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

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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.
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