USH83H - Dental antiplaque agents and inhibitors of connective tissue destruction - Google Patents

Dental antiplaque agents and inhibitors of connective tissue destruction Download PDF

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Publication number
USH83H
USH83H US06/710,771 US71077185A USH83H US H83 H USH83 H US H83H US 71077185 A US71077185 A US 71077185A US H83 H USH83 H US H83H
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bis
ureylenebis
hydroxy
naphthalenesulfonic acid
disodium salt
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US06/710,771
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John F. Poletto
Seymour Bernstein
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Wyeth Holdings LLC
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American Cyanamid Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • A61K8/466—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur containing sulfonic acid derivatives; Salts

Definitions

  • the present invention relates to certain [ureylenebis(phenylenesulfonylimino)]bis[hydroxynaphthalenesulfonic acids] and salts thereof, which are novel compounds useful as dental antiplaque agents and as inhibitors of connective tissue destruction.
  • connective tissue refers to a matrix of at least three protein molecules, namely collagen, proteoglycan and elastin. These molecules play an important role in the structural integrity of normal tissues. Collagen, the most abundant protein in the body occupies a central position in the connective tissue matrix [Biochemistry of Collagen, Ed. G. N. Ramachandran and A. H. Reddi, Academic Press, New York (1976); P. Bornstein, Ann. Rev. Biochem., 43, 567 (1974); J. Fessler and L. Fessler, Ann. Rev. Biochem., 47, 129 (1978)].
  • Collagen is, for example, the main structural component of the oral tissue (periodontal ligament, alveolar bone, gingiva, and cementum) [Fullmer, et al., J. Dental Research, 48, 646 (1969)]. Collagen amounts to 40% of cartilage protein, 90% of bone protein, and over 90% of dry dermis.
  • Articular cartilage the resilient tissue that covers the articulating extremities in synovial joints, consists of collagen fibers that are intimately meshed in a hydrated gel of proteoglycan.
  • Proteoglycan as it exists in cartilage, is a molecule in which sulfated polysaccharide chains are covalently linked to a protein backbone [Dynamics of Connective Tissue Macromolecules, Ed. P. M. Burleigh and A. R. Poole, North Holland, Amsterdam (1975)].
  • Elastin is a major connective tissue component of pulmonary structure [Elastin and Elastic Tissue, Ed. L. B. Sandberg, W. R. Gray, and C. Franzblau, Plenum Press, New York (1977)].
  • the breadkown of elastin of pulmonary connective tissue is considered the primary event in pulmonary emphysema [A. Janoff in "Proteases and Biological Control", Cold Spring Harbor Conference on Cell Proliferation, 2, 603 (1975)].
  • Degradation of fibrous collagen is initiated by a combination of neutral proteases and tissue collagenase as an integral part of a complex immunopathological process which results in the loss of collagen from normal tissue.
  • cellular mechanisms maintain a careful balance between the rates of collagen synthesis and degradation.
  • the ensuing elevated levels of neutral proteases and collagenase can result in rapid collagen degradation and tissue dysfunction.
  • the generated elevated levels of neutral proteases and collagenase in the gingival crevicular fluid rapidly degrade the fibrous collagen supporting the teeth.
  • Periodontal pockets result ultimately from collagen degradation and, as these pockets deepen, support of the teeth is lost and alveolar bone is resorbed [K. Ohlsson, I.
  • Such substances include, for example, ethylenediaminetetraacetate, 1,10-phenanthroline, cysteine, dithiothreitol and sodium auriothiomalate [D. E. Woolley, R. W. Glanville, D. R. Roberts, and J. M. Evanson, Biochem. J., 169, 265 (1978); S. Seifter and E. Harper, Chap. 18, "The Collagenases” in The Enzymes (3rd. Edition), 3, 649-697, Ed. by P. D. Boyer, Academic Press, N.Y. (1971)].
  • Naturally occurring collagenase inhibitors include the serum components ⁇ 2 -macroglobulin and ⁇ 1 -anticollagenase [D. E. Woolley, R. W. Glanville, D. R. Roberts and J. M. Evanson, Biochem. J., 169, 265 (1978)].
  • dental plaque on teeth is considered to be a precursor to dental caries, gingivitis and periodontal disease. Therefore methods and compositions useful for the prevention or inhibition of dental plaque formation on teeth are considered to be of major potential therapeutic importance.
  • Dental caries which always begin on the external surfaces of the teeth may be initiated by oral acidogenic bacteria which include Lactobacillis acidophilus and Streptococci, e.g., Streptococcus mutans, and yeasts capable of producing a pH of 5.5 or lower. Fermentable dietary carbohydrates serve as substrates for the microbial enzyme systems leading to the production of acidic metabolic products such as lactic, acetic, formic and butyric acids. Adherence of cariogenic bacteria such as Streptococcus mutans, and the like, to tooth enamel and their aggregation and colonization to dental plaque are prerequisites to the formation of carious lesions.
  • oral acidogenic bacteria which include Lactobacillis acidophilus and Streptococci, e.g., Streptococcus mutans, and yeasts capable of producing a pH of 5.5 or lower. Fermentable dietary carbohydrates serve as substrates for the microbial enzyme systems leading to the production of acidic metabolic products such as lactic, acetic, formic
  • Colonization on the tooth surface may serve as an area favorable to the production of the acidic metabolic products hereinabove described, providing protection from the buffering action of the saliva and causing the dissolution of the enamel in the vicinity of the plaque area resulting in decalcification.
  • Some proteolytic action on the organic structure may also take place.
  • Gingivitis which is an inflammation of the gums characterized by congested, red and swollen gingivae, frequently may occur due to dental calculus as the sole cause.
  • Periodontitis the most common form of periodontal disease is characterized by inflammatory tissue changes usually due to local irritation, which local causes include irritation resulting from calcareous deposits on the teeth.
  • dental caries can be prevented by eliminating cariogenic bacteria, especially Streptococcus mutans, from the mouth or by increasing the resistance of enamel to acid and/or the adherence of S. mutans to its surface.
  • Fluoride a known anticaries agent, is known to protect human tooth enamel from dissolution. Mechanistic studies indicate that fluoride binds to enamel and is incorporated into the hydroxyapatite fraction of the enamel. The resulting fluoroapatite is relatively resistant to acid.
  • U.S. Pat. No. 2,687,436 discloses substituted 3-(2-naphthyl)cyclohexanes useful in the treatment of collagen diseases.
  • British Pat. Nos. 856,357 and 1,246,141 disclose 2-aryl-hexahydro-quinolizines and 1-hydroxylpraline derivatives, respectively, useful for treating diseases affecting connective tissue.
  • the closest known structurally related compound to those of the present invention and disclosed as having collagenase inhibiting activity is found in Thromb. Res. 1977, 10(4), 605-11 wherein the trypanocidal agent trypan blue is reported as inhibiting the activity of collagenase, or a proteinase contaminant in the collagenase preparation.
  • While some compounds may inhibit the destructive effect of collagenase on connective tissue by acting directly on collagenase itself, other compounds may inhibit such destruction by coating, binding or competing with sights on the connective tissue in such a manner as to prevent collagenase from attacking it.
  • the present invention is not to be restricted or limited to any particular mechanism or mode of action. Suffice it to say, that the compounds of this invention have utility as inhibitors of connective tissue destruction albeit in whatever manner or mode.
  • This invention is concerned with the novel C-substituted naphthalenemonosulfonic ureides which may be represented by Formula I: ##STR1## wherein A is hydrogen or a pharmaceutically acceptable salt cation; B is hydrogen, lower(C 1 -C 6 )alkanoyl or alkali metal; and R is hydrogen or lower(C 1 -C 3 )alkyl.
  • a preferred form of the present invention is concerned with those ureides wherein neither the R nor the NH--group are ortho to the fixed position of the sulfoxamido group (--NHSO 2 --) in the bridgehead and such ureides may be represented by Formula II, III and IV: ##STR2## wherein A, B and R are as defined with reference to Formula I.
  • salt cation an alkali metal; an alkaline earth metal; ammonium; primary amine, e.g., ethylamine; secondary amine, e.g., diethylamine or diethanolamine; tertiary amine, e.g., pyridine, triethylamine or 2-dimethylaminomethyldibenzofuran; aliphatic amine, e.g., decamethylenediamine; or aromatic amine.
  • primary amine e.g., ethylamine
  • secondary amine e.g., diethylamine or diethanolamine
  • tertiary amine e.g., pyridine, triethylamine or 2-dimethylaminomethyldibenzofuran
  • aliphatic amine e.g., decamethylenediamine
  • aromatic amine aromatic amine
  • novel [ureylenebis(phenylenesulfonylimino)]-bis[hydroxynaphthalenesulfonic acids] and salts thereof of the present invention have been found to bind to various tooth components and also to inhibit the deposition of dental plaque onto the teeth of mammals.
  • the [ureylenebis(phenylenesulfonylimino)]bis-[hydroxynaphthalenesulfonates] of this invention are substantially soluble in water or water/organic solvent vehicles and are applied to teeth by various means from different dentifrice formulations.
  • Representative compounds encompassed within this invention include, for example, 6,6'-[ureylenebis(m-phenylenesulfonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis(p-phenylenesulfonylimino) ]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis(3-methyl-4,1-phenylenesulfonyl)imino]]bis [4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(m-phenylenesulfonylimino) ]bis[5-hydroxy-1-
  • This invention is also concerned with a method of inhibiting connective tissue destruction in a warm-blooded animal which comprises administering to said animal an effective inhibiting amount of a compound encompassed within Formulae I, II, III or IV.
  • this invention is concerned with a method of inhibiting the degradation sequelae of collagenase activity in a body fluid, such as crevicular fluid, synovial fluid and the like, which comprises subjecting body fluid collagenase to the action of an effective collagenase inhibiting amount of a compound encompassed within the above formulae.
  • Body fluid can include blood, plasma, serum, synovial fluid, crevicular fluid, ocular fluid, etc., containing collagenase.
  • the method of use aspect of this invention is further concerned with a method of inhibiting the action of collagenase in a warm-blooded animal which comprises internally administering to said animal an effective collagenase inhibiting amount of a compound encompassed with the above formulae.
  • a further method of use aspect of the present invention is concerned with a method for inibiting and preventing the deposition of dental plaque onto the surfaces of the teeth of warm-blooded animals, mainly, the deposition of dental plaque onto human teeth, which comprises applying the potential plaque barrier [ureylenebis-(phenylenesulfonylimino)]bis[hydroxynaphthalenesulfonic acids] and salts thereof of the present invention, which are substantially soluble in water or water/organic solvent vehicles, in the form of various dentifrice formulations such as pastes, ointments, creams, lotions, gels, powders, buccal tablets, lozenges, tooth paste, rinses and the like or other oral hygienic procedures.
  • the potential plaque barrier [ureylenebis-(phenylenesulfonylimino)]bis[hydroxynaphthalenesulfonic acids] and salts thereof of the present invention, which are substantially soluble in water or water/organic solvent vehicles, in the form of various dentifrice
  • the compounds of the present invention find utility as inhibitors of connective tissue destruction or as collagenase inhibitors in body fluids, as such they may be useful in ameliorating or preventing those pathological reactions resulting from the functioning of collagenase, and in the therapeutic treatment of warm-blooded animals having connective tissue disorders such as periodontal diseases and diseases of the teeth, osteoporosis, osteolysis, Paget's disease, hyperparathyroidism of renal failure, rheumatoid arthritis, septic arthritis, osteoarthritis, gout, acute synovitis, scleroderma, posoriasis, epidermolysis bullosa, keloids, blisters, cholesteatoma of the ear, and corneal ulceration.
  • the compounds of the present invention may also be useful in those pathological states where excessive activity of neutral proteases causes tissue damage.
  • the compounds of the present invention may be prepared according to the following Flowchart A. ##STR3##
  • a substituted-amino-naphthalenesulfonic acid (1) is dissolved in water, made basic with any suitable base such as, for example, an alkali acetate or alkali metal carbonate reacted with an alkali acetate such as sodium acetate, filtered and reacted under an inert atmosphere, e.g., nitrogen, with an excess of substituted nitrobenzenesulfonyl chloride (2), giving a substituted nitrobenzenesulfonamido-substituted -naphthalenesulfonic acid (3).
  • This nitro derivative (3) is then hydrogenated in the presence of a suitable catalyst, giving the corresponding amine derivative (4).
  • the amine (4) is dissolved in a basic solution of pyridine and water and then phosgenated.
  • the final ureide product (5) is extracted from conventional organic solvents such as ethanol or ether.
  • the resulting compound may be converted to its salt in a known manner.
  • a suspension of 2.0 g of 4-hydroxy-6-p-nitrobenzenesulfonamido-2-naphthalenesulfonic acid sodium salt in about 200 ml of water was converted to a solution by the addition of sufficient 10N sodium hydroxide.
  • the solution was filtered and to the filtrate was added 2.8 g of 10% palladium-on-carbon catalyst.
  • the mixture was hydrogenated in a Parr shaker until no further hydrogen was taken up.
  • the reaction mixture was filtered through diatomaceous earth and the filter was washed with water.
  • the filtrate and wash were combined and acidified with concentrated hydrochloric acid and gave a gum.
  • the gum was separated and triturated with ethanol. Filtration gave 3.0 g of the desired product as a grey solid.
  • a 4.0 g amount of 4-hydroxy-6-sulfanilamido-2-naphthalenesulfonic acid (prepared as described in Example 1) was suspended in 90 ml of water and 2.14 ml of 5N sodium hydroxide was added to yield a solution. The solution was filtered and 11.0 ml of pyridine was added to the filtrate. Phosgene was passed into the filtrate at 18°-28° C. (ice bath cooling) with vigorous stirring giving a gummy material. Phosgenation was continued until the mixture was strongly acidic. Then 5N sodium hydroxide was added again until solution was achieved, 11 ml of pyridine was added and the mixture was rephosgenated.
  • the supernatant was decanted and the residual gummy material was triturated with water.
  • the resulting solid was collected by filtration and air dried.
  • the solid was triturated with ethanol, filtered, and washed with ethanol, then ether and dried to give 3.0 g of a pink solid.
  • the solid was suspended in water and 5N sodium hydroxide was added to achieve solution at a total volume of about 30 ml. This solution was added with vigorous stirring to ethanol:ether (2:1). The precipitate formed was collected by filtration, washed with ether and dried and gave 1.75 g of pink solid.
  • the final tablet will weigh about 325 mg. and may be compressed into buccal tablets in flat faced or any other tooling shape convenient for buccal administration.
  • the ingredients are compressed into 5/8" flat based lozenge tooling. Other shapes may also be utilized.
  • the compounds of this invention may be administered internally to a warm-blooded animal to inhibit connective tissue destruction or collagenase, such inhibition being useful in the amelioration or prevention of those reactions causing connective tissue damage.
  • a range of doses may be employed depending on the mode of administration, the condition being treated and the particular compound being used. For example, for intravenous or subcutaneous use from about 5 to about 50 mg/kg/day, or every six hours for more rapidly excreted salts, may be used. For intra-articular use for large joints such as the knee, from about 2 to about 20 mg/joint per week may be used, with proportionally smaller doses for smaller joints.
  • the dosage range is to be adjusted to provide optimum therapeutic response in the warm-blooded animal being treated.
  • the amount of compound administered can vary over a wide range to provide from about 1.5 mg/kg to about 100 mg/kg of body weight of animal per day.
  • the usual daily dosage for a 70 kg subject may vary from about 100 mg to about 3.5 g.
  • Unit doses can contain from about 0.5 mg to about 500 mg.
  • sodium salts of the acids of the invention are suitable for parenteral use
  • other salts may also be prepared, such as those of primary amines, e.g., ethylamine; secondary amines, e.g., diethylamine or diethanolamine; tertiary amines, e.g., pyridine or triethylamine or 2-dimethylaminomethyldibenzofuran, aliphatic diamines, e.g., decamethylenediamine; and aromatoic diamines, can be prepared.
  • primary amines e.g., ethylamine
  • secondary amines e.g., diethylamine or diethanolamine
  • tertiary amines e.g., pyridine or triethylamine or 2-dimethylaminomethyldibenzofuran
  • aliphatic diamines e.g., decamethylenediamine
  • aromatoic diamines can be
  • alkali metals such as potassium and lithium; of ammonia; and of the alkaline earth metals, such as calcium or magnesium, may be employed. It will be apparent, therefore, that these salts embrace, in general, derivatives of salt-forming cations.
  • the compounds of this invention may be administered in the form of conventional pharmaceutical compositions.
  • Such compositions may be formulated so as to be suitable for oral or parenteral administration.
  • the active ingredient may be combined in admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, i.e., oral or parenteral.
  • the compounds of this invention can be used in compositions such as tablets.
  • the principle active ingredient is mixed with conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums, or similar materials as non-toxic pharmaceutically acceptable diluents or carriers.
  • the tablets or pills of the novel compositions can be laminated or otherwise compounded to provide a dosage form affording the advantage of prolonged or delayed action or predetermined successive action of the enclosed medication.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids or mixtures of polymeric acids with such materials as shellac, shellac and cetyl alcohol, cellulose acetate and the like.
  • a particularly advantageous enteric coating comprises a styrene maleic acid copolymer together with known materials contributing to the enteric properties of the coating.
  • the tablet or pill may be colored through the use of an appropriate nontoxic dye, so as to provide a pleasing appearance.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration include suitable flavored emulsions with edible oils, such as, cottonseed oil, sesame oil, coconut oil, peanut oil, and the like, as well as elixirs and similar pharmaceutical vehicles.
  • suitable flavored emulsions with edible oils such as, cottonseed oil, sesame oil, coconut oil, peanut oil, and the like
  • Sterile suspensions or solutions can be prepared for parenteral use. Isotonic preparations containing suitable preservatives are also desirable for injection use.
  • the compounds of the present invention may also be administered topically in the form of ointments, creams, lotions and the like, suitable for the treatment of connective tissue dependent dermatological disorders.
  • the compounds of the present invention may be administered in the form of dental pastes, ointments, buccal tablets and other compositions suitable for application periodontally for the treatment of periodontitis and related diseases of the oral cavity.
  • dosage form as described herein refers to physically discrete units suitable as unitary dosage for warm-blooded animal subjects, each unit containing a predetermined quantity of active component calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle.
  • the specification for the novel dosage forms of this invention are indicated by characteristics of the active component and the particular therapeutic effect to be achieved or the limitations inherent in the art of compounding such an active component for therapeutic use in warm-blooded animals as disclosed in this specification.
  • suitable oral dosage forms in accord with this invention are tablets, capsules, pills, powder packets, granules, wafers, cachets, teaspoonfuls, dropperfuls, ampules, vials, segregated multiples of any of the foregoing and other forms as herein described.
  • a collagenase assay was performed by a modification of the method of Harper, et al., Biochem., 10, 3035 (1971). In a typical assay (total volume of 0.45 ml), 100 ⁇ l of the activated enzyme was added to the 14 C-labeled collagen fibrils (250 ⁇ l) followed by 100 ⁇ l of 50 mM cacodylate, pH 7.4, containing 5 mM calcium chloride. After incubation at 37° C. for 16 hours, the tubes were centrifuged in a Beckman microfuge for five minutes at full speed. An aliquot (200 ⁇ l) of the supernatant, representing collagenase digestion products of the fibril, was assayed for radioactivity. The effect of the test compound on collagen degradation by collagenase was examined as follows:
  • Varying concentrations of the test compound (in distilled water) were added to the assay tubes containing active collagenase (total volume 450 ⁇ l) and after 16 hours the amount of radioactivity in the supernatant was determined. Appropriate blanks and trypsin controls were run in parallel.
  • Table I shows that a representative compound of the invention possesses the ability to inhibit collagen degradation.
  • the result is expressed as an ID 50 collagenase value which represents a ratio of the weight ( ⁇ g) of the representative compound required for 50% inhibition of collagenase over the weight ( ⁇ g) of 6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt required for 50% inhibition of collagenase.
  • the compound 6,6'-[ureylenebis(m-phenylenecarbonylimino]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt has been established as an inhibitor of the degradation of collagen in U.S. Pat. No. 4,297,372.
  • An ID 50 collagenase ratio of one indicates that the compound is as efficient as the reference compound in inhibiting collagen degradation. A value greater than one indicates that the test compound is less active.
  • the amount of 14 C-6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt bound is determined by washing away the unbound radioactive compound and counting CPM (counts per minute) of the insoluble tooth powder/ 14 C-6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt complex.
  • the assay may be used to determine the ability of a competing analog of 6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt to inhibit binding in the following manner: 14 C-6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt and a non-radioactive analog thereof were incubated with tooth powder.
  • the inhibiting effect of the test compound on binding compared to non-radioactive 6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt was determined as follows: A one mg amount of tooth powder was incubated in one ml of phosphate buffered saline (PBS) with 10 ⁇ g of 14 C-6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt and varying dose amounts (ranging from 0 to 2 mg) of the same cold (non-radioactive) compound.
  • PBS phosphate buffered saline
  • the unbound radioactive compound was washed away and the amount of radioactivity bound to the tooth powder was determined for each dose by counting (CPM).
  • the dose in ⁇ g of cold compound required to decrease the amount of radioactive agent by 50% (ID 50 ) was determined.
  • varying amounts of the test compound were substituted for cold 6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt in the above assay and the ID 50 for this compound was determined.
  • An ID 50 binding ratio of one indicates that the compound is as efficient as the reference compound in competition for binding sites in tooth powder. Values greater than one indicate the compound is less efficient than the reference compound.

Abstract

This invention concerns novel compounds useful in compositions and methods for preventing the attachment of dental plaque to the surfaces of the teeth of mammals and as inhibitors of connective tissue destruction. The compounds of this invention comprise certain [ureylenebis-(phenylenesulfonylimino)]bis[hydroxynaphthalenesulfonic acids] and salts thereof which may be combined with pharmaceutically acceptable carriers or diluents to be administered in the form of conventional pharmaceutical compositions.

Description

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to certain [ureylenebis(phenylenesulfonylimino)]bis[hydroxynaphthalenesulfonic acids] and salts thereof, which are novel compounds useful as dental antiplaque agents and as inhibitors of connective tissue destruction.
2. Description of the Prior Art
Abnormal destruction of connective tissue by collagenase and/or neutral proteases causes tissue damage and/or tissue dysfunction. In these conditions an inhibitor of connective tissue destruction acting directly or indirectly would be useful in preventing, retarding, or reversing tissue damage and/or collagen diseases.
The term connective tissue refers to a matrix of at least three protein molecules, namely collagen, proteoglycan and elastin. These molecules play an important role in the structural integrity of normal tissues. Collagen, the most abundant protein in the body occupies a central position in the connective tissue matrix [Biochemistry of Collagen, Ed. G. N. Ramachandran and A. H. Reddi, Academic Press, New York (1976); P. Bornstein, Ann. Rev. Biochem., 43, 567 (1974); J. Fessler and L. Fessler, Ann. Rev. Biochem., 47, 129 (1978)].
Collagen is, for example, the main structural component of the oral tissue (periodontal ligament, alveolar bone, gingiva, and cementum) [Fullmer, et al., J. Dental Research, 48, 646 (1969)]. Collagen amounts to 40% of cartilage protein, 90% of bone protein, and over 90% of dry dermis. Articular cartilage, the resilient tissue that covers the articulating extremities in synovial joints, consists of collagen fibers that are intimately meshed in a hydrated gel of proteoglycan.
Proteoglycan, as it exists in cartilage, is a molecule in which sulfated polysaccharide chains are covalently linked to a protein backbone [Dynamics of Connective Tissue Macromolecules, Ed. P. M. Burleigh and A. R. Poole, North Holland, Amsterdam (1975)].
Elastin is a major connective tissue component of pulmonary structure [Elastin and Elastic Tissue, Ed. L. B. Sandberg, W. R. Gray, and C. Franzblau, Plenum Press, New York (1977)]. The breadkown of elastin of pulmonary connective tissue is considered the primary event in pulmonary emphysema [A. Janoff in "Proteases and Biological Control", Cold Spring Harbor Conference on Cell Proliferation, 2, 603 (1975)].
Degradation of fibrous collagen is initiated by a combination of neutral proteases and tissue collagenase as an integral part of a complex immunopathological process which results in the loss of collagen from normal tissue. Under normal conditions cellular mechanisms maintain a careful balance between the rates of collagen synthesis and degradation. However, in certain pathological conditions, the ensuing elevated levels of neutral proteases and collagenase can result in rapid collagen degradation and tissue dysfunction. For example, in periodontal disease, the generated elevated levels of neutral proteases and collagenase in the gingival crevicular fluid rapidly degrade the fibrous collagen supporting the teeth. Periodontal pockets result ultimately from collagen degradation and, as these pockets deepen, support of the teeth is lost and alveolar bone is resorbed [K. Ohlsson, I. Ohlsson, and G. I. Basthall, Acta Odontol. Scand., 32, 51 (1974); L. M. Golub, S. Kenneth, H. McEwan, J. B. Curran, and N. S. Ramamurthy, J. Dental Research, 55, 177 (1976); L. M. Golub, J. E. Stakin and D. L. Singer, J. Dental Research, 53, 1501 (1974); L. M. Wahl, S. M. Wahl, S. E. Mergenhagen, and G. R. Martin, Proc. Natl. Acad. Sci. U.S., 71, 3598 (1974); Science, 187, 261 (1975)].
In arthritic conditions such as in rheumatoid arthritis, septic arthritis, and osteoarthritis, elevated degradation of collagen and proteoglycan initiate rapid destruction of articular tissue [J. M. Evanson, J. J. Jefferey, and S. M. Krane, Science, 158, 499 (1967); E. D. Harris, D. R. Dibona and S. M. Krane, J. Clin. Invest., 48, 2104 (1969); E. D. Harris in Rheumatoid Arthritis, Medcom. Press, N.Y. (1974); Z. Werb, C. L. Mainardi, C. A. Vater, and E. D. Harris, New Eng. J. Med., 296, 1017 (1977); J. M. Dayer, R. G. Russell, and S. M. Krane, Science, 195, 181 (1977); E. D. Harris, C. A. Vater, C. L. Mainardi, and Z. Werb, Agents and Actions, 8, 35 (1978); D. E. Woolley, E. D. Harris, C. L. Mainardi, and C. E. Brinkerhoff, Science, 200, 773 (1978); E. D. Harris, C. S. Faulkner, F. E. Brown, Clin. Orthoped., 110, 303 (1975); M. G. Ehrlich, H. J. Mankin, H. Jones, R. Wright, and C. Crisper, J. Bone Jt. Surg., 57A, 565 (1975); S. Gordon, W. Newman, and B. Bloom, Agents and Action, 8, 19 (1978); "Mechanisms of Tissue Injury With Reference to Rheumatoid Arthritis", Ed. R. J. Perper, Ann. N. Y. Acad. Sci., 256, 1-450 (1975)].
Increased collagen degradation in bone can result in abnormal bone destruction as in osteoporosis [C. G. Griffith, G. Nichols, J. D. Asher, and B. Flannagan, J. Am. Med. Assoc., 193, 91 (1965); B. Gardner, H. Gray, and G. Hedyati, Curr. Top. Surg. Res., 2, 175 (1970); B. Gardner, S. Wallach, H. Gray, and R. K. Baker, Surg. Forum, 22, 435 (1971)]. Collagenase activity has also resulted in tissue damage in cholesteatoma [M. Abramson, R. W. Schilling, C. C. Huang, and R. G. Salome, Ann. Otol. Rhinol. Faryngol., 81, 158 (1975); M. Abramson and C. C. Huang, Larynogoscope, 77, 1 (1976)]. In corneal ulcerations that progress to loss of corneal integrity and function, collagenase has been implicated as a direct factor in corneal destruction [S. I. Brown, C. W. Hook, and N. P. Tragakis, Invest. Ophthamol., 11, 149 (1972); M. B. Berman, C. H. Dohlman, P. F. Davison, and M. Ghadinger, Exptl. Eye Res., 11, 225 (1971)]. Elevated levels of collagenase have also been observed in patients with epidermolysis bullosa and a group of related genetic diseases of the skin [E. A. Bauer, T. G. Dahl, and A. Z. Eisen, J. Invest. Dermatology, 68, 119 (1977)].
Increased breakdown of elastin of the lung tissue by neutral proteases (elastase) may contribute to the lesions in pulmonary emphysema [I. Mandel, T. V. Darmle, J. A. Frierer, S. Keller, and G. M. Turino in Elastin and Elastic Tissue, Ed. L. B. Sandberg, W. R. Gray, and C. Franzblau, Plenum Press, N.Y., p 221 (1977)].
A variety of substances, both naturally occurring and synthetically prepared, have been found to be inhibitors of connective tissue destruction, e.g., inhibitors of collagen degradation, that is as collagenase inhibitors. Such substances include, for example, ethylenediaminetetraacetate, 1,10-phenanthroline, cysteine, dithiothreitol and sodium auriothiomalate [D. E. Woolley, R. W. Glanville, D. R. Roberts, and J. M. Evanson, Biochem. J., 169, 265 (1978); S. Seifter and E. Harper, Chap. 18, "The Collagenases" in The Enzymes (3rd. Edition), 3, 649-697, Ed. by P. D. Boyer, Academic Press, N.Y. (1971)].
In the eye, a number of studies using collagenase inhibitors directly applied to corneal ulcerations have been reported. Calcium ethylenediaminetetraacetate and acetylcysteine reduce the frequency of ulceration in the alkali burned rabbit [M. Berman and C. Dohlman, Arch. Ophthamol., 35, 95 (1975)]. Both cysteine and acetylcysteine have been effective in the treatment of acute and chronic corneal ulceration in the human, although the latter compound was preferred because of its greater stability [S. I. Brown, N. P. Tragakis, and D. B. Pease, Am. J. Ophthalmol., 74, 316 (1972); M. Berman in Trace Components of Plasma: Isolation and Clinical Significance, 7th Annual Red Cross Symposium, p 225, Alan R. Liss, Inc., N.Y. (1976)].
Naturally occurring collagenase inhibitors include the serum components α2 -macroglobulin and β1 -anticollagenase [D. E. Woolley, R. W. Glanville, D. R. Roberts and J. M. Evanson, Biochem. J., 169, 265 (1978)].
The deposition of dental plaque on teeth is considered to be a precursor to dental caries, gingivitis and periodontal disease. Therefore methods and compositions useful for the prevention or inhibition of dental plaque formation on teeth are considered to be of major potential therapeutic importance.
Dental caries which always begin on the external surfaces of the teeth may be initiated by oral acidogenic bacteria which include Lactobacillis acidophilus and Streptococci, e.g., Streptococcus mutans, and yeasts capable of producing a pH of 5.5 or lower. Fermentable dietary carbohydrates serve as substrates for the microbial enzyme systems leading to the production of acidic metabolic products such as lactic, acetic, formic and butyric acids. Adherence of cariogenic bacteria such as Streptococcus mutans, and the like, to tooth enamel and their aggregation and colonization to dental plaque are prerequisites to the formation of carious lesions. Sucrose, cell wall polysaccharides, pellicle components of saliva and calcium, participate in the formation of the lesion. Colonization on the tooth surface may serve as an area favorable to the production of the acidic metabolic products hereinabove described, providing protection from the buffering action of the saliva and causing the dissolution of the enamel in the vicinity of the plaque area resulting in decalcification. Some proteolytic action on the organic structure may also take place.
Gingivitis, which is an inflammation of the gums characterized by congested, red and swollen gingivae, frequently may occur due to dental calculus as the sole cause.
Periodontitis, the most common form of periodontal disease is characterized by inflammatory tissue changes usually due to local irritation, which local causes include irritation resulting from calcareous deposits on the teeth.
In theory, dental caries can be prevented by eliminating cariogenic bacteria, especially Streptococcus mutans, from the mouth or by increasing the resistance of enamel to acid and/or the adherence of S. mutans to its surface.
Agents that bind to tooth components have, at least on a theoretical basis, a utility in the treatment of dental diseases [S. Hamada and H. D. Slade, Microbiol. Rev., 44, 331 (1980)]. Support of this view is derived from results obtained with chlorohexidine [G. Rolla, H. Loe and C. R. Schiott, Arch. Oral Biol., 16, 1109 (1971)]. These studies have shown that chlorohexidine, an antibacterial agent, binds to pellicle and/or tooth components and this binding may contribute, at least in part, to its long acting antigingivitis properties.
Fluoride, a known anticaries agent, is known to protect human tooth enamel from dissolution. Mechanistic studies indicate that fluoride binds to enamel and is incorporated into the hydroxyapatite fraction of the enamel. The resulting fluoroapatite is relatively resistant to acid.
U.S. Pat. No. 2,687,436 discloses substituted 3-(2-naphthyl)cyclohexanes useful in the treatment of collagen diseases. British Pat. Nos. 856,357 and 1,246,141, disclose 2-aryl-hexahydro-quinolizines and 1-hydroxylpraline derivatives, respectively, useful for treating diseases affecting connective tissue. The closest known structurally related compound to those of the present invention and disclosed as having collagenase inhibiting activity is found in Thromb. Res. 1977, 10(4), 605-11 wherein the trypanocidal agent trypan blue is reported as inhibiting the activity of collagenase, or a proteinase contaminant in the collagenase preparation. It is interesting, however, that in this same article, the ureide Suramin is reported as not inhibiting the action of collagenase. Ureides similar to those of the present invention, but not disclosed as inhibitors, are found in Journal of the Chemical Society, 3068 (1927), and in U.S. Pat. Nos. 1,218,654 and 1,308,071. The generic disclosure of the '071 patent encompasses a vast number of ureides and with proper selection, among the many possible variables, some of the compounds of this invention may be encompassed within this broad generic disclosure. However, such disclosure by itself does not anticipate or render obvious the invention claimed herein.
While some compounds may inhibit the destructive effect of collagenase on connective tissue by acting directly on collagenase itself, other compounds may inhibit such destruction by coating, binding or competing with sights on the connective tissue in such a manner as to prevent collagenase from attacking it. The present invention, however, is not to be restricted or limited to any particular mechanism or mode of action. Suffice it to say, that the compounds of this invention have utility as inhibitors of connective tissue destruction albeit in whatever manner or mode.
SUMMARY OF THE INVENTION
This invention is concerned with the novel C-substituted naphthalenemonosulfonic ureides which may be represented by Formula I: ##STR1## wherein A is hydrogen or a pharmaceutically acceptable salt cation; B is hydrogen, lower(C1 -C6)alkanoyl or alkali metal; and R is hydrogen or lower(C1 -C3)alkyl.
A preferred form of the present invention is concerned with those ureides wherein neither the R nor the NH--group are ortho to the fixed position of the sulfoxamido group (--NHSO2 --) in the bridgehead and such ureides may be represented by Formula II, III and IV: ##STR2## wherein A, B and R are as defined with reference to Formula I.
By pharmacologically acceptable salt cation is meant an alkali metal; an alkaline earth metal; ammonium; primary amine, e.g., ethylamine; secondary amine, e.g., diethylamine or diethanolamine; tertiary amine, e.g., pyridine, triethylamine or 2-dimethylaminomethyldibenzofuran; aliphatic amine, e.g., decamethylenediamine; or aromatic amine.
The novel [ureylenebis(phenylenesulfonylimino)]-bis[hydroxynaphthalenesulfonic acids] and salts thereof of the present invention have been found to bind to various tooth components and also to inhibit the deposition of dental plaque onto the teeth of mammals.
The [ureylenebis(phenylenesulfonylimino)]bis-[hydroxynaphthalenesulfonates] of this invention are substantially soluble in water or water/organic solvent vehicles and are applied to teeth by various means from different dentifrice formulations.
While the mechanism of action of these sulfonated derivatives in retarding plaque desposition is not known with certainty, the present invention is not to be restricted or limited to any particular mechanism or mode.
Representative compounds encompassed within this invention include, for example, 6,6'-[ureylenebis(m-phenylenesulfonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis(p-phenylenesulfonylimino) ]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis(3-methyl-4,1-phenylenesulfonyl)imino]]bis [4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(m-phenylenesulfonylimino) ]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(p-phenylenesulfonylimino) ]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis-[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]-bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 3,3'-ureylenebis(m-phenylenesulfonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 3,3'-[ureylene-bis(p-phenylenesulfonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 3,3'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 3,3'-[ureylene-bis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylene-bis(m-phenylenesulfonylimino)]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis(p-phenylenesulfonylimino) ]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 3,3'-[ureylenebis(m-phenylenesulfonylimino)]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 3,3'-[ureylenebis(p-phenylenesulfonylimino)]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 3,3'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 3,3'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis(m-phenylenesulfonylimino) ]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis(p-phenylenesulfonylimino)]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]-bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]-bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis(m-phenylenesulfonylimino)]bis[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis(p-phenylenesulfonylimino)]bis[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis](6-methyl-3,1-phenylenesulfonyl)imino]]bis[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis](3-methyl-4,1-phenylenesulfonyl)imino]]bis[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis(m-phenylenesulfonylimino)]bis[8-hydroxy-1-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis(p-phenylenesulfonylimino)]bis[8-hydroxy-1-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis [8-hydroxy-1-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis[(3 -methyl-4,1-phenylenesulfonyl)imino]]bis [8-hydroxy-1-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis(m-phenylenesulfonylimino)]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 7,7'-ureylenebis(p-phenylenesulfonylimino)]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis(m-phenylenesulfonylimino)]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis(p-phenylenesulfonylimino)]bis[5-hydroxy-2-naphthalensulfonic acid], disodium salt; 7,7'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis-[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt, 6,6'-ureylenebis(m-phenylenesulfonylimino)]bis[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis(p-phenylenesulfonylimino)]bis[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis [8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(m-phenylenesulfonylimino)]bis[1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(p-phenylenesulfonylimino)]bis[1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(6methyl-3,1-phenylenesulfonyl)imino]]bis[1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 1,1'-[ureylenebis(m-phenylenesulfonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 1,1'-[ureylenebis(p-phenylenesulfonylimino)]bis [4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 1,1'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 1,1'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(m-phenylenesulfonylimino)]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(p-phenylenesulfonylimino)]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis [(6-methyl-3,1-phenylenesulfonyl)imino]]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(m-phenylenesulfonylimino)]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(p-phenylenesulonylimino)]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(m-phenylenesulfonylimino)]bis[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(p-phenylenesulfonylimino)]bis-[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis](3-methyl-4,1-phenylenesulfonyl)imino]]bis[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(m-phenylenesulfonylimino)]bis[8-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(p-phenylenesulfonylimino)]bis[8-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis[(6-methyl-3,1-phenylensulfonyl)imino]]bis[8-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[8-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(m-phenylenesulfonylimino)]bis[1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(p-phenylenesulfonylimino)]bis[1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis](6-methyl-3,1-phenylenesulfonyl)imino]]bis[1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(m-phenylenesulfonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(p-phenylenesulfonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(m-phenylenesulfonylimino)]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(p-phenylenesulfonylimino)]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[4hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 1,1'-[ureylenebis(m-phenylenesulfonylimino)]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 1,1'-[ureylenebis(p-phenylenesulfonylimino)]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 1,1'-ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 1,1'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[5-hydroxy-2-naphthalensulfonic acid], disodium salt; 4,4'-[ureylenebis(m-phenylenesulfonylimino)]bis[8-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(p-phenylensulfonylimino0]bis[8-hydroxy-1-naphthalensulfonic acid], disodium salt; 4,4'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis-[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[8-hydroxy-1-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis(m-phenylenesulfonylimino)]bis[1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis((p-phenylenesulfonylimino)]bis[1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6' -[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis[(3-methyl-4,1-phenylensulfonyl)imino]]bis(1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis(m-phenylenesulfonylimino)]bis [4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis(p-phenylenesulfonylimino)]bis[4-hydroxy-2-napththalenesulfonic acid], disodium salt; 7,7'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis(m-phenylenesulfonylimino)]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis(p-phenylenesulfonylimino)]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 2,2'-[ureylenebis(m-phenylenesulfonylimino) ]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 2,2'-[ureylenebis(p-phenylenesulfonylimino)]bis[5hydroxy-1-naphthalenesulfonic acid], disodium salt; 2,2'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 2,2'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[5-hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(m-phenylenesulfonylimino)]bis[1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(p-phenylenesulfonylimino)]bis[1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[1-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(m-phenylenesulfonylimino)]bis[4 -hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(p-phenylenesulfonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[4-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[4hydroxy-2-napththalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(m-phenylenesulfonylimino)]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(p-phenylenesulfonylimino)]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis](6-methyl-3,1-phenylenesulfonyl)imino]]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[4-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(m-phenylenesulfonylimino)]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(p-phenylenesulfonylimino)]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[5-hydroxy-2-naphthalenesulfonic acid], disodium salt; 1,1'-[ureylenebis(m-phenylenesulfonylimino)]bis[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 1,1'-[ureylenebis(p-phenylenesulfonylimino)]bis[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 1,1'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 1,1'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[8-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(m-phenylenesulfonylimino)]bis[3-hydoxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(p-phenylenesulfonylimino)]bis[3-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[3-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[3-hydroxy- 2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(m-phenylenesulfonylimino)]bis[3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(p-phenylenesulfonylimino)]bis[3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(m-phenylenesulfonylimino)]bis[6-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(p-phenylenesulfonylimino)]bis[6-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[6-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[6-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(m-phenylenesulfonylimino)]bis[6-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(p-phenylenesulfonylimino)]bis[6-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[6-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[6-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(m-phenylenesulfonylimino)]bis[7-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(p-phenylenesulfonylimino)]bis[7-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[7-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[7-hydroxy-2-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(m-phenylenesulfonylimino)]bis[7-hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(p-phenylenesulfonylimino)]bis[7-hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[7-hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[7-hydroxy-1-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis(m-phenylenesulfonylimino)]bis[7-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis(p-phenylenesulfonylimino)]bis[7-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[7-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[7-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-ureylenebis(m-phenylenesulfonylimino]bis]2-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(p-phenylenesulfonylimino)]bis[2-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[2-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[2-hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(m-phenylenesulfonylimino)]bis[3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis(p-phenylenesulfonylimino)]bis[3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 8,8'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(m-phenylenesulfonylimino)]bis[7-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(p-phenylenesulfonylimino)]bis[7-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[7-hydroxy-2-naphthalenesulfonic acid], disodium salt; 5,5'[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[7-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(m-phenylenesulfonylimino)]bis[7-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(p-phenylenesulfonylimino)]bis[7-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[7-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4' -[ureylenebis[(3-methyl-4,1- phenylenesulfonyl)imino]]bis[7-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(m-phenylenesulfonyl-imino)]bis[7-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(p-phenylenesulfonylimino)]bis[7-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[7-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[7-hydroxy-1naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis(m-phenylenesulfonylimino)]bis[3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis(p-phenylenesulfonylimino)]bis[3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 7,7'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 3,3'-[ureylenebis(m-phenylenesulfonylimino)]bis[7-hydroxy-1-naphthalenesulfonic acid], disodium salt; 3,3'-[ureylenebis(p-phenylenesulfonylimino)]bis[7-hydroxy-1-naphthalenesulfonic acid], disodium salt; 3,3'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[7-hydroxy-1-naphthalenesulfonic acid], disodium salt; 3,3'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[7-hydroxy-1-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis(m-phenylenesulfonylimino)]bis[3-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis(p-phenylenesulfonylimino)]bis-[3-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis[(6-methyl-3,1- phenylenesulfonyl)imino]]bis[3-hydroxy-2-naphthalenesulfonic acid], disodium salt; 6,6'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[3-hydroxy-2-naphthalenesulfonic acid], disodium salt; 3,3'-[ureylenebis(m-phenylenesulfonylimino)]bis[6-hydroxy-2-naphthalenesulfonic acid], disodium salt; 3,3'-[ureylenebis(p-phenylenesulfonylimino)]bis[6-hydroxy-2-naphthalenesulfonic acid], disodium salt; 3,3'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[6-hydroxy-2-naphthalenesulfonic acid], disodium salt; 3,3'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[6-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(m-phenylenesulfonylimino)]bis[6-hydroxy-1naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(p-phenylenesulfonylimino)]bis[6-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(6-methyl-3,1- phenylenesulfonyl)imino]]bis[6-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis]6-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(m-phenylenesulfonylimino)]bis[3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis(p-phenylenesulfonylimino)]bis[3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis [3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 5,5'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[3-hydroxy-1-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(m-phenylenesulfonylimino)]bis[6-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebisbis(p-phenylenesulfonylimino)]bis[6-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[6-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[6-hydroxy-2-naphthalenesulfonic acid], disodium salt; 4,4'-[ureylenebis(m-phenylenesulfonylimino)]bis[3-hydroxy-1-naphthalenesulfonic acid[, diacetate (diester); 4,4'-[ureylenebis(p-phenylenesulfonylimino)]bis[3-hydroxy-1-naphthalenesulfonic acid], diacetate (diester); 4,4'-[ureylenebis[(6-methyl-3,1-phenylenesulfonyl)imino]]bis[3-hydroxy-1-naphthalenesulfonic acid], diacetate (diester); 4,4'-[ureylenebis[(3-methyl-4,1-phenylenesulfonyl)imino]]bis[3-hydroxy-1-naphthalenesulfonic acid], diacetate (diester); 6,6'-[ureylenebis(p-phenylenesulfonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]tetrasodium salt; 6,6'-[ureylenebis(m-phenylenesulfonylimino)]bis[4-hydroxy-2 -naphthalenesulfonic acid]tetrasodium salt; 6,6'-[ureylenebis(4-methyl-3,1-phenylene)sulfonylimino]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt; and 6,6'-[ureylenebis(3-methyl-4,1-phenylene)sulfonylimino]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt.
This invention is also concerned with a method of inhibiting connective tissue destruction in a warm-blooded animal which comprises administering to said animal an effective inhibiting amount of a compound encompassed within Formulae I, II, III or IV. Moreover, this invention is concerned with a method of inhibiting the degradation sequelae of collagenase activity in a body fluid, such as crevicular fluid, synovial fluid and the like, which comprises subjecting body fluid collagenase to the action of an effective collagenase inhibiting amount of a compound encompassed within the above formulae. Body fluid can include blood, plasma, serum, synovial fluid, crevicular fluid, ocular fluid, etc., containing collagenase. The method of use aspect of this invention is further concerned with a method of inhibiting the action of collagenase in a warm-blooded animal which comprises internally administering to said animal an effective collagenase inhibiting amount of a compound encompassed with the above formulae.
A further method of use aspect of the present invention is concerned with a method for inibiting and preventing the deposition of dental plaque onto the surfaces of the teeth of warm-blooded animals, mainly, the deposition of dental plaque onto human teeth, which comprises applying the potential plaque barrier [ureylenebis-(phenylenesulfonylimino)]bis[hydroxynaphthalenesulfonic acids] and salts thereof of the present invention, which are substantially soluble in water or water/organic solvent vehicles, in the form of various dentifrice formulations such as pastes, ointments, creams, lotions, gels, powders, buccal tablets, lozenges, tooth paste, rinses and the like or other oral hygienic procedures.
Since the compounds of the present invention find utility as inhibitors of connective tissue destruction or as collagenase inhibitors in body fluids, as such they may be useful in ameliorating or preventing those pathological reactions resulting from the functioning of collagenase, and in the therapeutic treatment of warm-blooded animals having connective tissue disorders such as periodontal diseases and diseases of the teeth, osteoporosis, osteolysis, Paget's disease, hyperparathyroidism of renal failure, rheumatoid arthritis, septic arthritis, osteoarthritis, gout, acute synovitis, scleroderma, posoriasis, epidermolysis bullosa, keloids, blisters, cholesteatoma of the ear, and corneal ulceration. The compounds of the present invention may also be useful in those pathological states where excessive activity of neutral proteases causes tissue damage.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention may be prepared according to the following Flowchart A. ##STR3##
With reference to Flowchart A, a substituted-amino-naphthalenesulfonic acid (1) is dissolved in water, made basic with any suitable base such as, for example, an alkali acetate or alkali metal carbonate reacted with an alkali acetate such as sodium acetate, filtered and reacted under an inert atmosphere, e.g., nitrogen, with an excess of substituted nitrobenzenesulfonyl chloride (2), giving a substituted nitrobenzenesulfonamido-substituted -naphthalenesulfonic acid (3). This nitro derivative (3) is then hydrogenated in the presence of a suitable catalyst, giving the corresponding amine derivative (4). The amine (4) is dissolved in a basic solution of pyridine and water and then phosgenated. The final ureide product (5) is extracted from conventional organic solvents such as ethanol or ether. The resulting compound may be converted to its salt in a known manner.
The following Examples will serve to illustrate the invention in more detail and should not be construed to limit the scope of the invention in any way.
EXAMPLE 1 Amine Precursor 4-Hydroxy-6-sulfanilamido-2-naphthalenesulfonic acid
A suspension of 11.95 g of 6-amino-4-hydroxy-2-naphthalenesulfonic acid in 200 ml of water was adjusted to pH 8.0 with aqueous 5N sodium hydroxide, then 12.17 g of sodium acetate trihydrate was added to the stirred mixture followed by 15.06 g of p-nitrobenzenesulfonyl chloride. The mixture was stirred vigorously under nitrogen at room temperature for 16 hours producing a yellow solid. The mixture was filtered and the solid was washed with water, ethanol and then ether and dried in vacuo and gave 12.07 g of 4-hydroxy-6-p-nitrobenzenesulfonamido-2-naphthalenesulfonic acid sodium salt as a yellow solid.
A suspension of 2.0 g of 4-hydroxy-6-p-nitrobenzenesulfonamido-2-naphthalenesulfonic acid sodium salt in about 200 ml of water was converted to a solution by the addition of sufficient 10N sodium hydroxide. The solution was filtered and to the filtrate was added 2.8 g of 10% palladium-on-carbon catalyst. The mixture was hydrogenated in a Parr shaker until no further hydrogen was taken up. The reaction mixture was filtered through diatomaceous earth and the filter was washed with water. The filtrate and wash were combined and acidified with concentrated hydrochloric acid and gave a gum. The gum was separated and triturated with ethanol. Filtration gave 3.0 g of the desired product as a grey solid.
EXAMPLE 2 6,6'-[Ureylenebis(p-phenylenesulfonylimino)]bis-[4-hydroxy-2-naphthalenesulfonic acid]disodium salt
A 4.0 g amount of 4-hydroxy-6-sulfanilamido-2-naphthalenesulfonic acid (prepared as described in Example 1) was suspended in 90 ml of water and 2.14 ml of 5N sodium hydroxide was added to yield a solution. The solution was filtered and 11.0 ml of pyridine was added to the filtrate. Phosgene was passed into the filtrate at 18°-28° C. (ice bath cooling) with vigorous stirring giving a gummy material. Phosgenation was continued until the mixture was strongly acidic. Then 5N sodium hydroxide was added again until solution was achieved, 11 ml of pyridine was added and the mixture was rephosgenated. The supernatant was decanted and the residual gummy material was triturated with water. The resulting solid was collected by filtration and air dried. The solid was triturated with ethanol, filtered, and washed with ethanol, then ether and dried to give 3.0 g of a pink solid.
The solid was suspended in water and 5N sodium hydroxide was added to achieve solution at a total volume of about 30 ml. This solution was added with vigorous stirring to ethanol:ether (2:1). The precipitate formed was collected by filtration, washed with ether and dried and gave 1.75 g of pink solid.
The above solid was dissolved in 20 ml of water and adjusted to pH 6.0 with acetic acid. This solution was poured slowly into 360 ml of ethanol:ether (1:1) with vigorous stirring. The mixture was stirred for 30 minutes at room temperature then filtered. The solid was washed with ethanol:ether (2:1), then ether and dried to give 920 mg of the product of the Example as a pink solid.
EXAMPLE 3 
______________________________________                                    
Preparation of Compressed Tablet                                          
Ingredient           mg./Tablet                                           
______________________________________                                    
Active Compound       0.5-500                                             
Dibasic Calcium Phosphate N.F.                                            
                     qs                                                   
Starch USP           40                                                   
Modified Starch      10                                                   
Magnesium Stearate USP                                                    
                     1-5                                                  
______________________________________
EXAMPLE 4 
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Preparation of Compressed Tablet - Sustained Action                       
Ingredient          mg./Tablet                                            
______________________________________                                    
Active Compound as Aluminum                                               
                    0.5-500 (as acid                                      
Lake*, Micronized   equivalent)                                           
Dibasic Calcium Phsophate N.F                                             
                    qs                                                    
Alginic Acid        20                                                    
Starch USP          35                                                    
Magnesium Stearate USP                                                    
                    1-10                                                  
______________________________________                                    
 *Complement inhibitor plus aluminum sulfate yields aluminum complement   
 inhibitor. Complement inhibitor content in aluminum lake ranges from     
 5-30%.
EXAMPLE 5 
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Preparation of Hard Shell Capsule                                         
Ingredient       mg./Capsule                                              
______________________________________                                    
Active Compound  0.5-500                                                  
Lactose, Spray Dried                                                      
                 qs                                                       
Magnesium Stearate                                                        
                 1-10                                                     
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EXAMPLE 6 
______________________________________                                    
Preparation of Oral Liquid (Syrup)                                        
Ingredient        % W/V                                                   
______________________________________                                    
Active Compound   0.05-5                                                  
Liquid Sugar      75.0                                                    
Methyl Paraben USP                                                        
                  0.18                                                    
Propyl Paraben USP                                                        
                  0.02                                                    
Flavoring Agent   qs                                                      
Purified Water qs ad                                                      
                  100.0                                                   
______________________________________
EXAMPLE 7 
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Preparation of Oral Liquid (Elixir)                                       
Ingredient        % W/V                                                   
______________________________________                                    
Active Compound   0.05-5                                                  
Alcohol USP       12.5                                                    
Glycerin USP      45.0                                                    
Syrup USP         20.0                                                    
Flavoring Agent   qs                                                      
Purified Water qs ad                                                      
                  100.0                                                   
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EXAMPLE 8 
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Preparation of Oral Suspension (Syrup)                                    
Ingredient         % W/V                                                  
______________________________________                                    
Active Compound as Aluminum                                               
                   0.05-5                                                 
Lake, Micronized   (acid equivalent)                                      
Polysorbate 80 USP 0.1                                                    
Magnesium Aluminum Silicate,                                              
                   0.3                                                    
Colloidal                                                                 
Flavoring Agent    qs                                                     
Methyl Paraben USP 0.18                                                   
Propyl Paraben USP 0.02                                                   
Liquid Sugar       75.0                                                   
Purified Water qs ad                                                      
                   100.0                                                  
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EXAMPLE 9 
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Preparation of Injectable Solution                                        
Ingredient         % W/V                                                  
______________________________________                                    
Active Compound    0.05-5                                                 
Benzyl Alcohol N.F.                                                       
                    0.9                                                   
Water for Injection qs ad                                                 
                   100.0                                                  
______________________________________
EXAMPLE 10 
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Preparation of Injectable Oil                                             
Ingredient       % W/V                                                    
______________________________________                                    
Active Compound  0.05-5                                                   
Benzyl Alcohol    1.5                                                     
Sesame Oil qs ad 100.0                                                    
______________________________________
EXAMPLE 11 
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Preparation of Intra-Articular Product                                    
Ingredient           Amount                                               
______________________________________                                    
Active Compound      2-20 mg.                                             
NaCl (physiological saline)                                               
                     0.9%                                                 
Benzyl Alcohol       0.9%                                                 
Sodium Carboxymethylcellulose                                             
                     1-5%                                                 
pH adjusted to 5.0-7.5                                                    
Water for Injection qs ad                                                 
                     100%                                                 
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EXAMPLE 12 
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Preparation of Injectable Depo Suspension                                 
Ingredient         % W/V                                                  
______________________________________                                    
Active Compound    0.05-5                                                 
                   (acid equivalent)                                      
Polysorbate 80 USP 0.2                                                    
Polyethylene Glycol 4000 USP                                              
                   3.0                                                    
Sodium Chloride USP                                                       
                   0.8                                                    
Benzyl Alcohol N.F.                                                       
                   0.9                                                    
HCl to pH 6-8      qs                                                     
Water for Injection qs ad                                                 
                   100.0                                                  
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EXAMPLE 13 
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Preparation of Dental Paste                                               
Ingredient           % W/V                                                
______________________________________                                    
Active Compound      0.05-5                                               
Zinc Oxide           15                                                   
Polyethylene Glycol 4000 USP                                              
                     50                                                   
Distilled Water qs ad                                                     
                     100                                                  
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EXAMPLE 14 
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Preparation of Dental Ointment                                            
Ingredient         % W/W                                                  
______________________________________                                    
Active Compound    0.05-5                                                 
Petrolatum, White USP qs                                                  
                   100                                                    
______________________________________
EXAMPLE 15 
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Preparation of Dental Cream                                               
Ingredient          % W/W                                                 
______________________________________                                    
Active Compound     0.05-5                                                
Mineral Oil         50                                                    
Beeswax             15                                                    
Sorbitan Monostearate                                                     
                     2                                                    
Polyoxyethylene 20 Sorbitan                                               
                     3                                                    
Monostearate                                                              
Methyl Paraben USP  0.18                                                  
Propyl Paraben USP  0.02                                                  
Distilled Water qs  100                                                   
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EXAMPLE 16 
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Preparation of Topical Cream                                              
Ingredient         % W/W                                                  
______________________________________                                    
Active Compound    0.05-5                                                 
Sodium Lauryl Sulfate                                                     
                    1                                                     
Propylene Glycol   12                                                     
Stearyl Alcohol    25                                                     
Petrolatum, White USP                                                     
                   25                                                     
Methyl Paraben USP 0.18                                                   
Propyl Paraben USP 0.02                                                   
Purified Water qs  100                                                    
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EXAMPLE 17 
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Preparation of Topical Ointment                                           
Ingredient         % W/W                                                  
______________________________________                                    
Active Compound    0.05-5                                                 
Cholesterol        3                                                      
Stearyl Alcohol    3                                                      
White Wax          8                                                      
Petrolatum, White USP qs                                                  
                   100                                                    
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EXAMPLE 18 
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Preparation of Spray Lotion (Non-aerosol)                                 
Ingredient         % W/W                                                  
______________________________________                                    
Active Compound    0.05-5                                                 
Isopropyl Myristate                                                       
                    20                                                    
Alcohol (Denatured) qs                                                    
                   100                                                    
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EXAMPLE 19 
______________________________________                                    
Preparation of Buccal Tablet                                              
Ingredient          g./Tablet                                             
______________________________________                                    
Active Ingredient   0.00325                                               
6 × Sugar     0.29060                                               
Acacia              0.01453                                               
Soluble Starch      0.01453                                               
F.D. & C. Yellow No. 6 Dye                                                
                    0.00049                                               
Magnesium Stearate  0.00160                                               
                    0.32500                                               
______________________________________
The final tablet will weigh about 325 mg. and may be compressed into buccal tablets in flat faced or any other tooling shape convenient for buccal administration.
EXAMPLE 20 
______________________________________                                    
Preparation of Lozenge                                                    
Ingredient           g./Lozenge                                           
______________________________________                                    
Active Ingredient    0.0140                                               
Kompact ® Sugar (Sucrest Co.)                                         
                     0.7138                                               
6 × Sugar      0.4802                                               
Sorbitol (USP Crystalline)                                                
                     0.1038                                               
Flavor               0.0840                                               
Magnesium Stearate   0.0021                                               
Dye                  qs                                                   
Stearic Acid         0.0021                                               
                     1.4000                                               
______________________________________
The ingredients are compressed into 5/8" flat based lozenge tooling. Other shapes may also be utilized.
EXAMPLE 21 
______________________________________                                    
Preparation of Gelled Vehicles                                            
Ingredient         % W/W                                                  
______________________________________                                    
Active Compound      9-11                                                 
Sodium Chloride     0.9-1.2                                               
Buffer and Flavor qs                                                      
                   --                                                     
Purified Water qs ad                                                      
                   100                                                    
Active Compound    0.005-9                                                
Sodium Alginate    0.5-2                                                  
Buffer and Flavor qs                                                      
                   --                                                     
Purified Water qs ad                                                      
                   100                                                    
Active Compound    0.005-9                                                
Hydroxypropyl Cellulose                                                   
                   0.5-2                                                  
Buffer and Flavor qs                                                      
                   --                                                     
Purified Water qs ad                                                      
                   100                                                    
Active Compound    0.005-9                                                
Guar Gum           0.5-2                                                  
Buffer and Flavor qs                                                      
                   --                                                     
Purified Water qs ad                                                      
                   100                                                    
______________________________________
EXAMPLE 22 
______________________________________                                    
Preparation of Oral Mouth Rinse                                           
Ingredient         % W/V                                                  
______________________________________                                    
Active Compound    0.05-20                                                
Alcohol U.S.P.       0-20                                                 
Sorbitol             1-30                                                 
Buffer and Flavor qs                                                      
                   --                                                     
Polysorbate 80     0.1-3                                                  
Cetyl Pyridinium Chloride                                                 
                    0.025-0.20                                            
Purified Water qs ad                                                      
                   100                                                    
______________________________________
EXAMPLE 23 
______________________________________                                    
Preparation of Tooth Paste                                                
Ingredient           % W/W                                                
______________________________________                                    
Active Compound      0.05-15                                              
Glycerin               5-15                                               
Sorbitol               5-15                                               
Sodium Carboxymethylcellulose                                             
                     0.5-2                                                
Magnesium Aluminum Silicate                                               
                     0.1-1                                                
Carrageenin          0.25-2                                               
Preservative qs      --                                                   
Sodium Lauryl Sulfate                                                     
                     0.1-3                                                
Calcium Carbonate      25-45                                              
Flavor qs            --                                                   
Purified Water qs ad 100                                                  
______________________________________
EXAMPLE 24 
______________________________________                                    
Preparation of Dental Paste                                               
Ingredient        % W/W                                                   
______________________________________                                    
Active Compound   0.05-20                                                 
Carboxymethylcellulose                                                    
                  5-20                                                    
Pectin            5-20                                                    
Plastibase ®  20-70                                                   
Gelatin           5-20                                                    
______________________________________
EXAMPLE 25 
______________________________________                                    
Preparation of Dental Ointment                                            
Ingredient         % W/W                                                  
______________________________________                                    
Active Compound    0.05-20                                                
Polyethylene Glycol 4000                                                  
                   50-80                                                  
Polyethylene Glycol 400                                                   
                   10-40                                                  
______________________________________
EXAMPLE 26 
______________________________________                                    
Preparation of Dental Powder for Brushing or for                          
Use in Water Spray (e.g. Water Pik ® )                                
Ingredient       % W/W                                                    
______________________________________                                    
Active Compound  0.05-10                                                  
Flavor qs        --                                                       
Wetting Agents qs                                                         
                 --                                                       
Dextrin qs ad    100                                                      
______________________________________
EXAMPLE 27 
______________________________________                                    
Preparation of Stick for Application to Gums                              
Ingredient       % W/W                                                    
______________________________________                                    
Active Compound  0.05-10                                                  
Glycerin         5-10                                                     
Propylene Glycol 40-80                                                    
Sodium Stearate  6-10                                                     
Flavor qs        --                                                       
Water            0-10                                                     
______________________________________
EXAMPLE 28 
______________________________________                                    
Preparation of Periodontal Packing Paste                                  
Ingredient         % W/W                                                  
______________________________________                                    
Paste Part A                                                              
Active Compound    0.05-20                                                
Caprylic Acid      9.0                                                    
Lauric Acid        27.0                                                   
Ethylcellulose(100 cps.)                                                  
                   2.0                                                    
Polypale Resin*    39.0                                                   
Gum Elemi          4.0                                                    
Brominol**         4.0                                                    
Mica (powdered)    7.5                                                    
Chlorothymol       1.0                                                    
Zinc Acetate       2.0                                                    
Bay Oil(essential oil)                                                    
                   1.0                                                    
Ethanol            1.5                                                    
Paste Part B                                                              
Magnesium Oxide    43.0                                                   
Zinc Oxide         21.0                                                   
Calcium Hydroxide  3.5                                                    
Copper Oxide       2.0                                                    
Mineral Oil, Heavy 26.0                                                   
Rosin Oil          3.0                                                    
Chlorothymol       1.4                                                    
Cumarin (flavor)   0.1                                                    
When equal parts of A and B are mixed together at                         
25° C. a hard mass is formed in about 3 minutes.                   
______________________________________                                    
 *Partially polymerized rosin (i.e. modified rosin)                       
 **Brominated olive oil
EXAMPLE 29 
______________________________________                                    
Preparation of Periodontal Packing Paste                                  
Ingredient         % W/W                                                  
______________________________________                                    
Part A (powder)                                                           
Active Compound    0.05-20                                                
Canada Balsam, Neutral                                                    
                   8.5                                                    
Rosin NF           8.5                                                    
Calcium Hydroxide  34.4                                                   
Zinc Oxide U.S.P.  46.0                                                   
Part B (Liquid Hardener)                                                  
Eugenol            85.0                                                   
Turpentine Oil, Rectified                                                 
                   15.0                                                   
A mixture of three drops of Part B added to 130 mg                        
of Part A produces a hard mass in about 2-3 minutes at 30°         
______________________________________                                    
C.
The compounds of this invention may be administered internally to a warm-blooded animal to inhibit connective tissue destruction or collagenase, such inhibition being useful in the amelioration or prevention of those reactions causing connective tissue damage. A range of doses may be employed depending on the mode of administration, the condition being treated and the particular compound being used. For example, for intravenous or subcutaneous use from about 5 to about 50 mg/kg/day, or every six hours for more rapidly excreted salts, may be used. For intra-articular use for large joints such as the knee, from about 2 to about 20 mg/joint per week may be used, with proportionally smaller doses for smaller joints. The dosage range is to be adjusted to provide optimum therapeutic response in the warm-blooded animal being treated. In general, the amount of compound administered can vary over a wide range to provide from about 1.5 mg/kg to about 100 mg/kg of body weight of animal per day. The usual daily dosage for a 70 kg subject may vary from about 100 mg to about 3.5 g. Unit doses can contain from about 0.5 mg to about 500 mg.
While in general the sodium salts of the acids of the invention are suitable for parenteral use, other salts may also be prepared, such as those of primary amines, e.g., ethylamine; secondary amines, e.g., diethylamine or diethanolamine; tertiary amines, e.g., pyridine or triethylamine or 2-dimethylaminomethyldibenzofuran, aliphatic diamines, e.g., decamethylenediamine; and aromatoic diamines, can be prepared. Some of these are soluble in water, others are soluble in saline solution, and still others are insoluble and can be used for purposes of preparing suspensions for injection. Furthermore, as well as the sodium salt, those of the alkali metals, such as potassium and lithium; of ammonia; and of the alkaline earth metals, such as calcium or magnesium, may be employed. It will be apparent, therefore, that these salts embrace, in general, derivatives of salt-forming cations.
In therapeutic use, the compounds of this invention may be administered in the form of conventional pharmaceutical compositions. Such compositions may be formulated so as to be suitable for oral or parenteral administration. The active ingredient may be combined in admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, i.e., oral or parenteral.
The compounds of this invention can be used in compositions such as tablets. Here, the principle active ingredient is mixed with conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums, or similar materials as non-toxic pharmaceutically acceptable diluents or carriers.
The tablets or pills of the novel compositions can be laminated or otherwise compounded to provide a dosage form affording the advantage of prolonged or delayed action or predetermined successive action of the enclosed medication. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids or mixtures of polymeric acids with such materials as shellac, shellac and cetyl alcohol, cellulose acetate and the like. A particularly advantageous enteric coating comprises a styrene maleic acid copolymer together with known materials contributing to the enteric properties of the coating. The tablet or pill may be colored through the use of an appropriate nontoxic dye, so as to provide a pleasing appearance.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration include suitable flavored emulsions with edible oils, such as, cottonseed oil, sesame oil, coconut oil, peanut oil, and the like, as well as elixirs and similar pharmaceutical vehicles. Sterile suspensions or solutions can be prepared for parenteral use. Isotonic preparations containing suitable preservatives are also desirable for injection use.
The compounds of the present invention may also be administered topically in the form of ointments, creams, lotions and the like, suitable for the treatment of connective tissue dependent dermatological disorders.
Moreover, the compounds of the present invention may be administered in the form of dental pastes, ointments, buccal tablets and other compositions suitable for application periodontally for the treatment of periodontitis and related diseases of the oral cavity.
The term dosage form as described herein refers to physically discrete units suitable as unitary dosage for warm-blooded animal subjects, each unit containing a predetermined quantity of active component calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle. The specification for the novel dosage forms of this invention are indicated by characteristics of the active component and the particular therapeutic effect to be achieved or the limitations inherent in the art of compounding such an active component for therapeutic use in warm-blooded animals as disclosed in this specification. Examples of suitable oral dosage forms in accord with this invention are tablets, capsules, pills, powder packets, granules, wafers, cachets, teaspoonfuls, dropperfuls, ampules, vials, segregated multiples of any of the foregoing and other forms as herein described.
The inhibiting activity of a representative compound of the invention on the destruction of connective tissue has been demonstrated by the following identified test: (i) Collagenase Assay, Test Code 006--This test measures the ability of human skin fibroblast collagenase to degrade radiolabled native collagen fibrils. An active inhibitor inhibits the degradation of the collagen fibril.
(i) Collagenase Assay--Test Code 006
A collagenase assay was performed by a modification of the method of Harper, et al., Biochem., 10, 3035 (1971). In a typical assay (total volume of 0.45 ml), 100 μl of the activated enzyme was added to the 14 C-labeled collagen fibrils (250 μl) followed by 100 μl of 50 mM cacodylate, pH 7.4, containing 5 mM calcium chloride. After incubation at 37° C. for 16 hours, the tubes were centrifuged in a Beckman microfuge for five minutes at full speed. An aliquot (200 μl) of the supernatant, representing collagenase digestion products of the fibril, was assayed for radioactivity. The effect of the test compound on collagen degradation by collagenase was examined as follows:
Varying concentrations of the test compound (in distilled water) were added to the assay tubes containing active collagenase (total volume 450 μl) and after 16 hours the amount of radioactivity in the supernatant was determined. Appropriate blanks and trypsin controls were run in parallel.
Table I shows that a representative compound of the invention possesses the ability to inhibit collagen degradation. The result is expressed as an ID50 collagenase value which represents a ratio of the weight (μg) of the representative compound required for 50% inhibition of collagenase over the weight (μg) of 6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt required for 50% inhibition of collagenase. The compound 6,6'-[ureylenebis(m-phenylenecarbonylimino]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt has been established as an inhibitor of the degradation of collagen in U.S. Pat. No. 4,297,372. An ID50 collagenase ratio of one indicates that the compound is as efficient as the reference compound in inhibiting collagen degradation. A value greater than one indicates that the test compound is less active.
              TABLE I                                                     
______________________________________                                    
Biological Activity                                                       
(test conc.: 30 μg/ml)                                                 
                   ID.sub.50 Collagenase                                  
Compound           Ratio                                                  
______________________________________                                    
6,6'-[Ureylenebis( -p-phenylene-                                          
                   1.73                                                   
sulfonylimino)]bis[4-hydroxy-                                             
2-naphthalenesulfonic acid]-                                              
disodium salt                                                             
______________________________________
Binding Assay
It has been shown that 6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt will bind to insoluble collagenous structures such as teeth, dentin, gingiva and the like. This binding is saturable and reversible.
Using (radioactive) 14 C-6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt, an in vitro binding (competition) assay procedure has been established which involves an insoluble substrate such as tooth powder which will bind the 14 C-6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt. The amount of 14 C-6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt bound is determined by washing away the unbound radioactive compound and counting CPM (counts per minute) of the insoluble tooth powder/14 C-6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt complex. The assay may be used to determine the ability of a competing analog of 6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt to inhibit binding in the following manner: 14 C-6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt and a non-radioactive analog thereof were incubated with tooth powder. The inhibiting effect of the test compound on binding compared to non-radioactive 6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt was determined as follows: A one mg amount of tooth powder was incubated in one ml of phosphate buffered saline (PBS) with 10 μg of 14 C-6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt and varying dose amounts (ranging from 0 to 2 mg) of the same cold (non-radioactive) compound. After 60 minutes at 37° C., the unbound radioactive compound was washed away and the amount of radioactivity bound to the tooth powder was determined for each dose by counting (CPM). The dose in μg of cold compound required to decrease the amount of radioactive agent by 50% (ID50) was determined. Then varying amounts of the test compound were substituted for cold 6,6'-[ureylenebis(m-phenylenecarbonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt in the above assay and the ID50 for this compound was determined.
An ID50 ratio provides a biological comparison of all compounds as established by use of the following equation: ##EQU1##
Results of this test on a representative compound of the present invention appear in Table II.
              TABLE II                                                    
______________________________________                                    
Compound           ID.sub.50 Binding Ratio                                
______________________________________                                    
6,6'-[Ureylenebis( -p-phenylene-                                          
                   1.55                                                   
sulfonylimino)]bis[4-hydroxy-                                             
2-napthalenesulfonic acid]-                                               
disodium salt                                                             
______________________________________
An ID50 binding ratio of one indicates that the compound is as efficient as the reference compound in competition for binding sites in tooth powder. Values greater than one indicate the compound is less efficient than the reference compound.

Claims (12)

We claim:
1. A compound of the formula: ##STR4## wherein A is hydrogen or a pharmaceutically acceptable salt cation; B is hydrogen, lower(C1 -C6)alkanoyl or alkali metal; and R is hydrogen or lower(C1 -C3)alkyl.
2. A compound according to claim 1 of the formula: ##STR5## wherein A is hydrogen or a pharmaceutically acceptable salt cation; B is hydrogen, lower(C1 -C6)alkanoyl or alkali metal; and R is hydrogen or lower(C1 -C3)alkyl.
3. A compound according to claim 1 of the formula: ##STR6## wherein A is hydrogen or a pharmaceutically acceptable salt cation; B is hydrogen, lower(C1 -C6)alkanoyl or alkali metal; and R is hydrogen or lower(C1 -C3)alkyl.
4. A compound according to claim 1 of the formula: ##STR7## wherein A is hydrogen or a pharmaceutically acceptable salt cation; B is hydrogen, lower(C1 -C6)alkanoyl or alkali metal; and R is hydrogen or lower(C1 -C3)alkyl.
5. The compound according to claim 1; 6,6'-[ureylenebis(p-phenylenesulfonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt.
6. A composition of matter for the treatment of pathological reactions resulting from the functioning of collagenase or of connective tissue disorders, which comprises a compound as recited in claim 1 and a pharmaceutically acceptable carrier or diluent.
7. A composition of matter, as recited in claim 6, wherein the pharmaceutically acceptable carrier or diluent is an aqueous solution or an injectable solution.
8. A composition of matter for the topical treatment of pathological reactions resulting from the deposition of dental plaque or of connective tissue disorders which comprises a compound as recited in claim 1 and a pharmaceutically acceptable carrier or diluent adapted for topical administration.
9. A composition of matter, as recited in claim 8, wherein the pharmaceutically acceptable carrier or diluent is a gelled vehicle, a buccal tablet or a lozenge.
10. A dental preparation characterized in that said preparation contains as a topically effective, therapeutically active ingredient a compound as recited in claim 1.
11. A dental preparation, as recited in claim 10, wherein the preparation is a mouth rinse, a dental paste, a dental cream, a dental powder, a tooth paste, a periodontal packing paste, a periodontal packing powder or a dental stick.
12. The composition or preparation, as recited in claims 6, 7, 8, 9, 10 or 11 wherein said compound is 6,6'-[ureylenebis(p-phenylenesulfonylimino)]bis[4-hydroxy-2-naphthalenesulfonic acid]disodium salt.
US06/710,771 1985-03-11 1985-03-11 Dental antiplaque agents and inhibitors of connective tissue destruction Abandoned USH83H (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5648390A (en) * 1992-08-07 1997-07-15 The United States Of America As Represented By The Secretary Of Agriculture Repellents for ants
US9498414B1 (en) 2006-03-30 2016-11-22 Janet M. Wehrli System and method for reducing plaque on teeth
US9833386B2 (en) 2006-03-30 2017-12-05 James D. Welch Method of, and system for smoothing teeth
US10092488B1 (en) 2006-03-30 2018-10-09 Janet M. Wehrli System and method for reducing plaque on teeth
US10342646B2 (en) 2015-10-17 2019-07-09 James D. Welch Method of, and system for smoothing teeth
US11103732B1 (en) 2015-10-17 2021-08-31 James D. Welch Method of improving the condition of teeth

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GB856357A (en) 1958-03-24 1960-12-14 Wm S Merrell Co 2-aryl-hexahydro-quinolizines
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US4216165A (en) 1976-05-10 1980-08-05 American Cyanamid Company Amine precursors to ureide inhibitors of connective tissue destruction
US4216166A (en) 1976-05-10 1980-08-05 American Cyanamid Company Nitro precursors to amine precursors to ureide inhibitors of connective tissue destruction
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GB856357A (en) 1958-03-24 1960-12-14 Wm S Merrell Co 2-aryl-hexahydro-quinolizines
GB1246141A (en) 1967-09-14 1971-09-15 Paul Coirre Improvements in or relating to -hydroxylproline derivatives
US4131684A (en) 1976-05-10 1978-12-26 American Cyanamid Company Complement inhibitors
US4216164A (en) 1976-05-10 1980-08-05 American Cyanamid Company Ureide inhibitors of connective tissue destruction
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5648390A (en) * 1992-08-07 1997-07-15 The United States Of America As Represented By The Secretary Of Agriculture Repellents for ants
US6071973A (en) * 1992-08-07 2000-06-06 The United States Of America As Represented By The Secretary Of Agriculture Repellent for ants
US9498414B1 (en) 2006-03-30 2016-11-22 Janet M. Wehrli System and method for reducing plaque on teeth
US9833386B2 (en) 2006-03-30 2017-12-05 James D. Welch Method of, and system for smoothing teeth
US10092488B1 (en) 2006-03-30 2018-10-09 Janet M. Wehrli System and method for reducing plaque on teeth
US10342646B2 (en) 2015-10-17 2019-07-09 James D. Welch Method of, and system for smoothing teeth
US11103732B1 (en) 2015-10-17 2021-08-31 James D. Welch Method of improving the condition of teeth

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