United States Patent 19
`Conrow et al.
`
`11)
`45)
`
`4,275,076
`Jun. 23, 1981
`
`54 SUBSTITUTED NAPHTHOIC ACIDS
`75 Inventors: Ransom B. Conrow, Pearl River;
`Seymour Bernstein, New City, both
`of N.Y.
`73) Assignee: American Cyanamid Company,
`Stamford, Conn.
`21 Appl. No.: 118,006
`22 Filed:
`Feb. 4, 1980
`51) Int. Cl...................... A61K 31/24; CO7C 101/52
`52 U.S.C. .................................... 424/309; 424/263;
`424/285; 424/311; 424/316; 424/319; 560/34;
`560/21; 560/45; 560/139; 562/435; 562/439;
`562/.455; 546/347; 260/346.71; 260/501.11
`
`56)
`
`58) Field of Search ............... 424/309, 263, 285, 311,
`424/316, 319; 560/34, 139; 562/439; 546/347;
`260/346.71, 501.11
`References Cited
`U.S. PATENT DOCUMENTS
`4,123,455 10/1978 Conrow et al. ...................... 424/310
`4,129,590 12/1978 Conrow et al. .................. 260/507 R
`Primary Examiner-Natalie Trousof
`Assistant Examiner-G. T. Breitenstein
`57
`ABSTRACT
`Certain ureides of substituted naphthoic acids and salts
`useful as inhibitors of connective tissue destruction.
`
`14 Claims, No Drawings
`
`Apotex, Inc. (IPR2019-00400), Ex. 1019, p. 001
`
`

`

`1
`
`SUBSTITUTED NAPHTHOIC ACIDS
`
`4,275,076
`2
`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, 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. Gor
`don, W. Newmand and B. Bloom, Agents and Action, 8,
`19 (1978); “Mechanisms of Tissue Injury With Refer
`ence 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. Abram
`son, R. W. Schilling, C. C. Huang and R. G. Salome,
`Ann. Otol. Rhinol. Faryngol, 81, 158 (1975); M. Abram
`son and C. C. Huang, Laryngoscope, 77, 1 (1976)). In
`corneal ulcerations that progress to loss of corneal in
`tegrity 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 conii ibute to the lesions
`in pulmonary emphysema I. Mandel, T. V. Darmle, J.
`A. Frierer, S. Keller and G. M. Turino, Elastin and
`Elastic Tissue, Ed. L. B. Sandberg, W. R. Gray and C.
`Fransblau, 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 colla
`gen degradation, that is, as collagenase inhibitors. Such
`substances include, for example, ethylenediaminetetra
`acetate, 1,10-phenanthroline, cysteine, dithiothretol and
`sodium auriothiomalate D. E. Woolley, R. W. Glan
`ville, D. R. Roberts and J. M. Evanson, Biochen 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 collage
`nase inhibitors directly applied to corneal ulcerations
`have been reported. Calcium ethylenediaminetetraace
`tate and acetylcysteine reduce the frequency of ulcer
`
`50
`
`60
`
`10
`
`15
`
`20
`
`BACKGROUND OF THE INVENTION
`The present invention resides in the concept of cer- 5
`tain
`ureylenebis-(substituted
`or
`unsubstituted
`phenylenecarbonylimino)bis-(substituted-naphthoic
`acids) and salts thereof which are novel compounds
`useful as inhibitors of connective tissue destruction.
`Abnormal destruction of connective tissue by colla
`genase and/or neutral proteases causes tissue damage
`and/or tissue dysfunction. In these conditions an inhibi
`tor 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, 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. Rey. Biochem., 43, 567 (1974); J. Fessler and L.
`Fessler, Ann. Rey. Biochem, 47, 129 (1978).
`25
`Collagen is, for example, the main structural compo
`nent 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 30
`dry dermis. Articular cartilage is the resilient tissue that
`covers the articulating extremities in synovial joints. It
`consists of collagen fibres that are intimately meshed in
`a hydrated gel of proteoglycan.
`Proteoglycan, as it exists in cartilage, is a molecule in 35
`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 40
`pulmonary structure "Elastin and Elastic Tissue', Ed.
`L. B. Sandberg, W. R. Gray, and C. Franzblau, Plenum
`Press, New York (1977). The breakdown of elastin of
`pulmonary connective tissue is considered the primary
`event in pulmonary emphysema A. Janoff in "Pros- 45
`teases and Biological Control", Cold Spring Harbor
`Conference on Cell Proliferation, 2, 603 (1975)).
`Degradation of fibrous collagen is initiated by a com
`bination 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 con
`ditions, the ensuing elevated levels of neutral proteases
`55
`and collagenase can result in rapid collagen degradation
`and tissue dysfunction. For example, in periodontal
`disease, the generated elevated levels of neutral pro
`teases and collagenase in the gingival crevicular fluid
`rapidly degrade the fibrous collagen supporting the
`teeth. Periodontal pockets result ultimately from colla
`gen degradation, and as these pockets deepen, support
`of tooth is lost and alveolar bone is resorbed K. Ohl
`sson, I. Ohlsson, and G. I. Basthall, Acta Odontol.
`Scand., 32, 51 (1974); L. M. Golub, S. Kenneth, H.
`65
`McEwan, J. B. Curran, and N. S. Ramamurthy, J. Den
`tal Research, 55, 177 (1976); L. M. Golub, J. E. Stakin
`and D. L. Singer, J. Dental Research, 53, 1501 (1974); L.
`
`Apotex, Inc. (IPR2019-00400), Ex. 1019, p. 002
`
`

`

`BO
`
`AOOC
`
`15
`
`OB
`
`(II)
`
`NH
`
`NHCO
`
`CO
`
`R
`
`R
`
`2
`
`(III)
`
`CO
`
`4,275,076
`3
`4
`consisting of hydrogen, lower (C1-C6) alkanoyl and a
`ation in the alkali burned rabbit M. Berman and C.
`Dohlman, Arch. Ophthamol, 35, 95 (1975)). Both cyste
`pharmaceutically acceptable salt cation; and R is se
`ine and acetylcysteine have been effective in the treat
`lected from the group consisting of hydrogen and lower
`ment of acute and chronic corneal ulceration in the
`(C1-C3) alkyl.
`human, although the latter compound was preferred
`Of particular interest are the group of compounds
`because of its greater stability S. I. Brown, N. P. Traga
`encompassed within Formula I and illustrated by For
`kis and D. B. Pease, Am. J. Ophthalmol, 74, 316 (1972);
`mulas II and III:
`M. Berman, Trace Components of Plasma. Isolation and
`Clinical Significance, 7th Annual Red Cross Sympo
`sium, p. 225, Alan. R. Liss, Inc., N.Y. (1976)).
`10
`Naturally occurring collagenase inhibitors include
`the serum components a 2-macroglobulin and 61
`anticollagenase D. E. Woolley, R. W. Glanville, D. R.
`Roberts and J. M. Evanson, Biochen. J., 169, 265
`(1978).
`While some compound 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 compet
`ing with sights on the connective tissue in such a man
`20
`ner 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 destruc
`25
`tion albeit in whatever manner or mode.
`U.S. Pat. No. 2,687,436 discloses substituted 3-(2-
`naphthyl)-cyclohexanes useful in the treatment of colla
`gen diseases. British Pat. Nos. 856,357 and 1,246,141
`disclose 2-aryl-hexahydro-quinolizines and 1-hydroxyl
`30
`praline 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., 10(4), 605-11 (1977),
`wherein the trypanocidal agent trypan blue is reported
`as inhibiting the activity of collagenase, or a proteinase
`contaminant in the collagenase preparation. It is inter
`esting, however, that in this same article, the ureide
`Suramin is reported as not inhibiting the action of colla
`40
`genase. The closest known ureides to those of the pres
`ent invention, and not disclosed as inhibitors of connec
`tive tissue destruction or as collagenase inhibitors are
`those ureides found in Journal of the Chemical Society,
`3069 (1927), and in U.S. Pat. Nos. 1,218,654 and
`45
`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
`50
`disclosure by itself does not anticipate or render obvi
`ous the invention claimed herein.
`SUMMARY OF THE INVENTION
`This invention is concerned with novel C-substituted
`naphthoic acid ureides which may be represented by
`Formula I;
`
`AOOC
`
`NH
`
`wherein A, B and R are as defined with reference to
`Formula I.
`By pharmaceutically acceptable salt cation is meant
`an alkali metal; an alkaline earth metal; ammonium;
`primary amine, e.g. ethyl amine; secondary amine, e.g.
`diethylamine or diethanolamine; tertiary amine, e.g.
`pyridine, triethylamine or 2-dimethylaminomethyl
`dibenzofuran; aliphatic amine, e.g. decamethylenedia
`mine; or an aromatic amine.
`Representative compounds encompassed within this
`invention include, for example:
`6,6'-Ureylenebis(m-phenylenecarbonylimino)bis(4-
`hydroxy-2-naphthoic acid) diethyl ester diacetate
`6,6'-Ureylenebis(m-phenylenecarbonylimino)bis(4-
`hydroxy-2-naphthoic acid)
`6,6'-Ureylenebis(m-phenylenecarbonylimino)bis(4-
`hydroxy-2-naphthoic acid) diethyl ester
`This invention is also concerned with C-substituted
`aminobenzamido naphthoic acids which are intermedi
`ates for the preparation of the biologically active com
`pounds of Formula I and which may be represented by
`Formula IV:
`
`(IV)
`
`NH2
`
`BO
`
`wherein A, B and R are as defined with reference to
`Formula I.
`Of particular interest are the group of intermediate
`compounds encompassed within Formula IV and illus
`trated by Formulas V and VI:
`
`(V)
`
`NH2
`
`35
`
`55
`
`BO
`AOOC
`
`NHCO
`
`NH-
`
`I
`(I)
`
`60
`
`R
`
`CO
`
`2
`
`65
`wherein A is selected from the group consisting of
`hydrogen, lower (C1-C6) alkyl and a pharmaceutically
`acceptable salt cation; B is selected from the group
`
`BO
`
`...: CO R
`
`Apotex, Inc. (IPR2019-00400), Ex. 1019, p. 003
`
`

`

`5
`-continued
`
`OB
`
`4,275,076
`
`(VI)
`
`R
`
`NHCO
`
`5
`
`CO NH2
`
`AOOC
`
`BO
`AOOC
`
`6
`-continued
`Flowchart. A
`
`NHCO
`
`NO2
`
`10
`
`acid
`
`15
`
`BO
`
`BO
`AOOC
`
`4.
`
`NHCO
`
`NH2
`
`CO
`
`2
`
`wherein A, B and R are as defined with reference to
`Formula I.
`Representative compounds encompassed by Formula
`IV include, for example:
`6-(m-Aminobenzamido)-4-hydroxy-2-naphthoic
`ethyl ester acetate
`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
`20
`encompassed within Formula I. Moreover, this inven
`tion is concerned with a method of inhibiting the degra
`dation sequelae of collagenase activity in a body fluid,
`such as crevicular fluid, synovial fluid and the like,
`which comprises subjecting body fluid collagenase to
`25
`the action of an effective collagenase inhibiting amount
`of a compound encompassed within the above formula.
`Body fluid can include blood, plasma, serum, synovial
`fluid, crevicular fluid, ocular fluid, etc., containing col
`lagenase. The method of use aspect of this invention is
`30
`further concerned with a method of inhibiting the ac
`tion of collagenase in a warm-blooded animal which
`comprises internally administering to said animal an
`effective collagenase inhibiting amount of a compound
`encompassed within the above formula.
`35
`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 pathologi
`40
`cal reactions resulting from the functioning of collage
`nase, and in the therapeutic treatment of warm-blooded
`animals having connective tissue disorders such as peri
`odontal diseases and diseases of the teeth, osteoporosis,
`osteolysis, Paget's disease, hyperparathyroidism of
`45
`renal failure, rheumatoid arthritis, septic arthritis, osteo
`arthritis, gout, acute synovitis, scleroderma, psoriasis,
`epidermolysis bullosa, keloids, blisters, cholesteatoma
`of the ear, and corneal ulceration. The compounds of
`the present invention may also be useful in those patho
`50
`logical states where excessive activity of neutral pro
`teases causes tissue damage.
`DESCRIPTION OF THE INVENTION
`The compounds of the present invention may be
`prepared according to the following Flowchart A.
`
`With reference to Flowchart A, a substituted-amino
`naphthoic acid 1 is dissolved in pyridine, cooled and
`reacted with an excess substituted nitrobenzoylchloride
`2, giving a substituted nitrobenzamido-substituted naph
`thoic acid 3, which is hydrogenated in the presence of a
`suitable catalyst to give the corresponding amine deriv
`ative 4. The amine 4 is dissolved in pyridine and phos
`genated to give the final ureide product 5 which is
`isolated by conventional procedures.
`DETAILED DESCRIPTION OF THE
`INVENTION
`The following examples describe in detail the prepa
`ration and formulation of representative compounds of
`the present invention.
`EXAMPLE 1
`6-(m-Aminobenzamido)-4-hydroxy-2-naphthoic acid,
`ethyl ester, acetate
`A solution of 20 g. or 4-hydroxy-6-nitro-2-naphthoic
`acid W. F. Beech and N. Legg, J. Chem. Soc., 1887
`(1949)), 385 ml. of absolute ethanol and 20 ml. of con
`centrated sulfuric acid is refluxed for 4 hours, concen
`trated and diluted with water. The solid is collected by
`filtration, washed with water until neutral and crystal
`lized from 250 ml. of acetonitrile, giving 16.5 g. of 4
`hydroxy-6-nitro-2-naphthoic acid ethyl ester as yellow
`crystals.
`To a mixture of 22.47 g. of 4-hydroxy-6-nitro-2-naph
`thoic acid ethyl ester in 150 ml. of pyridine is added 8.5
`ml. of acetic anhydride. The mixture is stirred for 5
`minutes, warmed on a steam bath until solution is com
`
`55
`
`BO
`AOOC
`
`Flowchart A
`
`NH
`
`+
`
`COC
`
`NO2
`
`2
`
`60
`
`65
`
`Apotex, Inc. (IPR2019-00400), Ex. 1019, p. 004
`
`

`

`4,275,076
`7
`8
`plete and then allowed to stand for 10 minutes. The
`hydroxide, portionwise, with stirring, in a nitrogen
`solution is poured into one liter of ice water and then
`atmosphere. The mixture is stirred under nitrogen at
`filtered. The solid is dissolved in 500 ml. of methylene
`room temperature for 2 hours, then poured into 300 ml.
`chloride, dried over sodium sulfate, filtered and concen
`of water and filtered. The filtrate is acidified to pH 2
`trated to about 200 ml. A 300 ml. portion of ethanol is
`with the addition of 10 ml. of concentrated hydrochlo
`added and the product is allowed to crystallize, giving
`ric acid and 50 g. of sodium acetate trihydrate are
`25.1 g of 4-hydroxy-6-nitro-2-naphthoic acid ethyl
`added. The gel is filtered and washed with water, then
`ester acetate as pale yellow crystals.
`further washed with water in a centrifuge and dried by
`A mixture of 26.3.g. of 4-hydroxy-6-nitro-2-naphthoic
`co-evaporation with 750 ml. of n-propanol, giving a
`acid ethyl ester acetate, 250 ml. of tetrahydrofuran and
`2.5 g. of 10% palladium on carbon is hydrogenated on
`red-brown powder. This powder is dissolved in 25 ml.
`a Parr shaker at 40-20 psi over 45 minutes. The mixture
`of hot dimethylformamide, diluted slowly with 15 ml.
`is filtered through diatomaceous earth and evaporated
`of water and cooled in a refrigerator. The precipitate is
`in vacuo to an oil. This oil is crystallized from 200 ml. of
`collected by filtration, washed successively with 8 ml.
`ether, giving 21.8 g. of 6-amino-4-hydroxy-2-naphthoic
`of 50% aqueous dimethylformamide, ethanol:ether (1:1)
`15
`acid ethyl ester acetate as beige crystals.
`and finally ether, then dried overnight at 110° C., giving
`To a cooled (ice bath) solution of 9.02 g. of 6-amino
`1.6 g. of the desired product as a pale tan powder, m.p.
`4-hydroxy-2-naphthoic acid ethyl ester acetate in 50 ml.
`297-300° C. (dec.).
`of dry pyridine is added 6.74g. of m-nitrobenzoyl chlo
`ride. After 5 minutes the ice bath is removed and stir
`EXAMPLE 4
`20
`ring is continued at room temperature for 30 minutes.
`6,6'-Ureylenebis(m-phenylenecarbonylimino)bis(4-
`The solution is poured into 500 ml. of water and stirred
`hydroxy-2-naphthoic acid) diethyl ester
`until the precipitate solidifies. The solid is collected by
`filtration, washed with water, dried and crystallized
`To a cooled (water bath) solution of 2.0 g of 6,6'-
`from 250 ml. of acetonitrile at 5 C., giving 13.0 g of
`ureylenebis(m-phenylenecarbonylimino)bisa
`25
`4-hydroxy-6-m-nitrobenzamido-2-naphthoic acid ethyl
`hydroxy-2-naphthoic acid diethyl ester diacetate in 60
`ester acetate as beige crystals.
`ml. of dimethylformamide is added 40 ml. of 0.25 N
`A mixture of 13.0 g of 4-hydroxy-6-m-nitroben
`sodium hydroxide, dropwise with stirring over 10 min
`zamido-2-naphthoic acid ethyl ester acetate, 125 ml. of
`utes. The solution is stirred for an additional 10 minutes,
`tetrahydrofuran and 1.25 g. of 10% palladium on car
`30
`80 ml. of pyridine is added and the solution is poured
`bon is hydrogenated in a Parr shaker at 45-37 psi for
`with cooling into a mixture of 800 ml. of water and 85
`one hour. The mixture is filtered through diatomaceous
`ml. of concentrated hydrochloric acid. The solid is
`earth and the filtrate is evaporated in vacuo to a pale
`yellow glass. This glass is crystallized by trituration
`collected by filtration, washed with water and dried at
`with ether and the solid is recrystallized from 100 ml. of
`room temperature. This solid is dissolved in hot 2
`35
`acetonitrile at 5' C., giving 10.35g. of the desired prod
`methoxyethanol at a concentration of 4% (w/v). This
`uct as colorless crystals, m.p. 185-187 C.
`solution is then distilled with its volume of water and
`then cooled to room temperature. The precipitate is
`EXAMPLE 2
`6,6'-(Ureylenebis(m-phenylenecarbonylimino))bis(4-
`collected by filtration and washed with 50% aqueous
`2-methoxyethanol, ethanol, then ether. This solid is
`hydroxy-2-naphthoic aciddiethyl ester diacetate
`dissolved in a mixture of 2-methoxyethanol:dimethyl
`To a solution of 10.23g of 6-(m-aminobenzamido)-4-
`formamide (6.5:1) giving an approximate 4% (w/v)
`hydroxy-2-naphthoic acid ethyl ester acetate in 60 ml.
`solution, diluted with water and filtered. The solid is
`of dry pyridine is added a solution of 1.3.g. of phosgene
`washed as described above, then with acetone and dried
`in 5 ml. of dry ethylene glycol, dimethyl ether, drop
`45
`at 110° C., overnight giving 417 mg. of the desired
`wise, with stirring and cooling, during 2-3 minutes.
`product as a tan powder, m.p. 265-280 C. (dec.).
`Stirring is continued at room temperature for 2 hours,
`then the solution is poured into 800 ml. of water. The
`EXAMPLE 5
`gummy precipitate is triturated with water, giving a red
`solid. This solid is stirred and refluxed in 300 ml. of
`50
`ethanol, cooled, filtered and the solid is washed with
`ethanol, then ether. This solid is dissolved in 120 ml. of
`hot dimethylformamide, treated with charcoal and fil
`tered through diatomaceous earth. The filtrate is
`warmed to 80 C. and diluted slowly, with stirring with
`60 ml. of water. The mixture is cooled to room tempera
`ture and the solid is collected by filtration, washed with
`67% aqueous dimethylformamide, ethanol, then ether
`and dried overnight at 110° C., giving 8.45 g. of the
`desired product as a pale tan powder, m.p. 285-287 C.
`EXAMPLE 3
`6,6'-Ureylenebis(m-phenylenecarbonylimino)bis(4-
`hydroxy-2-naphthoic acid)
`To a cooled (water bath) solution of 4.06 g. of 6,6'-
`65
`ureylenebis(m-phenylenecarbonylimino)bis(4-
`hydroxy-2-naphthoic aciddiethyl ester diacetate in 60
`md. of dimethylsulfoxide is added 60 ml of 2 N sodium
`
`Preparation of Compressed Tablet - Sustained Action
`Ingredient
`mg/Tablet
`Active Compound as Aluminum
`0.5-500 (as acid
`equivalent)
`Lake, Micronized
`qS
`Dibasic Calcium Phosphate N.F.
`Alginic Acid
`20
`Starch U.S.P.
`35
`
`10
`
`55
`
`Ingredient
`Active Compound
`Dibasic Calcium Phosphate N.F.
`Starch U.S.P.
`Modified Starch
`Magnesium Stearate U.S.P.
`
`Preparation of Compressed Tablet
`mg/Tablet
`0.5-500
`qs
`40
`0
`1-5
`
`EXAMPLE 6
`
`Apotex, Inc. (IPR2019-00400), Ex. 1019, p. 005
`
`

`

`4,275,076
`
`9
`-continued
`Preparation of Compressed Tablet - Sustained Action
`Ingredient
`mg/Tablet
`Magnesium Stearate U.S.P.
`1-10
`*Collagenase inhibitor plus aluminum sulfate yields aluminum collagenase inhibitor.
`Collagenase inhibitor content in aluminum lake ranges from 5-30%.
`
`5
`
`O
`
`15
`
`20
`
`25
`
`EXAMPLE 7
`
`Preparation of Hard Shell Capsule
`Ingredient
`mg/Capsule
`Active Compound
`0.5-500
`Lact
`S
`Dried
`M ose, ES R
`o
`gnesium Steara
`
`EXAMPLE 8
`
`Preparation of Oral Liquid (Syrup)
`Ingredient
`% W/V
`Active Compound
`0.05-5
`Liquid Sugar
`750
`Methyl Paraben U.S.P.
`0.18
`Propyl Paraben U.S.P.
`0.02
`Flavoring Agent
`qs
`Purified Water qs ad
`100.0
`
`EXAMPLE 9
`
`Preparation of Oral Liquid (Elixir)
`Ingredient
`% W/V
`Active Compound
`0.05-5
`Alcohol U.S.P.
`12.5
`Glycerin U.S.P.
`45.0
`Syrup U.S.P.
`20.0
`Flavoring Agent
`qs
`Purified Water qsad
`100.0
`
`EXAMPLE 10
`
`Preparation of Oral Suspension (Syrup)
`Ingredient
`% W/V
`Active Compound as Aluminum
`0.05-5
`Lake, Micronized
`(acid equivalent)
`Polysorbate 80 U.S.P.
`O.
`Magnesium Aluminum Silicate,
`Coloidal
`Flavoring Agent
`Methyl Paraben U.S.P.
`Propyl Paraben U.S.P.
`Liquid Sugar
`Purified Water qsad
`
`0.3
`qs
`0.18
`0.02
`75.0
`100.0
`
`EXAMPLE 11,
`
`Preparation of Injectable Solution
`Ingredient
`% W/V
`Active Compound
`0.05-5
`Benzyl Alcohol N.F.
`0.9
`Water for Injection
`100.0
`
`10
`EXAMPLE 12
`
`Preparation of Injectable Oil
`Ingredient
`% W/V
`Active Compound
`0.05-5
`Benzyl Alcohol
`1.5
`Sesame Oil qs ad
`100.0
`
`EXAMPLE 13
`
`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%
`
`EXAMPLE 4
`
`dient
`I
`ngredien
`Active Compound
`
`Preparation of Injectable Depo Suspension
`% W/V
`0.05-5
`(acid equivalent)
`0.2
`3.0
`0.8
`0.9
`qs
`100.0
`
`Polysorbate 80 U.S.P.
`30 Polyethylene Glycol 4000 U.S.P.
`Sodium Chloride U.S.P.
`Benzyl Alcohol N.F.
`HCl to pH 6-8
`Water for Injection qsad
`
`35
`
`EXAMPLE 1.5
`
`Preparation of Dental Paste
`
`Ingredient
`Active Compound
`Zinc Oxide
`Polyethylene Glycol 4000 U.S.P.
`Distilled Water qs
`
`% W/W
`0.05-5
`15
`50
`100
`
`EXAMPLE 16
`
`Preparation of Dental Ointment
`Ingredient
`% W/W
`Active Compound
`0.05-5
`Petrolatum, White U.S.P. qs
`100
`
`EXAMPLE 1.7
`
`Preparation of Dental Cream
`
`Ingredient
`Active Compound
`Mineral Oil
`Beeswax
`Sorbitan Monostearate
`Polyoxyethylene 20 Sorbitan
`Monostearate
`Methyl Paraben U.S.P.
`Propyl Paraben U.S.P.
`Distilled Water qs
`
`% W/W
`0.05-5
`50
`15
`2
`
`3
`0.18
`0.02
`100
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Apotex, Inc. (IPR2019-00400), Ex. 1019, p. 006
`
`

`

`11
`EXAMPLE 1.8
`
`4,275,076
`
`12
`EXAMPLE 23
`
`Preparation of Topical Cream
`Ingredient
`% W/W
`Active Compound
`0.05-5
`Sodium Lauryl Sulfate
`l
`Propylene Glycol
`12.
`Stearyl Alcohol
`25
`Petrolatum, White U.S.P.
`25
`Methyl Paraben U.S.P.
`0.18
`Propyl Paraben U.S.P.
`0.02
`Purified Water qs
`100
`
`EXAMPLE 19
`
`Preparation of Topical Ointment
`Ingredient
`% W/W
`Active Compound
`0.05-5
`Cholesterol
`3
`Stearyl Alcohol
`3
`White Wax
`8
`Petrolatum, White U.S.P. qs
`100
`
`EXAMPLE 20
`
`Preparation of Spray Lotion (Non-Aerosol)
`Ingredient
`97, W/W
`Active Compound
`0.05-5
`Isopropyl Myristate
`20
`Alcohol (Denatured) qs
`100
`
`EXAMPLE 21
`
`Preparation of Buccal Tablet
`
`Ingredient
`Active Ingredient
`6 x Sugar
`Acacia
`Soluble Starch
`F. D. & C. Yellow No. 6 Dye
`Magnesium Stearate
`
`g/Tablet
`0.00325
`0.29060
`0.01453
`0.01453
`0.00049
`0.00E60
`0.32500
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`The final tablet will weigh about 325 mg. and may be
`compressed into buccal tablets in flat faced or any other 50
`tooling shape convenient for buccal administration.
`EXAMPLE 22
`
`Preparation of Lozenge
`
`Ingredient
`Active Ingredient
`Kompact (R) Sugar (Sucrest Co.)
`6 x Sugar
`Sorbitol (U.S.P. Crystalline)
`Flavor
`Magnesium Stearate
`Dye
`Stearic Acid
`
`g/Lozenge
`0.0140
`0.738
`0.4802
`0.1038
`0.0840.
`0.0021
`qs
`0.0021
`1.4000
`
`55
`
`60
`
`65
`
`The ingredients are compressed into 3" flat based
`lozenge tooling. Other shapes may also be utilized.
`
`Preparation of Gelled Vehicles
`Ingredient
`92 W/W
`Active Compound
`9-11
`Sodium Chloride
`0.9-1.2
`Buffer and Flavor qs
`-
`Purified Water qsad
`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 24
`
`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 qsad
`100
`
`EXAMPLE 25
`
`Preparation of Tooth Paste
`
`Ingredient
`Active Compound
`Glycerin
`Sorbitol
`Sodium Carboxymethylcellulose
`Magnesium Aluminum Silicate
`Carrageenin
`Preservative qs
`Sodium Lauryl Sulfate
`Calcium Carbonate
`Flavor qs
`Purified Water qsad
`
`% W/W
`0.05-15
`5-15
`5-15
`0.5-2
`0.1-1
`0.25-2
`--
`0.1-3
`25-45
`-
`100
`
`EXAMPLE 26
`
`Ingredient
`Active Compound
`Carboxymethylcellulose
`Pectin
`Plastibase (R)
`Gelatin
`
`Preparation of Dental Paste
`% W/W
`0.05-20
`5-20
`5-20
`20-70
`5-20
`
`EXAMPLE 27
`
`Preparation of Dental Ointment
`Ingredient
`% W/W
`Active Compound
`0.05-20
`Polyethylene Glycol 4000
`50-80
`
`Apotex, Inc. (IPR2019-00400), Ex. 1019, p. 007
`
`

`

`13
`-continued
`Preparation of Dental Ointment
`Ingredient
`% W/W
`Polyethylene Glycol 400
`10-40
`
`EXAMPLE 28
`
`Paris. RE SEWE "
`Ingredient
`% W/W
`Active Compound
`0.05-10
`Flavor qs
`---
`Wetting Agents qs
`-
`Dextrin qs ad
`100
`
`EXAMPLE 29
`
`a
`Preparation of Stick for Application to Gums
`Ingredient
`% W/W
`Active Compound
`0.05-10
`E.
`5-10
`ropylene Glycol
`40-80
`Sodium Stearate
`6-10
`Flavor qs
`-
`Water
`0-10
`
`EXAMPLE 30
`
`% W/W
`99-20
`270
`2.0
`39.0
`4.0
`4.0
`7.5
`1.0
`2.0
`
`43.0
`21.0
`3.5
`2.0
`26.0
`3.0
`1.4
`0.
`
`Preparation of Periodontal Packing Paste
`Paste Part A
`Ingredient
`At Sund
`Lauric Acid
`Ethylcellulose (100 cps.)
`Polypale Resin'
`St. Ele
`rominol
`Mica (Powdered)
`Chlorothymol
`Zinc Acetate
`E. (Essential Oil)
`Paste Part B
`Magnesium Oxide
`Zinc Oxide
`Calcium Hydroxide
`SE 9xide
`ineral Oil, Heavy
`Rosin Oil
`Chlorothymol
`Cumarin (Flavor)
`Partially polymerized rosin (i.e. modified rosin)
`**Brominated olive oil
`When equal parts of A and B are mixed together at
`25 C. a hard mass is formed in about 3 minutes.
`EXAMPLE 31
`-
`Preparation of Periodontal Packing Paste
`Part A (Powder)
`Ingredient
`Active Compound
`Salsam, Neutral
`Calcium Hydroxide
`Zinc Oxide U.S.P.
`
`4,275,076
`
`14
`-continued
`Preparation of Periodontal Packing Paste
`Part B (Liquid Hardener)
`Eugenol
`Turpentine Oil, Rectified
`
`85.0
`15.0
`
`5
`
`A mixture of three drops of Part Badded to 130 mg.
`of Part A produces a hard mass in about 2-3 minutes at
`10 30 C,
`The compounds of this invention may be adminis
`tered internally to a warm-blooded animal to inhibit
`connective tissue destruction or collagenase, such inhi
`bition being useful in the amelioration or prevention of
`15 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
`20 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
`25 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
`30 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
`35 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 trieth
`ylamine or 2-dimethylaminomethyldibenzofuran; ali
`phatic diamines, e.g., decamethylenediamine; and aro
`40 matic 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 pur
`poses of preparing suspensions for injection. Further
`more, as well as the sodium salt, those of the alkali
`45 metals, such as potassium and lithium; of ammonia; and
`of the alkaline earth metals, such as calcium or magne
`sium, 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