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United States Patent (19) 11 Patent Number: 5,242,905 Blank (45) Date of Patent: Sep

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United States Patent (19) 11 Patent Number: 5,242,905 Blank (45) Date of Patent: Sep US00524290SA United States Patent (19) 11 Patent Number: 5,242,905 Blank (45) Date of Patent: Sep. 7, 1993 (54) PHARMACEUTICAL COMPOSITIONS FOR Thaler et al., J. Invest. Dermatol. 75, 156-158 (1980). THE TREATMENT OF PSORASIS Steinert et al., Biochemistry of Normal and Abnormal Differentiation, eds. I. A. Bereinstein and M. Seiji, (75) Inventor: Izhak Blank, Kiriat Onu, Israel Tokyo University Press, pp. 391-406 (1980). 73 Assignee: Dexter Chemical Corporation, Bronx, J. Marach, Advanced Organic Chemistry, 3d ed., p. N.Y. 339, J. Wiley and Sons, New York (1985). (21) Appl. No. 732,342 Lochmueller, C. H. et al., Direct gas chromatographic resolution of enantiomers on optically active meso 22 Filed: Jul. 17, 1991 phases. IV. Effect of structure on selectivity and liquid crystalline behavior, J. Chromat. 178, 411-417 (1979). Related U.S. Application Data Meek, J. L., Derivatizing reagents for high-perfor 63 Continuation of Ser. No. 239,675, Sep. 2, 1988, aban mance liquid chromatography detection of peptides at doned. the picomole level, J. Chromat. 266, 401-408 (1983). 30 Foreign Application Priority Data Augustin, M., N-Maley amino acids and peptides, Z. Chem. 25, 18-19 (1985). Sep. 4, 1987 IL Israel ....................................... 83775 Portoghese, P. S. et al., Synthesis and opioid antagonist 51 int.C.'.............................................. A61K 37/02 potencies of Naltrexamine Bivalent Ligands with Con 52 U.S.C. ...................................................... 514/19 formationally Restricted Spacers, J. Med. Chem. 29, 58 Field of Search ........................... 514/19; 560/169 1650-1653 (1986). Schellenberger, V. et al., A. spectrophotometric assay (56) References Cited for the characterization of the S subsite specificity of U.S. PATENT DOCUMENTS a-chymotrypsin, Bioch, et Bioph. Acta 869, 54-60 3,458,304 7/1969 Hageman et al. ................... 560/169 (1986). 3,950,392 4/1976. D'Alelio .............................. 560/169 Nieboer C. et al., Systemic therapy with fumaric acid derivatives: New possibility in the treatment of psoria FOREIGN PATENT DOCUMENTS sis, J. Am. Acad. Derm. 20, 601-607 (1989). 7,8342 6/1965 Canada . Chemical Abstract No. 83-114855b. 0188749A2 12/1985 European Pat. Off. 2530372A1 7/1975 Fed. Rep. of Germany. Primary Examiner-Lester L. Lee 2621214C3 5/1976 Fed. Rep. of Germany. Attorney, Agent, or Firm-Curtis Morris & Safford 284.0498 9/1978 Fed. Rep. of Germany. 2901452 1/1979 Fed. Rep. of Germany . 57 ABSTRACT 3232883A1 9/1982 Fed. Rep. of Germany . The invention comprises compositions and methods for S86682 7/1968 France . the treatment of psoriasis. The compositions comprise OTHER PUBLICATIONS compounds of the formula: A. Lahti et al., Contact Dermatitis, 12, 139-140 (1985). A. Lahti et al., "Pharmaceutical Studies on Nonim COR munologic Contact Urticaria In Guinea Pigs', Arch. HC I Dermatol. Res., 299, 44-49 (1986). CH W. Raab, H&G Nr. 10 (1984). / Lahty et al., Contact Dermatitis 3, 139-140 (1985). COR2 Schafer G., Fumarsauretherapie der Psoriasis, Arz tliche Praxis 30, 61, 1757-58 (1978). Selecta 15, 1260-61 (1984). 1 Clain, No Drawings 5,242,905 1. 2 crystalline and can be used for the preparation of tab PHARMACEUTICAL COMPOSITIONS FOR THE lets, capsules, etc., in combination with metal salts of TREATMENT OF PSORASIS fumaric esters, as mentioned before, and also with the optional addition of amino acids such as cysteine and This application is a continuation of application Ser. 5 methionine, and of vitamin C. No. 239,675, filed Sept. 2, 1988, and now abandoned. There exist serious problems as to the use of the above in the therapy of psoriasis. Short-chain fumarate BACKGROUND OF THE INVENTION esters are in general irritating materials which fre Psoriasis is one or the most widespread chronic dis quently produce an unpleasant acidosis effect upon eases. It affects about two percent of the adult white 10 ingestion. Metal salts of the half esters are quickly con population, the most severe symptoms being shown by verted in the stomach into the free acid and the respec patients in the age groups between twenty and fifty tive metal hydrochloride. The same happens with the years old. caffein-ether salt. The esters are liquid at room tempera Psoriasis is characterized by a greatly accelerated ture and in order to convert them to tablets they have to rate of epidermal turnover. Instead of the normal period 15 be adsorbed on, or mixed with, a rather large quantity of 28 days from the time of cell division in the basal of inert carrier. Furthermore, they have a strong char layers until the cellis shed from the stratum corneum, in acteristic odor and their toxicology has not been studied psoriasis this takes only about four days. extensively. According to a study made with mice, The causes and mechanism of development of psoria monoethyl fumarate and dimethyl fumarate given per sis are unknown, and for this reason a completely effec os had an LD50 above 100 mg/kg. Monoethyl fumarate, tive treatment for this ailment does not yet exist. A great given intraperitoneally, was more toxic (W. Raab, H&G number of approaches have been tried, from the very Nr. 10 (1984)). These fumarate esters are highly irritat old, based on natural tars, to the more modern using ing to the skin and can produce contact urticaria (A. steroids, sporalene, etc. Tars are messy to apply and Lahti et al., Contact Dermatitis, 12, 139-140 (1985)). have only a limited effect. Their combination with sul 25 To summarize: mono and diesters of fumaric acid fur and salicylic acid are not much better. This therapy have been shown to be effective in the treatment of is frequently supplemented by the use of ultraviolet psoriasis, as the experience with several thousand pa (UV) radiation, either natural (sunshine) or artificial tients indicates (see, for instance: Schafer G. Fumar (lamps). Other compounds used are: steroids, azaribine, sauretherapie der Psoriasis, Arztliche Praxis 30, 61 p. methotrexate, psoralen, and retinoic acid derivatives. 30 1757-58 (1978); also, Selecta 15, p. 1260-61 (1984)). The All of these have a rather high toxicity and their long esters are irritating to the digestive system and to the term use may result in noxious side effects. skin and their toxicology has not been clearly estab A possible approach to the therapy of the disease is to lished; they are also difficult to formulate as tablets. try to influence cellular metabolism, which obviously is Recent studies have shown that in psoriatic skin the much more active in the psoriatic cells than in the nor 35 content of glycine and serine is about twenty-five per mal ones. cent lower than in normal skin (Thaler et al., J. Invest. A few years ago, a new treatment was proposed. This Dermatol. 75, 156-158 (1980); also, Steinert et al., Bio is based on the use of fumaric acid in the form of its chemistry of Normal and Abnormal Epidermal Differ simple mono- or diesters or its metal salts, based on the entiation, eds. I. A. Bereinstein and M. Seiji, Tokyo theory that in the psoriatic portions of the skin there University Press, p. 391-406 (1980)). This deficiency exists an unbalance in the dicarboxylic-acids cycle con may be related to the fumarate imbalance or to other ducive to lower levels of fumarate. This theory seems to unknown causes. The addition of glycine as such, to be confirmed by the fact that some amino acids, such as such formulations, cannot contribute much to the thera glycine, are present in lower quantities in the psoriatic peutic effect since this water-soluble material will be skin, compared to their content in normal skin. Since 45 quickly incorporated into the general metabolic pro these amino acids are also derived from the dicarboxy cesses, so, at best, its value will be like an added food. lic-acids cycle, their presence in lower quantities is an added corroboration to the above theory. BRIEF DESCRIPTION OF THE INVENTION A number of patent applications deal with the use of We have found that linking amino acids such as gly fumarate esters and salts for the treatment of psoriasis. 50 cine, serine, etc., to fumaric acid via a chemical link GP2530372 (13.1.77) describes the use of fumaric acid, such as via amide groups, results in conjugates which fumarate esters, such as monoethyl and monomethyl have a high efficacy in the treatment of psoriasis. The fumarate, dimethyl fumarate; some salts of the monoes conjugate compounds are mostly stable crystalline ters such as manganese, calcium, zinc, iron, etc. All of solids. They are easy to formulate as tablets, ointments, these can be mixed with other ingredients such as tar- 55 or similar galenic forms. The amide bond is known to be taric acid, citric acid, sugar, and inert fillers. Some of more stable to hydrolysis than an ester group (see, for these formulations are for internal use and some for instance, J. March, Advanced Organic Chemistry 3rd external (topical) application. Related applications, GP ed., p. 339, J. Wiley & Sons, New York (1985)), and 2840498 (104.80) and GP 2901452 (17.7.80), describe therefore the fumar-amidoamino acids are converted at the addition of glycine, 1-methionine, and 1-cysteine to 60 a much slower rate into the fumarate and the free amino the above mixtures of fumarate esters and salts. A recent acid. They are easily absorbed through the digestive European patent,0188749A2 (30.7.86) claims the use of system, since it is known that amides have good solubili fumarate esters of alcohols having one to eight carbon zation properties both with hydrophilic and lipophilic atoms, esters of higher alcohols (C6-C24), metal salts of compounds. the monoesters, and esters of diols, glycerol, and other 65 In its broadest aspects, therefore, the invention relates hydroxyl-containing compounds.
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