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United States Patent (19) 11 Patent Number: 4,829,061 Wolf Et Al

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United States Patent (19) 11 Patent Number: 4,829,061 Wolf Et Al United States Patent (19) 11 Patent Number: 4,829,061 Wolf et al. 45 Date of Patent: May 9, 1989 54 1-(4-HYDROXY-3,5-DI-TERT-BUTYLBEN 4,404,302 9/1983 Gupta et al. ........................ 524/100 ZOYL)HOMOPIPERAZINE, VARIOUS DERIVATIVES THEREOF, PROCESSES FOR FOREIGN PATENT DOCUMENTS THE PREPARATION OF THESE 190685 8/1986 European Pat. Off............. 544/39 COMPOUNDS, MEDICAMENTS CONTAINING THEM, AND THEIR USE OTHER PUBLICATIONS European Search Report. 75) Inventors: Erhard Wolf, Hofheim am Taunus; T. Takahashi et al., Chem. Abstr., vol. 77, No. 7, Erhard Rossmanith, 48520m (1972). Schwalbach/Taunus; Robert R. T. Takahashi et al., Chem. Abstr., vol. 75, No. 5,36162s Bartlett, Darmstadt; Rudolf (1971). Schleyerbach, Hofheim am Taunus, K. Brune, Eur. J. Rheumatol. Inflam., 5, 1982, pp. all of Fed. Rep. of Germany 335-349. 73) Assignee: Hoechst Aktiengesellschaft, Primary Examiner-Robert Gersti Frankfurt am Main, Fed. Rep. of Attorney, Agent, or Firm-Finnegan, Henderson, Germany Farabow, Garrett, & Dunner (21) Appl. No.: 149,602 (57) ABSTRACT (22 Filed: Jan. 28, 1988 1-(4-Hydroxy-3,5-di-tert-butylbenzoyl)homopipera (30) Foreign Application Priority Data zine and various derivatives thereof substituted on the nitrogen are prepared starting from 4-hydroxy-3,5-di Jan. 30, 1987 (DE) Fed. Rep. of Germany ....... 3702755 tert-butylbenzoic acid or its derivatives and homopip 51) Int. Cl." .................... CO7D 243/08; A61K 31/55 erazine or appropriate derivatives thereof. 52 U.S. C. ..................................... 514/218; 540/575 The compounds and their physiologically tolerated acid 58) Field of Search ......................... 540/575; 514/218 addition salts are suitable for the treatment of inflamma 56) References Cited tory and painful, in particular inflammatory rheumatic, disorders. U.S. PATENT DOCUMENTS 4,066,614 1/1978 Oppelt et al. ...................... 260/45.8 9 Claims, No Drawings 4,829,061 1. 2 1-(4-HYDROXY-3,5-DI-TERT-BUTYLBENZOYL)- C(CH3)3 (I) HOMOPIPERAZINE, VARIOUS DERIVATIVES THEREOF, PROCESSES FOR THE HO CO-o-N N-R1 PREPARATION OF THESE COMPOUNDS, V W MEDICAMENTS CONTAINING THEM, AND (CH2)3 THEIR USE C(CH3)3 The present invention relates to 1-(4-hydroxy-3,5-di O in which R represents H, a straight-chain or branched tert.-butylbenzoyl)homopiperazine, various derivatives (C1-C6)-alkoxycarbonyl radical (CH3OCO, C2H5OCO, thereof, processes for the preparation of these com tert.-C4H90CO, etc.) or the benzyloxycarbonyl radical, pounds and their use as active ingredients in medica which can be substituted in the phenyl radical, and their ments, mainly for the treatment of rheumatic disorders, physiologically tolerated salts. Examples of suitable in particular the forms which have a severe course, such 15 substituents on the phenyl nucleus in the benzyloxycar as chronic graft-versus-host diseases which it has hith bonyl radical are: erto been hardly possible to treat, and of autoimmune halogen (F, Cl, Br, I, preferably Cl), (C1-C4)-alkyl, diseases mediated by immune complexes, such as, for (C1-C4)-alkoxy, halogenoalkyl (preferably having 1-3 example, systemic lupus erythematosus, immune com carbon atoms, such as CF3, C2H4Cl, etc.), etc. plex glomerulonephritis and type I diabetes. 20 The compounds of the formula I which are preferred The substances which are preferably used for the are those in which Riis H, a straight-chain or branched treatment of rheumatic disorders are non-steroidal anti (C1-C4)-alkoxycarbonyl radical or the benzyloxycarbo rheumatics (=NSAID) which are preferably recruited nyl radical (unsubstituted in the phenyl radical); R1 is from the classes of aralkylcarboxylic acids, anthranilic particularly preferably only H or the benzyloxycarbo acid, oxicans, salicylic acid and pyrazoles. Although 25 nyl radical (unsubstituted in the phenyi radical). these antirheumatics are able to have beneficial effects The compounds of the formula I are advantageously on the pain associated with the disease, and the inflam prepared by reaction of 3,5-di-tert.-butyl-4-hydrox mation and swelling, they may lead to serious side ef ybenzoic acid and its derivatives of the formula II fects (cf. K. Brune, Eur. J. Rheumatol. Inflam. 5 (1982), 30 pages 335-349; Litera Rheumatologica 3, Symposium C(CH3)3 II report, F. J. Wagenhäuser, Nutzen und Risiken der O a Antirheumatika (Benefits and Risks of the Antirheumat HO C ics), Basle, 1985): apart from renal function disturbances N and allergic reactions, such as attacks of asthma, there 35 X are observed to be, in particular, gastrointestinal dis C(CH3)3 turbances, and it appears that the chemical structure of the NSAIDs which are used is of minor importance in which Xs (Coles, L.S. et al Amer. J Med. 74, 1983, page 820). A OH further disadvantage is the often narrow therapeutic halogen (F, Cl, Br or I), range of these compounds. N3 Moreover, treatment of the forms with a severe Oalkyl (preferably OC1-C4-alkyl) course is scarcely possible with NSAIDs, or is possible Oaryl (preferably OC6H5) only by accepting serious side effects when immunosup 45 pressants are used, such as, for example, cyclophospha O mide, cyclosporin A, methotrexate or glucocorticoids. The latter may lead to, inter alia, nausea, stomatitis, changes in the blood picture and hepato- or nephrotox (with Y= alkyl, aryl, aralkyl, preferably C1-C4-alkyl, icity. 50 It has now been found, surprisingly, that 1-(4- C6H5, CH2C6Hs) or hydroxy-3,5-di-tert-butylbenzoyl)homopiperazine and various derivatives thereof substituted on the nitrogen C(CH3)3 O are able to have beneficial effects on the chronic graft I versus-host diseases which it has hitherto been hardly 55 On-C OH possible to treat, and the autoimmune diseases mediated by immune complexes, while the tolerability is very good, the therapeutic range is advantageous, and the C(CH3)3 antiinflammatory property is retained. In contrast to this, the 3,5-di-tert-butyl-4-hydroxybenzamides dis 60 with amines of the formula III closed in U.S. Pat. No. 4,128,664 only have antiinflam matory activity, and thus are not suitable for the treat /-, III ment of the said severe disorders. HN N-R1 The present invention relates to 1-(4-hydroxy-3,5-di 65 V / tert.- butylbenzoyl)homopiperazine and derivatives (CH2)3 thereof substituted on the nitrogen, of the following general formula I in which R1 has the same meaning as in formula I. 4,829,061 3 4. The particularly preferred starting compound of the or p-toluenesulfonate or the salt of an organic acid such formula II is 3,5-di-tert-butyl-4-hydroxybenzoyl chlo as, for example, the maleate or citrate. It is particularly ride. advantageous to use the water-soluble hydrochloride, 3,5-Di-tert-butyl-4-hydroxybenzoic acid itself can be which is prepared by known processes-for example by obtained in a known manner, for example using Kolbe's reaction of the basic compound I in alcoholic solution synthesis from the corresponding phenol (2,6-di-tert.- or suspension with, preferably, the equivalent amount butylphenol) and CO2, by a Cannizzaro reaction or by of alcoholic or aqueous hydrochloric acid. oxidative means, for example from the corresponding The compounds of the formula I, according to the aldehyde or the methyl compound. The appropriate invention, and the corresponding physiologically toler derivatives of the formula II can be obtained from the O ated acid addition salts are suitable for use as medicines acid by customary processes. 2,6-Di-tert.-butylphenol is or as active ingredients in medicines. They display anti a commercially available product. inflammatory effects, but are particularly distinguished Examples of suitable starting amines of the formula by being suitable for the treatment of chronic graft III are: homopiperazine, N-ethoxycarbonylhomopiper versus-host diseases and of autoimmune diseases medi azine, N-tert.-butyloxycarbonyl- and N-benzyloxycar 5 ated by immune complexes, and having a favorable bonyl-homopiperazine. therapeutic range. Furthermore, they are very well Where starting compounds of the formula II with tolerated. X=OH, halogen, N3, Oalkyl, Oaryl or OC(O)CY are The appropriate medicaments contain-or comprise used, these compounds and the amines of the formula at least one compound of the formula I and/or at least III are preferably used in a molar ratio of 1: at least 20 one of its physiologically tolerated acid addition salts; about 1; where 3,5-di-tert-butylbenzoic anhydride is they are mainly used for the prevention and treatment used as starting compound of the formula II, the molar of rheumatic disorders, preferably for the forms having ratio to the amine III is preferably 1: at least about 2. a SeWee COSe. The reaction can be carried out without solvent. The medicaments are prepared by converting at least However, it is preferably carried out with the addition 25 one compound of the formula I, and/or at least one of an inert dispersant or solvent such as, for example, an physiologically tolerated acid addition salt of such a aliphatic amide (dimethylformamide, dimethylacetam compound, and/or at least one of the compounds ob ide etc.), nitrile (acetonitrile etc.), ether (diethyl or di tained by the process described above, into a suitable isopropyl ether, tetrahydrofuran, dioxane, glycol di dosage form with a physiologically tolerated vehicle ethyl ether, diethylene glycol dimethyl ether etc.) or 30 and, where appropriate, further additives and/or auxil alcohol (methanol, ethanol, propanol, isopropanol etc.). iaries. It may also be advantageous to increase the rate of Particularly suitable presentations are tablets, coated reaction by, for example, addition of a base or by cata tablets, capsules and suppositories; they can contain the lytic amounts of dimethylformamide etc. When the acid active ingredients either in the free form (compounds of halides-in particular the acid chloride-are used as 35 the formula I) or in the form of the appropriate physio starting compounds of the formula II, it is advantageous logically tolerated acid addition salts.
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