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ESSEE in Which R1 and R2 Are the Same Or Different And USOO5272153A United States Patent (19) 11 Patent Number: 5,272,153 Mandell et al. 45 Date of Patent: Dec. 21, 1993 (54)54 OFMETH E. NHIBITINSi6. CTVTY OTHER PUBLICATIONS Avido et al., Angiology 35, 407 (1984). 75 Inventors: St. Mel ES Suguira et al., Japanese Journal of Anesthesiology 32, va.8 William,Wan, CharlotteSVlie, Novici, Lebanon, O 435-41,35-41, with English translationtranslation. N.J. (List continued on next page.) 73) Assignees: Hoechst-Roussel Pharmaceuticals, Primary Examiner-Nathan M. Nutter Inc., Somerville, N.J.; University of Attorney, Agent, or Firm-Finnegan, Henderson, Virginia Alumni Patents Foundation, Farabow, Garrett & Dunner Charlottesville, Va. (*) Notice: The portion of the term of this patent 57) ABSTRACT E. to Jun 15, 2008 has been A family of compounds effective in inhibiting interleu SC. kin-1 (IL-1) activity, tumor necrosis factor (TNF) activ (21) Appl. No.: 908,929 ity, and the activity of other leukocyte derived cyto s kines is comprised of 7-(oxoalkyl) 1,3-dialkyl xanthines (22 Filed: Jul. 2, 1992 of the formula Related U.S. Application Data R (I) 63 Continuation of Ser. No. 700,522, May 15, 1991, aban- Y N-A-C-CH3 doned, which is a continuation of Ser. No. 622,138, Dec. 5, 1990, Pat. No. 5,096,906, which is a continua- al- 6 tion of Ser. No. 508,535, Apr. 11, 1990, abandoned, O N N which is a continuation of Ser. No. 239,761, Sep. 2, 1988, abandoned, which is a continuation of ser. No. R2 ESSEE selectedin which from R1 and the R2group are consistingthe same orof different straight-chain and are or 51) int. Cl. .............................................. A61K 31/52 branched alkyl radicals with 2 to 6 carbon atoms, cyclo 52 U.S.C. ..................................... 514/263; 514/929 hexyl, alkoxyalkyl and hydroxyalkyl radicals, and A 58 Field of Search ................................ 514/263,929 represents a hydrocarbon radical with up to 4 carbon w atoms which can be substituted by a methyl group. 56) References Cited Another family of effective compounds is identified as U.S. PATENT DOCUMENTS R r (II) 4,558,051 12/1985 Sunshine et al. .................... 514/261 4,880,791 11/1989 Weithmann et al. ... 54/26 4,965,271 10/1990 Mandell et al. .......... ... 514/929 N C) 4,975,432 12/1990 Weithmann et al. ............... S14/26 oes N R2 FOREIGN PATENT DOCUMENTS 0195496 9/1986 European Pat. Off. The inhibition of IL-1, TNF, and other cytokines in 0267676 5/1988 European Pat. Off. mammals is implicated in alleviation of a wide variety of 0344586 5/1988 European Pat. Off. disease conditions. 0279079 8/1988 European Pat. Off. 35 Claims, 6 Drawing Sheets 5,272,153 Page 2 OTHER PUBLICATIONS Chemical Abstracts, vol. 101, No. 19, issued Nov. 5, seret al., Journal of Leukocyte Biology, 40:747-54 1984, C.Abstract Robino No. 168805u. of Medicine, vol. 14, No. (1986). 2, 1983, Studies on Oesteoporoses.XI-Effects of Me. Chemical Abstracts, vol. 104, No. 25, issued Jun. 23, thylxanthine Drivative, pp. 137-145. 1986, Abstract No. 218828p. Clinical Aspects of White Cell Rheology Reference. U.S. Patent Dec. 21, 1993 Sheet 1 of 6 5,272,153 2.3 2. DIRECTED .9 MIGRATION (mm) 7 .5 3. O. FIG. DBUTY OXO PROPYL XANTHENE (g/ml) FIG 2 2.8 2.7 2.6 2.5 DIRECTED 24 MGRATION 2.2 2. 2O 9 DBOPX ug/ml U.S. Patent Dec. 21, 1993 Sheet 2 of 6 5,272,153 CONTROL FIG. 3 E. DBOPX OOlmM DBOPX mM IOO 90 / PMN ADHERENCE Bo 7O 6O O O. O O (DBOPX g/ml FIG. 4 U.S. Patent Dec. 21, 1993 Sheet 3 of 6 5,272,153 SUPEROXDE (nmoles per IO min million PMN) FIG. 6 O O. O IOO U.S. Patent Dec. 21, 1993 Sheet 4 of 6 5,272,153 lugº O $ SINNNY QNNNNNNNNNNNNNNNZZZZZZZZZZZZZ$ SSSSSSSSSSI?$ZZZZZZZZZZZZ.Ida ZZZZZZZZZZZZZZ.jszNE LPS(ZZZZZZZZ KINE U.S. Patent Dec. 21, 1993 Sheet 5 of 6 5,272,153 CELLOBJIC]NOIV89|W(uuuu) (\j-->-----C\!CN8€$$ FIG.9 KNNNNNNNNNNNNNNNNNNNC O ZZZZZZZZZZZZZZZZZZ)On [NNNNNNNNNNNN5 >>>>>>>]©ZZZZZZZZ?? ZZZZZZZZZZZZZZZZ$$ SSSSSSSSSSSSS|= FIG. NONE LPS CONT KINES LPS KINES NCUBATION OONDITIONS U.S. Patent Dec. 21, 1993 Sheet 6 of 6 5,272,153 CN CN ºg9)&5 7 -IO IO 3O 5O 7O 90 FIG. O L 5,272,153 1. 2 METHOD OF NHIBITING THE ACTIVITY OF O (I) LEUKOCYTE DERVED CYTOKNES R N CROSS-REFERENCE TO RELATED APPLI- 5 N N-a--ch, CATION o?als N 2 O This application is a continuation of application Ser. No. 07/700,522 filed May 15, 1991 and now abandoned, R2 which is a continuation of Ser. No. 07/622,138 filed Dec. 5, 1990 and now U.S. Pat. No. 5,096,906, which is 10 in which R1 and R2 are the same or different and are a continuation of Ser. No. 07/508,535 filed Apr. 11, independently selected from the group consisting of 1990 and now abandoned, which is a continuation of straight-chain or branched-chain alkyl radicals with 2 to Ser. No. 07/239,761 filed Sep. 2, 1988 and now aban 6 carbon atoms, cyclohexyl, straight chain or branched doned, which is a continuation of Ser. No. 06/947,905 15 chain alkoxyalkyl, and hydroxyalkyl radicals; and filed Dec. 31, 1986 and now abandoned, and is a contin A is a hydrocarbon radical with up to 4 carbon atoms uation of 07/131,785 filed Dec. 11, 1987 and now U.S. which can be substituted by a methyl group; or Pat. No. 4,965,271. a compound of the formula (II) BACKGROUND OF THE INVENTION 20 (II) This invention relates to the inhibition of activity of leukocyte derived cytokines, such as interleukin-1 and tumor necrosis factor, in humans and mammals. More specifically, this invention provides a method of inhibit ing the activity of cytokines to arrest or alleviate certain 25 disease and inflammatory states. Interleukin-1 (IL-1) and tumor necrosis factor (TNF) wherein at least one of R1 and R3 is either (a) a branched are biological substances produced by monocytes and hydroxyalkyl group of the formula other macrophages in mammals. IL-1 and TNF affect a 30 wide variety of cells and tissues, both in vitro and in vivo. Research has demonstrated that IL-1, TNF, and R4 other leukocyte derived cytokines are important, and (CH)--CH, even critical, mediators in a wide variety of inflamma OH tory states and diseases. The inhibition of IL-1, TNF, 35 and other leukocyte derived cytokines is of benefit in with a tertiary alcohol function, in which R stands for controlling, reducing, and alleviating many of these an alkyl group with 1 to 3 carbon atoms and n stands for conditions. a whole number from 2 to 5, the other R or R group Detection and inhibition of IL-1, TNF, and other that may optionally be present stands for a hydrogen leukocyte derived cytokines can be relatively easily atom or an aliphatic hydrocarbon group Rs with up to documented through in vitro analysis of polymorpho 6 carbon atoms, whose carbon chain may be interrupted nuclear neutrophil behavior. Among other activities by up to 2 oxygen atoms or may be substituted with a attributed to IL-1 and other leukocyte derived cyto hydroxy or oxo group, or (b) at least one of R or R3 is kines is the promotion of leukocyte adherence and the 45 an oxoallyl group of the formula inhibition of neutrophil chemotaxis, both directly con tributing to disease and inflammation syndromes. O Despite the desirability of inhibiting the activity of IL-1 and TNF and the activity of other leukocyte de R6-c-(CH2), rived cytokines and the ease with which inhibition can 50 wherein R6 is C1-C6 alkyl, and p=2, 3 or 4. The other be detected in vitro, there exists a need in the art for R or R3 being defined as above; and R2 represents an inhibitors of IL-1, TNF, and other cytokines, wherein alkyl group with 1 to 4 carbon atoms. The xanthine of the inhibitors are acceptable for in vivo administration. formula (I) or formula (II) is employed in an amount SUMMARY OF THE INVENTION that is effective in inhibiting the activity of IL-1, TNF, 55 and other leukocyte derived cytokines in the mammal. This invention aids in fulfilling these needs in the art Exemplary within the general formula (II), and estab by identifying a class of compounds that can be success lished as an effective IL-1 inhibitor, is the well known fully employed in alleviating conditions caused by, or and commercially available pharmaceutical pentoxifyl mediated by, IL-1, TNF, and other leukocyte derived 60 line. Although this compound has been used for some cytokines. The compounds exhibit marked inhibition of time as a pharmaceutical (clinical trials in 1971) it has cytokine activity, even at low concentrations of the not been reported effective as an IL-1 inhibitor. It has mediators as demonstrated through in vitro tests. been demonstrated in promoting directed migration of More particularly, this invention provides a method leukocytes. of inhibiting the activity of IL-1, TNF, and other leuko- 65 cyte derived cytokines in a mammal comprising admin BRIEF DESCRIPTION OF THE DRAWINGS istering thereto at least one 7-(oxoalkyl) 1,3-dialkyl This invention will be more fully described with xanthine of the formula (I) reference to the drawings in which: 5,272,153 3 4. FIG. 1 is a graph showing modulation by 1,3-dibutyl zyme secretion by macrophages, and factors that medi 7-(2-oxopropyl) xanthine (DBOPX) of the effect of ate secretion of oxidizing agents, such as oxygen, super interleukin-1 (IL-1) on polymorphonuclear leukocyte oxide, hydrogen peroxide, and hydroxyl radical.
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