Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/18—Sulfonamides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
  • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
  • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
  • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/42—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups

Definitions

• This invention relates to a group of biphenyl-sulfonamides which inhibit matrix metalloproteinase enzymes and thus are useful for treating diseases resulting from tissue breakdown, such as arthritis, atherosclerosis, restenosis, and osteoporosis.
• Matrix metalloproteinases are naturally occurring enzymes found in most mammals and are associated with the breakdown of connective tissues.
• the class includes gelatinase A and B, stromelysin-1, fibroblast collagenase, neutrophil collagenase, matrilysin, and other forms of collagenase.
• These enzymes have been implicated with a number of diseases which result from breakdown of connective tissue, such as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation which leads to restenosis and ischemic heart failure, and tumor metastasis.
• a method for preventing and treating these diseases is now recognized to be by inhibiting metalloproteinase enzymes, thereby curtailing and eliminating the breakdown of connective tissues that results in the disease states.
• metalloproteinases Several inhibitors of metalloproteinases have been identified. Many inhibitors arc complex peptides, for instance as described by Chapman, et al., in J. Med. Chem., 1993:36:4293-4301. Small peptide inhibitors are also known, for example as described in United States Patent Numbers 4,599,361 and 5,270,326 as well as non-peptide as in WO 95/35276.
• the need continues for small molecular weight molecules which can be economically prepared and yet are effective inhibitors of metalloproteinases.
• We have now discovered a group of biphenylsulfonamides which have exceptionally good inhibitory activity.
• An object of this invention is to provide such compounds, their pharmaceutical formulations, and a method for using them to treat diseases mediated by metall
• This invention provides biphenylsulfonamides which are inhibitors of metalloproteinases.
• the invention compounds have Formula I
• R 1 is Ci-C ⁇ alkyl, halo, nitro, (CH2) 0 -4-NR 4 R 5 , cyano, OR 4 , CH, CF 3> O
• R ⁇ is hydrogen or C1-C5 alkyl, optionally substituted by the following groups: phenyl, substituted phenyl, phenoxy, substituted phenoxy, NR 4 R ⁇ , OR ,
• R 3 is OH, O Cj-C ⁇ alkyl, or NHOH
• R 4 is hydrogen, Ci -Cg alkyl, or Cj -C ⁇ alkanoyl
• R6 is hydrogen, C1-C5 alkyl, Cj-Cg alkanoyl, phenyl, or substituted phenyl; and pharmaceutically acceptable salts and solvates thereof.
• Preferred compounds are those wherein R ⁇ is halo, and R 3 is OH. Additionally preferred are compounds are those wherein R2 is Ci-Cg alkyl.
• R 1 is C ⁇ -C 6 alkyl, halo, nitro, NR 4 R 5 , cyano, OR 4 , and COOR 4 ;
• R2 is C1 -C5 alkyl, optionally substituted by phenyl, substituted phenyl, NR 4 R ⁇ ,
• OR6 carboxy, carboxamido, H2N-C-HN-, thio, methylthio, indole, imidazole, and phthalimido;
• R 3 is OH, OCj-Cs alkyl, or NHOH;
• R 4 is hydrogen, Cj-Cg alkyl, or CJ-C6 alkanoyl;
• R5 is hydrogen or C ⁇ -C ⁇ alkyl;
• R6 is hydrogen, C]-C6 alkyl, Cj-C ⁇ alkanoyl, phenyl, or substituted phenyl.
• the most preferred compounds are those wherein Rl is at the 4'-position ofthe biphenyl ring system, and especially where R ⁇ is bromo.
• a further embodiment ofthe invention is a pharmaceutical formulation comprising a compound of Formula I admixed with a diluent, carrier, or excipient therefor.
• the invention also provides a method for inhibiting the action of a matrix metalloproteinase enzyme in a mammal comprising administering a matrix metalloproteinase inhibiting amount of a compound of Formula I.
• R* includes halo, which term refers to fluoro, chloro, bromo, and iodo, with chloro and bromo being preferred, and bromo being most preferred.
• C ⁇ -C ⁇ alkyl means straight and branched aliphatic groups having from 1 to 6 carbon atoms, examples of which include methyl, ethyl, isopropyl, tert.-butyl, n-hexyl, and isohexyl.
• R ⁇ alkyl group can be substituted with phenyl, e.g., benzyl, 3-phenylpropyl; or substituted phenyl, which term refers to phenyl substituted with one, two, or three groups independently selected from the groups defined by R ⁇ .
• Typical substituted phenyl groups thus include
• R alkyl group can also be substituted with groups such as hydroxy, alkoxy, alkanoyloxy, phenoxy, substituted phenoxy, amino, carboxy, thio, and the like.
• Typical substituted alkyl groups include hydroxymethyl, methoxymethyl, 1 -hydroxyethyl, 1-acetoxyethyl, 4-aminobutyl, 3-(4-chlorophenoxy)-hexyl, 4-(2-dimethylaminophenoxy)-butyl, 3-thiopropyl, l-hydroxy-3-aminopropyl, and the like.
• R 3 in Formula I means hydroxy, Cj-Cg alkoxy, or NHOH.
• the Rl substituent can be NR 4 R ⁇ , where R 4 can be hydrogen,
• R ⁇ can be hydrogen or Cj-Cg alkyl.
• Typical NR 4 R ⁇ groups thus include amino, methylamino, diethylamino, acetamido, N-methylacetamido, and the like.
• the invention includes pharmaceutically acceptable salts, for example salts ofthe acids when R 3 is OH. Such salts include those made by reaction ofthe acid with organic and inorganic bases such as diethylamine, benzylamine, sodium hydroxide, potassium hydroxide, and calcium hydroxide.
• the invention compounds of Formula I can also exist as hydrates and solvates, for example alcoholates such as ethanolate.
• the invention compounds are prepared by methods commonly utilized in the art of organic synthesis.
• a biphenylsulfonic acid which is activated with a leaving group, such as a halogen or active ester, readily reacts with an amino acid ester according to the following general scheme:
• L is a leaving group such as halo (e.g., chloro or bromo) or an active ester
• R ⁇ and R ⁇ are as defined above, and R 3 is alkoxy such as tert.-butoxy.
• the sulfonyl halides are preferred starting materials, and these are readily prepared by reacting a substituted biphenyl compound, for
• example R 1 with chlorosulfonic acid to produce the corresponding biphenylsulfonic acid, followed by reaction of the biphenylsulfonic acid with a halogenating agent such as phosphorous oxychloride, oxalyl chloride, or the like.
• a halogenating agent such as phosphorous oxychloride, oxalyl chloride, or the like.
• the resulting biphenyl sulfonyl halide is next reacted with an aminoacid ester to give an invention compound.
• This latter reaction typically is accomplished by mixing approximately equimolar quantities of the biphenylsulfonyl halide or active ester and aminoacid ester in a mutual unreactive solvent such as dichloromethane, chloroform, xylene, or the like.
• a base can be utilized, if desired, to act as an acid scavenger.
• Typical bases include triethylamine, N-methylmorpholine, and the like.
• the reaction generally is substantially complete within about 12 to 24 hours when carried out at a temperature of about 10°C to about 50°C.
• the product, a biphenylsulfonamide ester ofthe invention is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure.
• the product can be further purified, if desired, by standard techniques such as chromatography, for instance over solid supports such as silica gel, or crystallization from solvents such as methanol, diethyl ether, and the like.
• the preferred amino acid esters to be utilized in the above reaction are lower Cj-Cft alkyl esters ofthe naturally occurring amino acids which are constituents of proteins.
• Typical amino acids thus include glycine, alanine, valine, leucine, isoleucine, phenylalanine, serine, cysteinc, threonine, lysine, arginine, aspartic acid, asparagine, glutamic acid, glutamine, tyrosine, methionine, tryptophan, and histidine.
• esters, compounds of Formula I wherein R 3 is C ⁇ -C ⁇ alkoxy are useful intermediates to the acids and hydroxamic acids, in that they are readily hydrolyzed to the corresponding carboxylic acids by routine methods, for instance by reaction with a strong acid such as trifluoroacetic acid, polyphosphoric acid, sulfuric acid, or a strong base such as sodium hydroxide.
• the hydrolysis generally is carried out at a temperature of about 0°C to about 25°C, and normally is complete within about 2 to 24 hours.
• the product a compound of Formula I wherein R 3 is OH
• a water immiscible solvent such as ethyl acetate, dichloromethane, or the like
• the free carboxylic acids thus formed can be converted to salts by reaction with a base such as sodium hydroxide, calcium carbonate, or the like.
• the carboxylic acids also can be reacted with hydroxylamine hydrochloride to form the corresponding hydroxamic acids, ie, compounds of Formula I where R 3 is NHOH.
• An alternative method for preparing invention compounds of Formula I comprises reacting a 4-bromo or 4-iodo-benzene sulfonamide with a substituted benzene boronic acid according to the following scheme:
• R 1 and R 2 are as defined above, and R 3 preferably is alkyl.
• the coupling reaction is catalyzed by palladium, and generally is carried out aqueous sodium carbonate, and in a suitable solvent, for instance toluene or N,N- dimethylformamide.
• the coupling reaction generally is substantially complete within about 2 to 24 hours when carried out at a temperature of about 50°C to 120°C.
• the product biphenyl sulfonamide is readily isolated by pouring the reaction mixture into an aqueous acid such as dilute HCl, and extracting it into a water immiscible solvent such as ethyl acetate or dichloromethane.
• the organic solution is separated and the solvent is removed by evaporation under reduced pressure to afford the invention compound of Formula I, which can be further purified, if desired, by normal methods such as crystallization and chromatography.
• the esters, where R 3 is alkyl, are readily hydrolized to the corresponding acid by standard methods.
• the invention compounds contain at least one asymmetric carbon atom, and as such exist as optically active isomers.
• the invention contemplates the racemic forms as well as the individual isomers.
• the individual isomers can be prepared from optically pure starting materials, for example by utilizing naturally occurring amino acids, or by resolving the racemate by normal techniques such as chromatography and the like.
• the invention compounds have the (S) configuration corresponding to naturally occurring amino acids from which they are derived.
• the synthesis of typical biphenylsulfonamides of Formula I is illustrated by the following examples. The examples are representative only, and are not intended to be limiting in any respect.
• biphenylsulfonamides of Formula I can alternatively be prepared utilizing the following synthetic conditions:
• reaction mixture was refluxed for 3 hours, then cooled to room temperature.
• Ethyl acetate (25 mL) and aqueous HCl (1M, 25 mL) were added, the layers separated, and the organic portion was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo.
• the resulting solid was triturated with hexane/ethyl acetate (3:1) and was collected by filtration.
• EXAMPLE 23 2-(4'-Aminomethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid
• the invention compounds have been evaluated in standard in vitro assays and shown to be potent inhibitors of several matrix metalloproteinase enzymes. Specifically, the compounds have been evaluated for their ability to inhibit gelatinase A-catalyzed hydrolysis of thiopeptolide and gelatin, and the stromelysin-catalyzed hydrolysis of thiopeptolide. The compounds were evaluated at various concentrations in order to determine their respective IC50, the micromolar concentration of compound required to cause a 50% inhibition ofthe hydrolytic activity of the respective enzymes.
• G ⁇ CD refers to gelatinase A-catalytic domain hydrolysis of thiopeptolide substrate
• Gy ⁇ CD Gel
• SCD A-catalytic domain hydrolysis of gelatin substrate
• SCD (T) refers to stromelysin catalytic domain hydrolysis of thiopeptolide.
• the compounds ofthe present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
• the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
• the compounds ofthe present invention can be administered by inhalation, for example, intranasally.
• the compounds ofthe present invention can be administered transdermally.
• the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I.
• the active compound generally is present in a concentration of about 5% to about 95% by weight ofthe formulation.
• pharmaceutically acceptable carriers can be either solid or liquid.
• Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
• a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
• the carrier is a finely divided solid which is in a mixture with the finely divided active component.
• the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
• the powders and tablets preferably contain from five or ten to about seventy percent ofthe active compound.
• Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
• the term "preparation” is intended to include the formulation ofthe active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it.
• cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
• a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
• the active component is dispersed homogeneously therein, as by stirring.
• the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
• Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions.
• liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
• Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
• Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
• viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
• solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
• liquid forms include solutions, suspensions, and emulsions.
• These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
• the pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities ofthe active component.
• the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
• the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
• the quantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mg according to the particular application and the potency ofthe active component.
• the composition can, if desired, also contain other compatible therapeutic agents.
• the compounds utilized in the pharmaceutical method of this invention are administered at a dose that is effective to inhibit the hydrolytic activity of one or more matrix metalloproteinase enzymes.
• the initial dosage of about 1 mg to about 100 mg per kilogram daily will be effective.
• a daily dose range of about 25 mg to about 75 mg per kilogram is preferred.
• the dosages may be varied depending upon the requirements ofthe patient, the severity ofthe condition being treated, and the compound being employed.
• the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. Typical dosages will be from about 0.1 to about 500 mg/kg, and ideally about 25 to about 250 mg/kg, such that it will be an amount which is effective to treat the particular disease being prevented or controlled. The following examples illustrate typical formulations provided by the invention.
• the biphenylsulfonamide, lactose, and corn starch (for mix) are blended to uniformity.
• the corn starch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste.
• the paste is used to granulate the mixed powders.
• the wet granules are passed through a No. 8 hand screen and dried at 80°C.
• the dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet.
• Such tablets can be administered to a human from one to four times a day for treatment of atherosclerosis and arthritis.
• the sorbitol solution is added to 40 mL of distilled water, and the biphenylsulfonamide is dissolved therein.
• the saccharin, sodium benzoate, flavor, and dye are added and dissolved.
• the volume is adjusted to 100 mL with distilled water.
• Each milliliter of syrup contains 4 mg of invention compound.
• EXAMPLE 26 Parenteral Solution In a solution of 700 mL of propylene glycol and 200 mL of water for injection is suspended 20 g of (S)-2-(4'-amino-biphenyl-4-sulfonylamino)- 3-(3-ethoxyphenyl)-propionic acid. After suspension is complete, the pH is adjusted to 6.5 with 1 N sodium hydroxide, and the volume is made up to 1000 mL with water for injection. The formulation is sterilized, filled into 5.0 mL ampoules each containing 2.0 mL, and sealed under nitrogen.
• the compounds of Formula I are useful as agents for the treatment of multiple sclerosis. They are also useful as agents for the treatment of atherosclerotic plaque rupture, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound repair, heart failure, cancer metastasis, tumor angiogenesis, arthritis, and other inflammatory disorders dependent upon tissue invasion by leukocytes.

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