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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • 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
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems

Definitions

• the invention relates to a bicycloazaheterocyclyl carboxylic acid sulfonamide derivative of formula I herein, pharmaceutical preparation comprising it, process for preparing it and method for its pharmaceutical use.
• MMPs matrix metalloproteinases
• the MMPs form a group of Zn-dependent enzymes which are involved in the biological breakdown of the extracellular matrix (D. Yip et al. in Investigational New Drugs 17 (1999), 387-399 and Michaelides et al. in Current Pharmaceutical Design 5 (1999) 787-819).
• MMPs are able, in particular to break down fibrillar and nonfibrillar collagen and proteoglycans, both of which are important matrix constituents.
• MMPs are involved in processes of wound healing, tumor invasion, metastasis migration and in angiogenesis, multiple sclerosis and heart failure (Michaelides page 788; see above). In particular, they play an important role in the breakdown of the joint matrix in arthrosis and arthritis, whether this be osteoarthrosis, osteoarthritis or rheumatoid arthritis.
• the activity of the MMPs is furthermore essential for many of the processes which play a role in the formation of atherosclerotic plaques, such as the infiltration of inflammatory cells, the migration of smooth muscle cells, and proliferation and angiogenesis (S. J. George, Exp. Opin. Invest. Drugs (2000), 9 (5), 993-1007).
• degradation of the matrix by MMPs can cause anything from plaque instabilities through to ruptures, with this being able to lead to the clinical symptoms of atherosclerosis, unstable angina pectoris, myocardial infarction or stroke (E. J. M. Creemers et al., Circulation Res. 89, 201-210 (2001)).
• MMP tissue inhibitors of metalloproteases
• MMPs cleave matrix proteins, such as collagen, laminin, proteoglycans, elastin or gelatin, and also process (i.e., activate or deactivate), by means of a cleavage, a large number of other proteins and enzymes under physiological conditions, which means that they play an important role in the entire organism, with this role being of particular importance in connective tissue and bone.
• MMPs have rise to side effects.
• the side effects that are principally mentioned are musculoskeletal pains or anthralgias.
• the prior art states unambiguously that it is expected that more selective inhibitors will be able to reduce these said side effects (Yip, page 387, see above).
• Particular emphasis should be placed in this case on specificity in respect to MMP-1, as these undesirable side effects obviously occur to a greater extent with inhibition of MMP-1.
• MMP inhibitors therefore frequently suffer from the disadvantage of lacking specificity.
• Most MMP inhibitors inhibit many MMPs simultaneously because the structure of the catalytic domain in the MMPs is similar. As a consequence, the inhibitors have the undesirable property of acting on the enzymes including those that have a vital function (Massova, I., et al., The FASEB Journal (1998) 12, 1075-1095).
• the present invention satisfies the above needs by providing a compound that is a powerful inhibitor of the matrix metalloproteinases MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13 whereas it has only a weak inhibitory effect on MMP-1.
• the invention therefore relates to a compound of formula I wherein
• the invention also is directed to a method for preparing the compound according to the invention, a pharmaceutical preparation thereof, and its use for inhibiting matrix metalloproteinases MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13.
• (C 1 -C 6 )-alkyl means hydrocarbon radicals whose carbon chain is straight or branched and contains from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, 2,3-dimethylbutane or neohexyl.
• —(C 0 -C 4 )-alkylene means hydrocarbon radicals whose carbon chain is straight or branched and contains from 1 to 4 carbon atoms, for example methylene, ethylene, propylene, isopropylene, isobutylene, butylene or tertiary butylene. “—C 0 -alkylene” is a covalent bond.
• —(CH 2 ) n —, in which n is zero, 1 or 2 means, for n equal to zero, a covalent bond, for n equal to 1, the methylene radical and for n equal to 2, the ethylene radical.
• —(C 2 -C 4 )-alkenylene means hydrocarbon radicals whose carbon chain is straight or branched and contains from 2 to 4 carbon atoms and, depending on the chain length, possesses one or two double bonds, for example ethenylene, propenylene, isopropenylene, isobutenylene or butenylene; provided the possibility exists in principle, the substituents on the double bond can be arranged in the E configuration or the Z configuration.
• —(C 2 -C 6 )-alkynylene means hydrocarbon radicals whose carbon chain is straight or branched and contains from 2 to 6 carbon atoms and, depending on the chain length, possess 1 or 2 triple bonds, for example ethynylene, propenylene, isopropynylene, isobuthylynylene, butynylene, pentynylene or isomers of pentynylene or hexynylene or isomers of hexynylene.
• (C 3 -C 6 )-cycloalkyl means a radical that is derived from 3- to 6-membered monocycles such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• the radicals in the ring of the compound of formula I mean respectively —(CH 2 ) r — and —(CH 2 ) q — radicals wherein r and q are independently zero, 1, 2 or 3, where the variables n 1 or n 2 in each case indicate the number of the —CH 2 — radicals in the ring of the formula I.
• n 1 or n 2 has the value zero, a covalent bond is formed resulting in the ring consisting of a total of 4 ring atoms.
• n 1 or n 2 has the value 1
• a —CH 2 — radical is formed resulting in the ring consisting of 5 ring atoms.
• n 1 or n 2 has the value 2
• a —CH 2 —CH 2 — radical is formed resulting in the ring consisting of 6 ring atoms.
• n 1 or n 2 has the value 3
• a —CH 2 —CH 2 —CH 2 radical is formed resulting in the ring consisting of 7 ring atoms.
• —(C 6 -C 14 )-aryl means aromatic carbon radicals having from 6 to 14 carbon atoms in the ring.
• —(C 6 -C 14 )-aryl radicals are, for example, phenyl, naphthyl, for example 1-naphthyl or 2-naphthyl, anthryl or fluorenyl. Naphthyl radicals and, in particular, phenyl radicals are preferred aryl radicals.
• 5- or 6-membered aromatic heteroaryl ring means aromatic ring systems that contain one or two heteroatoms from the series oxygen, nitrogen and sulfur and can be derived from dihydrofuran, dioxole, dioxane, furan, imidazolidine, imidazoline, imidazole, isoxazole, isoxazolidine, 2-isoxazoline, isothiazole, isothiazolidine, 2-isothiazoline, morpholine, oxazole, oxothiolane, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazolidine, pyrazoline, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrahydrofuran, tetrahydropyridine, thiazole, thiomorpholine, thiophenyl or thiopyran.
• heteroaryl means a radical such as acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran[2,3-b]tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H,6H-1,5,2-dithiazinyl, fur
• the azaheterocyclyl is also partially unsaturated or substituted by one or two oxo.
• Particular azaheterocyclyl are selected from the group consisting of
• bicycloazaheterocyclyl carboxylic acid sulfonamide derivative pertains to the compound of formula I as defined.
• pyridyl such as 2-pyridyl, 3-pyridyl or 4-pyridyl
• pyrrolyl such as 2-pyrrolyl and 3-pyrrolyl
• furyl such as 2-furyl and 3-furyl
• thiophenyl, thienyl such as 2-thienyl and 3-thienyl
• Another particular embodiment of the invention is a process for the preparation of the compound according to formula I, comprising
• ester protecting group R e The groups that are used in Protective Groups in Organic Synthesis, T. H. Greene, P. G. M. Wuts, Wiley-Interscience, 1991, as groups for protecting esters can be employed as the ester protecting group R e .
• Examples of preferred ester protecting groups are methyl, ethyl, isopropyl, tert-butyl or benzyl.
• the starting compounds and reagents that are used can either be prepared using known methods or are commercially available.
• the reactions take place as depicted, for example, in WO 97/18194.
• the reaction in accordance with process step a) takes place in the presence of a base such as KOH, NaOH, LiOH, N,O-bis(trimethylsilyl)acetamide (BSA), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, collidine, imidazole or sodium carbonate in solvents such as tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide, dioxane, acetonitrile, toluene, chloroform or methylene chloride, or else in the presence of water.
• a base such as KOH, NaOH, LiOH, N,O-bis(trimethylsilyl)acetamide (BSA), N-methylmorpholine (NMM), N-ethy
• Modifications in the side chain F means that, for example, a nitro group is hydrogenated using the metal catalyst Pd/C or reacted with SnCl 2 or Zn under standard conditions and the resulting amino group can then be subjected to further modification, for example by reacting it with carbonyl chlorides, sulfonyl chlorides, chloroformic esters, isocyanates, isothiocyanates, or other reactive or activatable reagents, in order to arrive at the precursors of the novel compounds of formula I.
• R e is an ester in compound VI since side reactions are to be expected when the carboxylic acid is unprotected.
• the compound of formula I is separated, in process step c), into the pure stereoisomers either by means of chromatography on an optionally chiral support material or, provided the racemic compound of formula I is capable of salt formation, by means of fractional crystallization of the diastereomeric salts which have been formed using an optically active base or acid as auxiliary substance.
• suitable chiral stationary phases for the thin-layer or column chromatographic separation of enantiomers are modified silica gel supports (what are termed Pirkle phases) and also high molecular weight carbohydrates, such as triacetyl cellulose.
• the diastereomeric salts which differ in solubility, are formed using an optically active, as a rule commercially available, base such as ( ⁇ )-nicotine, (+)- and ( ⁇ )-phenylethylamine, quinine bases, L-lysine or L- and D-arginine, the more sparingly soluble component is isolated as a solid, the more readily soluble diastereomer is separated out from the mother liquor, and the pure enantiomers are isolated from the diastereomer salts which have been obtained in this way.
• base such as ( ⁇ )-nicotine, (+)- and ( ⁇ )-phenylethylamine, quinine bases, L-lysine or L- and D-arginine
• racemic compounds of the formula I which contain a basic group, such as amino group, can, in what is in principle the same manner, be converted into the pure enantiomers using optically active acids, such as (+)-camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L-lactic acid and (+) and ( ⁇ )-mandelic acid.
• optically active acids such as (+)-camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L-lactic acid and (+) and ( ⁇ )-mandelic acid.
• Chiral compounds which contain alcohol or amine functions can also be converted into the corresponding esters or amides using appropriately activated or optionally N-protected enantiomerically pure amino acids or, conversely, chiral carboxylic acids can be converted into the amides using carboxyl-protected enantiomerically pure amino acids or into the corresponding chiral esters using enantiomerically pure hydroxyl carboxylic acids such as lactic acid.
• the chirality of the amino acid or alcohol radical which has been introduced in enantiomerically pure form can then be used for separating the isomers by the diastereomers, which are now present, being separated by means of crystallization or chromatography on suitable stationary phases and, after that, using suitable methods to once again eliminate the entrained chiral molecule moiety.
• Acidic or basic products of the compound of the formula I may be present in the form of their salts or in free form. Preference is given to pharmacologically tolerated salts, e.g. alkali metal salts or alkaline earth metal salts or hydrochlorides, hydrobromides, sulfates, hemisulfates, all possible phosphates and also salts of the amino acids, natural bases or carboxylic acids.
• pharmacologically tolerated salts e.g. alkali metal salts or alkaline earth metal salts or hydrochlorides, hydrobromides, sulfates, hemisulfates, all possible phosphates and also salts of the amino acids, natural bases or carboxylic acids.
• Physiologically tolerated salts are prepared according to process step d) in a manner known per se from compounds of the formula I, including their stereoisomeric forms, which are capable of salt formation.
• the compounds of formula I form stable alkali metal salts, alkaline earth metal salts or optionally substituted ammonium salts with basic reagents such as hydroxides, carbonates, hydrogen carbonates, alkoxides and ammonia or organic bases, for example trimethylamine or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol or else basic amino acids, for example lysine, ornithine or arginine.
• basic reagents such as hydroxides, carbonates, hydrogen carbonates, alkoxides and ammonia or organic bases, for example trimethylamine or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol or else basic amino acids, for example lysine, ornithine or arginine.
• Both inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, cyclohexylamidosulfonic acid, trifluoromethylsulfonic acid, acetic acid, oxalic acid, tartaric acid, succinic acid glycerol phosphoric acid, lactic acid, malic acid, adipic acid, citric acid, fumaric acid, maleic acid, gluconic acid, glucuronic acid and trifluoroacetic acid are suitable for this purpose.
• the invention also relates to a pharmaceutical preparation comprising a pharmaceutically effective amount of at least one compound of formula I and/or of a physiologically tolerated salt of the compound of formula I and/or an optionally stereoisomeric form of the compound of formula I, together with a pharmaceutically suitable and physiologically tolerated carrier substance, additive and/or other active compounds and auxiliary substances.
• compounds according to the invention are suitable for the selective prophylaxis and therapy of all those diseases whose course involves an increase in the activity of the metalloproteinases.
• diseases include degenerative joint diseases, such as osteoarthroses, spondyloses, cartilage loss following joint trauma or a relatively long period of joint immobilization following meniscus injuries or patella injuries or ligament rupture.
• diseases of the connective tissue such as collagenoses, periodontal diseases, wound healing disturbances and chronic diseases of the locomotory apparatus, such as inflammatory, immunologically-determined or metabolism-determined acute and chronic arthritides, arthropathies, myalgias and disturbances in bone metabolism.
• the compound of formula I is suitable for treating ulceration, atherosclerosis and stenoses.
• the compound of formula I is furthermore suitable for treating inflammations, cancer diseases, tumor metastasis formation, cachexia, anorexia, heart failure and septic shock.
• the compound is also suitable for the prophylaxis of myocardial and cerebral infarcts.
• the pharmaceutical according to the invention can be administered by means of oral, inhalative, rectal or transdermal administration or by means of subcutaneous, intraarticular, intraperitoneal or intravenous injection. Oral administration is preferred.
• the invention also relates to a process for producing a pharmaceutical, in which process at least one compound of formula I is brought, together with a pharmaceutically suitable and physiologically tolerated excipient and, where appropriate, other suitable active compounds, additives or auxiliary substances, into a suitable form for administration.
• suitable solid or galenic preparation forms are granules, powders, sugar-coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, and also preparations involving a protracted release of active compound, in the production of which customary adjuvants such as carrier substances, disintegrants, binders, coating agents, swelling agents, glidants, lubricants, flavorings, sweeteners and solubilizers are used.
• customary adjuvants such as carrier substances, disintegrants, binders, coating agents, swelling agents, glidants, lubricants, flavorings, sweeteners and solubilizers are used.
• auxiliary substances which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycol and solvents, such as sterile water and monohydric or polyhydric alcohols such as glycerol.
• the pharmaceutical preparations are preferably produced and administered in dosage units, with each unit containing, as the active constituent, a defined dose of the novel compound of formula I.
• this dose can be up to about 1,000 mg, preferably, however, from about 50 to 300 mg, while it can be up to about 300 mg, preferably, however, from about 10 to 100 mg, in the case of injection solutions in ampoule form.
• daily doses of from about 20 mg to 1,000 mg of active compound, preferably of from about 100 mg to 500 mg, are indicated for treating an adult patient of about 70 kg in weight. However, higher or lower daily doses may also possibly be appropriate.
• the daily dose may be administered either by means of a once-only administration in the form of a single dosage unit or of several smaller dosage units or else by means of the multiple administration of subdivided doses at defined intervals.
• the starting materials and intermediates may be prepared by the application or adaptation of known methods, or their obvious chemical equivalents.
• end products are determined by means of mass-spectroscopic methods (FAB MS, ESI MS) and 1 H NMR (400 MHz, in DMSO-D6); the main peak or the two main peaks is/are given in each case. Temperatures are given in degrees centigrade; RT denotes room temperature (from 22° C. to 26° C.). Abbreviations that are used are either explained or conform to the customary conventions.
• the carboxylic acid (6.45 mmol) is dissolved in 20 ml of dimethylformamide (DMF), after which 3 equivalents of a 3N solution of NaOH (6.45 ml) are added at 0° C. After 10 min, a solution of the arylsulfonyl chloride (1.1 equivalents, 7.1 mmol) in from 10 to 15 ml of DMF was slowly added dropwise; after the mixture had reached room temperature, it was stirred for at most a further 12 hours (h) at temperatures of between 20° C. and 80° C. and the solvent was removed under reduced pressure. The crude product was purified chromatographically.
• DMF dimethylformamide
• the sulfonated carboxylic acid was dissolved in 10 ml of DMF, after which 1.1 equivalents of ethyl chloroformate, 2.2 equivalents of N-ethylmorpholine and 3 equivalents of trimethylsilylhydroxylamine were added. After the mixture had been heated at 80° C. for at least 4 h, the solvent was removed under reduced pressure and the crude product was purified using chromatographic methods.
• the IC 50 i.e., the inhibitor concentration that is required for 50% inhibition of the enzyme activity, is determined graphically by plotting the percentage inhibitions at different inhibitor concentrations.
• the enzyme solution contains 1.67 ⁇ g/ml of the enzyme domain.
• the substrate solution contains 0.75 mmol of the fluorogenic substrate (7-methoxycoumarin4-yl)acetyl-Pro-Leu-Gly-Leu-3-(2′, 4′-dinitrophenyl)-L-2,3-diaminopropionyl-Ala-Arg-NH 2 /l (Bachem, Heidelberg, Germany).

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• Plural Heterocyclic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Indole Compounds (AREA)

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• 2003
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• 2004
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• 2005
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• 2006
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