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Pharmaceutical Compositions for the Treatment of Psoriasis

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Pharmaceutical Compositions for the Treatment of Psoriasis Europaisches Patentamt European Patent Office © Publication number: 0 328 634 B1 Office europeen des brevets © EUROPEAN PATENT SPECIFICATION © Date of publication of patent specification: 05.07.95 © Int. CI.6: C07C 233/00, C07C 233/45 © Application number: 88908544.5 @ Date of filing: 01.09.88 © International application number: PCT/US88/02941 © International publication number: WO 89/01930 (09.03.89 89/06) The file contains technical information submitted after the application was filed and not included in this specification © PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF PSORIASIS. ® Priority: 04.09.87 IL 83775 © Proprietor: DEXTER CHEMICAL CORPORA- TION @ Date of publication of application: 845 Edgewater Road 23.08.89 Bulletin 89/34 Bronx, NY 10474 (US) © Publication of the grant of the patent: @ Inventor: BLANK, Izhak 05.07.95 Bulletin 95/27 23 Haogen Street 31 999 Haifa (IL) © Designated Contracting States: AT BE CH DE FR GB IT LI LU NL SE © Representative: Henkel, Feiler, Hanzel & Part- © References cited: ner DE-A- 2 252 345 Mohlstrasse 37 DE-A- 2 703 964 D-81675 Munchen (DE) US-A- 4 362 737 US-A- 4 433 154 US-A- 4 730 048 00 CO CO 00 CM CO Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid (Art. 99(1) European patent convention). Rank Xerox (UK) Business Services (3. 10/3.09/3.3.3) EP 0 328 634 B1 J. MED. CHEM. vol. 29, 1986, pages 1650-1 653, American Chemical Society; P.S. PORTOGHESE et al.: "Synthesis and opioid antagonist potencies of naltrexamine bival- ent ligands with conformational^ restricted spacers" BIOCHEM J. vol. 201, 1982, pages 189-198, The Biochemical Society, A.J. BARRETT et al. "L- transepoxysucclnyl- leucylamldo(4-guanldlno) butane (E-64) and Its analogues as Inhibitors of cysteine prot- einases Including cathepslns B,H and L." CHEMICAL ABSTRACTS, vol. 107, no. 7 Au- gust 17, 1987, page 780, abstract 59468q, Ohio, US; & JP-A-62 48 656 (SHOWA DENKO K.K.) Z. HAUTKR., vol. 59, no. 10, 25th January 1984, pages 671-679, Grosse Verlag, Berlin, DE. W. RAAB: "Treatment of psoriasis with fumarlc acid and fumarates" MICROBIOL IMMUNOL, vol. 28, no. 1. 1984, pages 85-97; T. AMAMAOTO et al: "Effect of E-64, thiol protease Inhibitor on the secon- dary antl-SRBC response In vitro" 2 1 EP 0 328 634 B1 2 Description tions, DE-A-2840498 (10.4.80) and DE-A-2901452 (17.7.80), describe the addition of glycine, 1- Psoriasis is one of the most widespread chron- methionine, and 1 -cysteine to the above mixtures ic diseases. It affects about two percent of the adult of fumarate esters and salts. A recent European white population, the most severe symptoms being 5 patent, EP-A-01887419 (30.7.86) claims the use of shown by patients in the age groups between twen- fumarate esters of alcohols having one to eight ty and fifty years old. carbon atoms, esters of higher alcohols (C6-C24), Psoriasis is characterized by a greatly acceler- metal salts of the monoesters, and esters of diols, ated rate of epidermal turnover. Instead of the glycerol, and other hydroxyl-containing com- normal period of 28 days from the time of cell io pounds. Another patent, DE-A-3232883 mentions division in the basal layers until the cell is shed the preparation of salts of fumaric acid with various from the stratum corneum, in psoriasis this takes caffein-8-ethers. The salts are crystalline and can only about four days. be used for the preparation of tablets, capsules, The causes and mechanism of development of etc., in combination with metal salts of fumaric psoriasis are unknown, and for this reason a com- 75 esters, as mentioned before, and also with the pletely effective treatment for this ailment does not optional addition of amino acids such as cysteine yet exist. A great number of approaches have been and methionine, and of vitamin C. tried, from the very old, based on natural tars, to DE-A-2703964 discloses pharmaceutical com- the more modern using steroids, sporalene, etc. positions for the treatment of psoriasis comprising Tars are messy to apply and have only a limited 20 fumaric acid or derivatives thereof in combination effect. Their combination with sulfur and salicylic with glycine and optional with sec. phosphates. acid are not much better. This therapy is frequently There exist serious problems as to the use of supplemented by the use of ultraviolet (UV) radi- the above in the therapy of psoriasis. Short-chain ation, either natural (sunshine) or artificial (lamps). fumarate esters are in general irritating materials Other compounds used are: steroids, azaribine, 25 which frequently produce an unpleasant acidosis methotrexate, psoralen, and retinoic acid deriva- effect upon ingestion. Metal salts of the half esters tives. All of these have a rather high toxicity and are quickly converted in the stomach into the free their long term use may result in noxious side acid and the respective metal hydrochloride. The effects. same happens with the caffein-ether salt. The es- A possible approach to the therapy of the dis- 30 ters are liquid at room temperature and in order to ease is to try to influence cellular metabolism, convert them to tablets they have to be adsorbed which obviously is much more active in the psori- on, or mixed with, a rather large quantity of inert atic cells than in the normal ones. carrier. Furthermore, they have a strong character- A few years ago, a new treatment was pro- istic odor and their toxicology has not been studied posed. This is based on the use of fumaric acid in 35 extensively. According to a study made with mice, the form of its simple mono- or diesters or its metal monoethyl fumarate and dimethyl fumarate given salts, based on the theory that in the psoriatic per os had an LD5o above 100 mg/kg. Monoethyl portions of the skin there exists an unbalance in the fumarate, given intraperitoneal^, was more toxic dicarboxylic-acids cycle conducive to lower levels (W. Raab, H&G Nr. 10 (1984)). These fumarate of fumarate. This theory seems to be confirmed by 40 esters are highly irritating to the skin and can the fact that some amino acids, such as glycine, produce contact urticaria (Lahty et al., Contact Der- are present in lower quantities in the psoriatic skin, matitis 3, 139-140 (1985)). compared to their content in normal skin. Since To summarize: mono and diesters of fumaric these amino acids are also derived from the dicar- acid have been shown to be effective in the treat- boxylic-acids cycle, their presence in lower quan- 45 ment of psoriasis, as the experience with several tities is an added corroboration to the above the- thousand patients indicates (see, for instance: ory. Schafer G. Fumarsauretherapie der Psoriasis, Arzt- A number of patent applications deal with the liche Praxis 30, 61 p. 1757-58 (1978); also, Selecta use of fumarate esters and salts for the treatment 15, p. 1260-61 (1984)). The esters are irritating to of psoriasis. DE-A-2530372 (13.1.77) describes the 50 the digestive system and to the skin and their use of fumaric acid, fumarate esters, such as mon- toxicology has not been clearly established; they oethyl and monomethyl fumarate, dimethyl are also difficult to formulate as tablets. fumarate; some salts of the monoesters such as Recent studies have shown that in psoriatic manganese, calcium, zinc, iron, etc. All of these skin the content of glycine and serine is about can be mixed with other ingredients such as tar- 55 twenty-five percent lower than in normal skin taric acid, citric acid, sugar, and inert fillers. Some (Thaler et al., J. Invest. Dermatol. 75, 156-158 of these formulations are for internal use and some (1980); also, Steinert et al., Biochemistry of Normal for external (topical) application. Related applica- and Abnormal Epidermal Differentiation, eds. I.A. 3 3 EP 0 328 634 B1 4 Bereinstein and M. Seiji, Tokyo University Press, p. (b) an OH group, provided that only one of said 391-406 (1980)). This deficiency may be related to R1 and R2 may be OH, where the amino acids the fumarate imbalance or to other unknown are selected from one or more of: glycine, causes. The addition of glycine as such, to such serine, valine, histidine, methionine, threonine, formulations, cannot contribute much to the thera- 5 leucine, isoleucine, cysteine, cystine, tyrosine, peutic effect since this water-soluble material will proline, hydroxyproline, tryptophan, aspartic be quickly incorporated into the general metabolic acid, glutamic acid, lysine, and arginine, as well processes, so, at best, its value will be like an as their derivatives, such as esters and salts added food. or a pharmaceutically acceptable salt thereof. io In the formulations it is possible to use the Brief Description of The Invention fumaramide of ethyl glycinate or of sodium glycinate. In other words, it is possible to make use We have found that linking amino acids such of the carboxylic acid group of the amino acid to as glycine, serine, etc., to fumaric acid via a chemi- further change the solubility and other characteris- cal link such as via amide groups, results in con- 15 tics of the compound. Furthermore, since fumaric jugates which have a high efficacy in the treatment acid has two carboxyl groups, it is possible to of psoriasis.
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