United States Patent (19) 11) Patent Number: 5,001,115 Sloan (45) Date of Patent: Mar

United States Patent (19) 11) Patent Number: 5,001,115 Sloan (45) Date of Patent: Mar. 19, 1991

54 PRODRUGS OF BIOLOGICALLY ACTIVE Primary Examiner-Mukund J. Shah HYDROXYAROMATIC COMPOUNDS Assistant Examiner-E. L. Ward Attorney, Agent, or Firm-Kerkam, Stowell, Kondracki (75 Inventor: Kenneth B. Sloan, Gainesville, Fla. & Clarke 73 Assignee: University of Florida, Gainesville, Fla, (57) ABSTRACT (21) Appl. No.: 352,919 Prodrugs of bio-active hydroxyaromatic drugs having 22 Filed: May 17, 1989 the structural formula: A pharmaceutically acceptable prodrug of a biologi (51] Int. Cl...... A61K 31/70; A61K 31/595; cally active, therapeutically effective hydroxyaromatic A61K 31/535; A61K 31/255 52 U.S. C...... 514/34: 514/289; drug, said prodrug being selected from the group con 514/169; 514/373; 514/222.8; 514/328; sisting of, (A) compounds having the structural for 514/360; 514/603; 514/417; 514/425; 514/518; mula: 546/44; 54.6/176; 546/75; 544/2; 536/64; 548/123; 548/209; 548/256; 548/417 DRUG-O-CR'R''-2) 58 Field of Search ...... 514/169,289, 373, 417, 514/425, 222.8, 328,360, 518, 603, 34; 536/64; wherein: 564/82, 155; 552/626; 546/44, 176, 75; 544/2; DRUG -O- is the hydroxyaromatic O-dehydro 548/123, 209, 256, 477, 595 residue of said drug; 56 References Cited R" and R' may be the same or different and may be H, PUBLICATIONS alkyl, aryl or electron withdrawing groups; 2 is a displaceable leaving group; and Katritzky, et al. J. Chem. Soc. Perkin Transactions 1, 1987, pp. 781-789. n is an integer in the range of from 1 to 3, and (B) Katritzky, Tetrahedron 36, 1980 pp. 679 to 699. pharmaceutically acceptable salts thereof. Foye, Principals of Medicinal Chemistry (Philadelphia, Lea and Fibiger, 1981) p. 733. 3 Claims, No Drawings 5,001,115 1. 2 may be interrupted by at least one N, S or O atom, PRODRUGS OF BIOLOGICALLY ACTIVE hydrocarbyl aryl groups, and in the case of HYDROXYAROMATIC COMPOUNDS -N(R')2 taken with the other R' group and N is a mono- or bi-cyclic saturated or unsaturated heter BACKGROUND OF THE INVENTION 5 ocyclic ring, wherein each ring consists of 3 to 7 1. Field of the Invention members selected from the group consisting of The present invention relates to prodrugs of thera carbon, nitrogen, oxygen and sulfur; peutic hydroxyaromatic compounds (HAC), e.g., phe 2 is a displaceable leaving group; and nols and catechols. n is an integer in the range of from 1 to 3, and (B) 1. Description of the Prior Art O pharmaceutically acceptable salts thereof; There are many drugs that contain phenol or cate the prodrug having enhanced stability against prema chol groups which suffer from premature metabolism at ture metabolism upon oral administration and the hydroxy group during absorption after oral adminis being chemically hydrolyzable to the HAC drug. tration. Previous efforts to protect the hydroxy groups It is a further object of the invention to provide a have been generally unsuccessful since the protecting 15 pharmaceutical composition in unit dosage form groups employed to date are either too labile (O-COR or OECR) or too stable (CH3). adapted for oral administration to a human or non It is an object of the present invention to provide human animal in need thereof comprising a therapeuti prodrugs of therapeutically effective phenols and cate cally effective amount of a prodrug described above chols which may be administered orally and are not 20 and a pharmaceutically acceptable carrier therefor. subject to premature metabolism but which hydrolyze It is still a further object of the present invention to readily at the intended site of treatment to release the provide a method of treatment comprising orally ad active drug. ministering to a human or nonhuman animal in need It is a further object of the present invention to pro thereof a therapeutically effective amount of a prodrug vide a pharmaceutical composition comprising a pro- 25 described above. drug which may be more readily orally administered than the corresponding drug. DETAILED DESCRIPTION OF THE It is a further object of the present invention to pro INVENTION vide a therapeutic method of treatment involving the The above-described prodrugs are more stable oral administration of a prodrug which has an enhanced 30 against premature metabolism than the free phenols, stability over the corresponding drug. catechols or HAC. Although oral administration of the phenolic or catecholic drugs is greatly enhanced by the SUMMARY OF THE INVENTION present invention, other routes of administration are The above and other objects are realized by the pres also improved. The present invention permits oral dos ent invention which provides a pharmaceutically ac 35 ing of drugs that must presently be administered IV ceptable prodrug of a biologically active, therapeuti thereby rendering administration of these drugs less cally effective hydroxyaromatic compound (HAC), costly and more convenient. said prodrug being selected from the group consisting The above-described hydroxy-protecting groups sta of (A) compounds having the structural formula: bilize the HAC against premature metabolism such as glucuronidation or sulfation in the gut or in the liver. As used in the present context, "premature hydrolysis" wherein: DRUG-O-is the HAC O-dehydro residue means hydrolysis before the prodrug reaches its target of the drug; organ and releases the parent HAC drug. Since a pro R" and R' may be the same or different and are se 45 drug (whether the mechanism of release of the parent lected from the group consisting of H, cycloalkyl drug is enzymatic, as in the ususal case, or chemical, as groups having up to 10 carbon atoms, straight or according to the present invention) releases the parent branched chain alkyl, alkenyl and alkynyl groups drug continually from the site of application to the of 1 to 10 carbon atoms, wherein the chains thereof target organ, 100% protection from premature hydroly (1) may be interrupted by at least one N, S or O 50 sis or metabolism is unattainable. However, the chemi atom, or (2) may be substituted by at least one cal nature of the mechanism of release in the present group selected from the group consisting of invention has the advantage over enzymatic mecha COR", COOR" and CONOR"), hydrocarbyl nisms in that it is not subject to the interpatient variabil aryl groups, aryl groups substituted by at least one ity associated with the latter. group selected from the group consisting of 55 The excellent "leaving' properties of Z enable a COR", COOR", CONOR"), N(R"), OR", facile chemical hydrolysis to the active drug, the rate of halogen, SR", NO2 and R", mono- and bi-cyclic which depends on the chemical structure of Z and the saturated or unsaturated heterocyclic rings, each pH of the environment. Thus, the prodrugs of the pres ring consisting of 3 to 7 members selected from the ent invention are more stable at an acidic pH and group consisting of carbon, nitrogen, oxygen and 60 would, therefore, remain relatively stable during pas sulfur, CN, COR", COOR", CONOR") and sage through the stomach but would hydrolyze to re C(halogen)3; lease the parent drug more readily in the higher pH's R" is selected from the group consisting of cycloal existing, for example, in plasma. The prodrugs of the kyl groups having up to 10 carbon atoms, straight present invention are relatively stable at acidic pH's and or branched chain alkyl, alkenyl and alkynyl 65 relatively labile at basic pH's. groups having 1 to i0 carbon atoms, straight or R" and R' are as defined above and may be any suit branched chain alkyl, alkenyl and alkynyl groups able electron withdrawing group such as those de of 1 to 10 carbon atoms wherein the chains thereof scribed above and those referenced in J. March, "Ad 5,001,115 3 4 s: Organic Chemistry", 3d. Ed., pp. 242-250 -continued The term "O-dehydro residue" of a bioaffecting hy- cool droxyaromatic compound (HAC) as used herein is in tended to include those radicals that would result from 5 removal of one or more of the protons from an OH group attached to the aromatic nucleus of an HAC, leaving a free or unsatisfied valence bond in its stead, i.e., that valence bond which defines the bridge to the salicylate residue Z-CR'R' moiety of the compounds of the above 10 structural formula (A). COOH Representative of such radicals are: F O OH CH3 15

O CH-CH-NH2 F .C4H6O6 diflunisal residue 20 metaraminol bitartrate residue O OH H (C2H5)2N(CH2)3NHCH2 N / O CH-CH2-N HC CH3 25 Cl phenylephrine hydrochloride residue clamoxyquin residue

g-Hs 30 HO c= O C2H5 diethylstilbestrol residue 35 . H2SO4

OH CH3CONH O morphine sulfate residue 40 acetaminophen residue C2H5

Olso CH3 45 C2H5 O diethylstilbestrol residue CH3 homosalate residue 50 O OH

O 55 CH2(CH2)4CH3 O CH2(CH2)4CH3 - 4-hexyl resorcinol residue 4-hexylresorcinol residue O O O 60 Cl S C

OH CH2(CH2)4CH3 4-hexylresorcinol residue bithionol residue 5,001,115 5 6 -continued the appropriate acid to form the corresponding salt. The salt is recovered by standard recovery techniques, H3C-N for example, by filtration of the desired salt or spontane ous separation from the solution, or it can be precipi tated by the addition of a solvent in which the salt is insoluble and recovered therefrom. Examples of suitable inorganic and organic solvents for performing the various reactions include any inor ganic or organic solvent that does not adversely affect O O HC O the reactants or the resulting product, including haloge apomorphine hydrochloride residue nated solvents such as methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, ether solvents O O O such as diethyl ether, dimethyl ether, and other solvents such as tetrahydrofuran, dioxane, diglyme, n-hexane, 5 cyclooctane, benzene, heptane, cyclohexane; mixtures thereof, and the like aliphatic, cycloaliphatic and aro H3C m O matic hydrocarbon solvents, water, acidified aqueous 9. solutions, mixed organic and inorganic solutions, ethyl acetate, propyl acetate, and the like. enodin residue 20 The bio-affecting HAC's from which the prodrugs of the present invention can be derived are legion. In es O sence, any compound which contains at least one ben COCH2OH Zene ring having at least one hydroxy group directly attached to the ring and which is biologically active can 25 be derivatized according to the invention to afford the H corresponding prodrugs of formula (A). Specifically, OCH3 O O H O included are the corresponding derivatives of natural H O sympathetic or sympathomimetic amines. Also, as will CH3 30 be clear from the discussion and examples which fol H H low, in some cases the parent HAC contain reactive H O H moieties in addition to the hydroxyaromatic group(s) H which should be protected during the reaction which NH forms the Z CR'R'' ethers. The protecting groups are 35 then subsequently removed to afford the desired com doxorubicin residue pounds. One important group of bio-affecting HAC which By "pharmaceutically acceptable salt", there are in can be derivatized according to the present invention tended the conventional non-toxic acid addition or qua consists of the sympathomimetic amines or adrenergic ternary ammonium salts of the compounds of the above agents and structurally related compounds. Especially structural formula (A), formed, e.g., from non-toxic significant members of this group are hydroxyampheta inorganic or organic acids. For example, such conven mine, hydroxyamphetamine hydrobromide, metarami tional non-toxic salts include those derived from inor nol, metaraminol bitartrate, phenylephrine hydrochlo ganic acids such as hydrochloric, hydrobromic, sulfu ride, oxymetazoline hydrochloride, albuterenol (al ric, sulfamic, phosphoric, nitric and the like; and the 45 buterol), carbuterol hydrochloride, deterenol hydro salts prepared from organic acids such as acetic, propi chloride, quinterenol sulfate, soterenol, sulfonterol hy onic, succinic, glycolic, stearic, lactic, malic, tartaric, drochloride, isoxuprine hydrochloride (isoxsuprine), citric, ascorbic, pamoic, maleic, hydroxymaleic, phen nylidrin hydrochloride, bannethan, bamethan sulfate, ylacetic, glutamic, benzoic, salicylic, sulfanilic, fumaric, mesuprine hydrochloride and ritodrine hydrochloride. toluenesulfonic, and the like. Preferred salts of the in vention are those derived from the same acids as are the 50 Examples of other parent phenols in this category in generally preferred salts of the parent phenols, e.g., the clude, without limitation, benserazide, dimethophrine, hydrochlorides in the case of phenylephrine deriva di-etillefrin, hordenine, p-hydroxyephedrine, ifenprodel, tives. leptodactyline chloride, leptodactyline picrate. norfene The pharmaceutically acceptable salts of the present frine, octopamine, phentolamine, pholedrine, syneph invention can be synthesized from the compounds em 55 rine, tyramine, and ethanivan. braced by the structural formula by conventional chen Another significant group of HAC which can be ical methods. Generally, the salts are prepared by react derivatized to form the compounds of formula (A) in ing the free base with stoichiometric amounts of, or cludes salicyclic acid, its derivatives and chemically with an excess of, the desired salt-forming inorganic or related compounds, e.g., non-steroidal anti-inflamma organic acid in a suitable solvent or various combina tory agents, non-narcotic analgesics, antipyretics, anti tions of solvents. For example, the free base can be tuberculars, antimicrobials, antibacterials, antifungals, dissolved in a mixed aqueous solution of the appropriate antirheumatics, sunscreening agents, anthelmintics, an acid and the salt recovered by standard techniques, for esthetics, topical antiinfectives, and miscallaneous other example, by evaporation of the solution. Alternatively, structurally related compounds. For example, there can the free base can be charged into or organic solvent 65 be mentioned acetaminophen, eugenol, p-animosalicylic such as a lower alkanol, a symmetrical or asymmetrical acid, 4-benzamidosalicylic acid, calcium benzoylpas, ether containing 2 to 10 carbon atoms, an alkyl ester, or biphenamine, buclosamide, homosalate, hydroxy mixtures thereof, and the like and then it is treated with procaine, methyl salicylate, oxybenzone, dioxybenzone, 5,001,115 7 8 phenyl aminosalicylate, salicyl alcohol (saligenin), sali quinaldol, 5-chloro-8-quinolinol, clamoxyquin, 8 cylamide, salicylic acid, salicylsalicylic acid (salsalate), hydroxy-7-iodo-5-quinolinesulfonic acid, iodochlorhy sodium salicylate, difunisal, dibromsalan, fursalan, droxyquin, octoquin methylsulfate and oxyquinoline metabromsalan, bensalan, salethamide, and salcolex. benzoate. Exemplary of other members of this class are Other examples of parent compounds encompassed by 8-hydroxyquinoline, chloroxine, amodioguin, diiodohy this group include p-amino-salicylic acid hydrazide, droxyquin and nitroxoline. ammonium salicylate, 5-bromo-4'-chlorosalicylanilide, Another important group of bio-affecting HAC com 5-bromosalicylhydroxamic acid, p-butylaminosalicylic prises the anthelmintics, which often consist of at least acid 2-diethylaminoethyl ester, 3'-carboxy-4-hydrox two variously substituted benzene rings, attached di ycinchophen, choline salicylate, 3,5- 10 rectly to each other or via a bridge (e.g., -S-, dibromosalicylaldehyde, fluorosalan, flopropione, gal -CH2-, etc.), at least one of the rings bearing at least lacetophenone, gentisic acid, 4-hydroxyisophthalic one nuclear hydroxy group. However, some anthelmin acid, hydroxytetracaine, N-isopropylsalicylamide, ni tics are one-ring systems, while yet others contain two closamide, osalmid, oxyclozanide, oxyphenbutazone, or more fused rings. Illustrative of anthelmintics which Pascaine (R) (hydroxyprocaine p-aminosalicylate), phen 15 can be derivatized according to the present invention etsal, phenyl salicylate, resorantel, salacetamide, salicyl, are bithionol, dichlorophene, 4-hexylresorcinol, rafoxa salicylanilide, salazosulfadimidine, salazosulfamide, sali nide, aspidin, aspidinol, carvacrol, harmalol, menichlo cylazosulfapyridine, 4-salicyloxymorphine, 4-sul pholan, 2-naphthol, disophenol and thymol. fanilamidosalicylic acid, o-thymotic acid, 3,4,5-tri Still another significant group of bioaffecting HAC chlorosalicylanilide, xipamide, amidan, bromosaligenin 20 whose members can be derivatized according to the and 3,5-diiodosalicylic acid. present invention comprises relatively simple one ring Yet another important group of parent HAC com (e.g., the phenols) and bridged systems (e.g., the Salans). prises the synthetic (non-steroidal) estrogens, for exam Many of the members of this group have germicidal, ple, benzestrol, dinestrol, diethystilbestrol, hexestrol, fungicidal, etc., properties and are useful as topical mestilbol and promethestrol. 25 antiinfectives, for example, fentichlor, phenol, penta Another group of HAC comprises Vitamins K and E chlorophenol, resorcinol, hexachlorophene, chloro and structurally related compounds having Vitamin K phene, dibromsalan, bensalan, fursalan, metabromsalan, or E type activity. In the Vitamin K (antihemorrhagic) tribromsalan, dimethylcyclohexyl phenol, 6-n-amyl-m- sub-group, one can mention Vitamin K5, 4-acetamido-2- cresol, acetomeroctol, butylparaben, 4-chloro-m-cresol, methyl-1-napthol and juglone. In the Vitamin E group, 30 p-chlorophenol, chlorothymol, 4-chloro-3,5-xylenol, in addition to Vitamin E (a-tocopherol), one can men chloraphine, p-cresol, 3,5-dibromo-4-hydroxybenzene tion g-tocopherol, y-tocopherol, 8-tocopherol and sulfonic acid, Dowicide 9, o-hydroxyphenylmercuric tocol antioxidant as suitable parent phenols for use in chloride, methylparaben, fluorosalan, p-pentyloxy the present invention. phenol, 2-phenyl-6-chlorophenol, o-phenylphenol, pic Another very significant group of HAC which can be 35 ric acid, propylparaben, pyrocatechol, pyrogallol, derivatized to form the prodrugs of formula (A) include 3,4,5,6-tetrabromo-o-cresol, 2,4,6-tribromo-m-cresol, morphine and other narcotic analgesics and narcotic 2,4,5-trichlorophenol and 2,4,6-trichlorophenol. Other antagonists. Particularly significant members of this members of this structural group include anacardiol group are apomorphine, hydromorphone hydrochlo (analeptic), apocynin (cardiotonic), gallic acid (astrin ride, ketobemidone, morphine, morphine hydrochlo gent), guaiacol (expectorant), bufeniode (antihyperten ride, morphine N-oxide, nalorphine hydrochloride, nal sive), capsaicin (counterirritant), cotoin (antidiarrheal), oxone hydrochloride, pentazocine, levorphanol tar cyclovalone (chlorectic), dobesilate calcium (vaso trate, metopon hydrochloride, buprenorphine hydro tropic), fendiazole (hypnotic), a-(p-methoxyphenol)-a- chloride, butophanol, cyclazocine, profadol hydrochlo 2-pyridyl-p-cresol (cathartic), mexenone (sunscreen), ride, levallorphan tartrate, alazocine, nalbufine hydro 45 monobenzone (depigmentor), orthocaine (topical anes chloride, oxilorphan, nalmexone hydrochloride, nal thetic), paroxypropione (pituitary gonadotropic hor trexone and apocodeine. Further illustrations of men mone inhibitor), 3-pentadecylcatechol (allergen), phe bers of this group are cyclorphan, desomorphine, dihy nolphthalol (cathartic), phloroglucinol (antispasmodic), dromorphine, 3-hydroxy-N-methylmorphinane, hy probucol (antichloesteremic), TFM (sea lamprey killer), droxypethidine, levophenacylmorphan, metazocine, 50 3,4-6-trichloro-2-nitrophenol (sea lamprey killer), uru norlevophanol, normorphine, oxymorphone, phenazo shiol (allergen, poison ivy desensitizer), vanitiolide cine, penomorphan, pholcodine and cyprenorphine. (chloeretic), hydroquinone (depigmenting agent) and Another group of bio-affecting HAC from which the monobenzone (depigmenting agent). instant prodrugs can be derived consists of the tetracy Yet another significant group of HAC which can be cline-type antibiotics. Particularly noteworthy mem 55 derivatized to form compounds of formula A consists of bers of this group include tetracycline, tetracycline antibiotic/antibacterial/antimicrobial agents, for exam hydrochloride, chlortetracycline, demeclocycline, ple, the rifamycins (e.g., rifamycin B, rifamycin SV), doxycycline, oxytetracycline, apicycline, clomocycline, xanthocillin (X, Y and Y2) and amoxicillin. Other mem guamecycline, methacycline, rollitetracycline, rollitetra bers of this group include celesticetin, chartreusin, no cycline nitrate sequihydrate, sancycline, lymecycline, vobiocin, resistomycin, rifamide, rifampin, albofungin, mepicycline and minocycline. Formecin A, hygromycin, Acroteben (R) (anti-tubercu A further group of bio-affecting HAC which can be lar), amindan, antranorin, azosulfamide, diathymosul derivatized according to the present invention com fone, Flavoteben (anti-tubercular), l-isonicotinoyl-2- prises 8-hydroxyquinoline and structurally related com salicylidenehydrazide (anti-tubercular), lasalocid, pounds, which variously possess activities such as anti 65 myxin (antifungal), siccanin (antifungal), tyrocidine A, bacterial, fungistatic, antimalarial and antiamebic. Many tyrocidine B, tyrocidine C and antinorhordine. of these compounds find utility as anti-infectives. Espe Another important group of HAC comprises antineo cially important members of this class include chlor plastic agents, for example, mycophenolic acid, anthra 5,001,115 10 mycin, carvicarcin, 5-hydroxytryptophan and pactany malarials, antiamebics, antiprotozoals, poultry coccidio Cl. stats and related veterinary products, e.g., bebeerine Yet another noteworthy group of HAC which can be (antimalarial), bialamicol (antiamebic), cephaeline (anti derivatized according to the present invention are typi amebic), diloxanide (antiamebic), lasalocid (poultry fied by an anthraquinone or anthracene-type structure. coccidiostat) and phlorizin (antimalarial). Also to be Exemplary of this group are enodin, aloeemodin, aloin, mentioned here are acetarsone (antitrichomonal; an danthron and frangulin, all of which have utility as tihistomonad in turkeys; spirochetocide in turkeys), catharitics. Other members of this structural group in acetarsone diethylamine salt (antisyphilitic; for Swine clude doxorubicin (antibiotic/neoplastic), anthrarobin dystentery), arsphenamine (antisyphilitic), arsthinol (parasiticide) and dithranol (antifungal). O (antiprotozoal), dichlorophenarsine hydrochloride (an Another group of parent bio-affecting HAC com tisyphilitic), neoarsphenamine (for equine petechial prises compounds containing a benzopyran-type struc fever), oxophenarsine hydrochloride (anti ture, for example, catechin (astringent), baicalein (as trypanosamol), phenarsone sulfoxylate (antiamebic), tringent), 3-dibutylaminomethyl-4,5,6-trihydroxy-1- roxarsone (control of enteric infections; to improve isobenzofuranone (antihistaminic), eridictyol (expecto 15 growth and feed efficiency), spirotrypan (antisyphilitic, rant), eupatorin (emetic), formononetin (diuretic) and antitrypanosomal), and sulfarsphenamine (antisyphi hymecromone (choleretic, antispasmodic). litic). Yet other bio-affecting HAC which can be deriva Another group of HAC for possible derivation ac tized to form the prodrugs of the invention include cording to the present invention include 2-cyclohexyl benzofuran-type, isobenzofuran-type, indanetype, and 20 2,6-dinitrophenol (insecticide), 2,4-dinitrophenol (weed other fused systems, which optionally contain one or killer), 4,6-dinitro-o-cresol (selective herbicide, insecti more hetero atoms. Such phenols include benzarone cide), MON-0585 (insecticide, especially for mosquito (for increased capillary fragility), benzbromarome (uri larvae) and pentachlorophenol (insecticide for termite cosuric), benziodarone (coronary vasodilator), bufote control). nin (hallucinogen), bismuth sugallate (astringent, ant 25 In addition, the present invention contemplates pro acid), counetarol (anticoagulant), 2-(2-hydroxy-1- drugs corresponding to formula (A) but wherein drug naphthyl)cyclohexanone (anti-tussive), quercetin (to -O-mono- or polydeprotonated residue of a bio-affect decrease capillary fragility), rutin (to decrease capillary ing heteroaromatic compound bearing at least one nu fragility), tioxolone (antiseborrheic), troxerutin (for clear hydroxy substituent. The parent heteroaromatic venous disordics) and chlorindanol (spermicide). Other 30 which can be derivatized according to the present in such phenols include phenolphthalein, phenolsulfon vention can be mono- or polycyclic. In the latter case, phthalein, phenoltetrachlorophthalein and sulfobromo one or more rings will be heteroaromatic. Exemplary of phthalein sodium, all of which are useful as catharitics such compounds are clopidol, buquinolate and and/or diagnostics for renal function. Still other such proguinolate (all of which are poultry coccidiostats), phenols include salsoline (antihypertensive), meralein 35 pyridoxine hydrochloride (Vitamin B6 hydrochloride), sodium (topical anti-infective), scarlet red (promotes and structurally related compounds such as pyrisuc wound healing), synhexyl (psychotomimetic), umbellif cideanol (an antidepressant) and pyrithioxin (a neuro erone (sunscreen), serotonin (smooth muscle stimulant) tropic agent). Accordingly, preferred parent heteroaro and Al tetrahydrocannabinol (hallucinogen). Other bio matics which can be derivatized according to the inven affecting phenols of relatively complex structures in tion contain at least one pyridine or quinoline ring sys clude boldine (diuretic), bulbocapnine (for Meniere's tem bearing at least one nuclear hydroxy substituent on disease and other muscular tremors), elagic acid (he the heteromatic ring. mostatic), hypericin (antidepressant), neohesperidin In the discussion which follows, for the sake of con dihydrochalcone (sweetening agent), polyamine-meth venience, the synthetic methods, pharmaceutical com ylene resin (antacid), silybin (in liver dysfunction), d 45 positions, etc., will be discussed in terms of the HAC of tubocurarine chloride (skeletal muscle relaxant, diag the invention. It is to be understood, however, that this nostic aid for myasthenia gravis), zearalenone and Zera discussion is equally applicable to the corresponding nol (anabolics), and fluorescein and fluorescein (diag compounds in which drug -O- is the mono- or nostics for corneal trauma). polydeprotonated residue of a bio-affecting heteroaro Yet another group of HAC which can be derivatized 50 matic compound bearing at least one nuclear hydroxy according to the present invention include tyrosine and substituent. thyroxine and their derivatives. These include 3,5- In the above structural formula, Z is preferably the dibromotyrosine, 3,5-diiodotyrosine and 3-fluoro-4- dehydro residue of the compound Z H, wherein the hydroxyphenylacetic acid (thyroid inhibitors); tyrosine, pKa of Z H-Z + His the range of from 1.0 to 12.0. m-tyrosine and dipeptides and polypeptides containing 55 Illustrative of such leaving groups are those described same; a-methyl-m-tyrosine (inhibitor of catecholamine by J. March, "Advanced Organic Chemistry, 3rd Ed., synthesis); a-methyl-ptyrosine (tyrosine hydroxylase pp. 310-316 (1985); J. Chem. Res., Vol. 12, p. 198 inhibitor, L-form as antihypertensive); L-a-aspartyl-L- (1979); Tetrahedron, Vol 36, p. 679 (1980) and Angew. tyrosine methyl ester (sweetening agent); hinderin (thy Chem. Int. Ed. Engl. Vol, 23, p. 420 (1984); e.g., roid inhibitor); sodium levothyroxine (thyroid hor mone); thyroxine (L-form as thyroid hormone, D-form O as anticholesteremic); dextrothyroxine sodium (anti I I C C cholesteremic); 3,3',5-triiodothyroacetic acid and 3,5,3'- V V triiodothyronine (thyroid replacement therapy); and W N- W N 3,3,5-triiodothyropropionic acid (in hypercholesterol 65 / W emia, myxedema or gout). S C Other bio-affecting HAC which can be derivatized Y V N Y according to the present invention include various anti O O 5,001,115 1. 12 -continued O "Protective Groups in Organic Synthesis", John Wiley & Sons, N.Y. (1981). O O O O EXAMPLE C C N S7 5 This example illustrates the preparation of the pro C VN-, V N-H W V N-, drugs of the invention using p-nitrophenol as a model phenolic drug and saccharinylmethyl ether as the OH c c s' protecting agent in the following reaction scheme: 5 Y AN 10 O O O OH O C V K2CO3 C C O 7 N V Ys?eo W N-CH.C. -- CO N- W N. 15 S d c1 N- N OVN O No. O O Y O O O O 20 C V W N / N-CH2O NO2 C-N-S-Go, (R-SN-, (R'c)-N- 25 y \, wherein W and Y may be the same or different and are selected from the group consisting of COR", The product hydrolyzed in pH = 7.1 buffer at room COOR", CONOR"), N(R"), OR", halogen, temperature with a half-life of about 17 min. (pKa of SR", NO2 and R' wherein R" has the meanings 30 ZH = 1.6). ascribed above. The compounds: The compounds X-CR'R' 2 may be prepared by the reaction of ZH with O=C-R'R' to yield (a) HOCR'R' 2 which is then allowed to react with a chlorinating agent (e.g., SOCl2, PCls, POCl3, etc.) to 35 yield ClCR'R'2 where X=Cl. The latter can be con C-NH-CH2-O NO2 and verted to X=I by the reaction of ClCR'R'2 with NaI in acetone. HOCR'R'2 can be converted to X=Brby reaction with SOBr2, etc., or to X=tosyl by reaction O (b) with tosyl chloride in the presence of an acid scavenger such as pyridine. The above-described prodrugs may be prepared by reacting n equivalents of the above compound having the structural formula: 45

wherein X is an anion such as Cl, Br, I, tosyl, etc., and were prepared similarly to the above product and their R", R'' and Z have the above ascribed meanings hydrolytic properties under similar conditions were with the HAC drug DRUG-(OH)n in the presence evaluated. Compound (a) was completely stable at of an acid scavenger (e.g., Et3N, K2CO3) accord 50 pH=7.1 (pKa of ZH = 16) whereas compound (b) hy ing to the following reaction formula: drolyzed with a half-life of about 6 hours (pKa of ZH =9.6). The compounds of the following examples were pre 55 pared according to the following general method: The reaction is preferably conducted in an inert solvent To an acetone (20 ml) solution of chloromethylsac for the reactants and reaction products (e.g., acetone, charin (2.3 g, 0.010 mole) and an equivalent amount of methylethylketone, 3-hexanone, etc.) at 0° C. to the anhydrous sodium iodide (1.5 g, 0.010 mole) was added reflux temperature of the solvent for 1-48 hours. anhydrous potassium carbonate (1.4g, 0.010 mole) and It will be apparent to those skilled in the art that the the desired phenol (0.010 mole) or catechol (0.0050 HAC may contain functional groups besides the hy mole). The suspension that resulted was stirred at room droxyaromatic groups which may be subject to alkyla temperature for one to two days. The suspension was tion under the above conditions. It will, accordingly, be diluted to 150 ml with dichloromethane and filtered. necessary to transiently protect such groups with con The filtrate was concentrated and the concentrate ei ventional protecting groups during formation of the 65 ther was crystallized directly from acetone or was parti prodrugs of the invention. Protecting groups for the tioned between dichloromethane and aqueous sodium various functional groups are well known in the art and hydroxide. In the latter case the dichloromethane solu are litsted, for example, in Theodora W. Greene's book tion was separated, dried over sodium sulfate and con

5,001,115 15 16 Anal. Calcd for C15H10NOs: C, 60.20; H, 3.34; N, sisting of 3 to 7 members selected from the group 9.36. Found: C, 60.33; H, 3.43; N, 9.32. consisting of carbon, nitrogen, oxygen and sulfur, CN, COR', COOR", CONOR") and C(halo EXAMPLE 14 gen)3; Phthalimidylmethoxybenzene 5 R" is selected from the group consisting of cycloal mp 140-143', lit (J. Org. Chem., (1963) 28, 2925) mp kyl groups having up to 10 carbon atoms, straight 140-141, 52% yield; TLC (silica gel, ether) R-0.50; or branched chain alkyl, alkenyl and alkynyl NMR (CDCl3) 88.0-7.7 (n, 4, aromatic-H), 7.5-6.95 groups having 1 to 10 carbon atoms, straight or (m, 5, aromatic-H), and 5.72 (s, 2, N-CH2O). branched chain alkyl, alkenyl and alkynyl groups Anal Calcd. for Cish Nos; C, 71.15, H, 4.38; N, ' of 1 to 10 carbon atoms wherein the chains thereof 5.53. Found: C, 71.23; H, 4.41; N, 5.49. may be interupted by at least one N, S or O atom, I claim: 1. A pharmaceutically acceptable prodrug of a bio hydrocarbyl aryl groups, and in the case of logically active, therapeutically effective hydroxyaro -N(R')2 taken with the other R' group an N is a 15 mono- or bi-cyclic saturated or unsaturated matic compound (HAC) drug, said prodrug being se hetereocyclic ring, wherein each ring consists of 3 lected from the group consisting of (A) compounds to 7 members selected from the group consisting of having the structural formula: carbon, nitrogen, oxygen and sulfur: . DRUG--O-CRTR'Z. 2 is a displaceable leaving group and is the dehydro 20 residue of the compound Z-H wherein the pKa of wherein: 2-H-Z + H+ is the range of from 1.0 to 12.0; DRUG-O-is the HAC O-dehydro residue of the and drug; n is an integer in the range of from 1 to 3, and R" and R" may be the same or different and are se (B) pharmaceutically acceptable salts thereof; lected from the group consisting of H, cycloalkyl 25 said prodrug having enhanced stability against pre groups having up to 10 carbon atoms, straight or mature metabolism upon oral administration and branched chain alkyl, alkenyl or alkynyl groups of being chemically hydrolyzable to the HAC drug. 1 to 10 carbon atoms, wherein the chains thereof 2. A pharmaceutical composition in unit dosage form (1) may be interrupted by at least one N, S or O adapted for oral or topical administration to a human or atom, or (2) may be substituted by at least one 30 non-human animal in need thereof comprising a thera group selected from the group consisting of peutically effective amount of a prodrug of claim 1 and COR", COOR" and CON(R"), hydrocarbyl a pharmaceutically acceptable carrier therefor. aryl groups, aryl groups substituted by at least one 3. A method of treatment comprising orally or topi group seelcted from teh goup consisting of COR', cally administering to a human or non-human animal in COOR", CONOR")2, N(R")2, OR", halogen, 35 need thereof a therapeutically effective amount of a SR", NO2 and R", mono- and bi-cyclic saturated prodrug of claim 1. or unsaturated heterocyclic rings, each ring con k k xx

UNITED STATES PATENT AND TRADEMARK OFFICE . CERTIFICATE OF CORRECTION

PATENT NO. : 5,001,115 DATED : March 19, 1991 NVENTOR(S) : Kenneth B. Sloan it is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Column 15, line 34 of claim 1 : delete "seelcted" and insert

-- selected-- ; delete 'teh goup' and substitute -- the group -- .

Column l6, line 13 of claim 1 : delete 'an' and insert --and--.

Column l6, line 21, before 'is' insert a space and after 'is' insert -- in--.

Signed and Sealed this

First Day of September, 1992

Attest:

DOUGLAS B. COMER

Attesting Officer Acting Commissioner of Patents and Trademarks