US 20060222601A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0222601 A1 Sabnis et al. (43) Pub. Date: Oct. 5, 2006

(54) ORAL CARE COMPOSITIONS WITH Related U.S. Application Data COLOR CHANGING INDICATOR (60) Provisional application No. 60/696,872, filed on Jul. 6, 2005. Provisional application No. 60/711,183, filed on Aug. 25, 2005. Provisional application No. 60/734, (76) Inventors: Ram W. Sabnis, Eagan, MN (US); 219, filed on Nov. 7, 2005. Provisional application Timothy D. Kehoe, St. Paul, MN (US); No. 60/763,708, filed on Jan. 31, 2006. Provisional Robert James Balchunis, St. Paul, MN application No. 60/666,028, filed on Mar. 29, 2005. (US) Publication Classification (51) Int. C. Correspondence Address: A6IR 8/368 (2006.01) DORSEY & WHITNEY LLP A61K 8/46 (2006.01) INTELLECTUAL PROPERTY DEPARTMENT (52) U.S. Cl...... 424/49 SUTE 15OO SO SOUTH SIXTH STREET (57) ABSTRACT MINNEAPOLIS, MN 55402-1498 (US) The invention describes color changing toothpastes and (21) Appl. No.: 11/391,671 mouthwashes which contains acid-base indicator(s) for interaction with the oral cavity to provide a color change (22) Filed: Mar. 28, 2006 indicative of treatment time. US 2006/0222601 A1 Oct. 5, 2006

ORAL CARE COMPOSITIONS WITH COLOR 0007 Generally an individual gargles or swishes the CHANGING INDICATOR mouthwash for a given period of time to treat a sore throat, to reduce bacteria, and/or to reduce or eliminate bad breath. CROSS REFERENCE TO RELATED There is no way to know when an appropriate time period APPLICATIONS has passed so that the individual knows that sufficient treatment of the mouthwash has occurred. 0001) This application claims benefit under 35 U.S.C. S 119(e) to U.S. Ser. Nos. 60/696,872, filed Jul. 6, 2005 0008. There remains a need for improved mouthwash and (Attorney docket number 186573/US), entitled “Color toothpaste compositions, particularly for use by children, Changing Compositions and Articles'. 60/711,183, filed which can be readily formulated, can produce a dynamic Aug. 25, 2005 (Attorney docket number 186978/US), color change during use and/or which reduce objectionable entitled “Substituted Phenol-Based Aqueous Indicators'. bacteria in the mouth during contact. 0002 This application also claims benefit under 35 BRIEF SUMMARY OF THE INVENTION U.S.C. S 119(e) to U.S. Ser. Nos. 60/734,219, filed Nov. 7, 2005 (Attorney docket number 187222/US), entitled “Color 0009 Among the several features of the invention may be Changing Toothpaste” and 60/763,708, filed Jan. 31, 2006 noted the provision of novel oral care compositions such as (Attorney docket number 187482/US), entitled “Mouthwash mouthwash and toothpaste compositions containing an acid Composition', the contents of which are incorporated herein base indicator(s) that is pH and/or time sensitive to provide by reference in their entirety. a color change indicative of contact time. The compositions can provide a color change that occurs independently of the FIELD OF THE INVENTION pH in the mouth or that can occur with a change in pH during contact with the mouth. The composition(s) can be readily 0003. The invention relates generally oral care composi formulated from available materials. tions that have an acid-based indicator that is pH sensitive. 0010. The present invention is directed to a oral care The colored oral care composition can change color from compositions, including but not limited to mouthwashes, colored to clear, clear to colored or from a first color to a toothpastes/gels containing acid-base indicators for interac second color dependent up on the choice of acid-base tion to provide a color change upon treatment with the oral indicator(s). cavity, the acid-based indicators comprising those described BACKGROUND OF THE INVENTION throughout the application vide infra. 0011 While multiple embodiments are disclosed, still 0004 As is known, inducing children (and adults to some other embodiments of the present invention will become extent) to brush their teeth on a regular basis presents a apparent to those skilled in the art from the following difficult challenge. The brushing of teeth is perceived as a detailed description. As will be apparent, the invention is bothersome necessity by many adults and even more so by capable of modifications in various obvious aspects, all children. Insofar as children are concerned, the problem is without departing from the spirit and scope of the present exacerbated by the fact that children are highly sensitive to bitter tastes, possess a heightened gag reflex and typically invention. Accordingly, the detailed descriptions are to be utilize an equal amount of toothpaste as adults while having regarded as illustrative in nature and not restrictive. a mouth that is one fourth the size of the adult mouth. Thus, not only is brushing of the teeth an uncomfortable experi DETAILED DESCRIPTION ence for children, but additionally a child’s lack of appre 0012. In accordance with the present invention, it has ciation of the benefits of regular brushing coupled with a now been found that a color-changing oral care composition, child's short attention span renders the twice daily brushing i.e., toothpaste or mouthwash, can be formulated by incor regimen devoid of any positive reinforcement for the typical porating acid-base indicators into the composition of interest child. to provide a color change indicative of appropriate contact 0005. The availability of a toothpaste or dentrifice which time. By producing a dynamic color change (from colorless would make brushing more enjoyable for children would to clear, from one color to another color, or from color to provide an inducement lacking in existing toothpaste and clear) after a predetermined contact time, the compositions dentrifice formulations. A toothpaste which produces a of the present invention advantageously makes basic oral dynamic color change, has a reduced bitter taste and less of hygiene more appealing, less aggravating and more effective the annoying foaming action that often chokes children's especially for children. Small mouths would permit the accomplishment of basic 0013 Suitable acid-base indicators used in the present oral hygiene with improved results and less aggravation. In invention are generally colored under basic condition and the past, efforts have been made to develop toothpaste change color or fade to clear in non-basic condition. Acid formulations which undergo a color change upon brushing. base indicators which are colored on alkaline pH side 0006 The formation of dental plaque leads to dental (pH>7) and turn clear on acidic pH (pH-7) are most useful. caries, gingival inflammation, periodontal disease, and even Typically, the acid-base indicators are colored at pH between tually tooth loss. Dental plaque is a mixture of bacteria, about 9 and 10, and turn clear at pH between about 6 and 8. epithelial cells, leukocytes, macrophages, and other oral 0014 Representative examples of acid-base indicators exudate. Said bacteria produce highly branched polysaccha useful in the compositions of the present invention include, rides which together with microorganisms from the oral but are not limited to, picric acid, matius yellow, 2.6- cavity form an adhesive matrix for the continued prolifera dinitrophenol. 2,4-dinitrophenol, phenacetolin, 2.5-dinitro tion of plaque. phenol, isopicramic acid, o-nitrophenol, m-nitrophenol, US 2006/0222601 A1 Oct. 5, 2006

p-nitrophenol, 6,8-dinitro-2,4-(1H.3H)quinazolinedione, ammonia, triethanolamine. Other amines or amino alcohols nitroamine, ethyl bis(2,4-dinitrophenyl)-acetate, 2,4,6-trini are suitable provided they are non-toxic. trotoluene, 1,3,5-trinitrobenzene, 2,4,6-tribromobenzoic acid, 2-(p-dimethylaminophenyl)aZopyridine, metanil yel 0018. The selection of the kind and the amount of basic low, p-methyl red, 4-phenylazodiphenylamine, benzopurpu reagent used enables control of fading time of the color after rin 4B, tropaeolin OO, fast garnet GBC base, alizarin yellow application. Suitable basic reagents which readily volatilize R, benzyl orange, m-methyl red, 4-(m-tolyl)-azo-N,N-dim at ambient temperatures, typically have a vapor pressure ethyl-aniline, oil yellow II, methyl orange, ethyl orange, higher than about 10 mm Hg at 20°C. The selection of the hessian purple N. congo red, N-pnehyl-1-naphthyl-aminoa base also depends on Solubility in water, toxicity and odor. Zobenzene-p-sulfonic acid, 4-(4-dimethylamino-1-naph Therefore, aminoalcohols useful in the compositions of the thyl)-azo-3-methoxy-benzenesulfonic acid, p-ethoxy present invention include, but are not limited to triethano chrysoidine, C.-naphthyl red, chrysoidine, lamine (TEA) and/or diethylamine. TEA, for example, is 1-naphthylaminoaZobenzene-p-sulfonic acid, methyl red, clear, non-toxic and does not emit a noxious odor. 2-(p-dimethylaminophenyl)-azopyridine, ethyl red, propyl 0019. The basic reagent(s) is generally present in the red, N-phenyl-1-naphthyl-aminoaZo-o-carboxybenzene, composition of the invention in an amount from about nitrazol yellow, brilliant yellow, brilliant yellow S, orange II, 0.01% up to about 20% by weight, from about 0.2% to about propyl-o-naphthyl orange, orange I, orange IV. hessian, 10% by weight and from about 0.5% to about 5% by weight. Bordeaux, diazo violet, C.-naphthol violet, alizarin yellow GG, chrome orange GR, sulfone acid blue R, lanacyl violet 0020. It should be understood that the term “comprising BF, tropaeolin O, orange G. crystal violet, methyl violet B, (or comprises) includes the more restrictive terms consisting malachite green, brilliant green, ethyl violet, methyl violet of and consisting essentially of 6B, ethyl/methyl green, basic fuchsine, acid, fuchsine, patent blue V, alkali blue, aniline blue, o-naphthol benzein, 0021 Particular phthaleins useful in the invention have pentamethoxy red, hexamethoxy red, tetrabromophenol the formula (I): phthalein ethyl ester K salt, tetraiodophenolsulfophthlein, bromochlorophenol blue, bromocresol green, chlorocresol green, chlorophenol red, bromocresol purple, Sulfonaphthyl (I) red, bromophenol red, dibromophenol-tetrabromophenol sulfophthlein, bromothymol blue, aurin, phenol red, o-cresol benzein, o-cresol red, C.-naphtholphthlein, m-cresol purple, p-xylenol blue, thymol blue, phenoltetrachlorophthlein, o-cresolphthalein, C.-naphtholbenzein, phenoltetraiodophth lein, phenolphthalein, thymolphthlein, eosin Y, erythrosine B, erythrosine, galleon, brilliant cresyl blue, resaZurin, lac moid, litmus, azolitmus, azolitmin, neutral red, nile blue 2B, nile blue A, hematoxylin, quinaldine red, pinachrome, indo oxine, quinoline blue, bis-5-bromovanillidenecyclohex anone, bis-(2-hydroxystyryl)ketone, curcumin, bis-(4-hy droxy-3-ethoxy-benzylidene)-cyclohexanone, thiazole yellow G, alizarin blue B, alizarin red S. carminic acid, alizarin orange, alizarin, rufianic acid, rufianic blue, alizarin 0022 wherein R. R. R. R. R7, R, R and R'' are blue SWR, and indigocarmine. each, independently of one another, selected from the group 0.015 With the suitable selection of acid-base indicators, consisting of hydrogen, —OH, -SH, —CN. —NO, halo, it is possible to produce any color. The acid-base indicators fluoro, chloro, bromo, iodo, lower alkyl, substituted lower are preferably in the form of a salt, such as a sodium salt alkyl, lower heteroalkyl, substituted lower heteroalkyl, generated by reacting the indicator with sodium hydroxide, cycloalkyl, Substituted cycloalkyl, cycloheteroalkyl, Substi So as to permit its solubilization into the present composi tuted cycloheteroalkyl, lower haloalkyl, monohalomethyl, tion. Additionally, combinations of two or more indicators dihalomethyl, trihalomethyl, trifluoromethyl, lower alky may be used. lthio, substituted lower alkylthio, lower alkoxy, substituted lower alkoxy, methoxy, substituted methoxy, lower het 0016. Acid-base indicators are usually effective when eroalkoxy, Substituted lower heteroalkoxy, cycloalkoxy, Sub present in Small amounts in the compositions of the inven stituted cycloalkoxy, cycloheteroalkoxy, Substituted cyclo tion but generally are present in amounts from about 0.01% heteroalkoxy, lower haloalkoxy, monohalomethoxy, up to about 20% by weight, from about 0.5% to about 10% dihalomethoxy, trihalomethoxy, trifluoromethoxy, amino, by weight and from about 0.8% to about 8% by weight of the lower di- or monoalkylamino, substituted lower di- or total weight of the composition. monoalkylamino, aryl, Substituted aryl, aryloxy, Substituted 0017 Selection of an appropriate basic material is impor aryloxy, phenoxy, Substituted phenoxy, arylalkyl, Substituted tant for color change of acidic dye indicators in the colored arylalkyl, arylalkyloxy, Substituted arylalkyloxy, benzyl, compositions of the present invention. Desirable basic benzyloxy, heteroaryl, substituted heteroaryl, heteroaryloxy, reagents, which should readily Volatilize at ambient tem substituted heteroaryloxy, heteroarylalkyl, substituted het peratures for use in the present compositions, include, but eroarylalkyl, heteroarylalkyloxy, substituted heteroarylalky are not limited to, aminoalcohols, such as alkylamines, such loxy, carboxyl, lower alkoxycarbonyl, substituted lower as methylamine, dimethylamine, ethylamine, diethylamine, alkoxycarbonyl, aryloxycarbonyl, Substituted aryloxycarbo triethylamine, ethyleneamine, diethyleneamine, morpholine, nyl, arylalkyloxycarbonyl, Substituted arylalkyloxycarbo US 2006/0222601 A1 Oct. 5, 2006 nyl, carbamate, Substituted carbamate, carbamoyl, Substi 0033. It should be understood, that the salt form of the tuted carbamoyl, sulfamoyl or substituted sulfamoyl. indicator can be isolated prior to use or prepared in situ. 0023) Alternatively, R and R, R and R or R and R, Ideally, the salt is formed as a mono-salt or a di-salt, and R and R can form cyclic ring structures that are meaning that excess base is not present and either 1 or 2 heterocyclic, heteroaromatic, aromatic or nonaromatic and equivalents of base react with the acidic protons of the can contain one or more heteroatoms to form, for example, indicator. a quinoline, napthalene, etc. 0034. The following table provides phthaleins of particu 0024. Additionally, R7 and R, R and R, R and R' or lar interest. combinations thereof can form cyclic ring structures that are heterocyclic, heteroaromatic, aromatic or nonaromatic and can contain one or more heteroatoms to form, for example, a quinoline, napthalene, etc. R2 R3 R R6 Color 0025 Optionally, one of the carbons connected to R. R. R or R' can be substituted with a nitrogen atom. phenyl purple 0026 M' and M are each independently a hydrogen i-propyl i-propyl violet atom, a metal ion or an ammonium ion. Me Me blue 0027). In certain embodiments, R is selected from the OMe OMe eal group consisting of hydrogen, nitro, amino and alkyl; R is Me Me purple selected from the group consisting of hydrogen, phenyl, Et magenta alkyl, nitro, acetamido and alkoxy; R is selected from the i-propyl pink group consisting of hydrogen, halo, and alkyl; and R is OMe blue selected from the group consisting of hydrogen and alkyl. Me Me Me eal 0028. In certain other embodiments, R is selected from Me magenta the group consisting of hydrogen and methyl; R is selected i-propyl Me blue from the group consisting of hydrogen, phenyl, isopropyl. Me Br purple methyl, ethyl, sec-butyl, nitro and methoxy; R is selected i-propyl Br Me eal from the group consisting of hydrogen, bromo, methoxy, sec-butyl pink isopropyl and methyl; and R is selected from the group NO, yellow consisting of hydrogen and methyl. 0029. In other embodiments, R is hydrogen, Riis Me, and R. R. R. R. RandR'' are all hydrogenatoms, or R 0035) In another aspect, the acid-base indicator can be a is Me, R is a hydrogen atom, R is an iso-propyl group and substituted phenol of formula (II): R. R. R. R. and R' are all hydrogen atoms, or R is H, Riis Me, R is Brand R. R. R. RandR'' are all hydrogen atoms, or R is Me, R is Br. Riis an isopropyl and R. R. (II) R, R and R' are all hydrogen atoms. In certain embodi OMI ments, one or more of these compounds may be excluded from certain aspects of the invention. 0030) In still other embodiments, R is H, R is phenyl and R. R. R. R. RandR'' are all hydrogenatoms, or R is H. Rand Rare isopropyl and R. R. R. Rand R'' are all hydrogen atoms, or R is H, R is methyl, R is H, R is methyl, R. R. R. and R" are all hydrogen atoms, or R is H. Rand Rare methoxy and R. R. R. Rand R'' are all hydrogen atoms, or R is H. R. and R are methyl and R. 0036) wherein R. R. R. Rand M areas defined above R7, R, R and R'' are all hydrogen atoms, or R is H, R is and R is selected from the same group as R. R. Rand R. ethyl and R. R. R. R. Rand R'' are all hydrogenatoms, or R is H, R is isopropyl and R. R. R. R. R. and R' 0037 Alternatively, R and R, R and R, R and R, or are all hydrogen atoms, or R is H. R is methoxide and R. Rand R' can form cyclic ring structures that are heterocy R. R. R. RandR'' are all hydrogen atoms, or R, R and clic, heteroaromatic, aromatic or nonaromatic and can con Rare all methyl and R. R. R. RandR'' are all hydrogen tain one or more heteroatoms to form, for example, a atoms, or R. R. R. R. R. R. R. R'' are all hydrogen quinoline, napthalene, etc. atoms and R is sec-butyl, or R. R. R. R. R. R. R. R' are all hydrogen atoms and R is nitro. 0038. In one aspect, one or more of R through R', 0031. In one aspect, the compound where R. R. R. R. independently, is a nitro (—NO) group and the remaining R. R. RandR'' are all hydrogen atoms is excluded from R groups are selected from those provided above. the compositions. 0039. Additionally, substituted hydrazides are useful in 0032). In particular, at least one of M" or M is a metal or the compositions of the invention and can have one of two ammonium ion. formulae: US 2006/0222601 A1 Oct. 5, 2006

pan-2-yl, cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta (III) 1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, R8 R9 cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, R 13 R' but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. V CONN R10 or 0044) The term “alkyl is specifically intended to include groups having any degree or level of Saturation, i.e., groups R6 R2 having exclusively single carbon-carbon bonds, groups hav R12 R11 ing one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having R5 R3 mixtures of single, double and triple carbon-carbon bonds. R4 Where a specific level of saturation is intended, the expres IV sions “alkanyl.”“alkenyl, and “alkynyl are used. Prefer CONR 13NR 14R 15 (IV) ably, an alkyl group comprises from 1 to 15 carbon atoms (C-C, alkyl), more preferably from 1 to 10 carbon atoms R6 R2 (C-C alkyl) and even more preferably from 1 to 6 carbon atoms (C-C alkyl or lower alkyl). R5 R3 0045 “Alkanyl.” by itself or as part of another substitu ent, refers to a saturated branched, straight-chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include, but are not limited to, methanyl: 0040 wherein R through Rare as defined above and R' ethanyl; propanyls such as propan-1-yl, propan-2-yl (iso through R'' are the same substituents as R through R. R', propyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, R'' and R' (if present) are each, independently of one butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), another, a hydrogen atom, an alkyl group, a Substituted alkyl 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and group, any aryl group or a Substituted aryl group. the like. 0041. In certain embodiments for compound formulae 0046 “Alkenyl,” by itself or as part of another substitu (II), R' and R'' are hydrogen atoms and for compound ent, refers to an unsaturated branched, straight-chain or formulae (III), R', R'' and R' are all hydrogen atoms. cyclic alkyl radical having at least one carbon-carbon double 0042. In certain aspects, compounds of formulae (III) can bond derived by the removal of one hydrogen atom from a have one or more hydroxyl groups, which can be deproto single carbon atom of a parent alkene. The group may be in nated to form a salt. For example, formulae (IIIa) provides either the cis or trans conformation about the double bond(s). Typical alkenyl groups include, but are not limited one isomer where a hydroxyl is present at the R position as to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2- a salt. M' is as defined above for M'. It should be understood yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1- that one or more of R through R' could have a hydroxylat yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, that given position, and that hydroxyl could be in a salt form. but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but 2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien (IIIa) 2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3- R8 R9 dien-1-yl, etc.; and the like. R 13 R' \ | 0047 “Alkynyl.” by itself or as part of another substitu CONN R10 ent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple R6 OM2 bond derived by the removal of one hydrogen atom from a R12 RI single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls R5 R3 Such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the R4 like. 0048 “Alkyldiyl by itself or as part of another substitu 0.043 “Alkyl, by itself or as part of another substituent, ent refers to a saturated or unsaturated, branched, straight refers to a saturated or unsaturated, branched, straight-chain chain or cyclic divalent hydrocarbon group derived by the or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from each of two different removal of one hydrogen atom from a single carbon atom of carbon atoms of a parent alkane, alkene or alkyne, or by the a parent alkane, alkene or alkyne. Typical alkyl groups removal of two hydrogen atoms from a single carbon atom include, but are not limited to, methyl ethyls such as of a parent alkane, alkene or alkyne. The two monovalent ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, pro radical centers or each valency of the divalent radical center pan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, can form bonds with the same or different atoms. Typical prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl, cycloprop-2-en alkyldiyl groups include, but are not limited to, methandiyl; 1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as ethyldiyls such as ethan-1,1-diyl ethan-1,2-diyl, ethen-1,1- butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-pro diyl ethen-1,2-diyl; propyldiyls such as propan-1,1-diyl. US 2006/0222601 A1 Oct. 5, 2006 propan-1,2-diyl, propan-2.2-diyl, propan-1,3-diyl, cyclopro 0053 “Aryl,” by itself or as part of another substituent, pan-1,1-diyl, cyclopropan-1,2-diyl, prop-1-en-1,1-diyl. refers to a monovalent aromatic hydrocarbon group derived prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3-diyl. by the removal of one hydrogen atom from a single carbon cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl cyclo atom of a parent aromatic ring system, as defined herein. prop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such Typical aryl groups include, but are not limited to, groups as, butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4- derived from aceanthrylene, acenaphthylene, acephenan diyl, butan-2,2-diyl, 2-methyl-propan-1,1-diyl 2-methyl thrylene, anthracene, aZulene, benzene, chrysene, coronene, propan-1,2-diyl, cyclobutan-1,1-diyl; cyclobutan-1,2-diyl. fluoranthene, fluorene, hexacene, hexaphene, hexalene, as cyclobutan-1,3-diyl, but-1-en-1,1-diy1, but-1-en-1,2-diyl. indacene, S-indacene, indane, indene, naphthalene, octacene, but-1-en-1,3-diyl, but-1-en-1,4-diyl 2-methyl-prop-1-en-1, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, 1-diyl 2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1- pentalene, pentaphene, perylene, phenalene, phenanthrene, diyl, buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1, picene, pleiadene, pyrene, pyranthrene, rubicene, triph 3-dien-1,4-diyl, cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3- enylene, trinaphthalene and the like. Preferably, an aryl diyl, cyclobut-2-en-1,2-diyl, cyclobuta-1,3-dien-1,2-diyl. group comprises from 6 to 20 carbon atoms (Co-Co aryl), cyclobuta-1,3-dien-1,3-diy1, but-1-yn-1,3-diyl, but-1-yn-1, more preferably from 6 to 15 carbon atoms (C-C aryl) and 4-diyl, buta-1,3-diyn-1,4-diyl, etc.; and the like. Where even more preferably from 6 to 10 carbon atoms (C-Co specific levels of Saturation are intended, the nomenclature aryl). alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used. Where it 005.4 "Arylalkyl,” by itself or as part of another substitu is specifically intended that the two valencies are on the ent, refers to an acyclic alkyl group in which one of the same carbon atom, the nomenclature “alkylidene' is used. In hydrogen atoms bonded to a carbon atom, typically a preferred embodiments, the alkyldiyl group comprises from terminal or sp carbon atom, is replaced with an aryl group 1 to 6 carbon atoms (C1-C6 alkyldiyl). Also preferred are as, as defined herein. Typical arylalkyl groups include, but saturated acyclic alkanyldiyl groups in which the radical are not limited to, benzyl, 2-phenylethan-1-yl, 2-phe centers are at the terminal carbons, e.g., methandiyl nylethen-1-yl, naphthylmethyl 2-naphthylethan-1-yl, (methano); ethan-1,2-diyl (ethano); propan-1,3-diyl (pro 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenyle pano); butan-1,4-diyl (butano); and the like (also referred to than-1-yl and the like. Where specific alkyl moieties are as alkylenos, defined infra). intended, the nomenclature arylalkanyl, arylalkenyl and/or 0049) “Alkyleno.” by itself or as part of another substitu arylalkynyl is used. Preferably, an arylalkyl group is (C- ent, refers to a straight-chain Saturated or unsaturated alky Co) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of ldiyl group having two terminal monovalent radical centers the arylalkyl group is (C-C) alkyl and the aryl moiety is derived by the removal of one hydrogen atom from each of (Co-Co) aryl, more preferably, an arylalkyl group is (C- the two terminal carbon atoms of straight-chain parent Co) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of alkane, alkene or alkyne. The locant of a double bond or the arylalkyl group is (C-C) alkyl and the aryl moiety is triple bond, if present, in a particular alkyleno is indicated in (C-C) aryl, and even more preferably, an arylalkyl group square brackets. Typical alkyleno groups include, but are not is (C-Cs) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl limited to, methano; ethylenos Such as ethano, etheno, moiety of the arylalkyl group is (C-C) alkyl and the aryl ethyno: propylenos such as propano, propleno, propal, moiety is (C-C) aryl. 2dieno, prop lyno, etc.; butylenos such as butano, but 1 eno, but 2eno, buta1,3dieno, but lyno, but2yno, buta 0.055 “Aryloxy.” by itself or as part of another substitu 1.3diyno, etc.; and the like. Where specific levels of ent, refers to a radical of the formula —O-aryl, where aryl saturation are intended, the nomenclature alkano, alkeno is as defined herein. and/or alkyno is used. In preferred embodiments, the alky 0056 "Arylalkyloxy, by itself or as part of another sub leno group is (C1-C6) or (C1-C3) alkyleno. Also preferred stituent, refers to a radical of the formula —O-arylalkyl, are straight-chain Saturated alkano groups, e.g., methano, where arylalkyl is as defined herein. ethano, propano, butano, and the like. 0057 “Aryloxycarbonyl,” by itself or as part of another 0050 “Alkoxy.” by itself or as part of another substituent, substituent, refers to a radical of the formula —C(O)—O- refers to a radical of the formula —OR, where R is an alkyl aryl, where aryl is as defined herein. or cycloalkyl group as defined herein. Representative examples alkoxy groups include, but are not limited to, 0.058 “Carbamoyl,” by itself or as part of another sub methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, stituent, refers to a radical of the formula —C(O)NR'R'", cyclopropyloxy, cyclopentyloxy, cyclohexyloxy and the where R' and R" are each, independently of one another, like. selected from the group consisting of hydrogen, alkyl and cycloalkyl as defined herein, or alternatively, R and R", 0051 "Alkoxycarbonyl.” by itself or as part of another taken together with the nitrogen atom to which they are substituent, refers to a radical of the formula—C(O)-alkoxy, bonded, form a 5-, 6- or 7-membered cycloheteroalkyl ring where alkoxy is as defined herein. as defined herein, which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from 0.052 “Alkylthio.” by itself or as part of another substitu the group consisting of O. S and N. ent, refers to a radical of the formula —SR, where R is an alkyl or cycloalkyl group as defined herein. Representative 0059) “Compounds of the invention” refers to com examples of Alkylthio groups include, but are not limited to, pounds encompassed by the various descriptions and struc methylthio, ethylthio, propylthio, isopropylthio, butylthio tural formulae disclosed herein. The compounds of the tert-butylthio, cyclopropylthio, cyclopentylthio, cyclohexy invention may be identified by either their chemical struc lthio, and the like. ture and/or chemical name. When the chemical structure and US 2006/0222601 A1 Oct. 5, 2006

chemical name conflict, the chemical structure is determi group. As specific examples, N-methyl-imidazolidinyl, native of the identity of the compound. The compounds of N-methyl-morpholinyl, N-methyl-piperazinyl, N-methyl-pi the invention may contain one or more chiral centers and/or peridinyl, N-methyl-pyrazolidinyl and N-methyl-pyrrolidi double bonds and therefore may exist as stereoisomers. Such nyl are included within the definition of “cycloheteroalkyl.” as double-bond isomers (i.e., geometric isomers), rotamers, A cycloheteralkyl group may be attached to the remainder of enantiomers or diastereomers. Accordingly, when stere the molecule via a ring carbon atom or a ring heteroatom. ochemistry at chiral centers is not specified, the chemical 0063) “Dialkylamino” or “Monoalkylamino,” by them structures depicted herein encompass all possible configu selves or as part of other substituents, refer to radicals of the rations at those chiral centers including the stereoisomeri formula —NRR and NHR, respectively, where each R is cally pure form (e.g., geometrically pure, enantiomerically independently selected from the group consisting of alkyl pure or diastereomerically pure) and enantiomeric and Ste and cycloalkyl, as defined herein. Representative examples reoisomeric mixtures. Enantiomeric and stereoisomeric of dialkylamino groups include, but are not limited to, mixtures can be resolved into their component enantiomers dimethylamino, methylethylamino, di-(1-methylethy or stereoisomers using separation techniques or chiral Syn l)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethy thesis techniques well known to the skilled artisan. The compounds of the invention may also exist in several l)amino, (cyclohexyl)(propyl)amino and the like. Represen tautomeric forms including the enol form, the keto form and tative examples of monalkylamino groups include, but are mixtures thereof. Accordingly, the chemical structures not limited to, methylamino, ethylamino, propylamino, iso depicted herein encompass all possible tautomeric forms of propylamino, cyclohexylamino, and the like. the illustrated compounds. The compounds of the invention 0064). “Halogen' or “Halo,” by themselves or as part of may also include isotopically labeled compounds where one another substituent, refer to a fluoro, chloro, bromo and/or or more atoms have an atomic mass different from the iodo radical. atomic mass conventionally found in nature. Examples of 0065) “Haloalkyl,” by itself or as part of another sub isotopes that may be incorporated into the compounds of the stituent, refers to an alkyl group as defined herein in which invention include, but are not limited to, H, H, C, C, one or more of the hydrogen atoms is replaced with a halo *C, N, O, 7.O. P. P. 35S, F and C1. Compounds group. The term “haloalkyl is specifically meant to include of the invention may exist in unsolvated forms as well as monohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to per Solvated forms, including hydrated forms and as N-oxides. haloalkyls. The halo groups Substituting a haloalkyl can be In general, the hydrated, solvated and N-oxide forms are the same, or they can be different. For example, the expres within the scope of the present invention. Certain com sion "(C-C) haloalkyl includes 1-fluoromethyl, 1-fluoro pounds of the present invention may exist in multiple 2-chloroethyl, difluoromethyl, trifluoromethyl, 1-fluoroet crystalline or amorphous forms. In general, all physical hyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, forms are equivalent for the uses contemplated by the perfluoroethyl, etc. “Haloalkyloxy.” by itself or as part of present invention and are intended to be within the scope of another Substituent, refers to a group of the formula —O- the present invention. haloalkyl, where haloalkyl is as defined herein. 0060 “Cycloalkyl.” by itself or as part of another sub stituent, refers to a saturated or unsaturated cyclic alkyl 0.066 “Heteroalkyl,”“Heteroalkanyl,”“Heteroalkenyl, radical, as defined herein. Where a specific level of satura “Heteroalkynyl,”“Heteroalkyldiyl and “Heteroalkyleno.” tion is intended, the nomenclature “cycloalkanyl' or by themselves or as part of other substituents, refer to alkyl, “cycloalkenyl' is used. Typical cycloalkyl groups include, alkanyl, alkenyl, alkynyl, alkyldiyl and alkyleno groups, but are not limited to, groups derived from cyclopropane, respectively, in which one or more of the carbon atoms (and cyclobutane, cyclopentane, cyclohexane, and the like. Pref optionally any associated hydrogen atoms), are each, inde erably, the cycloalkyl group comprises from 3 to 10 ring pendently of one another, replaced with the same or different atoms (C-C cycloalkyl) and more preferably from 3 to 7 heteroatoms or heteroatomic groups. Typical heteroatoms or ring atoms (C-C, cycloalkyl). heteroatomic groups which can replace the carbon atoms include, but are not limited to, O, S, N, Si, —NH , 0061 “Cycloheteroalkyl.” by itself or as part of another S(O)— —S(O) —S(O)NH —S(O)NH and the Substituent, refers to a saturated or unsaturated cyclic alkyl like and combinations thereof. The heteroatoms or hetero radical in which one or more carbon atoms (and optionally atomic groups may be placed at any interior position of the any associated hydrogen atoms) are independently replaced alkyl, alkenyl or alkynyl groups. Examples of Such het with the same or different heteroatom. Typical heteroatoms eroalkyl, heteroalkanyl, heteroalkenyl and/or heteroalkynyl to replace the carbon atom(s) include, but are not limited to, groups include —CH2—CH2—O—CH, —CH2—CH2 N. P. O. S. Si, etc. Where a specific level of saturation is NH CH, —CH2—CH N(CH)—CH, —CH2—S intended, the nomenclature “cycloheteroalkanyl or “cyclo CH, —CH2—CH2—S(O)—CH, —CH2—CH2—S(O) heteroalkenyl is used. Typical cycloheteroalkyl groups CH, -CH=CH-O-CH, -CH-CH=N-O CH, include, but are not limited to, groups derived from and —CH, CH, O C=CH. For heteroalkyldiyl and epoxides, azirines, thiranes, imidazolidine, morpholine, heteroalkyleno groups, the heteratom or heteratomic group piperazine, piperidine, pyrazolidine, pyrrolidone, quinucli can also occupy either or both chain termini. For Such dine, and the like. Preferably, the cycloheteroalkyl group groups, no orientation of the group is implied. comprises from 3 to 10 ring atoms (3-10 membered cyclo heteroalkyl) and more preferably from 5 to 7 ring atoms (5-7 0067) “Heteroaryl,” by itself or as part of another sub stituent, refers to a monovalent heteroaromatic radical membered cycloheteroalkyl). derived by the removal of one hydrogen atom from a single 0062. A cycloheteroalkyl group may be substituted at a atom of a parent heteroaromatic ring systems, as defined heteroatom, for example, a nitrogenatom, with a lower alkyl herein. Typical heteroaryl groups include, but are not limited US 2006/0222601 A1 Oct. 5, 2006

to, groups derived from acridine, B-carboline, chromane, dine, oxadiazole, oxazole, perimidine, phenanthridine, chromene, cinnoline, furan, imidazole, indazole, indole, phenanthroline, phenazine, phthalazine, pteridine, purine, indoline, indolizine, isobenzofuran, isochromene, isoindole, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyri pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, dine, oxadiazole, oxazole, perimidine, phenanthridine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, tria phenanthroline, phenazine, phthalazine, pteridine, purine, Zole, Xanthene and the like. pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, 0.071) “Metal ion” or “Metal Salt” refers to a salt of a compound of the invention which is made with counterions quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, tria understood in the art to be generally acceptable for phar Zole, xanthene, and the like. Preferably, the heteroaryl group maceutical uses and which possesses the desired pharma comprises from 5 to 20 ring atoms (5-20 membered het cological activity of the parent compound. Such salts eroaryl), more preferably from 5 to 10 ring atoms (5-10 include: (1) acid addition salts, formed with inorganic acids membered heteroaryl). Preferred heteroaryl groups are those Such as hydrochloric acid, hydrobromic acid, Sulfuric acid, derived from furan, thiophene, pyrrole, benzothiophene, nitric acid, phosphoric acid, and the like; or formed with benzofuran, benzimidazole, indole, pyridine, pyrazole, organic acids such as acetic acid, propionic acid, hexanoic quinoline, imidazole, oxazole, isoxazole and pyrazine. acid, cyclopentanepropionic acid, glycolic acid, pyruvic 0068 “Heteroarylalkyl” by itself or as part of another acid, lactic acid, malonic acid. Succinic acid, malic acid, Substituent refers to an acyclic alkyl group in which one of maleic acid, fumaric acid, tartaric acid, citric acid, benzoic the hydrogen atoms bonded to a carbon atom, typically a acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, terminal or sp carbon atom, is replaced with a heteroaryl mandelic acid, methanesulfonic acid, ethanesulfonic acid, group. Where specific alkyl moieties are intended, the 1.2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, nomenclature heteroarylalkanyl, heteroarylakenyl and/or benzenesulfonic acid, 4-chlorobenzenesulfonic acid, heteroarylalkynyl is used. In preferred embodiments, the 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, cam heteroarylalkyl group is a 6-21 membered heteroarylalkyl, phorsulfonic acid, 4-methylbicyclo2.2.2-oct-2-ene-1-car e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroary boxylic acid, glucoheptonic acid, 3-phenylpropionic acid, lalkyl is (C1-C6) alkyl and the heteroaryl moiety is a trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric 5-15-membered heteroaryl. In particularly preferred acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, embodiments, the heteroarylalkyl is a 6-13 membered het salicylic acid, Stearic acid, muconic acid and the like; or (2) eroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety is salts formed when an acidic proton present in the parent (C1-C3) alkyl and the heteroaryl moiety is a 5-10 membered compound is replaced by a metal ion, e.g., an alkali metal heteroaryl. ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, 0069. “Parent Aromatic Ring System” refers to an unsat triethanolamine, N-methylglucamine, morpholine, piperi urated cyclic or polycyclic ring system having a conjugated dine, dimethylamine, diethylamine and the like. Also It electron system. Specifically included within the definition included are salts of amino acids Such as arginates and the of "parent aromatic ring system” are fused ring systems in like, and salts of organic acids like glucurmic or galactunoric which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for acids and the like (see, e.g., Berge et al., 1977, J. Pharm. Sci. example, fluorene, indane, indene, phenalene, etc. Typical 66:1-19). parent aromatic ring systems include, but are not limited to, 0072 “Pharmaceutically acceptable vehicle' refers to a aceanthrylene, acenaphthylene, acephenanthrylene, diluent, adjuvant, excipient or carrier with which a com anthracene, aZulene, benzene, chrysene, coronene, fluoran pound of the invention is administered. thene, fluorene, hexacene, hexaphene, hexalene, as-in dacene, S-indacene, indane, indene, naphthalene, octacene, 0.073 “Substituted,” when used to modify a specified octaphene, octalene, ovalene, penta-2,4-diene, pentacene, group or radical, means that one or more hydrogen atoms of pentalene, pentaphene, perylene, phenalene, phenanthrene, the specified group or radical are each, independently of one picene, pleiadene, pyrene, pyranthrene, rubicene, triph another, replaced with the same or different substituent(s). enylene, trinaphthalene and the like. Substituent groups useful for Substituting Saturated carbon atoms in the specified group or radical include, but are not 0070) “Parent Heteroaromatic Ring System” refers to a limited to R', halo, -O, =O, -OR. -SR, S, =S, parent aromatic ring system in which one or more carbon NRR, =NR, =N OR, trihalomethyl, CF, CN, atoms (and optionally any associated hydrogen atoms) are OCN, -SCN, NO, NO =N - N - S(O).R. each independently replaced with the same or different —S(O),O, -S(O).OR, —OS(O).R. —OS(O),O, heteroatom. Typical heteroatoms to replace the carbonatoms OS(O),OR, -P(O)(O), - P(O)(OR)(O), include, but are not limited to, N. P. O, S, Si, etc. Specifically P(O)(OR)(OR), C(O)R, C(S)R, C(NR)R, included within the definition of “parent heteroaromatic ring C(O)C, C(O)OR, C(S)OR, C(O)NRR, system” are fused ring systems in which one or more of the C(NR)NR'R'', OC(O)R, OC(S)R, OC(O)O, rings are aromatic and one or more of the rings are saturated OC(O)OR, OC(S)OR, NRC(O)R, NRC or unsaturated, such as, for example, benzodioxan, benzo (S)R, NRC(O)O, NRC(O)OR, NRC(S)OR, furan, chromane, chromene, indole, indoline, Xanthene, etc. NRC(O)NR'R'', NRC(NR)R and NRC(NR)N- Typical parent heteroaromatic ring systems include, but are RR, where R is selected from the group consisting of not limited to, arsindole, carbazole, B-carboline, chromane, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, aryla chromene, cinnoline, furan, imidazole, indazole, indole, lkyl, heteroaryl and heteroarylalkyl; each R is indepen indoline, indolizine, isobenzofuran, isochromene, isoindole, dently hydrogen or R'; and each R is independently R or isoindoline, isoquinoline, isothiazole, isoxazole, naphthyri alternatively, the two Rs are taken together with the nitro US 2006/0222601 A1 Oct. 5, 2006

gen atom to which they are bonded form a 5-, 6- or 1996): “Beilstein Handbook of Organic Chemistry,” Beil 7-membered cycloheteroalkyl which may optionally include stein Institute of Organic Chemistry, Frankfurt, Germany; from 1 to 4 of the same or different additional heteroatoms Feiser et al., “Reagents for Organic Synthesis.” Volumes selected from the group consisting of O. N and S. As specific 1-21, Wiley Interscience; Trost et al., “Comprehensive examples, NRR is meant to include —NH —NH Organic Synthesis.” Pergamon Press, 1991; “Theilheimer's alkyl, N-pyrrolidinyl and N-morpholinyl. Synthetic Methods of Organic Chemistry, Volumes 1-45, 0074 Similarly, substituent groups useful for substituting Karger, March 1991; "Advanced Organic Chemistry.” Wiley unsaturated carbon atoms in the specified group or radical Interscience, 1991; Larock “Comprehensive Organic Trans include, but are not limited to, —R', halo, —O— —OR, formations.” VCH Publishers, 1989; Paquette, “Encyclope —SR, -S-, - NRR, trihalomethyl, -CF, —CN, dia of Reagents for Organic Synthesis, 3d Edition, John OCN, -SCN, NO, NO, N, -S(O).R. Wiley & Sons, 1995). Other methods for synthesis of the S(O),O, 13 S(O),OR, OS(O).R, OS(O)OR, compounds described herein and/or starting materials are -P(O)(O), -P(O)(OR)(O), -P(O)(OR)(OR), either described in the art or will be readily apparent to the C(O)R, C(S)R, C(NR)R, C(O)O, C(O- skilled artisan. )OR, C(S)OR, C(O)NR'R'', C(NR)NRR, 0081. A typical synthesis is depicted in Scheme I, OC(O)R, OC(S)R, OC(O)C, OC(O)CR, wherein 2 equivalents of a phenol or phenol equivalent are OC(S)OR, NRC(O)R, NRC(S)R, NR. condensed with 1 equivalent of a phthalic anhydride or C(O)O, NRC(O)OR, NRC(S)OR, NRC(O)N- equivalent under essentially acid -anhydrous conditions. RR, NRC(NR)R and NRC(NR)NR'R'', where R", R and R are as previously defined. 0075 Substituent groups useful for substituting nitrogen atoms in heteroalkyl and cycloheteroalkyl groups include, but are not limited to, R', O , —OR, SR, S, O —NRR, trihalomethyl, -CF, CN, NO, NO,

O Heacid

O C(O)NR'R'', C(NR)NR'R'', OC(O)R, OC(S)R, OC(O)OR, OC(S)OR, NRC(O)R, NRC (S)R, NRC(O)OR, NRC(S)OR, NRC(O)NR R, NRC(NR)R and NRC(NR)NR'R'', where R', R and R are as previously defined. base Heacid (optional) 0.076 Substituent groups from the above lists useful for Substituting other specified groups or atoms will be apparent to those of skill in the art. 0077. The substituents used to substitute a specified group can be further Substituted, typically with one or more of the same or different groups selected from the various groups specified above. 0078 “Sulfamoyl,” by itself or as part of another sub stituent, refers to a radical of the formula —S(O)NR'R'", where R' and R" are each, independently of one another, selected from the group consisting of hydrogen, alkyl and cycloalkyl as defined herein, or alternatively, R' and R", taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered cycloheteroalkyl ring as defined herein, which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O. S and N. Methods of Synthesis 0079 The particular phthaleins described above can be obtained via synthetic methods illustrated below. It should be understood that in R. R. R. R. R. R. Rand R', are as previously defined for structural formula (I) and (Ia). 0082 Generally, the phenol and anhydride are condensed 0080 Starting materials useful for preparing compounds in the presence of an acid under anhydrous conditions. For of the invention and intermediates thereof are commercially example, polyphosphoric acid and Zinc chloride can be available or can be prepared by well-known synthetic meth utilized. The carbon atom at 4-position -position with ods (see, e.g., Harrison et al., “Compendium of Synthetic respect to the aromatic hydroxyl group must not be substi Organic Methods”, Vols. 1-8 (John Wiley and Sons, 1971 tuted as it is necessary for reaction. Polyphosphoric acid acts US 2006/0222601 A1 Oct. 5, 2006 as a condensing agent as well as reaction medium. The diisopropoxyphenol, 2,3-dibutoxyphenol, 2.5- reaction with only polyphosphoric acid afforded tarry prod dibutoxyphenol, 2,6-dibutoxyphenol, 2,3- ucts but when very small amount of zinc chloride was added disobutoxyphenol, 2,5-diisobutoxyphenol, 2,6- to polyphosphoric acid, clean product was isolated. Very disobutoxyphenol, 2,3-dipentoxyphenol, 2.5- Small amount of Zinc chloride was found to increase yield dipentoxyphenol, 2,6-dipentoxyphenol, 2,3- and purity of the product. Polyphosphoric acid can be dihexoxyphenol. 2,5-dihexoxyphenol. 2,6-dihexoxyphenol, replaced with orthophosphoric acid, chlorosulfonic acid, 2,3-diheptoxyphenol. 2,5-diheptoxyphenol. 2,6-diheptox methane Sulfonic acid, trifluoroacetic acid or other acids yphenol. 2,3-dioctoxyphenol. 2,5-dioctoxyphenol. 2,6-dio under anhydrous conditions. Suitable solvents include non ctoxyphenol. 2,3-dinonoxyphenol. 2,5-dinonoxyphenol, protic solvents known in the art Such as tetrahydrofuran, 2,6-dinonoxyphenol. 2,3-didecyloxyphenol. 2,5-didecylox dioxane, methylene chloride, ether, etc. yphenol. 2,6-didecyloxyphenol, 2,3-dichlorophenol, 2.5- 0083. The reaction proceeds with the formation of an dichlorophenol. 2,6-dichlorophenol, 2,3-dibromophenol, isobenzofuranone (Ia), which is then treated with a base 2,5-dibromophenol. 2,6-dibromophenol, 2,3-diiodophenol, under aqueous conditions. The salt can be isolated or the 2,5-diiodophenol. 2,6-diiodophenol, 2,3-difluorophenol, solution can be acidified to produce the protonated phenol/ 2,5-difluorophenol. 2,6-difluorophenol, 2,3-diaminophenol, carboxylic acid. For example, one molar equivalent of Ia 2,5-diaminophenol. 2,6-diaminophenol. 2,3-diacetami was condensed with either two molar equivalent of sodium dophenol. 2,5-diacetamidophenol. 2,6-diacetamidophenol, hydroxide in 85% ethanol or two molar equivalent of 2,3-dicyanophenol. 2,5-dicyanophenol. 2,6-dicyanophenol, Sodium ethoxide in ethanol. The products are generally 2,3-diallylphenol. 2,5-diallylphenol. 2,6-diallylphenol, 2.3- Solids and can be easily purified via filtration, crystallization, divinylphenol. 2,5-divinylphenol. 2,6-divinylphenol, 2.3- and other methods known in the art. diphenylphenol. 2,5-diphenylphenol. 2,6-diphenylphenol, 0084 Suitable phenols include, but are not limited to 2,3-diphenoxyphenol. 2,5-diphenoxyphenol. 2,6-diphenox 2-nitrophenol, 3-nitrophenol, 2-chlorophenol, 3-chlorophe yphenol. 2,3-dicycloproylphenol. 2,5-dicyclopropylphenol, nol, 2-bromophenol, 3-bromophenol, 2-iodophenol, 3-io 2,6-dicyclopropylphenol, 2,3-dicyclobutylphenol. 2,5-dicy dophenol, 2-fluorophenol, 3-fluorophenol, 2-aminophenol, clobutylphenol. 2,6-dicyclobutylphenol. 2,3-dicyclopen 3-aminophenol, 2-acetamidophenol, 3-acetamidophenol, tylphenol. 2,5-dicyclopentylphenol. 2,6-dicyclopentylphe 2-cyanophenol, 3-cyanophenol, 2-methylphenol, 3-meth nol, 2,3-dicyclohexylphenol. 2,5-dicyclohexylphenol. 2,6- ylphenol, 2-ethylphenol, 3-ethylphenol, 2-proylphenol, dicyclohexylphenol, 2,3-dicycloheptylphenol, 2.5- 3-proylphenol, 2-isoproylphenol, 3-isoproylphenol, 2-bu dicycloheptylphenol, 2,6-dicycloheptylphenol, 2,3- tylphenol, 3-butylphenol, 2-isobutylphenol, 3-isobutylphe dicyclooctylphenol, 2,5-dicyclooctylphenol, 2,6- nol, 2-pentylphenol, 3-pentylphenol 2-hexylphenol, 3-hexy dicyclooctylphenol, 2,3-dicyclononylphenol, 2.5- lphenol, 2-heptylphenol, 3-heptylphenol, 2-octylphenol, dicyclononylphenol, 2,6-dicyclononylphenol, 2,3- 3-octylphenol, 2-nonylphenol, 3-nonylphenol, 2-decylphe dicyclodecylphenol, 2,5-dicyclodecylphenol, 2,6- nol, 3-decylphenol, 2-decylphenol, 2-methoxyphenol, dicyclodecylphenol, 2,3,5-trimethylphenol, 2,3,6- 3-methoxyphenol, 2-ethoxyphenol, 3-ethoxyphenol. 2-pro trimethylphenol 2,3,5-triethylphenol, 2.3,6-triethylphenol, poxyphenol, 3-propoxyphenol, 2-isopropoxyphenol, 3-iso 2,3,5-tripropylphenol, 2.3,6-tripropylphenol. 2,3,5-tribu propoxyphenol, 2-butoxyphenol, 3-butoxyphenol, 2-isobu tylphenol, 2.3,6-tributylphenol, 2,3,5-trichlorophenol, 2.3.6- toxyphenol, 3-isobutoxylphenol, 2-allylphenol, trichlorophenol, 2,3,5-tribromophenol, 2.3,6-tribromophe 3-allylphenol, 2-vinylphenol, 3-vinylphenol, 2-phenylphe nol, 2,3,5-triiodophenol, 2.3,6-triiodophenol, 2,3,5- nol, 3-phenylphenol. 2-phenoxyphenol, 3-phenoxyphenol, trifluorophenol, 2.3,6-trifluorophenol, 2,3,5-trivinylphenol, 2-cyclopropylphenol, 3-cyclopropylphenol, 2-cyclobu 2.3,6-trivinylphenol. 2,3,5-triallylphenol, 2.3,6-triallylphe tylphenol, 3-cyclobutylphenol, 2-cyclopentylphenol, 3-cy nol, 2,3,5-triphenylphenol, 2.3,6-triphenylphenol. 2,3,5- clopentylphenol, 2-cyclohexylphenol, 3-cyclohexylphenol, triphenoxyphenol, 2.3,6-triphenoxyphenol. 2,3,5-trimethox 2-cycloheptylphenol, 3-cycloheptylphenol, 2-cyclooc yphenol, 2.3,6-trimethoxyphenol, 2,3,5-triethoxyphenol, tylphenol, 3-cyclooctylphenol, 2-cyclononylphenol, 3-cy 2.3,6-triethoxyphenol. 2,3,5-tripropoxyphenol, 2.3,6-tripro clononylphenol, 2-cyclodecylphenol, 3-cyclodecylphenol, poxyphenol, 2,3,5-tributoxyphenol, 2.3,6-tributoxyphenol, 2,3-dinitrophenol. 2,5-dinitrophenol, 2,6-dinitrophenol, 2.3- 2,3,5-trinitrophenol, 2.3,6-trinitrophenol. 2,3,5-triami dimethylphenol. 2,5-dimethylphenol. 2,6-dimethylphenol, nophenol. 2.3.6-triaminophenol. 2,3,5-triacetamidophenol, 2,3-diethylphenol. 2,5-diethylphenol. 2,6-diethylphenol, 2.3,6-triacetamidophenol. 2,3,5-tricyanophenol, 2.3.6-tricy 2,3-diproplylphenol. 2,5-dipropylphenol. 2,6-dipropylphe anophenol, 3-(N,N-diethylamino)phenol, 2-tert-butyl-5-me nol. 2,3-diisoproplylphenol. 2,5-diisopropylphenol. 2,6-di thylphenol, 2-tert-butyl-6-methylphenol, 3-methyl-2-nitro isopropylphenol, 2,3-dibutylphenol. 2,5-dibutylphenol. 2.6- phenol, 5-methyl-2-nitrophenol, 6-methyl-2-nitrophenol, dibutylphenol, 2,3-diisobutylphenol. 2,5-diisobutylphenol, 3-ethyl-2-nitrophenol, 5-ethyl-2-nitrophenol, 6-ethyl-2-ni 2,6-diisobutylphenol, 2,3-dipentylphenol. 2,5-dipentylphe trophenol, 3-methoxyl-2-nitrophenol, 5-methoxy-2-nitro nol. 2,6-dipentylphenol, 2,3-dihexylphenol. 2,5-dihexylphe phenol, 6-methoxy-2-nitrophenol. 1-naphthaol, 2-naphthaol, nol. 2,6-dihexylphenol. 2,3-diheptylphenol. 2,5-dihep 2-nitro-1-naphthol, 3-nitro-1-naphthol, 5-nitro-1-naphthol, tylphenol. 2,6-diheptylphenol, 2,3-dioctylphenol. 2.5- 6-nitro-1-naphthol, 7-nitro-1-naphthol, 8-nitro-1-naphthol, dioctylphenol. 2,6-dioctylphenol. 2,3-dinonylphenol, 2.5- 2-methyl-1-naphthol, 3-methyl-1-naphthol, 5-methyl-1- dinonylphenol. 2,6-dinonylphenol. 2,3-didecylphenol. 2.5- naphthol, 6-methyl-1-naphthol, 7-methyl-1-naphthol, 8-me didecylphenol. 2,6-didecylphenol. 2,3-dimethoxyphenol, thyl-1-naphthol, 2-methoxy-1-naphthol, 3-methoxy-1-naph 2,5-dimethoxyphenol. 2,6-dimethoxyphenol. 2,3-diethox thol, 5-methoxy-1-naphthol, 6-methoxy-1-naphthol, yphenol. 2,5-diethoxyphenol. 2,6-diethoxyphenol. 2,3- 7-methoxy-1-naphthol, 8-methoxy-1-naphthol, 2-chloro-1- dipropoxyphenol. 2,5-dipropoxyphenol. 2,6-dipropoxyphe naphthol, 3-chloro-1-naphthol, 5-chloro-1-naphthol, nol. 2,3-diisopropoxyphenol. 2,5-diisopropoxyphenol. 2.6- 6-chloro-1-naphthol, 7-chloro-1-naphthol, 8-chloro-1-naph US 2006/0222601 A1 Oct. 5, 2006 thol, 2-bromo-1-naphthol, 3-bromo-1-naphthol, 5-bromo-1- above, R7 and R, for example, form an aromatic, hetero naphthol, 6-bromo-1-naphthol, 7-bromo-1-naphthol, cyclic, or non-aromatic ring. Suitable compounds include 8-bromo-1-naphthol, 2-iodo-1-naphthol, 3-iodo-1-naphthol, naphthols for example. 5-iodo-1-naphthol, 6-iodo-1-naphthol, 7-iodo-1-naphthol, Synthesis of Phenols and Hydrazides 8-iodo-1-naphthol, 2-fluoro-1-naphthol, 3-fluoro-1-naph thol, 5-fluoro-1-naphthol, 6-fluoro-1-naphthol, 7-bromo-1- 0088. The compounds of the invention may be obtained naphthol, 8-fluoro-1-naphthol, 2-cyano-1-naphthol, 3-cy via synthetic methods illustrated below. It should be under ano-1-naphthol, 5-cyano-1-naphthol, 6-cyano-1-naphthol, stood that in R, R. R. R. R. R. R. R. R. R'', R', 7-cyano-1-naphthol, 8-cyano-1-naphthol, 8-hydroxyquinal R", R'' and R'' are as previously defined for structural dine and 2-quinoxalinol. formulae (II), (III), (IIIa) and (IV). 0089 Starting materials useful for preparing compounds 0085. The term “phenol equivalent” is intended to of the invention and intermediates thereof are commercially include those compounds where, as described above, R and available or can be prepared by well-known synthetic meth R. for example, form an aromatic, heterocyclic, or non ods (see, e.g., Harrison et al., “Compendium of Synthetic aromatic ring. Suitable compounds include naphthols for Organic Methods'', Vols. 1-8 (John Wiley and Sons, 1971 example. 1996): “Beilstein Handbook of Organic Chemistry,” Beil 0.086 Suitable phthalic anhydrides include but are not stein Institute of Organic Chemistry, Frankfurt, Germany; limited to phthalic anhydride, 3-nitrophthalic anhydride, Feiser et al., “Reagents for Organic Synthesis.” Volumes 4-nitrophthalic anhydride, 5-nitrophthalic anhydride, 6-ni 1-21, Wiley Interscience; Trost et al., “Comprehensive trophthalic anhydride, 3-chlorophthalic anhydride, 4-chlo Organic Synthesis.” Pergamon Press, 1991; “Theilheimer's rophthalic anhydride, 5-chlorophthalic anhydride, 6-chlo Synthetic Methods of Organic Chemistry, Volumes 1-45, rophthalic anhydride, 3-bromophthalic anhydride, Karger, March 1991; "Advanced Organic Chemistry.” Wiley 4-bromophthalic anhydride, 5-bromophthalic anhydride, Interscience, 1991; Larock “Comprehensive Organic Trans 6-bromophthalic anhydride, 3-iodophthalic anhydride, 4-io formations.” VCH Publishers, 1989; Paquette, “Encyclope dophthalic anhydride, 5-iodophthalic anhydride, 6-iodoph dia of Reagents for Organic Synthesis, 3d Edition, John thalic anhydride, 3-fluorophthalic anhydride, 4-fluo Wiley & Sons, 1995). Other methods for synthesis of the rophthalic anhydride, 5-fluorophthalic anhydride, compounds described herein and/or starting materials are 6-fluorophthalic anhydride, 3-methylphthalic anhydride, either described in the art or will be readily apparent to the 4-methylphthalic anhydride, 5-methylphthalic anhydride, skilled artisan. 6-methylphthalic anhydride, 3-ethylphthalic anhydride, 4-ethylphthalic anhydride, 5-ethylphthalic anhydride, 6-eth 0090. A typical synthesis for substituted phenols is ylphthalic anhydride, 3-methoxyphthalic anhydride, depicted in Scheme II, wherein a phenol is treated with a 4-methoxyphthalic anhydride, 5-methoxyphthalic anhy base to form the phenolic salt. Advantageously, the phenolic dride, 6-methoxyphthalic anhydride, 3-cyanophthalic anhy salts are water soluble, which is useful in the applications dride, 4-cyanophthalic anhydride, 5-cyanophthalic anhy detailed throughout the specification. dride, 6-cyanophthalic anhydride, 3-aminophthalic anhydride, 4-aminophthalic anhydride, 5-aminophthalic anhydride, 6-aminophthalic anhydride, 3-acetamidophthalic Scheme II anhydride, 4-acetamidophthalic anhydride, 5-acetamidoph OH ONa thalic anhydride, 6-acetamidophthalic anhydride, 3,4,5,6- tetrachlorophthalic anhydride, 3,4,5,6-tetrabromophthalic R6 R2 R6 R2 NaOH anhydride, 3,4,5,6-tetraiodophthalic anhydride, 3,4,5,6-tet He rafluorophthalic anhydride, 3,4,5,6-tetranitrophthalic anhy EtOH dride, 3,4,5,6-tetramethylphthalic anhydride, 3,4,5,6-tetra Rs R3 Rs R3 ethylphthalic anhydride, 3,4,5,6-tetramethoxyphthalic anhydride, 3,4,5,6-tetracyanophthalic anhydride, 3,4,5,6-tet R4 R4 raaminophthalic anhydride, 3,4,5,6-tetraacetamidophthalic anhydride, naphthalic anhydride, 2-chloronaphthalic anhy dride, 3-chloronaphthalic anhydride, 4-chloronaphthalic 0091 Generally, the phenol mixed with the base and the anhydride, 5-chloronaphthalic anhydride, 6-chloronaph salt is formed. The solution may be heated to facilitate the thalic anhydride, 7-chloronaphthalic anhydride, 2-bro rate of reaction. monaphthalic anhydride, 3-bromonaphthalic anhydride, 4-bromonaphthalic anhydride, 5-bromonaphthalic anhy 0092 Suitable phenols include, but are not limited to dride, 6-bromonaphthalic anhydride, 7-bromonaphthalic 2-nitrophenol, 3-nitrophenol, 4-nitrophenol, 2-chlorophe anhydride, 2-iodonaphthalic anhydride, 3-iodonaphthalic nol, 3-chlorophenol, 4-chlorophenol, 2-bromophenol, 3-bro anhydride, 4-iodonaphthalic anhydride, 5-iodonaphthalic mophenol, 4-bromophenol, 2-iodophenol, 3-iodophenol, anhydride, 6-iodonaphthalic anhydride, 7-iodonaphthalic 4-iodophenol, 2-aminophenol, 3-aminophenol, 4-aminophe anhydride, 2-fluoronaphthalic anhydride, 3-fluoronaphthalic nol, 2-cyanophenol, 3-cyanophenol, 4-cyanophenol, 2-vi anhydride, 4-fluoronaphthalic anhydride, 5-fluoronaphthalic nylphenol, 3-vinylphenol, 4-vinylphenol, 2,3-dichlorophe anhydride, 6-fluoronaphthalic anhydride, 7-fluoronaphthalic nol, 2,4-dichlorophenol, 2,5-dichlorophenol, 2,6- anhydride, 2-nitronaphthalic anhydride, 3-nitronaphthalic dichlorophenol, 2,3-dibromophenol. 2,4-dibromophenol, anhydride, 4-nitronaphthalic anhydride, 5-nitronaphthalic 2,5-dibromophenol. 2,6-dibromophenol, 2,3-diiodophenol, anhydride, 6-nitronaphthalic anhydride and 7-nitronaph 2,4-diiodophenol. 2,5-diiodophenol. 2,6-diiodophenol, 2.3- diaminophenol. 2,4-diaminophenol. 2,5-diaminophenol, thalic anhydride. 2,6-diaminophenol. 2,3-dicyanophenol. 2,4-dicyanophenol, 0087. The term “phthalic anhydride equivalent” is 2,5-dicyanophenol. 2,6-dicyanophenol. 2,3-divinylphenol, intended to include those compounds where, as described 2,4-divinylphenol. 2,5-divinylphenol. 2,6-divinylphenol, US 2006/0222601 A1 Oct. 5, 2006

2,3-diphenylphenol, 2,3,4-trichlorophenol, 2,3,5-trichlo 0096 Suitable salicylic derivatives include, but not lim rophenol, 2.3,6-trichlorophenol, 2,3,4-tribromophenol, 2.3, ited to Salicylic acid, 3-methylsalicylic acid, 4-methylsali 5-tribromophenol, 2.3,6-tribromophenol. 2,3,4-triiodophe cylic acid, 5-methylsalicylic acid, 6-methylsalicylic acid, nol. 2,3,5-triiodophenol, 2.3,6-triiodophenol, 2,3,4- 3-ethylsalicylic acid, 4-ethylsalicylic acid, 5-ethylsalicylic trivinylphenol, 2,3,5-trivinylphenol, 2.3,6-trivinylphenol, acid, 6-ethylsalicylic acid, 3-propylsalicylic acid, 4-propyl 2,3,4-trinitrophenol. 2,3,5-trinitrophenol, 2.3,6-trinitrophe salicylic acid, 5-propylsalicylic acid, 6-propylsalicylic acid, nol. 2,3,4-triaminophenol. 2,3,5-triaminophenol. 2.3.6-tri aminophenol. 2,3,4-tricyanophenol. 2,3,5-tricyanophenol, 3-isopropylsalicylic acid, 4-isopropylsalicylic acid, 5-iso 2.3,6-tricyanophenol, 3-(N,N-diethylamino)phenol, 3-me propylsalicylic acid, 6-isopropylsalicylic acid, 3-butylsali thyl-2-nitrophenol, 5-methyl-2-nitrophenol, 6-methyl-2-ni cylic acid, 4-butylsalicylic acid, 5-butylsalicylic acid, 6-bu trophenol, 3-ethyl-2-nitrophenol, 5-ethyl-2-nitrophenol, tylsalicylic acid, 3-isobutylsalicylic acid, 4-isobutylsalicylic 6-ethyl-2-nitrophenol, 3-methoxyl-2-nitrophenol, 5-meth acid, 5-isobutylsalicylic acid, 6-isobutylsalicylic acid, oxy-2-nitrophenol, 6-methoxy-2-nitrophenol, 2-nitro-1- 3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-meth naphthol, 3-nitro-1-naphthol, 4-nitro-1-naphthol, 5-nitro-1- oxysalicylic acid, 6-methoxysalicylic acid, 3-ethoxysali naphthol, 6-nitro-1-naphthol, 7-nitro-1-naphthol, 8-nitro-1- cylic acid, 4-ethoxysalicylic acid, 5-ethoxysalicylic acid, naphthol, 2-chloro-1-naphthol, 3-chloro-1-naphthol, 6-ethoxysalicylic acid, 3-propoxysalicylic acid, 4-pro 4-chloro-1-naphthol, 5-chloro-1-naphthol, 6-chloro-1-naph poxysalicylic acid, 5-propoxysalicylic acid, 6-propoxysali thol, 7-chloro-1-naphthol, 8-chloro-1-naphthol, 2-bromo-1- cylic acid, 3-butoxysalicylic acid, 4-butoxysalicylic acid, naphthol, 3-bromo-1-naphthol, 4-bromo-1-naphthol, 5-butoxysalicylic acid, 6-butoxysalicylic acid, 3-nitrosali 5-bromo-1-naphthol, 6-bromo-1-naphthol, 7-bromo-1-naph cylic acid, 4-nitrosalicylic acid, 5-nitrosalicylic acid, 6-nit thol, 8-bromo-1-naphthol, 2-iodo-1-naphthol, 3-iodo-1- rosalicylic acid, 3-chlorosalicylic acid, 4-chlorosalicylic naphthol, 4-iodo-1-naphthol, 5-iodo-1-naphthol, 6-iodo-1- acid, 5-chlorosalicylic acid, 6-chlorosalicylic acid, 3-bromo naphthol, 7-iodo-1-naphthol, 8-iodo-1-naphthol, 2-cyano-1- salicylic acid, 4-bromosalicylic acid, 5-bromosalicylic acid, naphthol, 3-cyano-1-naphthol, 4-cyano-1-naphthol, 6-bromosalicylic acid, 3-iodosalicylic acid, 4-iodosalicylic 5-cyano-1-naphthol, 6-cyano-1-naphthol, 7-cyano-1-naph acid, 5-iodosalicylic acid, 6-iodoosalicylic acid, 3-fluoro thol, 8-cyano-1-naphthol and 8-hydroxyquinaldine. salicylic acid, 4-fluorosalicylic acid, 5-fluorosalicylic acid, 0093. The term “phenol equivalent” is intended to 6-fluorosalicylic acid, 3-aminosalicylic acid, 4-aminosali include those compounds where, as described above, R and cylic acid, 5-aminosalicylic acid, 6-aminosalicylic acid, R. for example, form an aromatic, heterocyclic, or non 3-acetamidosalicylic acid, 4-acetamidosalicylic acid, 5-ac aromatic ring. Suitable compounds include naphthols for etamidosalicylic acid, 6-acetamidosalicylic acid, 3-cy example. anoSalicylic acid, 4-cyanosalicylic acid, 5-cyanosalicylic 0094. A typical synthesis of hydrazines is depicted in acid, 6-cyanosalicylic acid, 3-sulfosalicylic acid, 4-sul Scheme III, where a hydrazine (NH-NH R', wherein R' fosalicylic acid, 5-sulfosalicylic acid, 6-sulfosalicylic acid, can be a hydrogen atom or as described above) and an ester 3,5-dimethylsalicylic acid, 3,5-diethylsalicylic acid, 3.5- are condensed to form the hydrazide. dipropylsalicylic acid, 3,5-dibutylsalicylic acid, 3.5- dimethoxysalicylic acid, 3,5-diethoxysalicylic acid, 3.5- dipropoxysalicylic acid, 3,5-dibutoxysalicylic acid, 3.5- Scheme III dichlorosalicylic acid, 3,5-dibromosalicylic acid, 3.5- diiodosalicylic acid, 3,5-difluorosalicylic acid, 3.5- Rs R9 dinitrosalicylic acid, 3,5-diaminosalicylic acid, 3.5- diacetamidosalicylic acid, 3.5-dicyanosalicylic acid, 3.5- COOEt HNHN R10 disulfosalicylic acid, substituted/unsubstituted alkyl salicylic acid, Substituted/unsubstituted alkoxy salicylic R6 R2 acid, Substituted/unsubstituted aryl Salicylic acid, Substi R12 R11 tuted/unsubstituted cycloalkyl salicylic acid and substituted/ EtOH unsubstituted hetaryl salicylic acid. Rs R3 0097 Suitable hydrazines include but not limited to hydrazine hydrate, 4-nitrophenylhydrazine, 3-nitrophenyl R4 hydrazine, 2-nitrophenylhydrazine, 4-nitrobenzoic Rs Ro hydrazide, 3-nitrobenzoic hydrazide, 2-nitrobenzoic hydrazide, p-toluenesulfonylhydrazide, m-toluenesulfonyl CONHNH R10 hydrazide, o-toluenesulfonyl-hydrazide, 2,4-dinitrophenyl hydrazine (2,4-DNP), 1-naphthoic hydrazide, 2-naphthoic R6 R hydrazide, nicotinic hydrazide, substituted/unsubstituted R12 R11 alkyl hydrazide, substituted/unsubstituted alkoxyhydrazide, substituted/unsubstituted aryl hydrazide, substituted/unsub Rs R3 stituted cycloalkyl hydrazide and substituted/unsubstituted hetaryl hydrazide. R4 0098. In compositions where color is not desired (clear to color), a base is not included in the composition, but is 0.095 Typically the ester and the hydrazine are combined provided, for example) by the surface of the substrate acted in a solvent, such as a protic solvent, e.g., an alcohol. Such upon, i.e., the oral cavity, saliva, etc. as ethanol, and heated, e.g., to reflux. Upon cooling, the hydrazide generally precipitates from Solution and can be 0099 Alternatively, the composition can be basic and collected. highly colored by use of a fugative base or a base that is not US 2006/0222601 A1 Oct. 5, 2006

fugitive in nature, such as a metal hydroxide. The pH of the for an increased amount of time while encouraging them to substrate will then determine whether the color of the utilize enough mechanical scrubbing force to properly brush composition is unchanged upon application, disappears or their teeth. changes color. Therefore, by choice of dye and pH of the composition and pH of the Surface of the Substrate, compo 0104. As used herein, the term “toothpaste' is intended to sitions are provided that can be colored and remain so, can encompass formulations of both the paste and gel form, the change from color to clear, or color to color, or uncolored to two forms being generally identical except that the paste a color. It is the combination of the acid-base dye and the form contains titanium dioxide. The components or ingre Substrate surface that determines how the color change, or dients discussed and enumerated above may be used in both maintenance, is effected. the paste and gel forms of the present invention and, as previously indicated, a white paste containing titanium 0100. In general, the amount of color components incor dioxide may be used as a partition interposed between porated into the oral care composition of the invention may separate layers of toothpaste containing the respective color range from approximately 0.01% to approximately 10% by components. weight. 0105. In an optional embodiment of the invention, the 0101. In general, the oral care compositions of the inven mouthwash may contain a flavoring agent or component, tion contain no foaming agent since any significant amount Such as spearmint or wintergreen, or constituted by encap of such an agent tends to diminish the visibility of the color Sulated or agglomerated flavoring crystals, ingredients or change occurring and thereby render the color change less components known to those in the art and which upon evident or perceptible. If a foaming agent incorporated in the mechanical agitation bring about a time release (5 to 20 oral care composition of the invention, no more than second delayed) flavoring of the mouthwash. The incorpo approximately 0.05% by weight should be present in order ration of Such a time released flavor burst in conjunction to minimize the disadvantageous effect imparted by foaming with the color changing properties of the mouthwash of the agents. Various conventional foaming agents may be used invention advantageously induces children to treat the oral Such as Sodium lauryl Sulfate, sodium N-lauroyl sarcosinate cavity for an increased amount of time while encouraging or cocomonoglyceride Sulfonate may be used in the practice them to utilize enough Swishing force to properly treat their of the invention with the use of sodium lauryl sulfate being throat, oral cavity and teeth. preferred. 0106 As used herein, the term “mouthwash” is intended 0102) The toothpaste of the invention may also contain to encompass aqueous based compositions that are known in other conventional ingredients or components such as gel the art and generally include water, a Surfactant, a flavoring ling agents or binders, polishing agents, vehicles, humec agent, optionally fluoride and optionally, an astringent, Such tants, flavoring agents, Sweeteners, and a fluoride containing as an alcohol. Mouthwashes, including plaque removing compound. Thus, from approximately 0.5 to approximately liquids, typically comprise a waterfalcohol Solution, flavour, 18% by weight of a gelling agent or binder may be used, the humectant, Sweetener, foaming agent, colorant, and option gelling agent being selected from known gelling agents such ally enzymes. as sodium carboxymethyl cellulose, Xanthan gum, polyvinyl pyrrolidone, hydroxyethyl cellulose, polyvinyl alcohol, Irish 0.107 Suitable humectants for use in oral care products moss extract, Sodium alginate and mixtures thereof. From according to the invention include the following compounds approximately 15% to approximately 90% by weight of a and mixtures thereof glycerol, polyol, Sorbitol, polyethyl polishing agent Such as silica gel, silica, Sodium aluminum ene glycols (PEG), propylene glycol, 1,3-propanediol, 1,4- silicate, hydrated alumina, dicalcium phosphate, calcium butanediol, hydrogenated partially hydrolysed polysaccha pyrophosphate, calcium carbonate and mixtures thereof may rides and the like. Humectants are in general present in from be incorporated into the toothpaste of the invention. From 0% to 80% by weight in the mouthwash. approximately 10% to approximately 80% by weight of a humectant such as Sorbitol, maltitol, polyethylene glycol, 0.108 Suitable surfactant include, anionic, cationic, non glycerin and mixtures thereof may be utilized in the practice ionic, amphoteric and/or Zwitterionic Surfactants. These can of the invention. It is highly preferred that the toothpaste of be present at levels of from about 0.01% to about 15%, the invention contain between approximately 0.1 and particularly from about 0.1 to about 13%, more particularly approximately 2% by weight of a fluoride with sodium from about 0.25 to about 10% by weight of the final product. fluoride or stannous fluoride being especially preferred. The 0.109 Examples of anionic, nonionic, cationic and flavoring agents and Sweeteners known to those in the amphoteric Surface-active agents that are Suitable for use in toothpaste art may constitute from approximately 0.1 to the present invention are described in Kirk-Othmer, Ency approximately 10% by weight of the toothpaste, and water clopedia of Chemical Technology. Third Edition, Volume constitutes the most common toothpaste vehicle. 22, pages 347-387, and McCutcheon's Detergents and 0103) In an optional embodiment of the invention, the Emulsifiers, North American Edition, 1983, both of which toothpaste may contain a flavoring agent or component are incorporated herein by reference. constituted by encapsulated or agglomerated flavoring crys 0.110) Surfactants, for example, include fatty alcohol sul tals, ingredients or components known to those in the art and phates, salts of Sulphonated mono-glycerides or fatty acids which upon mechanical agitation bring about a time release having 10 to 20 carbon atoms, fatty acid-albumen conden (5 to 20 second delayed) flavoring of the toothpaste. The sation products, salts of fatty acids amides and taurines incorporation of Such a time released flavor burst in con junction with the color changing properties of the toothpaste and/or salts of fatty acid esters of isethionic acid. of the invention advantageously induces children to brush 0.111 Suitable sweeteners include saccharin. US 2006/0222601 A1 Oct. 5, 2006

0112 Flavours, such as spearmint, wintergreen and the like, are usually present in low amounts, such as from about -continued 0.01% to about 5% by weight, especially from about 0.1% to about 5%. Chemical Component Weight in grams 0113. The following examples illustrate the practice of the invention. Zinc chloride O.OOS 0114. A mouthwash of the invention (in weight % of the Methyl salicylate O.1 final mouthwash composition) can include the following Menthol O.1 ingredients: o-Cresolphthalein O.S Sodium hydroxide O.11 Deionized water 89.535 O-20% Humectant Liquid Germall Plus O.1 O-8% Surfactant O-5% disinfecting cleaners, antimicrobial agents, Sweetners, flavors, preservatives, etc O-20% Ethanol (or other pharmaceutically acceptable alcohol) O.O1-5% acid-base indicator of the invention 0.120. In a beaker, deionized water (50 g) was stirred and O 90% Water heated at 50° C. Pluronic F108 was slowly added and reaction mixture was further stirred at 50° C. for 15 minutes. The mixture was cooled to room temperature followed by MOUTHWASH EXAMPLES addition of Colonial SLS, glycerin, Sodium saccharin, Zinc chloride, methyl salicylate, menthol, o-cresolphthalein, Example 1 Sodium hydroxide, liquid germall plus and remaining deion 0115) ized water. The reaction mixture was further stirred for 2 hours at room temperature. 0121 Color of the solution: Magenta Chemical Component Weight in grams Pluronic F108 O.S 0.122 Color change: Magenta to colorless Colonial SLS 1 Glycerin 8 Example 3 Sodium saccharin O.OS Zinc chloride O.OOS Methyl salicylate O.1 0123) Menthol O.1 Thymolphthalein O.S Sodium hydroxide O.09 Deionized water 89.555 Chemical Component Weight in grams Liquid Germall Plus O.1 Pluronic F108 O.S Colonial SLS 1 Glycerin 8 0116. In a beaker, deionized water (50 g) was stirred and Sodium saccharin O.OS heated at 50° C. Pluronic F108 was slowly added and Zinc chloride O.OOS reaction mixture was further stirred at 50° C. for 15 minutes. Methyl salicylate O.1 Menthol O.1 The mixture was cooled to room temperature followed by 3,3-bis-(4-hydroxy-3-phenylphenyl)- O.S addition of Colonial SLS, glycerin, Sodium saccharin, Zinc 1-(3H)-isobenzofuranone chloride, methyl salicylate, menthol, thymolphthalein, Sodium hydroxide O.08 Sodium hydroxide, liquid germall plus and remaining deion Deionized water 89.56S ized water. The reaction mixture was further stirred for 2 Liquid Germall Plus O.1 hours at room temperature. 0117 Color of the solution: Blue 0.124. In a beaker, deionized water (50 g) was stirred and 0118 Color change: Blue to colorless heated at 50° C. Pluronic F108 was slowly added and reaction mixture was further stirred at 50° C. for 15 minutes. Example 2 The mixture was cooled to room temperature followed by addition of Colonial SLS, glycerin, Sodium saccharin, Zinc 0119) chloride, methyl salicylate, menthol, 3.3-bis-(4-hydroxy-3- phenylphenyl)-1-(3H)-isobenzofuranone, sodium hydrox ide, liquid germall plus and remaining deionized water. The Chemical Component Weight in grams reaction mixture was further stirred for 2 hours at room Pluronic F108 O.S temperature. Colonial SLS 1 Glycerin 8 0.125 Color of the solution: Purple Sodium saccharin O.OS 0.126 Color change: Purple to colorless US 2006/0222601 A1 Oct. 5, 2006

Example 4 Example 6 O127) 0135)

Chemical Component Weight in grams Chemical Component Weight in grams Pluronic F108 O.S Pluronic F108 O.S Colonial SLS 1 Colonial SLS 1 Glycerin 8 Glycerin 8 Sodium saccharin O.OS Sodium saccharin O.OS Zinc chloride O.OOS Zinc chloride O.OOS Methyl salicylate O.1 Methyl salicylate O.1 Menthol O.1 Menthol O.1 3,3-bis-(4-hydroxy-3,5-diisopropylphenyl)- O.S 3,3-bis-(4-hydroxy-3,5-dimethylphenyl)- O.S 1-(3H)-isobenzofuranone 1-(3H)-isobenzofuranone Sodium hydroxide O.08 Sodium hydroxide O.1 Deionized water 89.56S Deionized water 89.545 Liquid Germall Plus O.1 Liquid Germall Plus O.1

0128. In a beaker, deionized water (50 g) was stirred and 0.136. In a beaker, deionized water (50 g) was stirred and heated at 50° C. Pluronic F108 was slowly added and heated at 50° C. Pluronic F108 was slowly added and reaction mixture was further stirred at 50° C. for 15 minutes. reaction mixture was further stirred at 50° C. for 15 minutes. The mixture was cooled to room temperature followed by The mixture was cooled to room temperature followed by addition of Colonial SLS, glycerin, Sodium saccharin, Zinc addition of Colonial SLS, glycerin, Sodium saccharin, Zinc chloride, methyl salicylate, menthol, 3.3-bis-(4-hydroxy-3, chloride, methyl salicylate, menthol, 3.3-bis-(4-hydroxy-3, 5-diisopropylphenyl)-1-(3H)-isobenzofuranone, Sodium 5-dimethylphenyl)-1-(3H)-isobenzofuranone, Sodium hydroxide, liquid germall plus and remaining deionized hydroxide, liquid germall plus and remaining deionized water. The reaction mixture was further stirred for 2 hours at water. The reaction mixture was further stirred for 2 hours at room temperature. room temperature. 0129. Color of the solution: Violet 0.137 Color of the solution: Purple 0130 Color change: Violet to colorless 0.138 Color change: Purple to colorless Example 5 Example 7 0131) 0139)

Chemical Component Weight in grams Chemical Component Weight in grams Pluronic F108 O.S Pluronic F108 O.S Colonial SLS 1 Colonial SLS 1 Glycerin 8 Glycerin 8 Sodium saccharin O.OS Sodium saccharin O.OS Zinc chloride O.OOS Zinc chloride O.OOS Methyl salicylate O.1 Methyl salicylate O.1 Menthol O.1 Menthol O.1 3,3-bis-(4-hydroxy-3,5-dimethoxyphenyl)- O.S 3,3-bis-(4-hydroxy-3,6-dimethylphenyl)- O.S 1-(3H)-isobenzofuranone 1-(3H)-isobenzofuranone Sodium hydroxide O.09 Sodium hydroxide O.1 Deionized water 89.555 Deionized water 89.545 Liquid Germall Plus O.1 Liquid Germall Plus O.1

0132) In a beaker, deionized water (50 g) was stirred and 0140. In a beaker, deionized water (50 g) was stirred and heated at 50° C. Pluronic F108 was slowly added and heated at 50° C. Pluronic F108 was slowly added and reaction mixture was further stirred at 50° C. for 15 minutes. reaction mixture was further stirred at 50° C. for 15 minutes. The mixture was cooled to room temperature followed by The mixture was cooled to room temperature followed by addition of Colonial SLS, glycerin, Sodium saccharin, Zinc addition of Colonial SLS, glycerin, Sodium saccharin, Zinc chloride, methyl salicylate, menthol, 3.3-bis-(4-hydroxy-3, chloride, methyl salicylate, menthol, 3.3-bis-(4-hydroxy-3, 5-dimethoxyphenyl)-1-(3H)-isobenzofuranone, Sodium 6-dimethylphenyl)-1-(3H)-isobenzofuranone, Sodium hydroxide, liquid germall plus and remaining deionized hydroxide, liquid germall plus and remaining deionized water. The reaction mixture was further stirred for 2 hours at water. The reaction mixture was further stirred for 2 hours at room temperature. room temperature. 0133) Color of the solution: Teal 0141 Color of the solution: Blue 0134 Color change: Teal to colorless 0.142 Color change: Blue to colorless US 2006/0222601 A1 Oct. 5, 2006

Example 8 Example 10 0143) 0151)

Chemical Component Weight in grams Chemical Component Weight in grams Pluronic F108 O.S Pluronic F108 O.S Colonial SLS 1 Colonial SLS 1 Glycerin 8 Glycerin 8 Sodium saccharin O.OS Sodium saccharin O.OS Zinc chloride O.OOS Zinc chloride O.OOS Methyl salicylate O.1 Methyl salicylate O.1 Menthol O.1 Menthol O.1 3,3-bis-(4-hydroxy-3-ethylphenyl)- O.S 3,3-bis-(4-hydroxy-3-methoxyphenyl)- O.S 1-(3H)-isobenzofuranone 1-(3H)-isobenzofuranone Sodium hydroxide O.1 Sodium hydroxide O.1 Deionized water 89.545 Deionized water 89.545 Liquid Germall Plus O.1 Liquid Germall Plus O.1

0144. In a beaker, deionized water (50 g) was stirred and 0152. In a beaker, deionized water (50 g) was stirred and heated at 50° C. Pluronic F108 was slowly added and heated at 50° C. Pluronic F108 was slowly added and reaction mixture was further stirred at 50° C. for 15 minutes. reaction mixture was further stirred at 50° C. for 15 minutes. The mixture was cooled to room temperature followed by The mixture was cooled to room temperature followed by addition of Colonial SLS, glycerin, Sodium saccharin, Zinc addition of Colonial SLS, glycerin, Sodium saccharin, Zinc chloride, methyl salicylate, menthol, 3.3-bis-(4-hydroxy-3- chloride, methyl salicylate, menthol, 3.3-bis-(4-hydroxy-3- ethylphenyl)-1-(3H)-isobenzofuranone, sodium hydroxide, methoxyphenyl)-1-(3H)-isobenzofuranone, sodium hydrox liquid germall plus and remaining deionized water. The ide, liquid germall plus and remaining deionized water. The reaction mixture was further stirred for 2 hours at room reaction mixture was further stirred for 2 hours at room temperature. temperature. 0145 Color of the solution: Magenta 0153 Color of the solution: Blue 0146 Color change: Magenta to colorless 0154 Color change: Blue to colorless Example 9 Example 11 0147) O155)

Chemical Component Weight in grams Chemical Component Weight in grams Pluronic F108 O.S Pluronic F108 O.S Colonial SLS 1 Colonial SLS 1 Glycerin 8 Glycerin 8 Sodium saccharin O.OS Sodium saccharin O.OS Zinc chloride O.OOS Zinc chloride O.OOS Methyl salicylate O.1 Methyl salicylate O.1 Menthol O.1 Menthol O.1 3,3-bis-(4-hydroxy-3-isopropylphenyl)- O.S 3,3-bis-(4-hydroxy-2,3,5-trimethylphenyl)- O.S 1-(3H)-isobenzofuranone 1-(3H)-isobenzofuranone Sodium hydroxide O.09 Sodium hydroxide O.09 Deionized water 89.555 Deionized water 89.555 Liquid Germall Plus O.1 Liquid Germall Plus O.1

0148. In a beaker, deionized water (50 g) was stirred and 0.156. In a beaker, deionized water (50 g) was stirred and heated at 50° C. Pluronic F108 was slowly added and heated at 50° C. Pluronic F108 was slowly added and reaction mixture was further stirred at 50° C. for 15 minutes. reaction mixture was further stirred at 50° C. for 15 minutes. The mixture was cooled to room temperature followed by The mixture was cooled to room temperature followed by addition of Colonial SLS, glycerin, Sodium saccharin, Zinc addition of Colonial SLS, glycerin, Sodium saccharin, Zinc chloride, methyl salicylate, menthol, 3.3-bis-(4-hydroxy-3- chloride, methyl salicylate, menthol, 3.3-bis-(4-hydroxy-2, isopropylphenyl)-1-(3H)-isobenzofuranone, Sodium 3,5-trimethylphenyl)-1-(3H)-isobenzofuranone, Sodium hydroxide, liquid germall plus and remaining deionized hydroxide, liquid germall plus and remaining deionized water. The reaction mixture was further stirred for 2 hours at water. The reaction mixture was further stirred for 2 hours at room temperature. room temperature. 0149 Color of the solution: Pink O157 Color of the solution: Teal 0150 Color change: Pink to colorless 0158 Color change: Teal to colorless US 2006/0222601 A1 Oct. 5, 2006

Example 12 Example 14 0159) 0167)

Chemical Component Weight in grams Chemical Component Weight in grams Pluronic F108 O.S Pluronic F108 O.S Colonial SLS 1 Colonial SLS 1 Glycerin 8 Glycerin 8 Sodium saccharin O.OS Sodium saccharin O.OS Zinc chloride O.OOS Zinc chloride O.OOS Methyl salicylate O.1 Methyl salicylate O.1 Menthol O.1 Menthol O.1 Bromo-thymolphthalein O.S 3,3-bis-(4-hydroxy-3-sec-butylphenyl)- O.S Sodium hydroxide O.08 1-(3H)-isobenzofuranone Deionized water 89.56S Sodium hydroxide O.08 Deionized water 89.56S Liquid Germall Plus O.1 Liquid Germall Plus O.1

0160 In a beaker, deionized water (50 g) was stirred and 0.168. In a beaker, deionized water (50 g) was stirred and heated at 50° C. Pluronic F108 was slowly added and heated at 50° C. Pluronic F108 was slowly added and reaction mixture was further stirred at 50° C. for 15 minutes. reaction mixture was further stirred at 50° C. for 15 minutes. The mixture was cooled to room temperature followed by The mixture was cooled to room temperature followed by addition of Colonial SLS, glycerin, Sodium saccharin, Zinc addition of Colonial SLS, glycerin, Sodium saccharin, Zinc chloride, methyl salicylate, menthol, 3.3-bis-(4-hydroxy-3- chloride, methyl salicylate, menthol, bromo-thymolphtha sec-butylphenyl)-1-(3H)-isobenzofuranone, sodium hydrox lein, Sodium hydroxide, liquid germall plus and remaining ide, liquid germall plus and remaining deionized water. The deionized water. The reaction mixture was further stirred for reaction mixture was further stirred for 2 hours at room 2 hours at room temperature. temperature. 0161 Color of the solution: Teal 0169 Color of the solution: Pink 0162 Color change: Teal to colorless 0170 Color change: Pink to colorless Example 13 Example 15 0163) 0171

Chemical Component Weight in grams Chemical Component Weight in grams Pluronic F108 O.S Pluronic F108 O.S Colonial SLS 1 Colonial SLS 1 Glycerin 8 Glycerin 8 Sodium saccharin O.OS Sodium saccharin O.OS Zinc chloride O.OOS Zinc chloride O.OOS Methyl salicylate O.1 Methyl salicylate O.1 Menthol O.1 Menthol O.1 3,3-bis-(4-hydroxy-3-nitrophenyl)- O.S Bromo-o-cresolphthalein O.S 1-(3H)-isobenzofuranone Sodium hydroxide O.1 Sodium hydroxide O.08 Deionized water 89.545 Deionized water 89.56S Liquid Germall Plus O.1 Liquid Germall Plus O.1

0164. In a beaker, deionized water (50 g) was stirred and 0.172. In a beaker, deionized water (50 g) was stirred and heated at 50° C. Pluronic F108 was slowly added and heated at 50° C. Pluronic F108 was slowly added and reaction mixture was further stirred at 50° C. for 15 minutes. reaction mixture was further stirred at 50° C. for 15 minutes. The mixture was cooled to room temperature followed by The mixture was cooled to room temperature followed by addition of Colonial SLS, glycerin, Sodium saccharin, Zinc addition of Colonial SLS, glycerin, Sodium saccharin, Zinc chloride, methyl salicylate, menthol, 3.3-bis-(4-hydroxy-3- chloride, methyl salicylate, menthol, bromo-o-cresolphtha nitrophenyl)-1-(3H)-isobenzofuranone, sodium hydroxide, lein, Sodium hydroxide, liquid germall plus and remaining liquid germall plus and remaining deionized water. The deionized water. The reaction mixture was further stirred for reaction mixture was further stirred for 2 hours at room 2 hours at room temperature. temperature. 0165 Color of the solution: Purple 0173 Color of the solution: Yellow 0166 Color change: Purple to colorless 0.174 Color change: Yellow to colorless US 2006/0222601 A1 Oct. 5, 2006

Example 16 0185. The mouth wash can be in non-diluted form (i.e. 0175) must be diluted before use). TOOTHPASTE EXAMPLES 0186 A toothpaste of the invention (in weight % of the Chemical Component Weight in grams final toothpaste composition) can include the following Pluronic F108 O.S ingredients: Colonial SLS 1 Glycerin 8 Sodium saccharin O.OS Zinc chloride O.OOS O-20% Humectant Methyl salicylate O.1 O-8% Surfactant (Gelling agent or binder) Menthol O.1 O- 40% Polishing agent m-Nitrophenol O.S O 70% Thickners viscosifiers Sodium hydroxide O.08 O-5% optional ingredients, i.e., sodium fluoride, enzymes, Deionized water 89.56S disinfecting cleaners, antimicrobial agents, Sweetners, Liquid Germall Plus O.1 flavors, gums, preservatives etc. O-20% Ethanol (or other pharmaceutically acceptable alcohol) O.O1-5% acid-base indicator of the invention 0176). In a beaker, deionized water (50 g) was stirred and O- 40% Water heated at 50° C. Pluronic F108 was slowly added and reaction mixture was further stirred at 50° C. for 15 minutes. The mixture was cooled to room temperature followed by Example 1 addition of Colonial SLS, glycerin, Sodium saccharin, Zinc chloride, methyl salicylate, menthol, m-nitrophenol, Sodium 0187) hydroxide, liquid germall plus and remaining deionized water. The reaction mixture was further stirred for 2 hours at room temperature. Chemical Component Weight in grams 0177 Color of the solution: Golden yellow Pluronic F127 O.S 0178 Color change: Golden yellow to colorless Aerosil 200 O.1 Methocel A4M (2% solution) 62.12 Example 17 Colonial SLS 1 Glycerin 10 0179 Sodium saccharin O.O7 Menthol O.2 Sodium fluoride 0.4 Thymolphthalein O.S Chemical Component Weight in grams Sodium hydroxide O.09 Deionized water 25 Scope Mouthwash 50 Liquid Germall Plus O.O2 Dye O.S Sodium hydroxide 2 equivalent Scope Mouthwash: Ingredients include water, alcohol, glycerin, flavor, 0188 In a beaker, deionized water was stirred and heated polysorbate 80, Sodium saccharin, Sodium benzoate, cetyl pyridinium chlo at 40° C. Pluronic F127 and Aerosil 200 were slowly added ride benzoid acid, Blue 1. and reaction mixture was further stirred at 40° C. for 20 Dye: All the above dyes were used. minutes. The mixture was cooled to room temperature followed by addition of Colonial SLS, glycerin, sodium 0180. In a beaker containing Scope mouthwash was saccharin, menthol, Sodium fluoride, thymolphthalein, added dye and sodium hydroxide. The reaction mixture was sodium hydroxide, Methocel A4M and liquid germall plus. further stirred for 2 hours at room temperature. The reaction mixture was further stirred for 2 hours at room 0181 Test procedure model: A solution of citric acid was temperature. prepared by adding 0.050 g of citric acid to 5 mL of water. The solution was stirred until the citric acid was dissolved. 0189 Color of the solution: Blue A few drops of the solution were added to the palm of a 0.190 Color change: Blue to colorless hand, rubbed over the hand and placed over a 25 mL container with the 10 mL of the above-prepared solution. Example 2 The mouthwash solution was shaken so that the mouthwash 0191) solution was contacted with the wetted palm. 0182. The color remained for approximately 30 seconds during shaking and completely faded in about 1 minute. Chemical Component Weight in grams 0183) Similarly, LISTERINE, CEPACOL or CREST Pluronic F127 O.S mouthwash compositions can be prepared with indicator Aerosil 200 O.1 dyes of the invention. Methocel A4M (2% solution) 62.12 Colonial SLS 1 0184 The mouthwash composition may be buffered with Glycerin 10 an appropriate buffer e.g. sodium citrate or phosphate in the Sodium saccharin O.O7 pH-range 6-8.5. US 2006/0222601 A1 Oct. 5, 2006 18

Example 4 -continued 0.199) Chemical Component Weight in grams Chemical Component Weight in grams Menthol O.2 Sodium fluoride 0.4 Pluronic F127 O.S Aerosil 200 O.1 o-Cresolphthalein O.S Methocel A4M (2% solution) 62.12 Sodium hydroxide O.11 Colonial SLS 1 Glycerin 10 Deionized water 24.98 Sodium saccharin O.O7 Liquid Germall Plus O.O2 Menthol O.2 Sodium fluoride 0.4 3,3-bis-(4-hydroxy-3,5-diisopropylphenyl)- O.S 1-(3H)-isobenzofuranone Sodium hydroxide O.08 0192 In a beaker, deionized water was stirred and heated Deionized water 2SO1 at 40° C. Pluronic F127 and Aerosil 200 were slowly added Liquid Germall Plus O.O2 and reaction mixture was further stirred at 40° C. for 20 minutes. The mixture was cooled to room temperature 0200. In a beaker, deionized water was stirred and heated followed by addition of Colonial SLS, glycerin, sodium at 40° C. Pluronic F127 and Aerosil 200 were slowly added saccharin, menthol, Sodium fluoride, o-cresolphthalein, and reaction mixture was further stirred at 40° C. for 20 sodium hydroxide, Methocel A4M and liquid germall plus. minutes. The mixture was cooled to room temperature The reaction mixture was further stirred for 2 hours at room followed by addition of Colonial SLS, glycerin, sodium temperature. saccharin, menthol, sodium fluoride, 3.3-bis-(4-hydroxy-3, 5-diisopropylphenyl)-1-(3H)-isobenzofuranone, Sodium 0193 Color of the solution: Magenta hydroxide, Methocel A4M and liquid germall plus. The reaction mixture was further stirred for 2 hours at room 0194 Color change: Magenta to colorless temperature. Example 3 0201 Color of the solution: Violet 0202 Color change: Violet to colorless 0195 Example 5 0203) Chemical Component Weight in grams Pluronic F127 O.S Aerosil 200 O.1 Chemical Component Weight in grams Methocel A4M (2% solution) 62.12 Pluronic F127 O.S Colonial SLS 1 Aerosil 200 O.1 Glycerin 10 Methocel A4M (2% solution) 62.12 Sodium saccharin O.O7 Colonial SLS 1 Menthol O.2 Glycerin 10 Sodium fluoride 0.4 Sodium saccharin O.O7 3,3-bis-(4-hydroxy-3-phenylphenyl)- O.S Menthol O.2 1-(3H)-isobenzofuranone Sodium fluoride 0.4 Sodium hydroxide O.08 3,3-bis-(4-hydroxy-3,5-dimethoxyphenyl)- O.S 1-(3H)-isobenzofuranone Deionized water 2SO1 Sodium hydroxide O.09 Liquid Germall Plus O.O2 Deionized water 25 Liquid Germall Plus O.O2 0196. In a beaker, deionized water was stirred and heated 0204. In a beaker, deionized water was stirred and heated at 40° C. Pluronic F127 and Aerosil 200 were slowly added at 40° C. Pluronic F127 and Aerosil 200 were slowly added and reaction mixture was further stirred at 40° C. for 20 and reaction mixture was further stirred at 40° C. for 20 minutes. The mixture was cooled to room temperature minutes. The mixture was cooled to room temperature followed by addition of Colonial SLS, glycerin, sodium followed by addition of Colonial SLS, glycerin, sodium saccharin, menthol, sodium fluoride, 3.3-bis-(4-hydroxy-3- saccharin, menthol, sodium fluoride, 3.3-bis-(4-hydroxy-3, phenylphenyl)-1-(3H)-isobenzofuranone, sodium hydrox 5-dimethoxyphenyl)-1-(3H)-isobenzofuranone, Sodium ide, Methocel A4M and liquid germall plus. The reaction hydroxide, Methocel A4M and liquid germall plus. The mixture was further stirred for 2 hours at room temperature. reaction mixture was further stirred for 2 hours at room temperature. 0197) Color of the solution: Purple 0205 Color of the solution: Teal 0198 Color change: Purple to colorless 0206 Color change: Teal to colorless US 2006/0222601 A1 Oct. 5, 2006 19

Example 6 Example 8 0207 0215)

Chemical Component Weight in grams Chemical Component Weight in grams Pluronic F127 O.S Pluronic F127 O.S Aerosil 200 O.1 Aerosil 200 O.1 Methocel A4M (2% solution) 62.12 Methocel A4M (2% solution) 62.12 Colonial SLS 1 Colonial SLS 1 Glycerin 10 Glycerin 10 Sodium saccharin O.O7 Sodium saccharin O.O7 Menthol O.2 Menthol O.2 Sodium fluoride 0.4 Sodium fluoride 0.4 3,3-bis-(4-hydroxy-3,5-dimethylphenyl)- O.S 3,3-bis-(4-hydroxy-3-ethylphenyl)- O.S 1-(3H)-isobenzofuranone 1-(3H)-isobenzofuranone Sodium hydroxide O.1 Sodium hydroxide O.1 Deionized water 24.99 Deionized water 24.99 Liquid Germall Plus O.O2 Liquid Germall Plus O.O2

0208. In a beaker, deionized water was stirred and heated 0216) In a beaker, deionized water was stirred and heated at 40° C. Pluronic F127 and Aerosil 200 were slowly added at 40° C. Pluronic F127 and Aerosil 200 were slowly added and reaction mixture was further stirred at 40° C. for 20 and reaction mixture was further stirred at 40° C. for 20 minutes. The mixture was cooled to room temperature minutes. The mixture was cooled to room temperature followed by addition of Colonial SLS, glycerin, sodium followed by addition of Colonial SLS, glycerin, sodium saccharin, menthol, sodium fluoride, 3.3-bis-(4-hydroxy-3, saccharin, menthol, sodium fluoride, 3.3-bis-(4-hydroxy-3- 5-dimethylphenyl)-1-(3H)-isobenzofuranone, Sodium ethylphenyl)-1-(3H)-isobenzofuranone, sodium hydroxide, hydroxide, Methocel A4M and liquid germall plus. The Methocel A4M and liquid germall plus. The reaction mix reaction mixture was further stirred for 2 hours at room ture was further stirred for 2 hours at room temperature. temperature. 0217 Color of the solution: Magenta 0209 Color of the solution: Purple 0210 Color change: Purple to colorless 0218 Color change: Magenta to colorless Example 7 Example 9 0211 0219)

Chemical Component Weight in grams Chemical Component Weight in grams Pluronic F127 O.S Pluronic F127 O.S Aerosil 200 O.1 Aerosil 200 O.1 Methocel A4M (2% solution) 62.12 Methocel A4M (2% solution) 62.12 Colonial SLS 1 Colonial SLS 1 Glycerin 10 Glycerin 10 Sodium saccharin O.O7 Sodium saccharin O.O7 Menthol O.2 Menthol O.2 Sodium fluoride 0.4 Sodium fluoride 0.4 3,3-bis-(4-hydroxy-3,6-dimethylphenyl)- O.S 3,3-bis-(4-hydroxy-3-isopropylphenyl)- O.S 1-(3H)-isobenzofuranone 1-(3H)-isobenzofuranone Sodium hydroxide O.1 Sodium hydroxide O.09 Deionized water 24.99 Deionized water 25 Liquid Germall Plus O.O2 Liquid Germall Plus O.O2

0212. In a beaker, deionized water was stirred and heated 0220. In a beaker, deionized water was stirred and heated at 40° C. Pluronic F127 and Aerosil 200 were slowly added at 40° C. Pluronic F127 and Aerosil 200 were slowly added and reaction mixture was further stirred at 40° C. for 20 and reaction mixture was further stirred at 40° C. for 20 minutes. The mixture was cooled to room temperature minutes. The mixture was cooled to room temperature followed by addition of Colonial SLS, glycerin, sodium followed by addition of Colonial SLS, glycerin, sodium saccharin, menthol, sodium fluoride, 3.3-bis-(4-hydroxy-3, saccharin, menthol, sodium fluoride, 3.3-bis-(4-hydroxy-3- 6-dimethylphenyl)-1-(3H)-isobenzofuranone, Sodium isopropylphenyl)-1-(3H)-isobenzofuranone, Sodium hydroxide, Methocel A4M and liquid germall plus. The hydroxide, Methocel A4M and liquid germall plus. The reaction mixture was further stirred for 2 hours at room reaction mixture was further stirred for 2 hours at room temperature. temperature. 0213 Color of the solution: Blue 0221) Color of the solution: Pink 0214 Color change: Blue to colorless 0222 Color change: Pink to colorless US 2006/0222601 A1 Oct. 5, 2006 20

Example 10 Example 12 0223) 0231

Chemical Component Weight in grams Chemical Component Weight in grams Pluronic F127 O.S Pluronic F127 O.S Aerosil 200 O.1 Aerosil 200 O.1 Methocel A4M (2% solution) 62.12 Methocel A4M (2% solution) 62.12 Colonial SLS 1 Colonial SLS 1 Glycerin 10 Glycerin 10 Sodium saccharin O.O7 Sodium saccharin O.O7 Menthol O.2 Menthol O.2 Sodium fluoride 0.4 Sodium fluoride 0.4 3,3-bis-(4-hydroxy-3-methoxyphenyl)- O.S Bromo-thymolphthalein O.S 1-(3H)-isobenzofuranone Sodium hydroxide O.08 Sodium hydroxide O.1 Deionized water 2SO1 Deionized water 24.99 Liquid Germall Plus O.O2 Liquid Germall Plus O.O2

0224. In a beaker, deionized water was stirred and heated 0232. In a beaker, deionized water was stirred and heated at 40° C. Pluronic F127 and Aerosil 200 were slowly added at 40° C. Pluronic F127 and Aerosil 200 were slowly added and reaction mixture was further stirred at 40° C. for 20 and reaction mixture was further stirred at 40° C. for 20 minutes. The mixture was cooled to room temperature minutes. The mixture was cooled to room temperature followed by addition of Colonial SLS, glycerin, sodium followed by addition of Colonial SLS, glycerin, sodium saccharin, menthol, sodium fluoride, 3.3-bis-(4-hydroxy-3- saccharin, menthol, Sodium fluoride, bromo-thymolphtha methoxyphenyl)-1-(3H)-isobenzofuranone, sodium hydrox lein, sodium hydroxide, Methocel A4M and liquid germall ide, Methocel A4M and liquid germall plus. The reaction plus. The reaction mixture was further stirred for 2 hours at mixture was further stirred for 2 hours at room temperature. room temperature. 0225 Color of the solution: Blue 0233 Color of the solution: Teal 0226 Color change: Blue to colorless 0234 Color change: Teal to colorless Example 11 Example 13 0227 0235)

Chemical Component Weight in grams Chemical Component Weight in grams Pluronic F127 O.S Aerosil 200 O.1 Pluronic F127 O.S Methocel A4M (2% solution) 62.12 Aerosil 200 O.1 Colonial SLS 1 Methocel A4M (2% solution) 62.12 Glycerin 10 Colonial SLS 1 Sodium saccharin O.O7 Glycerin 10 Menthol O.2 Sodium saccharin O.O7 Sodium fluoride 0.4 Menthol O.2 3,3-bis-(4-hydroxy-2,3,5-trimethylphenyl)- O.S Sodium fluoride 0.4 1-(3H)-isobenzofuranone Bromo-o-cresolphthalein O.S Sodium hydroxide O.09 Sodium hydroxide O.1 Deionized water 25 Deionized water 24.99 Liquid Germall Plus O.O2 Liquid Germall Plus O.O2

0228. In a beaker, deionized water was stirred and heated at 40° C. Pluronic F127 and Aerosil 200 were slowly added 0236. In a beaker, deionized water was stirred and heated and reaction mixture was further stirred at 40° C. for 20 at 40° C. Pluronic F127 and Aerosil 200 were slowly added minutes. The mixture was cooled to room temperature and reaction mixture was further stirred at 40° C. for 20 followed by addition of Colonial SLS, glycerin, sodium minutes. The mixture was cooled to room temperature saccharin, menthol, Sodium fluoride, 3.3-bis-(4-hydroxy-2, followed by addition of Colonial SLS, glycerin, sodium 3,5-trimethylphenyl)-1-(3H)-isobenzofuranone, Sodium saccharin, menthol, Sodium fluoride, bromo-o-cresolphtha hydroxide, Methocel A4M and liquid germall plus. The lein, sodium hydroxide, Methocel A4M and liquid germall reaction mixture was further stirred for 2 hours at room plus. The reaction mixture was further stirred for 2 hours at temperature. room temperature. 0229 Color of the solution: Teal 0237 Color of the solution: Purple 0230 Color change: Teal to colorless 0238 Color change: Purple to colorless US 2006/0222601 A1 Oct. 5, 2006 21

Example 14 Example 16 0239) 0247

Chemical Component Weight in grams Chemical Component Weight in grams Pluronic F127 O.S Pluronic F127 O.S Aerosil 200 O.1 Aerosil 200 O.1 Methocel A4M (2% solution) 62.12 Methocel A4M (2% solution) 62.12 Colonial SLS 1 Colonial SLS 1 Glycerin 10 Glycerin 10 Sodium saccharin O.O7 Sodium saccharin O.O7 Menthol O.2 Menthol O.2 Sodium fluoride 0.4 Sodium fluoride 0.4 3,3-bis-(4-hydroxy-3-sec-butylphenyl)- O.S m-Nitrophenol O.S 1-(3H)-isobenzofuranone Sodium hydroxide O.08 Sodium hydroxide O.08 Deionized water 2SO1 Deionized water 2SO1 Liquid Germall Plus O.O2 Liquid Germall Plus O.O2 0248. In a beaker, deionized water was stirred and heated 0240. In a beaker, deionized water was stirred and heated at 400C. Pluronic F 127 and Aerosil 200 were slowly added at 40° C. Pluronic F127 and Aerosil 200 were slowly added and reaction mixture was further stirred at 40° C. for 20 and reaction mixture was further stirred at 40° C. for 20 minutes. The mixture was cooled to room temperature minutes. The mixture was cooled to room temperature followed by addition of Colonial SLS, glycerin, sodium followed by addition of Colonial SLS, glycerin, sodium saccharin, menthol, Sodium fluoride, m-nitrophenol, Sodium saccharin, menthol, sodium fluoride, 3.3-bis-(4-hydroxy-3- hydroxide, Methocel A4M and liquid germall plus. The sec-butylphenyl)-1-(3H)-isobenzofuranone, sodium hydrox reaction mixture was further stirred for 2 hours at room ide, Methocel A4M and liquid germall plus. The reaction temperature. mixture was further stirred for 2 hours at room temperature. 0249 Color of the solution: Golden yellow 0241 Color of the solution: Pink 0250 Color change: Golden yellow to colorless 0242 Color change: Pink to colorless Example 17 Example 15 0251) 0243)

Chemical Component Weight in grams Chemical Component Weight in grams Commercial Toothpaste a.be 25 Pluronic F127 O.S Dyeb O.25 Aerosil 200 O.1 Sodium hydroxide 2 equivalent Methocel A4M (2% solution) 62.12 Colonial SLS 1 Commercial Toothpaste" include but not limited to Colgate and Crest tooth Glycerin 10 paste Sodium saccharin O.O7 Commercial Toothpaste"Colgate ingredients include sodium monofluoro Menthol O.2 phosphate, dicalcium phosphate dehydrate, water, glycerin, Sodium lauryl Sodium fluoride 0.4 Sulfate, cellulose gum, flavor, tetrasodium pyrophosphate, sodium saccha 3,3-bis-(4-hydroxy-3-nitrophenyl)- O.S ill. 1-(3H)-isobenzofuranone Commercial Toothpaste Crest ingredients include sodium fluoride, water, Sodium hydroxide O.08 hydrated silica, Sorbitol, glycerin, tetrapotassium pyrophosphate, PEG-6, Deionized water 2SO1 disodium pyrophosphate, tetrasodium pyrophosphate, flavor, sodium lauryl Liquid Germall Plus O.O2 Sulfate, Xanthum gum, Sodium saccharin, carbomer 956, polysorbate 80, Sodium benzoate, cetyl pyridinium chloride, benzoid acid, domiphen bro mide, titanium dioxide, Blue 1, Yellow 5. Dye': All the above dyes were used. 0244. In a beaker, deionized water was stirred and heated at 40° C. Pluronic F127 and Aerosil 200 were slowly added 0252) In a beaker containing commercial toothpaste was and reaction mixture was further stirred at 40° C. for 20 added dye and sodium hydroxide. The reaction mixture was minutes. The mixture was cooled to room temperature further stirred for 2 hours at room temperature. followed by addition of Colonial SLS, glycerin, sodium saccharin, menthol, sodium fluoride, 3.3-bis-(4-hydroxy-3- Test Procedure: nitrophenyl)-1-(3H)-isobenzofuranone, sodium hydroxide, 0253 Colored toothpaste from any of the above examples Methocel A4M and liquid germall plus. The reaction mix was taken on a toothbrush. Artificial teeth were then brushed ture was further stirred for 2 hours at room temperature. with the toothbrush containing toothpaste from the above examples. Water was added couple of times during the 0245 Color of the solution: Yellow brushing. The respective color disappears in 30 seconds to 1 0246 Color change: Yellow to colorless minute US 2006/0222601 A1 Oct. 5, 2006 22

Synthesis of Acid-base Indicators: ride (0.01M), was stirred and heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and Example 1 added to ice-water mixture when the product precipitated. Synthesis of 3.3-bis-(4-hydroxy-3-isopropylphenyl)- The product was filtered, thoroughly washed with water and dried. Recrystallization from ethanol with charcoal treat 1-(3H)-isobenzofuranone ment furnished pure 3.3-bis-(4-hydroxy-2-nitrophenyl)-1- 0254. A mixture of 2-isopropylphenol (0.2M), phthalic (3H)-isobenzofuranone in 81% yield. anhydride (0.1M), polyphosphoric acid (0.25M), and Zinc chloride (0.01M), was stirred and heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature HO OH and added to ice-water mixture when the product precipi tated. The product was filtered, thoroughly washed with water and dried. Recrystallization from ethanol with char O coal treatment furnished pure 3.3-bis-(4-hydroxy-3-isopro NO pylphenyl)-1-(3H)-isobenzofuranone in 96% yield. NO O

HO OH

O Example 4 Synthesis of 3,3-bis-(4-hydroxy-3-nitrophenyl)-1- Crs (3H)-isobenzofuranone 0257. A mixture of 2-nitrophenol (0.2M), phthalic anhy dride (0.1M), polyphosphoric acid (0.25M), and zinc chlo Example2 ride (0.01M), was stirred and heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and Synthesis of 3,3-bis-(4-hydroxy-3,5-diisopropylphe added to ice-water mixture when the product precipitated. nyl)-1-(3H)-isobenzofuranone The product was filtered, thoroughly washed with water and 0255. A mixture of 2,6-diisopropylphenol (0.2M). dried. Recrystallization from ethanol with charcoal treat phthalic anhydride (0.1M), polyphosphoric acid (0.25M), ment furnished pure 3.3-bis-(4-hydroxy-3-nitrophenyl)-1- and Zinc chloride (0.01M), was stirred and heated at 100° C. (3H)-isobenzofuranone in 89% yield. for 3 hours. The reaction mixture was cooled to room temperature and added to ice-water mixture when the prod uct precipitated. The product was filtered, thoroughly HO OH washed with water and dried. Recrystallization from ethanol with charcoal treatment furnished pure 3.3-bis-(4-hydroxy 3,5-diisopropylphenyl)-1-(3H)-isobenzofuranone in 98% ON O NO yield. O O

HO OH Example 5 O Synthesis of 3,3-bis-14-hydroxy-2-(N,N-diethylami no)phenyl-1-(3H)-isobenzofuranone O O 0258. A mixture of 3-(N,N-diethylamino)phenol (0.2M). phthalic anhydride (0.1M), polyphosphoric acid (0.25M), and zinc chloride (0.01M), was stirred and heated at 100° C. for 3 hours. The reaction mixture was cooled to room Example 3 temperature and added to ice-water mixture when the prod uct precipitated. The product was filtered, thoroughly Synthesis of 3,3-bis-(4-hydroxy-2-nitrophenyl)-1- washed with water and dried. Recrystallization from ethanol (3H)-isobenzofuranone with charcoal treatment furnished pure 3.3-bis-4-hydroxy 0256 A mixture of 3-nitrophenol (0.2M), phthalic anhy 2-(N,N-diethylamino)phenyl)-1-(3H)-isobenzofuranone in dride (0.1M), polyphosphoric acid (0.25M), and zinc chlo 93% yield. US 2006/0222601 A1 Oct. 5, 2006 23

Example 8 Synthesis of 3,3-bis-(4-hydroxy-3-acetamidophe nyl)-1-(3H)-isobenzofuranone 0261) A mixture of 2-acetamidophenol (0.2M), phthalic anhydride (0.1M), polyphosphoric acid (0.25M), and zinc chloride (0.01M), was stirred and heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and added to ice-water mixture when the product precipi tated. The product was filtered, thoroughly washed with water and dried. Recrystallization from ethanol with char coal treatment furnished pure 3,3-bis-(4-hydroxy-3-acetami dophenyl)-1-(3H)-isobenzofuranone in 83% yield. Example 6 HO OH Synthesis of 3,3-bis-(4-hydroxy-3-ethylphenyl)-1- (3H)-isobenzofuranone H3COCHN O NHCOCH 0259. A mixture of 2-ethylphenol (0.2M), phthalic anhy dride (0.1M), polyphosphoric acid (0.25M), and zinc chlo ride (0.01M), was stirred and heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and O O added to ice-water mixture when the product precipitated. The product was filtered, thoroughly washed with water and dried. Recrystallization from ethanol with charcoal treat ment furnished pure 3,3-bis-(4-hydroxy-3-ethylphenyl)-1- Example 9 (3H)-isobenzofuranone in 92% yield. Synthesis of 3,3-bis-(4-hydroxy-6-methyl-3-nitro HO OH phenyl)-1-(3H)-isobenzofuranone 0262. A mixture of 5-methyl-2-nitrophenol (0.2M). phthalic anhydride (0.1M), polyphosphoric acid (0.25M), O and zinc chloride (0.01M), was stirred and heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and added to ice-water mixture when the prod uct precipitated. The product was filtered, thoroughly O O washed with water and dried. Recrystallization from ethanol with charcoal treatment furnished pure 3.3-bis-(4-hydroxy 6-methyl-3-nitrophenyl)-1-(3H)-isobenzofuranone in 81% yield. Example 7 HO OH Synthesis of 3.3-bis-(4-hydroxy-3-ethoxyphenyl)-1- (3H)-isobenzofuranone ON O NO 0260 A mixture of 2-ethoxyphenol (0.2M), phthalic anhydride (0.1M), polyphosphoric acid (0.25M), and Zinc chloride (0.01M), was stirred and heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature O O and added to ice-water mixture when the product precipi tated. The product was filtered, thoroughly washed with water and dried. Recrystallization from ethanol with char coal treatment furnished pure 3,3-bis-(4-hydroxy-3-ethox Example 10 yphenyl)-1-(3H)-isobenzofuranone in 85% yield.

Synthesis of 3,3-bis-(4-hydroxy-6-methyl-5-quino tin-1-yl)-1-(3H)-isobenzofuranone 0263. A mixture of 8-hydroxyquinaldine (0.2M), phthalic anhydride (0.1M), polyphosphoric acid (0.25M), and zinc chloride (0.01M), was stirred and heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and added to ice-water mixture when the product precipi tated. The product was filtered, thoroughly washed with water and dried. Recrystallization from ethanol with char coal treatment furnished pure 3,3-bis-(4-hydroxy-6-methyl 5-quinolin-1-yl)-1-(3H)-isobenzofuranone in 88% yield. US 2006/0222601 A1 Oct. 5, 2006 24

Example 13 Synthesis of 3.3-bis-(4-hydroxy-3-phenylphenyl)-1- (3H)-isobenzofuranone 0266. A mixture of 2-phenylphenol (0.133 mol), phthalic anhydride (0.074 mol), reaction medium (0.416 mol), and Lewis acid (0.029 mol), was stirred and heated at 90° C. for 5 hours. The reaction mixture was cooled to room tempera ture and added to ice-water mixture when the product precipitated. The product was filtered, thoroughly washed with water and dried. Recrystallization from methanol with charcoal treatment furnished pure 3.3-bis-(4-hydroxy-3- phenylphenyl)-1-(3H)-isobenzofuranone as white crystals in 94% yield. 'H-NMR (DMSO-d 300 MHz): 8 9.89 (s. 2H, Example 11 2OH), 6.97-7.18 (m, 6H, aromatic), 7.26-7.47 (m, 10H, aromatic), 7.63-7.92 (m, 4H, aromatic) ppm. Mass spectra: Synthesis of 3,3-bis-(4-hydroxy-3-pyridin-1-yl)-1- m/z 470 (M). (3H)-isobenzofuranone

0264. A mixture of 2-hydroxypyridine (0.2M), phthalic HO OH anhydride (0.1M), polyphosphoric acid (0.25M), and Zinc chloride (0.01M), was stirred and heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and added to ice-water mixture when the product precipi C6Hs O C6Hs tated. The product was filtered, thoroughly washed with water and dried. Recrystallization from ethanol with char coal treatment furnished pure 3,3-bis-(4-hydroxy-3-pyridin 1-yl)-1-(3H)-isobenzofuranone in 80% yield. O O

Example 14 Synthesis of 3,3-bis-(4-hydroxy-3,5-diisopropylphe nyl)-1-(3H)-isobenzofuranone 0267 A mixture of 2,6-diisopropylphenol (0.133 mol), phthalic anhydride (0.074 mol), reaction medium (0.416 mol), and Lewis acid (0.029 mol), was stirred and heated at 90° C. for 5 hours. The reaction mixture was cooled to room Example 12 temperature and added to ice-water mixture when the prod uct precipitated. The product was filtered, thoroughly Synthesis of 3,3-bis-(4-hydroxy-2-pyridin-1-yl)-1- washed with water and dried. Recrystallization from metha nol with charcoal treatment furnished pure 3,3-bis-(4-hy (3H)-isobenzofuranone droxy-3,5-diisopropylphenyl)-1-(3H)-isobenzofuranone as 0265 A mixture of 3-hydroxypyridine (0.2M), phthalic white crystals in 89% yield. IR (KBr): 3506, 1734, 1609 anhydride (0.1M), polyphosphoric acid (0.25M), and Zinc cm'. 'H-NMR (DMSO-d): 8 9.56 (s. 2H, 2OH), 1.02-1.05 chloride (0.01M), was stirred and heated at 100° C. for 3 (dd, 24H, 8CH), 3.22-3.31 (heptate, 4H, 4CH), 6.74-7.00 hours. The reaction mixture was cooled to room temperature (m, 4H, aromatic), 7.59-7.92 (m, 4H, aromatic) ppm. Mass and added to ice-water mixture when the product precipi spectra: m/z. 486 (M). tated. The product was filtered, thoroughly washed with water and dried. Recrystallization from ethanol with char coal treatment furnished pure 3,3-bis-(4-hydroxy-2-pyridin 1-yl)-1-(3H)-isobenzofuranone in 82% yield.

US 2006/0222601 A1 Oct. 5, 2006

Example 15 Example 17 Synthesis of 3,3-bis-(4-hydroxy-3,5-dimethoxyphe Synthesis of 3.3-bis-(4-hydroxy-3,6-dimethylphe nyl)-1-(3H)-isobenzofuranone nyl)-1-(3H)-isobenzofuranone 0268 A mixture of 2,6-dimethoxyphenol (0.133 mol), 0270. A mixture of 2,5-dimethylphenol (0.133 mol), phthalic anhydride (0.074 mol), reaction medium (0.416 phthalic anhydride (0.074 mol), reaction medium (0.416 mol), and Lewis acid (0.029 mol), was stirred and heated at mol), and Lewis acid (0.029 mol), was stirred and heated at 90° C. for 5 hours. The reaction mixture was cooled to room 90° C. for 5 hours. The reaction mixture was cooled to room temperature and added to ice-water mixture when the prod temperature and added to ice-water mixture when the prod uct precipitated. The product was filtered, thoroughly uct precipitated. The product was filtered, thoroughly washed with water and dried. Recrystallization from metha nol with charcoal treatment furnished pure 3,3-bis-(4-hy washed with water and dried. Recrystallization from metha droxy-3,5-dimethoxyphenyl)-1-(3H)-isobenzofuranone as nol with charcoal treatment furnished pure 3,3-bis-(4-hy white crystals in 84% yield. IR (KBr): 3388, 1769, 1606, droxy-3,6-dimethylphenyl)-1-(3H)-isobenzofuranone as 1369 cm'. 'H-NMR (DMSO-d): 88.71 (s. 2H, 2OH), 3.66 pale yellow crystals in 85% yield. IR (KBr): 3393, 1729, (s, 12H, 4OCH), 7.65-7.68 (m, 4H, aromatic), 7.83-7.96 1611 cm'. 'H-NMR (DMSO-d): 8 9.40 (s. 2H, 2OH), 1.95 (m, 4H, aromatic) ppm. Mass spectra: m/z 438 (M). (s, 12H, 4CH), 6.59-6.63 (m, 4H, aromatic), 7.46-7.91 (m, 4H, aromatic) ppm. Mass spectra: m/z. 374 (M'.). OCH OCH HO OH HO OH

HCO O OCH O

O O

Example 16 Example 18 Synthesis of 3,3-bis-(4-hydroxy-3,5-dimethylphe Synthesis of 3,3-bis-(4-hydroxy-3-ethylphenyl)-1- nyl)-1-(3H)-isobenzofuranone (3n)-isobenzofuranone 0269. A mixture of 2,6-dimethylphenol (0.133 mol), 0271. A mixture of 2-ethylphenol (0.133 mol), phthalic phthalic anhydride (0.074 mol), reaction medium (0.416 anhydride (0.074 mol), reaction medium (0.416 mol), and mol), and Lewis acid (0.029 mol), was stirred and heated at Lewis acid (0.029 mol), was stirred and heated at 90° C. for 90° C. for 5 hours. The reaction mixture was cooled to room 5 hours. The reaction mixture was cooled to room tempera temperature and added to ice-water mixture when the prod ture and added to ice-water mixture when the product uct precipitated. The product was filtered, thoroughly precipitated. The product was filtered, thoroughly washed washed with water and dried. Recrystallization from metha with water and dried. Recrystallization from ethyl acetate nol with charcoal treatment furnished pure 3,3-bis-(4-hy :petroleum ether (1:1) with charcoal treatment furnished droxy-3,5-dimethylphenyl)-1-(3H)-isobenzofuranone aS pure 3,3-bis-(4-hydroxy-3-ethylphenyl)-1-(3H)-isobenzo white crystals in 91% yield. IR (KBr): 3582, 3386, 1746, furanone as white crystals in 81% yield. IR (KBr): 3389, 1605 cm'. 'H-NMR (DMSO-d): 8 8.45 (s. 2H, 2OH), 2.10 1783, 1718, 1605 cm'. 'H-NMR (DMSO-d): 8 9.54 (s, (s, 12H, 4CH), 7.58-7.63 (m, 4H, aromatic), 7.78-7.87 (m, 2H, 2OH), 2.43-2.50 (q, 4H, 2CH), 1.00-1.05 (t, 6H, 4H, aromatic) ppm. Mass spectra: m/z. 374 (M'.). 2CH), 6.74-6.96 (m, 6H, aromatic), 7.57-7.89 (m, 4H, aromatic) ppm. Mass spectra: m/z. 374 (M'.).

US 2006/0222601 A1 Oct. 5, 2006 26

Example 19 Example 21 Synthesis of 3.3-bis-(4-hydroxy-3-isopropylphenyl)- Synthesis of 3.3-bis-(4-hydroxy-2,3,5-trimethylphe 1-(3H)-isobenzofuranone nyl)-1-(3H)-isobenzofuranone 0272. A mixture of 2-isopropylphenol (0.133 mol), 0274. A mixture of 2.3,6-trimethylphenol (0.133 mol), phthalic anhydride (0.074 mol), reaction medium (0.416 phthalic anhydride (0.074 mol), reaction medium (0.416 mol), and Lewis acid (0.029 mol), was stirred and heated at mol), and Lewis acid (0.029 mol), was stirred and heated at 90° C. for 5 hours. The reaction mixture was cooled to room 90° C. for 5 hours. The reaction mixture was cooled to room temperature and added to ice-water mixture when the prod temperature and added to ice-water mixture when the prod uct precipitated. The product was filtered, thoroughly uct precipitated. The product was filtered, thoroughly washed with water and dried. Recrystallization from metha washed with water and dried. Recrystallization from metha nol with charcoal treatment furnished pure 3,3-bis-(4-hy nol: water (1:1) with charcoal treatment furnished pure 33.3- droxy-2,3,5-trimethylphenyl)-1-(3H)-isobenzofuranone as bis-(4-hydroxy-3-isopropylphenyl)-1-(3H)-isobenzofura white crystals in 73% yield. IR (KBr): 3510, 3390, 1746, none as white crystals in 83% yield. IR (KBr): 3383, 1733, 1609, cm'. 'H-NMR (DMSO-d): 8 9.44 (s. 2H, 2OH), 1608 cm'. 'H-NMR (DMSO-d): 8 9.57 (s. 2H, 2OH), 2.05 (s, 18H, 6CH), 6.55 (s. 2H, aromatic), 7.46-7.90 (m, 1.05-1.07 (dd. 12H, 4CH), 3.11-3.18 (heptate, 2H, 20H), 4H, aromatic) ppm. Mass spectra: m/z, 402 (M). 6.75-7.01 (m, 6H, aromatic), 7.59-7.90 (m, 4H, aromatic) ppm. Mass spectra: m/z, 402 (M).

HO OH HO OH

O O O O

Example 22 Example 20 Synthesis of 3.3-bis-(4-hydroxy-3-sec-butylphenyl)- Synthesis of 3.3-bis-(4-hydroxy-3-methoxyphenyl)- 1-(3H)-isobenzofuranone 1-(3H)-isobenzofuranone 0275 A mixture of 2-sec-butylphenol (0.133 mol), 0273 A mixture of 2-methoxyphenol (0.133 mol), phthalic anhydride (0.074 mol), reaction medium (0.416 mol), and Lewis acid (0.029 mol), was stirred and heated at phthalic anhydride (0.074 mol), reaction medium (0.416 90° C. for 5 hours. The reaction mixture was cooled to room mol), and Lewis acid (0.029 mol), was stirred and heated at temperature and added to ice-water mixture when the prod 90° C. for 5 hours. The reaction mixture was cooled to room uct precipitated. The product was filtered, thoroughly temperature and added to ice-water mixture when the prod washed with water and dried. Recrystallization from metha uct precipitated. The product was filtered, thoroughly nol with charcoal treatment furnished pure 3,3-bis-(4-hy washed with water and dried. Recrystallization from metha droxy-3-sec-butylphenyl)-1-(3H)-isobenzofuranone aS nol with charcoal treatment furnished pure 3,3-bis-(4-hy white crystals in 77% yield. IR (KBr): 3400, 1722, 1607 droxy-3-methoxyphenyl)-1-(3H)-isobenzofuranone as white cm'. 'H-NMR (DMSO-d): 8 9.50 (s. 2H, 2OH), 0.80 (t, crystals in 79% yield. IR (KBr): 3517, 1747, 1701, 1279 6H, 2CH), 1.35-1.39 (p, 4H, 2CH), 1.22 (d. 6H, 2CH), cm'. 'H-NMR (DMSO-d): 8 9.27 (s. 2H, 2OH), 3.66 (s, 2.89-2.97 (sextate, 2H, 2CH), 6.73-6.93 (m, 6H, aromatic), 6H, 2OCH), 6.65-6.78 (m, 6H, aromatic), 7.61-7.90 (m, 7.59-7.90 (m, 4H, aromatic) ppm. Mass spectra: m/z 430 4H, aromatic) ppm. Mass spectra: m/z. 378 (M). (Mt).

HO OH HO OH

HCO O OCH O O O O US 2006/0222601 A1 Oct. 5, 2006 27

Example 23 Example 2 Synthesis of 3,3-bis-(4-hydroxy-3-nitrophenyl)-1- Synthesis of disodium salt of 3,3-bis-(4-hydroxy-3, (3H)-isobenzofuranone 5-diisopropylphenyl)-1-(3H)-isobenzofuranone 0278 A mixture of 3,3-bis-(4-hydroxy-3,5-diisopropy 0276 A mixture of phenolphthalein (0.062 mol) in acetic lphenyl)-1-(3H)-isobenzofuranone (0.01M) in ethanol (50 acid (290 mL) was stirred at 15° C. Concentrated nitric acid mL, 85%) was stirred followed by addition of sodium (0.136 mol. 65%) in acetic acid (10 mL) was slowly added hydroxide (0.02M) in ethanol (50 mL, 85%). The reaction to stirring mixture at 15°C. The reaction mixture was further mixture was stirred and refluxed for 2 hours, cooled to room stirred for 6 hours at room temperature and added to temperature. The solvent was evaporated on rotary evapo ice-water mixture when the yellow colored product precipi tated. The product was filtered, thoroughly washed with rator, isolated the crude product and dried. Recrystallization water and dried. Recrystallization from ethanol with char from ethanol furnished pure disodium salt in 94% yield. coal treatment furnished pure 3.3-bis-(4-hydroxy-3-nitro phenyl)-1-(3H)-isobenzofuranone as pale yellow crystals in 78% yield. IR (KBr): 3262, 1766, 1627, 1538, 1423 cm. 'H-NMR (DMSO-d): 8 9.67 (s. 2H, 2OH), 6.71-7.16 (m, 6H, aromatic), 7.46-7.98 (m, 4H, aromatic) ppm. Mass spectra: m/z 408 (M). HO OH

O HNO3/AcOH --

O O Example 3 HO OH Synthesis of disodium salt of 3.3-bis-(4-hydroxy-2- nitrophenyl)-1-(3H)-isobenzofuranone ON O NO 0279 A mixture of 3.3-bis-(4-hydroxy-2-nitrophenyl)-1- (3H)-isobenzofuranone (0.01M) in ethanol (50 mL, 85%) was stirred followed by addition of sodium hydroxide (0.02M) in ethanol (50 mL. 85%). The reaction mixture was O O stirred and refluxed for 2 hours, cooled to room temperature. The solvent was evaporated on rotary evaporator, isolated the crude product and dried. Recrystallization from ethanol Synthesis of Disodium Salts of Acid-base Indicators for furnished pure disodium salt in 88% yield. Water Based Systems:

Example 1 Synthesis of disodium salt of 3.3-bis-(4-hydroxy-3- isopropylphenyl)-1-(3H1)-isobenzofuranone 0277. A mixture of 3.3-bis-(4-hydroxy-3-isopropylphe nyl)-1-(3H)-isobenzofuranone (0.01M) in ethanol (50 mL. 85%) was stirred followed by addition of sodium hydroxide (0.02M) in ethanol (50 mL. 85%). The reaction mixture was stirred and refluxed for 2 hours, cooled to room temperature. The solvent was evaporated on rotary evaporator, isolated the crude product and dried. Recrystallization from ethanol Example 4 furnished pure disodium salt in 98% yield. Synthesis of disodium salt of 3.3-bis-(4-hydroxy-3- nitrophenyl)-1-(3H1)-isobenzofuranone 0280 A mixture of 3.3-bis-(4-hydroxy-3-nitrophenyl)-1- (3H)-isobenzofuranone (0.01M) in ethanol (50 mL, 85%) was stirred followed by addition of sodium hydroxide (0.02M) in ethanol (50 mL. 85%). The reaction mixture was stirred and refluxed for 2 hours, cooled to room temperature. The solvent was evaporated on rotary evaporator, isolated the crude product and dried. Recrystallization from ethanol furnished pure disodium salt in 91% yield. US 2006/0222601 A1 Oct. 5, 2006 28

Example 7

NaO Synthesis of disodium salt of 3.3-bis-(4-hydroxy-3- ethoxyphenyl)-1-(3H1)-isobenzofuranone 0283. A mixture of 3.3-bis-(4-hydroxy-3-ethoxyphenyl)- ON O 2 O NOO 1-(3H)-isobenzofuranone (0.01M) in ethanol (50 mL, 85%) was stirred followed by addition of sodium hydroxide (0.02M) in ethanol (50 mL. 85%). The reaction mixture was stirred and refluxed for 2 hours, cooled to room temperature. O COONa The solvent was evaporated on rotary evaporator, isolated the crude product and dried. Recrystallization from ethanol furnished pure disodium salt in 94% yield. Example 5

Synthesis of disodium salt of 3.3-bis-4-hydroxy-2- (N,N-diethylamino)phenyl-1-(3H)-isobenzofura O 0281. A mixture of 3,3-bis-4-hydroxy-2-(N,N-diethy lamino)phenyl)-1-(3H)-isobenzofuranone (0.01 M) in etha nol (50 mL. 85%) was stirred followed by addition of sodium hydroxide (0.02M) in ethanol (50 mL. 85%). The reaction mixture was stirred and refluxed for 2 hours, cooled to room temperature. The solvent was evaporated on rotary evaporator, isolated the crude product and dried. Recrystal Example 8 lization from ethanol furnished pure, disodium salt in 89% yield. Synthesis of disodium salt of 3,3-bis-(4-hydroxy-3- acetamidophenyl)-1-(3H)-isobenzofuranone 0284. A mixture of 3,3-bis-(4-hydroxy-3-acetamidophe nyl)-1-(3H)-isobenzofuranone (0.01M) in ethanol (50 mL. 85%) was stirred followed by addition of sodium hydroxide (0.02M) in ethanol (50 mL. 85%). The reaction mixture was stirred and refluxed for 2 hours, cooled to room temperature. The solvent was evaporated on rotary evaporator, isolated the crude product and dried. Recrystallization from ethanol furnished pure disodium salt in 92% yield.

Example 6 NaO O Synthesis of disodium salt of 3.3-bis-(4-hydroxy-3- ethylphenyl)-1-(3H)-isobenzofuranone H3COCHN 2 NHCOCH 0282. A mixture of 3.3-bis-(4-hydroxy-3-ethylphenyl)-1- (3H)-isobenzofuranone (0.01M) in ethanol (50 mL, 85%) O COONa was stirred followed by addition of sodium hydroxide (0.02M) in ethanol (50 mL. 85%). The reaction mixture was stirred and refluxed for 2 hours, cooled to room temperature. The solvent was evaporated on rotary evaporator, isolated the crude product and dried. Recrystallization from ethanol Example 9 furnished pure disodium salt in 97% yield. Synthesis of disodium salt of 3.3-bis-(4-hydroxy-6- methyl-3-nitrophenyl)-1-(3H)-isobenzofuranone 0285) A mixture of 3,3-bis-(4-hydroxy-6-methyl-3-nitro phenyl)-1-(3H)-isobenzofuranone (0.01M) in ethanol (50 mL, 85%) was stirred followed by addition of sodium hydroxide (0.02M) in ethanol (50 mL, 85%). The reaction mixture was stirred and refluxed for 2 hours, cooled to room temperature. The solvent was evaporated on rotary evapo rator, isolated the crude product and dried. Recrystallization from ethanol furnished pure disodium salt in 97% yield. US 2006/0222601 A1 Oct. 5, 2006 29

Example 12

NaO Synthesis of disodium salt of 3.3-bis-(4-hydroxy-2- pyridin-1-yl)-1-(3H)-isobenzofuranone O 2 O NOO 0288 A mixture of 3.3-bis-(4-hydroxy-2-pyridin-1-yl)-1- ON (3H)-isobenzofuranone (0.01M) in ethanol (50 mL, 85%) was stirred followed by addition of sodium hydroxide (0.02M) in ethanol (50 mL. 85%). The reaction mixture was O COONa stirred and refluxed for 2 hours, cooled to room temperature. The solvent was evaporated on rotary evaporator, isolated the crude product and dried. Recrystallization from ethanol Example 10 furnished pure disodium salt in 84% yield.

Synthesis of disodium salt of 3.3-bis-(4-hydroxy-6- methyl-5-quinolin-1-yl)-1-(3H)-isobenzofuranone 0286 A mixture of 3.3-bis-(4-hydroxy-6-methyl-5- quinolin-1-yl)-1-(3H)-isobenzofuranone (0.01M) in ethanol (50 mL. 85%) was stirred followed by addition of sodium hydroxide (0.02M) in ethanol (50 mL, 85%). The reaction mixture was stirred and refluxed for 2 hours, cooled to room temperature. The solvent was evaporated on rotary evapo rator, isolated the crude product and dried. Recrystallization from ethanol furnished pure disodium salt in 94% yield. Example 13

Synthesis of disodium salt of 3.3-bis-(4-hydroxy-3- phenylphenyl)-1-(3H)-isobenzofuranone 0289. A mixture of 3.3-bis-(4-hydroxy-3-phenylphenyl)- 1-(3H)-isobenzofuranone (0.01 mol) in ethanol (50 mL. 85%) was stirred followed by addition of sodium hydroxide (0.02 mol) in ethanol (50 mL. 85%). The reaction mixture was stirred and refluxed for 2 hours, cooled to room tem perature. The solvent was evaporated on rotary evaporator, isolated the crude product and dried. Recrystallization from ethanol furnished pure disodium salt in 96% yield. 'H-NMR (DMSO-de, 300 MHz): 8 6.25-6.74 (m, 6H, aromatic), 6.88-7.45 (m. 10H, aromatic), 7.53-7.84 (m, 4H, aromatic) Example 11 ppm. Mass spectra: m/z 514 (M'.). Synthesis of disodium salt of 3.3-bis-(4-hydroxy-3- pyridin-1-yl)-1-(3H)-isobenzofuranone NaO O 0287. A mixture of 3.3-bis-(4-hydroxy-3-pyridin-1-yl)-1- (3H)-isobenzofuranone (0.01M) in ethanol (50 mL, 85%) C6Hs 2 C6H5 was stirred followed by addition of sodium hydroxide (0.02M) in ethanol (50 mL. 85%). The reaction mixture was stirred and refluxed for 2 hours, cooled to room temperature. The solvent was evaporated on rotary evaporator, isolated O COONa the crude product and dried. Recrystallization from ethanol furnished pure disodium salt in 81% yield. Example 14 Synthesis of disodium salt of 3,3-bis-(4-hydroxy-3, 5-diisopropylphenyl)-1-(3H)-isobenzofuranone 0290. A mixture of 3,3-bis-(4-hydroxy-3,5-diisopropy lphenyl)-1-(3H)-isobenzofuranone (0.01 mol) in ethanol (50 mL, 85%) was stirred followed by addition of sodium hydroxide (0.02 mol) in ethanol (50 mL. 85%). The reaction mixture was stirred and refluxed for 2 hours, cooled to room temperature. The solvent was evaporated on rotary evapo US 2006/0222601 A1 Oct. 5, 2006 30 rator, isolated the crude product and dried. Recrystallization aromatic), 7.23-7.84 (m, 4H, aromatic) ppm. Mass spectra: from ethanol furnished pure disodium salt in 92% yield. m/z 418 (M). 'H-NMR (DMSO-d): & 1.00-121 (dd, 24H, 8CH), 3.06 3.36 (heptate, 4H, 4CH), 6.74-6.96 (m, 4H, aromatic), 7.05-7.83 (m, 4H, aromatic) ppm. Mass spectra: m/z 530 (Mt).

Example 17 Synthesis of disodium salt of 3,3-bis-(4-hydroxy-3, 6-dimethylphenyl)-1-(3H)-isobenzofuranone Example 15 0293. A mixture of 3.3-bis-(4-hydroxy-3,6-dimethylphe Synthesis of disodium salt of 3,3-bis-(4-hydroxy-3, nyl)-1-(3H)-isobenzofuranone (0.01 mol) in ethanol (50 mL. 5-dimethoxyphenyl)-1-(3H)-isobenzofuranone 85%) was stirred followed by addition of sodium hydroxide 0291. A mixture of 3,3-bis-(4-hydroxy-3,5-dimethox (0.02 mol) in ethanol (50 mL. 85%). The reaction mixture yphenyl)-1-(3H)-isobenzofuranone (0.01 mol) in ethanol was stirred and refluxed for 2 hours, cooled to room tem (50 mL. 85%) was stirred followed by addition of sodium perature. The solvent was evaporated on rotary evaporator, hydroxide (0.02 mol) in ethanol (50 mL, 85%). The reaction isolated the crude product and dried. Recrystallization from mixture was stirred and refluxed for 2 hours, cooled to room temperature. The solvent was evaporated on rotary evapo ethanol furnished pure disodium salt in 88% yield. 'H-NMR rator, isolated the crude product and dried. Recrystallization (DMSO-d): 8 2.01 (s, 12H, 4CH), 6.04-6.82 (m, 4H, from ethanol furnished pure disodium salt in 90% yield. aromatic), 7.10-7.72 (m, 4H, aromatic) ppm. Mass spectra: 'H-NMR (DMSO-d): a 3.61 (s, 12H, 40CH), 6.45-6.52 m/z 418 (M). (m, 4H, aromatic), 7.04-7.78 (m, 4H, aromatic) ppm. Mass spectra: m/z 482 (M).

OCH OCH NaO O O 21 OCH

O COONa Example 18 Synthesis of disodium salt of 3.3-bis-(4-hydroxy-3- Example 16 ethylphenyl)-1-(3H)-isobenzofuranone Synthesis of disodium salt of 3,3-bis-(4-hydroxy-3, 0294. A mixture of 3.3-bis-(4-hydroxy-3-ethylphenyl)-1- 5-dimethylphenyl)-1-(3H)-isobenzofuranone (3H)-isobenzofuranone (0.01 mol) in ethanol (50 mL. 85%) was stirred followed by addition of sodium hydroxide (0.02 0292 A mixture of 3.3-bis-(4-hydroxy-3,5-dimethylphe nyl)-1-(3H)-isobenzofuranone (0.01 mol) in ethanol (50 mL. mol) in ethanol (50 mL. 85%). The reaction mixture was 85%) was stirred followed by addition of sodium hydroxide stirred and refluxed for 2 hours, cooled to room temperature. (0.02 mol) in ethanol (50 mL. 85%). The reaction mixture The solvent was evaporated on rotary evaporator, isolated was stirred and refluxed for 2 hours, cooled to room tem the crude product and dried. Recrystallization from ethanol perature. The solvent was evaporated on rotary evaporator, furnished pure disodium salt in 86% yield. 'H-NMR isolated the crude product and dried. Recrystallization from (DMSO-d): 8 2.30-2.51 (q, 4H, 2CH), 1.00- 1.10 (t, 6H, ethanol furnished pure disodium salt in 95% yield. 'H-NMR 2CH), 6.20-6.75 (m, 6H, aromatic), 7.12-7.84 (m, 4H. (DMSO-d): 8 2.11 (s, 12H, 4CH), 6.81-6.87 (im, 4H, aromatic) ppm. Mass spectra: m/z 418 (M). US 2006/0222601 A1 Oct. 5, 2006 31

(50 mL. 85%) was stirred followed by addition of sodium NaO O hydroxide (0.02 mol) in ethanol (50 mL. 85%). The reaction mixture was stirred and refluxed for 2 hours, cooled to room temperature. The solvent was evaporated on rotary evapo C2H5 21 C2H5 rator, isolated the crude product and dried. Recrystallization from ethanol furnished pure disodium salt in 80% yield. O COONa

Example 19 Synthesis of disodium salt of 3.3-bis-(4-hydroxy-3- isopropylphenyl)-1-(3H)-isobenzofuranone 0295) A mixture of 3.3-bis-(4-hydroxy-3-isopropylphe nyl)-1-(3H)-isobenzofuranone (0.01 mol) in ethanol (50 mL. 85%) was stirred followed by addition of sodium hydroxide (0.02 mol) in ethanol (50 mL. 85%). The reaction mixture was stirred and refluxed for 2 hours, cooled to room tem perature. The solvent was evaporated on rotary evaporator, isolated the crude product and dried. Recrystallization from ethanol furnished pure disodium salt in 81% yield. 'H-NMR Example 22 (DMSO-d): & 1.02-1.14 (dd. 12H, 4CH), 3.12-3.45 (hep tate, 2H, 2CH), 6.32-6.76 (m, 6H, aromatic), 7.30-7.83 (m, Synthesis of disodium salt of 3.3-bis-(4-hydroxy-3- 4H, aromatic) ppm. Mass spectra: m/z. 446 (M). sec-butylphenyl)-1-(3H)-isobenzofuranone NaO O 0298. A mixture of 3.3-bis-(4-hydroxy-3-sec-butylphe nyl)-1-(3H)-isobenzofuranone (0.01 mol) in ethanol (50 mL. 85%) was stirred followed by addition of sodium hydroxide 2 O (0.02 mol) in ethanol (50 mL. 85%). The reaction mixture was stirred and refluxed for 2 hours, cooled to room tem perature. The 5 solvent was evaporated on rotary evaporator, O COONa isolated the crude product and dried. Recrystallization from ethanol furnished pure disodium salt in 82% yield. 'H-NMR (DMSO-d): 8 0.80 (t, 6H, 2CH), 1.29-1.37 (p., 4H, 2CH), Example 20 1.20 (d. 6H, 2CH), 2.88-2.96 (sextate, 2H, 2CH), 6.08-6.75 Synthesis of disodium salt of 3.3-bis-(4-hydroxy-3- (m, 6H, aromatic), 7.37-7.81 (m, 4H, aromatic) ppm. methoxyphenyl)-1-(3H)-isobenzofuranone NaO O 0296. A mixture of 3.3-bis-(4-hydroxy-3-methoxyphe nyl)-1-(3H)-isobenzofuranone (0.01 mol) in ethanol (50 mL. 85%) was stirred followed by addition of sodium hydroxide O 1C (0.02 mol) in ethanol (50 mL. 85%). The reaction mixture was stirred and refluxed for 2 hours, cooled to room tem perature. The solvent was evaporated on rotary evaporator, COONa isolated the crude product and dried. Recrystallization from ethanol furnished pure disodium salt in 88% yield. NaO O

Example 23 H3CO 2 OCH Synthesis of disodium salt of 3.3-bis-(4-hydroxy-3- nitrophenyl)-1-(3H)-isobenzofuranone O COONa 0299. A mixture of 3.3-bis-(4-hydroxy-3-nitrophenyl)-1- (3H)-isobenzofuranone (0.01 mol) in ethanol (50 mL. 85%) Example 21 was stirred followed by addition of sodium hydroxide (0.02 mol) in ethanol (50 mL. 85%). The reaction mixture was Synthesis of disodium salt of 3,3-bis-(4-hydroxy-2, stirred and refluxed for 2 hours, cooled to room temperature. 3,5-trimethylphenyl)-1-(3H)-isobenzofuranone The solvent was evaporated on rotary evaporator, isolated 0297. A mixture of 3,3-bis-(4-hydroxy-2,3,5-trimeth the crude product and dried. Recrystallization from ethanol ylphenyl)-1-(3H)-isobenzofuranone (0.01 mol) in ethanol furnished pure disodium salt in 92% yield. US 2006/0222601 A1 Oct. 5, 2006 32

NaO -continued O O O ON ON 21 NO CONHNH NO O COONa OH

Synthesis of Phenol and Hydrazine Acid-Base Indicators Example 1 Example 4 Synthesis of sodium salt of 5-methyl-2-nitrophenol Synthesis of sodium salt of hydrazide 0300. A mixture of 5-methyl-2-nitrophenol (0.1M) in 0303) A mixture of hydrazide (0.1M) in ethanol (25 mL) ethanol (25 mL, 85%) was stirred followed by addition of was stirred followed by addition of sodium ethoxide (0.1M) sodium hydroxide (0.1M) in ethanol (25 mL, 85%). The in ethanol (25 mL). The reaction mixture was stirred and reaction mixture was stirred at room temperature for 2 hours. refluxed at for 4 hours, cooled to room temperature. The The separated golden yellow solid was filtered, washed with Solvent was evaporated on rotary evaporator, isolated the ethanol and dried. Recrystallization from ethanol furnished pure sodium salt in 96% yield. crude yellow product and dried. Recrystallization from OH ONa ethanol furnished pure sodium salt in 92% yield. NO NO ON NaOH EtOH CONHNH NO HC OH NaOEt He Example 2 NaOH

Synthesis of p-nitrobenzhydrazide ON 0301 A mixture of ethyl p-nitrobenzoate (0.1M), hydra zine hydrate (0.11M) in ethanol (100 mL) was stirred at room temperature for 2 hours. The separated pale yellow CONHNH NO solid was filtered, washed with ethanol and dried. Recrys ONa tallization from ethanol furnished pure hydrazide in 88% yield. COOEt CONHNH2

NH-NH2-H2O --- Example 5 Synthesis of hydrazide NO NO 0304. A mixture of ethyl salicylate (0.1M), 4-nitrophe nylhydrazine (0.1M) in ethanol (150 mL) was stirred at room temperature for 2 hours. The separated yellow solid Example 3 was filtered, washed with ethanol and dried. Recrystalliza Synthesis of hydrazide tion from ethanol furnished pure hydrazide in 89% yield. 0302) A mixture of ethyl salicylate (0.1M), 2,4-dinitro COOEt phenylhydrazine (0.1M) in ethanol (150 mL) was stirred at room temperature for 2 hours. The separated orange Solid OH in-K)- NO was filtered, washed with ethanol and dried. Recrystalliza -- tion from ethanol furnished pure hydrazide in 94% yield. ON COOEt

oni-O-soOH OH HNHN NO

--- US 2006/0222601 A1 Oct. 5, 2006

Example 6 R is selected from the group consisting of hydrogen, aryl, alkyl, nitro, acetamido and alkoxide; Synthesis of sodium salt of hydrazide R is selected from the group consisting of hydrogen, 0305) A mixture of hydrazide (0.1M) in ethanol (25 mL) halo, alkoxide and alkyl, was stirred followed by addition of sodium ethoxide (0.1M) in ethanol (25 mL). The reaction mixture was stirred and R is selected from the group consisting of hydrogen and refluxed at for 4 hours, cooled to room temperature. The alkyl: Solvent was evaporated on rotary evaporator, isolated the crude yellow product and dried. Recrystallization from R7, R, R and R'' are all hydrogen; ethanol furnished pure sodium salt in 84% yield. optionally, one of the carbons connected to R. R. Ror R” can be substituted with a nitrogen atom; on-()– NO M' and M are each independently a hydrogen atom, a OH NaOEt metal ion or an ammonium ion, provided that at least --- one of M" or M is a metal ion or an ammonium ion; NaOH a gelling agent; and a polishing agent. 2. The toothpaste of claim 1, wherein wherein R is selected from the group consisting of hydrogen and methyl; oni-O-soONa R is selected from the group consisting of hydrogen, phenyl, isopropyl, methyl, ethyl, Sec-butyl, nitro and meth oxy; R is selected from the group consisting of hydrogen, bromo, methoxy, isopropyl and methyl; and R is selected from the group consisting of hydrogen and methyl. 0306 As various changes could be made in the above 3. The toothpaste of claim 1, wherein R is hydrogen, R products, without departing from the scope of the invention, is Me, and R. R. R. R. R. and R' are hydrogen atoms, it is intended that all matter contained in the above descrip or R is Me, Risa hydrogenatom, R is an iso-propyl group, tion shall be interpreted as illustrative and not in a limiting R. R. R. RandR'' are hydrogen atoms or R is H, R is SCSC. Me, R is Brand R. R. R. Rand R'' are hydrogenatoms 0307 Although the present invention has been described or R is Me, Riis Br, R is an isopropyl and R. R. R. R. with reference to preferred embodiments, persons skilled in and R' are hydrogen atoms. the art will recognize that changes may be made in form and 4. The toothpaste of claim 1, wherein R is H. Ris phenyl detail without departing from the spirit and scope of the and R. R. R. R. RandR'' are all hydrogenatoms, or R invention. is H. Rand Rare isopropyl and R. R. R. RandR'' are 0308 Those skilled in the art will recognize, or be able to all hydrogen atoms, or R is H, R is methyl, R is H. Ris ascertain, using no more than routine experimentation, many methyl, R. R. R. and R'' are all hydrogen atoms, or R is equivalents to specific embodiments of the invention H. Rand Rare methoxy and R. R. R. Rand R'' are all described specifically herein. Such equivalents are intended hydrogen atoms, or R is H. R. and Rare methyl and R. to be encompassed in the scope of the following claim. R. R. Rand R'' are all hydrogen atoms, or R is H, R is ethyl and R. R. R. R. RandR'' are all hydrogenatoms, What is claimed is: or R is H, Ris isopropyl and R. R. R. R. RandR'' are 1. A toothpaste comprising: all hydrogen atoms, or R is H. Ris methoxide and R. R. R. R. RandR'' are all hydrogenatoms or R is H, Rand a Surfactant; and Rare all methyl and R. R. R. RandR'' are all hydrogen an acid-base indicator comprising: atoms, or R. R. R. R. R. R. R. R'' are all hydrogen atoms and R is sec-butyl, or R. R. R. R. R. R. R. R' (I) are all hydrogen atoms and R is nitro. 5. The toothpaste of claim 1, further comprising a base. 6. The toothpaste of claim 5, wherein the base is a metal hydroxide. 7. The toothpaste of claim 1, wherein said polishing agent is selected from the group consisting of silica gel, silica, Sodium aluminum silicate, hydrated alumina, dicalcium phosphate, calcium pyrophosphate, calcium carbonate and mixtures thereof. 8. The toothpaste of claim 1, wherein from approximately 0.5 to approximately 18% by weight of a gelling agent is incorporated therein. 9. The toothpaste of claim 8, wherein said gelling agent is selected from the group consisting of sodium carboxymethyl wherein cellulose, Xanthan gum, polyvinyl pyrrolidone, hydroxy R is selected from the group consisting of hydrogen, ethyl cellulose, polyvinyl alcohol, Irish moss extract, nitro, amino and alkyl, Sodium alginate and mixtures thereof. US 2006/0222601 A1 Oct. 5, 2006 34

10. A method to indicate when brushing of the teeth is H. Rand Rare methoxy and R. R. R. Rand R'' are all complete, comprising the step of: hydrogen atoms, or R is H. R. and Rare methyl and R. R. R. Rand R' are all hydrogen atoms, or R is H, R is applying a toothpaste composition to a tooth comprising ethyl and R. R. R. R. RandR'' are all hydrogenatoms, a Surfactant; and or R is H, R is isopropyl and R. R. R. R. R. and R' are all hydrogen atoms, or R is H. R is methoxide and R. an acid-base indicator comprising: R. R. R. Rand R'' are all hydrogenatoms or R, R and Rare all methyl and R. R. R. RandR'' are all hydrogen (I) atoms, or R. R. R. R. R. R. R. R'' are all hydrogen atoms and R is sec-butyl, or R. R. R. R. R. R. R. R' are all hydrogen atoms and R is nitro. 14. The method of claim 10, further comprising a base. 15. The method of claim 14, wherein the base is a metal hydroxide. 16. The method of claim 10 wherein said polishing agent is selected from the group consisting of silica gel, silica, Sodium aluminum silicate, hydrated alumina, dicalcium phosphate, calcium pyrophosphate, calcium carbonate and mixtures thereof. 17. The method of claim 10, wherein from approximately 0.5 to approximately 18% by weight of a gelling agent is wherein incorporated therein. 18. The method of claim 17, wherein said gelling agent is R is selected from the group consisting of hydrogen, selected from the group consisting of sodium carboxymethyl nitro, amino and alkyl, cellulose, Xanthan gum, polyvinyl pyrrolidone, hydroxy R is selected from the group consisting of hydrogen, aryl, ethyl cellulose, polyvinyl alcohol, Irish moss extract, alkyl, nitro, acetamido and alkoxide; Sodium alginate and mixtures thereof. R is selected from the group consisting of hydrogen, 19. A mouthwash composition comprising: halo, alkoxide and alkyl: a Surfactant; and R is selected from the group consisting of hydrogen and an acid-base indicator comprising: alkyl: (I) R7, R, R and R'' are all hydrogen: optionally, one of the carbons connected to R, R, R or R can be substituted with a nitrogen atom; M' and M are each independently a hydrogen atom, a metal ion or an ammonium ion, provided that at least one of M' or M is a metal ion or an ammonium ion; a gelling agent; a polishing agent; and brushing the composition for a period of time Sufficient Such that the color of the indicator changes. 11. The method of claim 10, wherein R is selected from wherein the group consisting of hydrogen and methyl; R is selected R is selected from the group consisting of hydrogen, from the group consisting of hydrogen, phenyl, isopropyl. nitro, amino and alkyl, methyl, ethyl, sec-butyl, nitro and methoxy; R is selected R is selected from the group consisting of hydrogen, aryl, from the group consisting of hydrogen, bromo, methoxy, isopropyl and methyl; and R is selected from the group alkyl, nitro, acetamido and alkoxide; consisting of hydrogen and methyl. R is selected from the group consisting of hydrogen, 12. The method of claim 10, wherein R is hydrogen, R halo, alkoxide and alkyl, is Me, and R. R. R. R. R. and R'' are hydrogen atoms, R is selected from the group consisting of hydrogen and or R is Me, R is a hydrogen atom, R is an iso-propyl alkyl: group, R. R. R. R. and R' are hydrogen atoms or R is R7, R, R and R'' are all hydrogen: H, R is Me, R is Br and R. R. R. R and R'' are hydrogenatoms or R is Me, R is Br, R is an isopropyl and optionally, one of the carbons connected to R. R. Ror R. R. R. R. and R' are hydrogen atoms. R” can be substituted with a nitrogen atom; 13. The method of claim 10, wherein R is H, R is phenyl M' and M are each independently a hydrogen atom, a and R. R. R. R. RandR'' are all hydrogenatoms, or R metal ion or an ammonium ion, provided that at least is H. Rand Rare isopropyl and R. R. R. Rand R'' are one of M" or M is a metal ion or an ammonium ion; all hydrogen atoms, or R is H. Riis methyl, R is H. R is and methyl, R. R. R. and R" are all hydrogen atoms, or R is a humectant. US 2006/0222601 A1 Oct. 5, 2006

20. The mouthwash of claim 19, wherein R is selected wherein from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen, phenyl, R is selected from the group consisting of hydrogen, isopropyl, methyl, ethyl, sec-butyl, nitro and methoxy; R is nitro, amino and alkyl, selected from the group consisting of hydrogen, bromo, R is selected from the group consisting of hydrogen, aryl, methoxy, isopropyl and methyl; and R is selected from the alkyl, nitro, acetamido and alkoxide; group consisting of hydrogen and methyl. R is selected from the group consisting of hydrogen, 21. The mouthwash of claim 19, wherein R is hydrogen, halo, alkoxide and alkyl, Riis Me, and R. R. R. R. RandR'' are hydrogenatoms, or R is Me, R is a hydrogen atom, R is an iso-propyl R is selected from the group consisting of hydrogen and group, R. R. R. R. and R' are hydrogen atoms or R is alkyl: H. Riis Me, R is Brand R. R. R. RandR'' are hydrogen R7, R, R and R'' are all hydrogen; atoms or R is Me, Ris Br, R is an isopropyl and R. R. R, R and R'' are hydrogen atoms. optionally, one of the carbons connected to R. R. R. or 22. The mouthwash of claim 19, wherein R is H. Ris R” can be substituted with a nitrogen atom; phenyl and R. R. R. R. R. and R'' are all hydrogen M' and M are each independently a hydrogen atom, a atoms, or R is H. R. and Rare isopropyl and R. R. R. metal ion or an ammonium ion, provided that at least RandR'' are all hydrogen atoms, or R is H. R is methyl, one of M' or M is a metal ion or an ammonium ion; R is H, R is methyl, R. R. R. and R'' are all hydrogen a humectant; and atoms, or R is H. Rand Rare methoxy and R. R. R. R. contacting the oral cavity for a period of time Sufficient and R'' are all hydrogen atoms, or R is H. R. and Rand Such that the color of the indicator changes. methyl and R. R. R. Rand R'' are all hydrogen atoms, 27. The method of claim 26, wherein R is selected from or R is H, R is ethyl and R. R. R7, R, R and Rare all the group consisting of hydrogen and methyl; R is selected hydrogen atoms, or R is H, R is isopropyl and R. R. R. from the group consisting of hydrogen, phenyl, isopropyl. R, R and R'' are all hydrogen atoms, or R is H, R is methyl, ethyl, sec-butyl, nitro and methoxy; R is selected methoxide and R. R. R. R. R. and R' are all hydrogen from the group consisting of hydrogen, bromo, methoxy, atoms, or R, R and Rare all methyland R. R. R. Rand isopropyl and methyl; and R is selected from the group R are all hydrogen atoms, or R. R. R. R. R. R. R. consisting of hydrogen and methyl. Rare all hydrogenatoms and R is sec-butyl, or R. R. R. 28. The method of claim 26, wherein R is hydrogen, Ris R. R. R. R. R'' are all hydrogen atoms and R is nitro. Me, and R. R. R. R. R. and R'' are hydrogen atoms, or 23. The mouthwash of claim 19, further comprising a R’ is Me, R is a hydrogen atom, R is an iso-propyl group, base. R. R. R. RandR'' are hydrogen atoms or R is H, R is 24. The mouthwash of claim 23, wherein the base is a Me, R is Brand R. R. R. Rand R'' are hydrogen atoms metal hydroxide. or R is Me, Riis Br, R is an isopropyl and R. R. R. R. 25. The mouthwash of claim 19, wherein the humectant is and R' are hydrogen atoms. glycerine. 29. The method of claim 26, wherein R is H, R is phenyl 26. A method to indicate when treatment of the oral cavity and R. R. R. R. RandR'' are all hydrogenatoms, or R is complete, comprising the step of is H. Rand Rare isopropyl and R. R. R. RandR'' are contacting a mouthwash composition to the oral cavity all hydrogen atoms, or R is H. R is methyl, R is H. R is comprising methyl, R. R. R. and R" are all hydrogen atoms, or R is H. Rand Rare methoxy and R. R. R. Rand R'' are all a Surfactant; and hydrogen atoms, or R is H. R. and Rare methyl and R. an acid-base indicator comprising: R. R. Rand R'' are all hydrogen atoms, or R is H, R is ethyl and R. R. R. R. RandR'' are all hydrogenatoms, (I) or R is H, R is isopropyl and R. R. R. R. R. and R' are all hydrogen atoms, or R is H. R is methoxide and R. R. R. R. RandR'' are all hydrogen atoms, or R, R and Rare all methyl and R. R. R. RandR'' are all hydrogen atoms, or R. R. R. R. R. R. R. R'' are all hydrogen atoms and Riis sec-butyl, or R. R. R. R. R7, R. R. R. are all hydrogen atoms and R is nitro. 30. The method of claim 26, further comprising a base. 31. The method of claim 30, wherein the base is a metal hydroxide. 32. The method of claim 26, wherein the humectant is glycerine.