After cooling, the solid was removed by filtration, and the solvent was removed by evaporation. The residue was dissolved in ethyl acetate. After washing the organic phase, drying and evaporation, a residue was obtained, which was purified by chromatography on silica, using a mixture of ethyl acetate / ethanol (80/20) as eluent. The expected product was obtained after crystallization of the residual oil.
Step B: 4 '- [2-pyrrolidin-l-yl] ethoxy] -bi-enyl-4-sulfoniso acid The expected product was obtained according to the process described in Step B of preparation A, starting from the product described in Stage A.
Step C: Chloride of the acid '- [2-pyrrolidin-1-yl) ethoxy] -biphenyl-4-sulfonic acid The expected product was obtained according to the process described in Step C of preparation A, starting from the product described in Step B, maintaining a reflux for 9 hours and filtering off the resulting precipitate. Melting point: 234 ° C
PREPARATION C: Chloride of 4 '- [(pyridin-4-yl) phenoxy] biphenyl-4-sulphonic acid The expected product was obtained according to the process described in Preparation B, in Step A using 4- (4- chlorophenyl) pyridine instead of l- (2-chloroethyl) pyrrolidine.
PREPARATION D: Chloride of 4 '- [(2-ptorfolino) -ethoxy] bi eni 1-4 -sulfonic acid The expected product was obtained according to the process described in Preparation B, in Step A using 4- (2-chloroethyl) ) morpholine instead of l- (2-chloroethyl) pyrrolidine.
PREPARATION E: Chloride of 4 '- [(2-piperidino) -ethoxy] bifeni 1-4-sulfonic acid The expected product was obtained according to the process described in Preparation B, in Step A using 1- (2-chloroethyl) ) piperidine instead of l- (2-chloroethyl) pyrrolidine.
PREPARATION F: Chloride of 4 '- (imidazol-1-yl) biphenyl-4-sulfonic acid The expected product was obtained according to the process described in Preparation B, in Step A using imidazole instead of 1- (2- chloroethyl) pyrrolidine and 4-bromobi phenyl instead of 4-hydroxy-phenyl.
PREPARATION G: 4 '- [2 - (Perhydroazepin-1-yl) ethoxy] bipheni-4-sulfonic acid chloride The expected product was obtained according to the process described in Preparation B, in Step A using 1- (2 -chloroethyl) perhydroazepine instead of l- (2-chloroethyl) pyrrolidine.
PREPARATION H: '- [3- (Pyrrolidin-1-yl) propoxy] bipheni-4-phonic acid chloride The expected product was obtained according to the procedure described in Preparation B, in Step A using 1- (3 -chloropropyl) pyrrolidine instead of l- (2-chloroethyl) pyrrolidine.
PREPARATION I: Chloride of 4 '- [2 ~ (1, 3-dihydroisoindol-2-yl) ethoxy] biphenyl-sulfonisole The expected product was obtained according to the process described in Preparation B, in Step A using 2 - (2-chloroethyl) -1,3-dihydroisoindole instead of 1- (2-chloroethyl) pyrrolidine.
PREPARATION J: Chloride of 4 '- [2- (cyclopenta [c] -pyrrolidin-2-yl) ethoxy] bipheni-4-sulfonic acid The expected product was obtained according to the process described in Preparation B, in Step A using 2- (2-chloroethyl) -cyclopenta [c] pyrrolidine instead of 1- (2-chloroethyl) pyrrolidine.
PREPARATION K: Chloride of the acid - (pyrrolidin-1-yl) -bifeni 1-4-sulfonic acid The expected product was obtained according to the process described in Preparation B, in Step A using pyrrolidine instead of 1- (2 -chloroethyl) -pyrrolidine and 4-bromo phenyl in ve z of 4-hydroxybiphenyl.
PREPARATION L: Chloride of 4 '- (piperidino) -biphenyl-4-sulfonic acid The expected product was obtained according to the process described in Preparation B, in Step A using piperidine instead of 1- (2-chloroethyl) pyrrolidine and 4-bromobiphenyl instead of 4-hydroxy-phenyl.
PREPARATION M: Chloride of 4 '- (morpholino) biphenyl-4-sulfonic acid The expected product was obtained according to the process described in Preparation B, in Step A using morpholine instead of 1- (2-chloroeti 1) pyrrolidine , and 4-bromobiphenyl instead of 4-hydroxybiphenyl.
PREPARATION N: 4 '- (Cyclopenta [c] -pyrrol idin-2-yl) biphenyl-sulfonic acid chloride The expected product was obtained according to the process described in Preparation B, in Step A using cyclopenta [c] pyrrolidine instead of l- (2-chloroethyl) pyrrolidine and 4-bromobiphenyl instead of 4-hydroxybiphenyl.
PREPARATION O: 4 '- [2- (Perhydroaepin-1-yl) ethoxy] biphenyl-4-sulfonic acid chloride The expected product was obtained according to the process described in Preparation B, in Step A using 1, 3- dihydroisoindole instead of l- (2-chloroethyl) irrolidine, and 4-bromobiphenyl instead of 4-hydroxy-phenyl.
PREPARATION P: Chloride of the acid '- [4- (1, 3, 4-triazol-1-yl) phenoxy] bifeni 1-4 -sulfonic The expected product was obtained according to the process described in Preparation A, in the Stage A using 1- (4-phenoxyphenyl) -1,3,4-triazole instead of l- (4-phenoxyphenyl) imidazole.
PREPARATION Q: 4- [4- (1, 2, 4-triazol-1-yl) phenoxy] benzenesulonic acid chloride The expected product was obtained according to the process described in Preparation A, in Step A using 1- (4-phenoxy phenyl) -1,2, 4-triazole instead of l- (4-phenoxyphenyl) imidazole.
PREPARATION R: 4 - [4 - (Pyrrol-1-yl) -phenoxy] -benzenesulfonic acid chloride The expected product was obtained according to the process described in Preparation A, in Step A using 1- (4-phenoxy phenyl) pyrrole instead of l- (4-phenoxyphenyl) imidazole.
PREPARATION S: 4- [4- (Pyrazol-1-yl) enoxy] benzenesulfonic acid chloride The expected product was obtained according to the process described in Preparation A, in Step A using 1- (4-phenoxy phenyl) pyrazole instead of l- (4-phenoxyphenyl) imidazole.
PREPARATION T: Acid chloride 4 - [4 -. { imidazol-2-yl) phenoxy] benzenesulfonic The expected product was obtained according to the process described in Preparation A, in Step A using 2- (4-phenoxyphenyl) imidazole instead of l- (4-phenoxyphenyl) imidazole.
PREPARATION U: 4- [4- (Benzimidazol-1-yl) enoxy] benzenesulfonic acid chloride The expected product was obtained according to the process described in Preparation A, in Step A using 1- (4-phenoxyphenyl) -benzimidazole instead of l- (4-phenoxyphenyl) imidazole.
PREPARATION V: 4- [4- (Pyridin-4-yl) phenoxy] benzenesulfonic acid chloride The expected product was obtained according to the process described in Preparation A, in Step A using 4- (4-phenoxyphenyl) pyridine in instead of l- (4-phenoxyphenyl) imidazole.
PREPARATION W: 4- [4- (Pyrimidin-5-yl) phenoxy] benzenesulfonic acid chloride The expected product was obtained according to the process described in Preparation A, in Step A using 5- (4-phenoxyphenyl) pyrimidine in instead of l- (4-phenoxyphenyl) imidazole.
PREPARATION X: 4 - [4- (Pyrimidin-2-yl) phenoxy] benzenesulfonic acid chloride The expected product was obtained according to the process described in Preparation A, in Step A using 2- (4-phenoxy phenyl) pyr imidine instead of l- (4-phenoxyphenyl) imidazole.
PREPARATION Y: Chloride of 4 - [2- (imidazol-1-yl) pyridin-5-yloxy] bensensulfonisoide The expected product was obtained according to the process described in Preparation A, in Step A using 1- (5- phenoxypyridin-2-yl) imidazole instead of l- (4-phenoxyphenyl) imidazole.
PREPARATION Z: 4- [5- (Imidazol-1-yl) pyridin-2-yloxy] benzenesulfonic acid chloride The expected product was obtained according to the process described in Preparation A, in Step A using 1- (2- phenoxypyridin-5-yl) imidazole instead of l- (4-phenoxyphenyl) imidazole.
PREPARATION AA: 4- [4 '- (Imidazol-1-yl) biphenyl-4-oxyphenoxy] benzenesulfonic acid chloride The expected product was obtained according to the process described in Preparation A, in Step A using 1- [4 '-phenoxy-4-biphenyl] imidazole instead of l- (4-phenoxyphenyl) imidazole.
PREPARATION AB: 4 '- [4- (Imidazol-1-yl) phenoxy] biphenyl-sulphonisoide chloride The expected product was obtained according to the process described in Preparation B, in Step A using 1- (4- chlorophenyl) imidazoi instead of l- (2-chloroethyl) pyrrolidine.
PREPARATION AC: 4- [(4-Chloropyrazol-1-yl) enoxy] bensensulfoniso acid chloride The expected product was obtained according to the process described in Preparation A, in Step A using 1- (4-phenoxyphenyl) -4 -chloropyrazole instead of l- (4-phenoxyphenyl) imidazole.
PREPARATION AD: Chloride of 4- [4- (imidazol-1-yl) phenylthio] benzenesulfonic acid The expected product was obtained according to the process described in Preparation A, in Step A using 1- (4-phenylthiophenyl) imidazole in instead of l- (4-phenoxyphenyl) imidazole.
PREPARATION AE: Chloride of the 4- [4- (pyridin-3-yl) phenoxy] bensensulfonisoide The expected product was obtained according to the process described in Preparation A, in Step A using 3- (4-phenoxyphenyl) pyridine in instead of l- (4-phenoxyphenyl) imidazole.
PREPARATION AF: Chloride of the acid 4- [4- (1, 3, 4-triazol-1-yl) phenyl thio] bensensulfoniso The expected product was obtained according to the process described in Preparation A, in Step A using 1- (4-phenylthiophenyl) -1,3,4-triazole instead of 1- (4-phenoxy phenyl) imidazole.
EXAMPLE 1: Sodium salt of the acid 6-. { 4- [4- (imidazol-1-yl) phenoxy] benaensulfonyl} -4,5,6,7-tetrahydro ro [2, 3-s] pyridine- (5R) -arboxylic acid Step A: Ter-butyliso ester of the acid 6-. { 4- [4- (imidazol-1-yl) phenoxy] bensensulfonyl} -4, 5, 6, 7-tetrahydrofuro [2, 3-s] pyridine- (5R) -sarboxylyl 30 mmoles of 4-, 5, 6, 7-tetrahydrofuro-tert-butyl ester [2, 3-c] were dissolved. ] pyridine- (5R) -carboxylic acid (obtained according to the method described by MS Alien, Synth, Comm. 22 (14), 2077-2102, 1992) in 60 ml of pyridine. 33 mmoles of the compound described in Preparation A were then added in fractions. The mixture was stirred at room temperature overnight, and then poured into 300 ml of water.
After extraction with ethyl acetate, the organic phase was washed with water and then dried. After filtration and removal of the solvent by evaporation, the residue was purified by chromatography on silica gel, using a mixture of ethyl acetate / pentane (8/2) as eluent to provide the expected product.
Stage B: Agate sodium salt 6-. { 4- [4 - (imidazol-1-yl) phenoxy] bensensulfonyl} 4, 5, 6, 7-tetrahydrofuro [2, 3-c] pyridin-5R) -arboxyisole 10 mmoles of the ester obtained in Step A were dissolved in 70 ml of methylene chloride. 10 mmol of anisole were then added, followed, at 0 ° C, by 70 ml of trifluoroacetic acid. The reaction mixture was then stirred at room temperature overnight. After evaporation, the resulting residue was purified by chromatography on silica gel, using a mixture of dichloromethane / ethanol (9/1) as eluent, and gave the expected product after lyophilization of the corresponding sodium salt.
Elemental Microanalysis C H N S Calculated: 56.67 3.72 8.62 6.58 Found 56.93 3.81 8.59 6.86
EXAMPLE 2: 6- Hydrochloride. { 4- [4 - (imidazol-1-yl) phenoxy] bensensulfonyl} -4, 5, 6, 7-tetrahydrofuro [2,3-a] pyridi - (5R) - (N-hydroxy) sarboxamide Stage A: 6-. { 4- [4 - (imidazol-1-yl) phenoxy] benzenesulfonyl} 4,5,6,7-tetrahydrofuro [2,3-c] pyridin- (5R) - (N-allyloxy) carboxamide 9 mmoles of the compound described in Example 1 were dissolved in 70 ml of dichloromethane and 10 ml of dimethylformamide . Then, 45 mmoles of diisopropylethylamine, 9 mmoles of dihydroxybenzotriazole, 13 mmoles of O-allylhydroxylamine hydrochloride and 11 mmoles of tetrafluoroborate of O- (benzotriazol-1-yl) -N, N, N ', N' were added to the preceding mixture. -tetramethyluronium. After one night at room temperature, the mixture was evaporated. The residue was dissolved in dichloromethane. After drying, the solution was filtered and evaporated. The residue was purified by chromatography on silica gel, using a mixture of dichloromethane / ethanol (95/5) as eluent to provide the expected product.
Stage B: 6- Hydrochloride. { 4- [4- (imidazol-1-yl) phenoxy] benzenesulfonyl} -4, 5, 6, 7- tetrahydrof [2, 3-c] pyridine- (5R) - (N-hydroxy) carboxamide 8.5 mmoles of the compound described in the preceding Step were dissolved in 120 ml of dichloromethane. 0.4 mmol of (Ph3P) 2PdCl2 and 2.5 mmol of acetic acid were added to the preceding mixture, and the whole was stirred for 5 minutes before the addition of 4.8 ml of tributyltin hydride. After 5 minutes of stirring, the solvent was removed by evaporation, and the residue was dissolved in a mixture of acetonitrile / methanol. After washing with hexane and evaporation, the residue was purified by reverse phase column chromatography using a mixture of acetonitrile / methanol as eluent. After lyophilization, the resulting solid was dissolved in acetonitrile, and converted to the corresponding hydrochloride by the addition of 4.32 ml of 1 N HCl. The title product was then obtained by lyophilization.
Elemental Microanalysis:% C H N Cl S Calculated: 53.44 4.09 10.84 6.86 6.20 Found: 54.05 4.13 10.82 6.61 6.07
The following Examples were prepared according to the processes described in Example 1 or 2, starting from the corresponding starting materials.
EXAMPLE 3: Sodium salt of acid 6-. { 4 '- [2- (pyrrolidin-1-yl) ethoxy] biphenyl-4-sulfonyl} -4, 5, 6, 7- tetrahydro uro [2,3-c] pyridin- (5R) -carboxylism The title product was obtained according to the process described in Example 1, starting from the product described in Preparation B. Elemental Microanalysis:% CHNS Calculated: 55.08 4.79 4.59 5.25 Found: 54.83 4.50 4.57 5.09
EXAMPLE 4: 6- Hydrochloride. { '- [2- (pyrrolidin-1-yl) ethoxy] biphenyl-4-sulfonyl} -4,5,6,7-tetrahydrofuro [2,3-a] pyridin- (5R) - (N-hydroxy) sarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 3. Elemental Microanalysis:% CHN Cl S
Calculated: 56.98 5.52 7.67 6.47 5.85 Found: 56.64 5.49 7.48 7.14 5.59
EXAMPLE 5: Sodium salt of the acid 6-. { 4 '- [4- (pyridin-4-yl) enoxy] bi eni 1-4 -sil onyl} -4, 5, 6, 7-tetrahydrofuro [2,3-s] pyridi - (5R) ~ carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation C.
EXAMPLE 6: 6- Hydrochloride. { 4 '- [4 - (pyridin-4-yl) enoxy] bi enyl -4 -sul onyl} -4,5,6,7-tetrahydrofuro [2, 3-s] pyridine- (5R) - (N-hydroxy) sarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 5
EXAMPLE 7: Agate sodium salt 6-. { 4 '- [2- (morpholino) -ethoxy] biphenyl-4-sulfonyl} -4,5,6,7-tetrahydrofuro [2,3-a] pyridin- (5R) ~ sarboxiliso The title product was obtained according to the process described in Example 1, starting from the product described in Preparation D.
EXAMPLE 8: 6- Hydrochloride. { 4 '- [2- (morolin) -ethoxy] biphenyl-4-sulfonyl} -4, 5, 6, 7- tetrahydro uro [2,3-s] pyridine- (5R) - (N-hydroxy) sarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 7.
Elemental Microanalysis:% C H N Cl S
Calculated: 55.36 5.36 7.45 6.29 5.68
Found: 55.63 5.44 7.41 6.63 5.65
EXAMPLE 9: Sodium salt of the acid 6-. { 4 '- [2- (piperidino) ethoxy] bipheni-4-sulfonyl} 4,5,6,7-tetrahydrofuro [2,3-c] pyridin- (5R) -arboxylisoiso The title product was obtained according to the process described in Example 1, starting from the product described in Preparation E.
EXAMPLE 10: 6- Hydrochloride. { 4 '- [2- (piperidino) -ethoxy] bipheni-4-sulfonyl} -, 5, 6, 7-tetrahydrofuro [2,3-a] pyridine- (5R) - (N-hydroxy) sarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 9. Elemental Microanalysis:% CHN Cl S Calculated: 57.70 5.74 7.48 6.31 5.70 Found: 57.97 5.79 7.47 6.54 5.55 EXAMPLE 11: Acid hydrochloride 6-. { 4 '- (imidazol-1-yl) biphenyl-4-sulfonyl} -4, 5,6,7-tetrahydrofuro [2,3-c] pyridin- (5R) -carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation F. Microanalysis Elementary:% CHN Cl S Calculated: 56.85 4.15 8.65 7.30 6.60 Found: 56.69 4.20 8.57 6.52 6.73
EXAMPLE 12: 6- Hydrochloride. { 4 '- (imidazol-1-yl) biphenyl-4-sulfonyl} -4, 5,6,7-tetrahydrof [2, 3-s] pyridine- (5R) - (N-hydroxy) aarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 11. Elemental Microanalysis:% CHN Cl S Calculated: 55.14 4.23 11.18 7.08 6.40 Found: 55.41 4.18 11.01 7.27 6.36 EXAMPLE 13: Sodium salt of acid 6-. { 4 '- [2- (perhydroazepin-1-yl) ethoxy] bipheni-4-sulfonyl} -4, 5, 6, 7-tetrahydrofuro [2,3-s] pyridin- (5R) -carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation G.EXAMPLE 14: 6- Hydrochloride. { 4 '- [2- (perhydroazepin-1-yl) ethoxy] bipheni-4-sulfonyl} -4,5,6,7-tetrahydrofuro [2,3-c] pyridin- (5R) - (N-hydroxy) -carboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 13.
EXAMPLE 15: Sodium salt of the acid 6-. { 4 '- [3-pyrrolidin-1-ylpropoxy] bipheni-1-4 -sulfonyl} -4, 5, 6, 7- tetrahydrof [2, 3-c] pyridine- (5R) -carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation H.
EXAMPLE 16: 6- Hydrochloride. { 4 '- [3-pyrrolidin-1-ylpropoxy] biphenyl-4-sulfonyl} -4, 5, 6, 7 - tetrahydrof ro [2,3-c] pyridine- (5R) - (N-hydroxy) aarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 15.
EXAMPLE 17: Sodium salt of the acid 6-. { '- [2- (1, 3-dihydroisoindol-2-yl) ethoxy] bifeni 1-4-sulfonyl} -4, 5, 6, 7 -tetrahyd ofuro [2,3-c] pyridin- (5R) -carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation I.
EXAMPLE 18: 6- Hydrochloride. { 4 '- [2- (1, 3-dihydroisoindol-2-yl) ethoxy] bi eni 1-4 -sulfonyl} -4, 5, 6, 7-tetrahydrofuro [2,3-c] pyridin- (5R) - (N-hydroxy) aarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 17.
EXAMPLE 19: Sodium salt of the acid 6-. { 4 '- [2- (isopentant [s] pyrrolidin-2-yl) -ethoxy] bipheni-1-4 -sulfonyl} -4,5,6,7-tetrhydrofuro [2,3-s] pyridin- (5R) -carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation J.
EXAMPLE 20: 6- Hydrochloride. { 4 '- [2- (sialopenta [c] pyrrolidin-2-yl) -ethoxy] bi eni1- -sul onyl} -4,5,6,7-tetrahydrofuro [2,3-s] pyridine- (5R) - (N-hydroxy) carboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 19.
EXAMPLE 21: Sodium salt of acid 6-. { 4 '- (pyrrolidin-1-II) bifeni 1-4 -sulfonyl} -4, 5, 6,7-tetrahydro-ro [2,3-s] pyridine- (5R) -carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation K.
EXAMPLE 22: 6- Hydrochloride. { 4 '- (pyrrolidin-1-II) bipheni-1-4 -sulfonyl} -4, 5, 6, 7-tetrahydrofuro [2,3-c] pyridin- (5R) - (N-hydroxy) sarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 21.
EXAMPLE 23: Sodium salt of the acid 6-. { 4 '- (piperidino) -biphenyl-4-sulfonyl} -4, 5, 6, 7- tetrahydrof [2, 3-s] pyridine- (5R) -arboxylia The title product was obtained according to the process described in Example 1, starting from the product described in Preparation L.
EXAMPLE 24: 6- Hydrochloride. { 4 '- (piperidino) -bifeni 1-4 -sulfonyl} -4, 5, 6, 7-tetrahydrofuro [2,3-s] pyridin- (5R) - (N-hydroxy) sarboxamide 1 The title product was obtained according to the process described in Example 2, starting from the product described in Example 23.
EXAMPLE 25: Sodium salt of the acid 6-. { 4 '- (morpholino) -biphenyl-4-sulfonyl} -4, 5, 6, 7-tetrahydrofuro [2,3-s] pyridin- (5R) sarboxíliao The title product was obtained according to the process described in Example 1, starting from the product described in Preparation M.
EXAMPLE 26: 6- Hydrochloride. { 4 '- (morpholino) -biphenyl-4-sulfonyl} -4, 5, 6, 7 - tetrahydrofuro [2, 3-a] pyridin- (5R) - (N-hydroxy) sarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 25.
EXAMPLE 21 .- Sodium salt of the acid 6-. { '- (sislopenta- [s] pyrrolidin-2-yl) bipheni-1-4 -sulfonyl} 4,5,6,7-tetrahydro-ro [2,3-s] pyridine- (5R) -carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation N.
EXAMPLE 28: 6- Hydrochloride. { 4 '- (Cialopenta- [a] pyrrole idin-2-yl) bipheni-1-4 -sulfonyl} 4,5,6,7-tetrahydrof ro [2, 3-c] pyridine- (5R) - (N-hydroxy) sarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 27.
EXAMPLE 29: Sodium salt of the acid 6-. { 4 '- (1,3-dihydro-isoindol-2-yl) biphenyl-4-sulfonyl} 4,5,6,7-tetrahydro-ro [2,3-c] pyridine- (5R) -carboxylyl The title product was obtained according to the process described in Example 1, starting from the product described in Preparation O.
EXAMPLE 30: 6- Hydrochloride. { 4 '- (1,3-dihydro-isoindol-2-yl) bi eni 1-4 -suitable} 4,5,6,7-tetrahydrof ro [2,3-c] pyridine- (5R) ~ (N-hydroxy) sarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 29.
EXAMPLE 31: Sodium salt of the acid 6-. { 4 - [4 - (1, 3, 4-triazol-1-yl) phenoxy] benzenesulfonyl} 4,5,6,7-tetrahydrofuro [2,3-s] pyridine- (5R) -sarboxylyl The title product was obtained according to the process described in Example 1, starting from the product described in Preparation P.
EXAMPLE 32: 6- Hydrochloride. { 4- [4- (1, 3, 4-triazol-1-yl) enoxy] benaensulfonyl} 4,5,6,7-tetrahydro-ro [2,3-s] pyridine- (5R) - (N-hydroxy) carboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 31. Elemental Microanalysis:% Calculated CHNS: 54.88 3.98 14.55 6.66 Found: 54.88 4.01 14.16 6.57
EXAMPLE 33: Sodium salt of the acid 6-. { 4 - [4- (1, 2, 4-triazol-1-yl) phenoxy] benzenesulfonyl} 4,5,6,7-tetrahydrofuro [2,3-c] pyridin- (5R) -sarboxylyl The title product was obtained according to the process described in Example 1, starting from the product described in Preparation Q.
EXAMPLE 34: Hydrochloride of 6-. { 4 - [4 - (1, 2, 4-triazol-1-yl) phenoxy] bensensulfonyl} 4,5,6,7-tetrahydrofuro [2,3-c] pyridin- (5R) - (N-hydroxy) carboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 33. Elemental Microanalysis:% Calculated CHNS: 54.88 3.98 14.55 6.66 Found: 54.77 4.14 13.70 6.55
EXAMPLE 35: Sodium salt of the acid 6-. { 4 - [4 - (pyrrol-1-yl) phenoxy] benzenesulfonyl} -4, 5, 6, 7-tetrahydrofuro [2,3-c] pyridin- (5R) -carboxylyl The title product was obtained according to the process described in Example 1, starting from the product described in Preparation R.
EXAMPLE 36: 6- Hydrochloride. { 4- [4- (pyrrol-1-yl) phenoxy] benzenesulfonyl} -4, 5, 6, 7-tetrahydrofuro [2,3-s] pyridin- (5R) - (N-hydroxy) sarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 35
EXAMPLE 37: Sodium salt of the acid 6-. { 4 - [4 - (pyrazol-1-yl) phenoxy] bensensulfonyl} -4, 5, 6, 7-tetrahydrof [2,3-c] pyridine- (5R) -carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation S.
EXAMPLE 38: 6- Hydrochloride. { 4 - [4 - (pyrazol-1-yl) phenoxy] benzenesul fonyl] -4,5,6,7-tetrahydrofuro [2,3-c] pyridin- (5R) - (N-hydroxy) carboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 37.
EXAMPLE 39: Sodium salt of the acid 6-. { 4 - [4 - (imidazol-2-yl) enoxy] benzenesulfonyl} -4, 5, 6, 7-tetrahydrofuro [2,3-c] pyridin- (5R) -sarboxylyl The title product was obtained according to the process described in Example 1, starting from the product described in Preparation T.
EXAMPLE 40: 6- Hydrochloride. { - [4- (imidazol-2-yl) phenoxy] benaensul onyl} -4, 5, 6, 7-tetrahydro-ro [2,3-c] pyridine- (5R) - (N-hydroxy) carboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 39.
EXAMPLE 41: Sodium salt of acid 6-. { 4- [4- (benzimidazol-1-yl) phenoxy] benzenesulfonyl} 4,5,6,7-tetrahydro-ro [2,3-c] pyridine- (5R) -carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation U.
EXAMPLE 42: Hydrochloride of 6-. { 4 - [4 - (bensimidazol-1-yl) phenoxy] benzenesulfonyl} -4, 5, 6, 7 - tetrahydrof [2, 3-c] pyridine- (5R) - (N-hydroxy) carboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 41. Elemental Microanalysis:% CHN Cl S Calculated: 57.19 4.09 9.88 6.25 5.65 Found: 57.31 4.10 9.86 5.61 5.66
EXAMPLE 43: Sodium salt of the acid 6-. { 4- [4- (pyridin-4-yl) phenoxy] benzenesulfonyl} -4, 5, 6, 7-tetrahydrofuro [2,3-a] pyridine- (5R) -carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation V.
EXAMPLE 44: 6- Hydrochloride. { 4- [4- (pyridin-4-yl) phenoxy] benzenesul onyl} -4, 5, 6, 7-tetrahydrofuro [2,3-c] pyridin- (5R) - (N-hydroxy) sarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 43
EXAMPLE 45: Sodium salt of the acid 6-. { 4 - [4 - (Pyrimidin-5-yl) enoxy] benzenesulfonyl} -4, 5, 6, 7-tetrahydrofuro [2,3-c] pyridin- (5R) -arboxylyl The title product was obtained according to the process described in Example 1, starting from the product described in Preparation W.
EXAMPLE 46: 6- Hydrochloride. { 4- [4 - (Pyrimidin-5-yl) phenoxy] bensensulfonyl] -4,5,6,7-tetrahydrof [2,3-s] pyridin- (5R) - (N-hydroxy) sarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 45. Elemental Microanalysis:% CHN Cl S Calculated: 54.50 4.00 10.59 6.06 6.70 Found: 54.90 4.13 10.28 5.74 6.73
EXAMPLE 47: Sodium salt of the acid 6-. { 4 - [4- (Pyrimidin-2-yl) phenoxy] bensensulfonyl] -4,5,6,7-tetrahydrof [2, 3-c] pyridine- (5R) -arboxylic acid The title product was obtained according to process described in Example 1, starting from the product described in Preparation X.
EXAMPLE 48: 6- Hydrochloride. { 4 - [4 - (pyrimidin-2-yl) phenoxy] benzenesulfonyl] • -4,5,6,7-tetrahydrofuro [2,3-c] pyridine- (5R) - (N-hydroxy) sarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 47.
EXAMPLE 49: Sodium salt of the acid 6-. { - [2- (imidazol-1-yl) pyridin-5-yloxy] bensensulfonyl} 4,5,6,7-tetrahydrofuro [2,3-s] pyridine- (5R) -carboxylyl The title product was obtained according to the process described in Example 1, starting from the product described in Preparation Y.
EXAMPLE 50: 6- Hydrochloride. { 4 - [2- (imidazol-1-yl) -pyridin-5-yloxy] benzenesulfonyl} -4, 5, 6, 7-tetrahydro-ro [2,3-c] pyridine- (5R) - (N-hydroxy) carboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 49.
EXAMPLE 51: Sodium salt of the acid 6-. { 4 - [5- (imidazol-1-yl) pyridin-2-yloxy] benzenesulfonyl} 4,5,6,7-tetrahydrofuro [2,3-c] pyridine- (5R) -carboxylyl The title product was obtained according to the procedure described in Example 1, starting from the product described in Preparation Z.
EXAMPLE 52: 6- Hydrochloride. { 4 - [5- (imidazol-1-yl) -pyridin-2-yloxy] benzenesulfonyl} -4, 5, 6, 7-tetrahydrofuro [2, 3-c] piridin- (5R) - (N-hydroxy) carboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 51
EXAMPLE 53: Sodium salt of the acid 6-. { 4 - [4 '- (imidazol-1-yl) bipheni-4-oxy] benzenesulfonyl} 4,5,6,7-tetrahydro-ro [2,3-c] pyridine- (5R) -carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation .AA .
EXAMPLE 54: 6- Hydrochloride. { 4 - [4 '- (imidazol-1-yl) - Bi enyl -4 -oxy] benzenesul fonyl} -4, 5, 6, 7- tetrahydro uro [2,3-c] pyridin- (5R) - (N-hydroxy) sarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 53. Elemental Microanalysis:% CHN Cl S Calculated: 58.73 4.25 9.45 5.41 5.98 Found 59.09 4.27 9.23 5.21 5.97
EXAMPLE 55: Sodium salt of the acid 6-. { '- [4- (imidazol-1-yl) phenoxy] biphenyl-4-sulphonyl} 4,5,6,7-tetrahydrofuro [2,3-a] pyridine- (5R) -carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation AB.
EXAMPLE 56: 6- Hydrochloride. { '- [4 - (imidazol-1-yl) -phenoxy] bipheni-1-4 -sulfonyl} -4, 5, 6, 7-tetrahydrofuro [2,3-c] pyridin- (5R) - (N-hydroxy) aarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 55.
EXAMPLE 57: Sodium salt of the acid 6-. { 4- [4- (4- sloropyrazol-1-yl) phenoxy] bensensulfonyl} 4,5,6,7-tetrahydrofuro [2,3-c] pyridine- (5R) -carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation AC.
EXAMPLE 58: 6- Hydrochloride. { 4- [4 - (4-chloropyrazol-1-yl) enoxy] benzenesulfonyl} -4, 5, 6, 7 - tetrahydrofuro [2, 3-s] piridin- (5R) - (N-hydroxy) aarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 57.
Elementary Microanalysis% C H N Cl S
Calculated: 53.65 3.72 1 0. 8 8 6. 8 8 6. 23 Found 53.40 3.81 1 0. 64 6. 8 8 6. 07
EXAMPLE 59: Sodium salt of the acid 6-. { - [4 - (imidazol-1-yl) phenylthio] benzenesulfonyl} -4, 5, 6, 7-tetrahydrofuro [2,3-c] pyridin- (5R) -carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation AD.
EXAMPLE 60: 6- Hydrochloride. { 4 - [4- (imidazol-1-yl) -enylthio] benzenesulfonyl} -4, 5, 6, 7-tetrahydrofuro [2,3-c] pyridin- (5R) - (N-hydroxy) sarboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 59. Elemental Microanalysis:% CHN Cl S Calculated: 51.83 3.97 10.51 12.03 6.65 Found: 51.04 3.99 10.11 12.26 7.65 EXAMPLE 61: Sodium salt of the acid 6-. { 4 - (pyridin-3-yl) phenoxy] benzenesul onyl} -4, 5, 6, 7- tetrahydro uro [2, 3-c] pyridine- (5R) -carboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation AE .
EXAMPLE 62: 6- Hydrochloride. { 4- (Pyridin-3-yl) -enoxi] -benzenesulfonyl} -4, 5, 6, 7-tetrahydrofuro [2, 3-c] iridin- (5R) - (N-hydroxy) carboxamide The title product was obtained according to the process described in Example 2, starting from the product described in Example 61. Elemental Microanalysis:% CHN Cl S Calculated: 56.87 4.20 7.96 6.07 6.71 Found: 56.88 4.35 8.06 5.94 7.22
EXAMPLE 63: Sodium salt of the acid 6-. { - [4- (1, 3, 4-triazol-1-yl) phenyl thio] bensensulfonyl} 4,5,6,7-tetrahydrofuro [2,3-c] pyridin- (5R) -arboxylic acid The title product was obtained according to the process described in Example 1, starting from the product described in Preparation AF.
EXAMPLE 64: 6- Hydrochloride. { 4 - [4 - (1, 3, 4-triazol-1-yl) phenyl thio] benzenesulfonyl} -4,5,6,7-tetrahydrof [2, 3-c] pyridine- (5R) - (N-hydroxy) carboxamide The expected product was obtained according to the process described in Example 63.
EXAMPLE 65: 6- Hydrochloride of the ethyl ester. { 4 - [4- (imidazol-1-yl) phenoxy] benzenesul onyl} -4, 5, 6, 7 -tehydrofuro [2,3-c] pyridin- (5R) -carboxylic acid The expected product was obtained according to the process described in Step A of Example 1, starting from the ethyl ester , 5, 6, 7-tetrahydrofuro [2,3-c] pyridine- (5R) -carboxylic acid and the product described in Preparation A.
Elemental Microanalysis C H N Cl S
Calculated: 56.66 4.56 7.96 6.69 6.05 Found 56.80 4.67 7.94 6.88 5.87
PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION EXAMPLE A: Enzymatic inhibition of metalloproteases Six human recombinant enzymes, MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), MMP-8 (collagenase neutrophil), MMP-9 (gelatinase B) and MMP-13 (collagenase 3) were activated with APMA (4-aminophenylmercuric acetate). Enzymatic tests on MMP-1, -2, -8, -9 and -13 were carried out using the following peptidomimetic substrate:
DnpProGhaGlyCys (Me) HisAlaLys (Nma) NH2,
which is hydrolyzed between glycine and cysteine, to provide a fluorescent product described by
D. M. BICKETT et al. (Anal. Biochem., 212, 58-64,
1993). The enzymatic test on MMP-3 was carried out using the following peptidomimetic substrate:
McaArgProLysProTyrAlaNvaTrpMetLys (Dnp) NH2,
which is hydrolyzed between alanine and norvaline to provide a fluorescent product described by H. NAGASE et al. (J. Biol. Chem., 269, 20952-20957, 1994). The reactions, carried out in a buffer solution of 50 mM Tris, 200 mM NaCl, 5 mM CaC12, 0.1% Brij 35 at pH 7.7, were started using 20 μM of substrate in a total volume of 100 μl at 37 ° C The fluorescence obtained after six hours was read on a 96-well plate in a fluorimeter equipped with a combination of 360 nm and 460 nm filters for excitation and emission. Compounds of the invention exhibited IC 50 values from 10 -10 10 'M for all MMPs, with the exception of MMP-1. The collagenases MMP-13 and MMP-8 exhibited a specificity of a factor of 1000 compared to collagenase MMP-1.
EXAMPLE B: In vitro degradation of the cartilage matrix the compounds of the invention were studied in a model of damage to the cartilage matrix induced by IL-1β. The test, carried out in rabbit cartilage, is related: on the one hand, to the degradation of collagen: colorimetric measurement, according to the Grant technique (GRANT RA OH-proline estimation by the lifting autoanal, J. Clin Path., 17, 685,
1964), of the OH-proline fraction released by the tissue in contact with IL-lβ (10 ng / ml) and plasmin (0.1 U / ml) for 2 days. On the other hand, to the degradation of proteoglycans: measurement by radioisotopes of the fraction of giicosaminoglicanos released after 24 hours of stimulation with IL-lβ (10 ng / ml) by the pre-arcing with 35S04, during the course of 24 hours in contact with APMA (5 x 10 ~ 4 M). The compounds of the invention were studied by addition to the culture medium for the 3 days of the test. For concentrations from 10"8 to 10" 6 M, they strongly inhibited the degradation of collagen and proteoglycans. By way of example, the activities of some of the compounds of the invention are as follows:
EXAMPLE C: In vitro angiogenesis Portions of the thoracic aorta of male Fischer 344 rats aged 8 to 12 weeks were immersed in a collagen type I gel according to the method of
Nicosia and Ottinetti (1990). After five days of culture in a serum-free medium, the preparations were examined using a microscope, and the formation of pseudo-vessels was quantified in terms of vascular density after fingering and image analysis.
By way of example, the IC50 of the compound of Example 2 is 2.3 nM, and that of the compound of Example 4 is 100 nM.
EXAMPLE D: Absorption after treatment via the oral route in mice - plasma bioactivity The absorption of the compounds was evaluated in the circulation after oral treatment in mice (CDI, male, 25-30 g) by measuring the potential of the plasma to inhibit MMP-13 under conditions identical to those used in vitro (Example A). The bioactivity was determined in plasma, after removal of the proteins by ethyl alcohol (18 hours at -20 ° C), at various times after the administration of the compounds. By way of example,% inhibition of MMP-13 obtained after 30 mg / kg are as follows:
EXAMPLE E: Arthritis with Freund's adjuvant in rat - Protection against joint degradation The protective activity of the compounds against the degradation of joint tissue was studied in the arthritis model with Freund's adjuvant in rat (Lewis, female, 62 days). The autoimmune pathology induced by the intraplantar injection of 0.1 ml of adjuvant
(Mycobacterium butyricum 4 mg / ml) on one of the hind legs causes joint damage in addition to an inflammatory reaction. After 21 days, the damage to the leg that had not received an injection was evaluated in terms of the bones (densitometric measurement of the proximal portion of the femur) and of the patellar cartilage (content of OH-proline and glycosaminoglycan measured according to the technique of Farndale et al. (Biphysica Acta, 1986, 883, 173-177) and that described by Grant (J. Clin. Path., 1964, 17, 685), respectively). By way of example, the compound of Example 2 administered orally twice daily at a dose of 40 mg / kg (10 animals / group) caused a reduction in the loss of bone mineral content in the proximal femur of arthritic control animals. by 42% (P <0.01) and a reduction in the loss of glycosaminoglycans and OH-proline from patellar cartilage by 61% (P <0.05) and 98% (P <0.01), respectively.
EXAMPLE F: Farmasynthesis Composition Formulation for the preparation of 1000 tablets containing a dose of 100 mg Compound of Example 2 100 mg
Hydroxypropyl cellulose 2 g
Wheat starch 10 g
Lactose 100 g
Magnesium stearate 3 g
Talc 3 g
Claims (16)
- RE IVINDICACIONE S 1. Compounds of formula (I) wherein: Ri represents a hydrogen or halogen atom, or an alkyl group of 1 to 6 straight or branched carbon atoms, or straight or branched alkoxy of 1 to 6 carbon atoms, R2 represents a hydroxy group, alkoxy of 1 to 6 straight or branched carbon atoms, or -NHOH, ARi represents a phenylene or biphenylene group, X represents an oxygen or sulfur atom, a group NR, a group -C = C-, or a bond, R represents a carbon atom, hydrogen or an alkyl group of 1 to 6 straight or branched carbon atoms, n is an integer from 0 to 6 inclusive, AR2 represents: a phenyl group substituted by a heteroaryl group, a biphenyl group substituted by a heteroaryl group, a pyridinyl group substituted by a heteroaryl group, a heterocyclic group, its isomers and addition salts thereof with a pharmaceutically acceptable acid or base, it being understood that: "heteroaryl group" is understood to mean a mono-cyclic aromatic group or aromatic group bi- cyclic wherein at least one cycle is aromatic, containing one, two or three identical or different heteroatoms, selected from nitrogen, oxygen and sulfur, optionally substituted by one or more identical or different groups selected from halogen, alkyl of 1 to 6 atoms linear or branched carbon, straight or branched alkoxy of 1 to 6 carbon atoms, trihalo-alkyl of 1 to 6 straight or branched carbon atoms, trihalo-alkoxy of 1 to 6 straight or branched carbon atoms, and hydroxy, " "heterocyclic group" is understood to mean a saturated or partially saturated non-aromatic, mono- or bi-cyclic group containing one, two or three identical or different heteroatoms, selected from nitrogen, oxygen and sulfur, optionally substituted by one or more identical groups or different selected from halogen, linear or branched alkyl of 1 to 6 carbon atoms, straight or branched alkoxy of 1 to 6 carbon atoms, trihalo-alkyl of 1 to 6 linear or branched carbon atoms, trihalo-alkoxy of 1 to 6 straight or branched carbon atoms, and hydroxy.
- 2. Compounds of formula (I) according to claim 1, characterized in that X represents an oxygen atom or a sulfur atom.
- 3. Compounds of formula (I) according to any of claims 1 or 2, characterized in that R2 represents a group -NHOH.
- 4. Compounds of formula (I) according to any of claims 1, 2 or 3, characterized in that ri represents a phenylene group and n is zero.
- 5. Compounds of formula (I) according to claim 4, characterized in that Ar 2 represents a phenyl group substituted by a heteroaryl group.
- 6. Compounds of formula (I) according to claim 5, characterized in that Ar 2 represents a phenyl group substituted by a group selected from imidazolyl, triazolyl and pyridinyl.
- 7. Compounds of formula (I) according to any of claims 1 to 6, characterized in that X represents an oxygen or sulfur atom, R2 represents a group -NHOH, Arx represents a phenylene group, n is zero, and Ar2 represents a phenyl group substituted by a group selected from imidazolyl, triazolyl and pyridinyl.
- 8. Compounds of formula (I) according to any of claims 1, 2 and 3, characterized in that ri represents a biphenylene group, and Ar 2 represents a heterocyclic group.
- 9. Compound of formula (I) according to claim 1, characterized in that it is 6-. { 4- [4- (imidazol-1-yl) phenoxy] benzenesulfonyl} -4, 5, 6, furo [2, 3-c] pyridine- (5R) - (N-hydroxy) carboxamide, and their addition salts with a pharmaceutically acceptable acid or base.
- 10. Compound of formula (I) according to claim 1, characterized in that it is 6-. { 4 '- [2- (pyrrolidin-1-yl) ethoxy] biphenyl-4-sulfonyl} -4, 5, 6, 7-tetrahydro furo [2, 3-c] pyridine- (5R) - (N-hydroxy) carboxamide, and its addition salts with a pharmaceutically acceptable acid or base.
- 11. Compound of formula (I) according to claim 1, characterized in that it is 6-. { 4- [4- (1, 3, 4-triazol-1-yl) phenoxy] benzenesulfonyl} 4, 5, 6, 7-tetrahydro-furo [2, 3-c] pyridine- (5R) - (N-hydroxy) -carboxamide, and its addition salts with a pharmaceutically acceptable acid or base.
- 12. Compound of formula (I) according to claim 1, characterized in that it is 6-. { 4- [4- (pyridin-4-yl) phenoxy] benzenesulfonyl} -4,5,6,7-tetrahydrofuro [2, 3-c] pyridine- (5R) - (N-hydroxy) -carboxamide and its addition salts with a pharmaceutically acceptable acid or base.
- 13. Compound of formula (I) according to claim 1, characterized in that it is 6-. { 4 - [(4- (1, 3, 4-triazol-1-yl) phenylthio] benzenesulfonyl} -4,5,6,7-tetrahydrofuro [2,3-c] pyridine- (5R) - (N -hydroxy) -carboxamide, and its addition salts with a pharmaceutically acceptable acid or base.
- 14. Process for the preparation of compounds of formula (I) according to claim 1, characterized in that a compound of formula (II), in racemic form or in the form of a specific isomer is used as the starting material: Where Ri is as defined for formula (I), and R 'represents a hydrogen atom or an alkyl group of 1 to 6 straight or branched carbon atoms, the amine function of which is substituted by a halogen compound of Formula (III): ClS02-Ar? -X- (CH2) n-Ar2 (III) Wherein ri, X, n and Ar2 are as defined for formula (I), to provide: when R 'represents a hydrogen atom, a compound of formula (I / a), a particular case of the compounds of formula (I) I): wherein Ri, Ari, X, n and Ar2 are as defined in the above, - or, when R 'represents a group (R ") alkyl of 1 to 6 straight or branched carbon atoms, a compound of formula (I / ai), a particular case of the compounds of formula (I): wherein Ri, Ari, X, n, Ar2 and R "are as defined above, the quad can be subjected to the action of an acid, to provide a compound of formula (I / a) described in the above, * the compound of formula (I / a): is subjected, if desired, to the action of a hydroxylamine O-subs tute, to provide, then ee of the deprotection of the hydroxylamine function, a compound of formula (I / b): wherein Ri, Ari, X, n and Ar2 are as defined above, * the compounds of formulas (I / a), (I / ai) and (I / b) constitute the totality of the compounds of formula (I), which are purified, if necessary, according to a conventional purification technique, are separated, when appropriate, into their isomers according to a conventional separation technique, and are converted, if desired, to its addition salts with a pharmaceutically acceptable p-base acid.
- 15. Pharmaceutical compositions comprising as active ingredient a compound according to any of the rei indications 1 to 13, in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
- 16. Pharmaceutical compositions according to claim 15, which comprises as active ingredient a compound according to any of claims 1 to 13, for use as metalloprotease inhibitors.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR99.08448 | 1999-07-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00006424A true MXPA00006424A (en) | 2002-07-25 |
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