| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | April 2, 2002 |
| PATENT TITLE |
Methimazole derivatives and tautomeric cyclic thiones to treat autoimmune diseases |
| PATENT ABSTRACT | The present invention provides methods for treating autoimmune diseases in mammals and for preventing or treating transplantation rejection in a transplant recipient. These methods utilize specifically-defined methimazole derivatives and tautomeric cyclic thione compounds, as well as pharmaceutical compositions containing those compounds. These compounds and compositions have been found to be at least as effective as methimazole in terms of pharmaceutical activity, while having less of an adverse affect on thyroid function. They are also more soluble in conventional pharmaceutical vehicles than methimazole. An assay for screening the activity of compounds useful against autoimmune diseases (ability to suppress expression of MHC Class I and II molecules) is also taught |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | August 25, 1999 |
| PATENT REFERENCES CITED |
Kjellin and Sandstrom, Acta Chemica Scandinavica, 23: (1969) 2879-2887. Kjellin and Sandstrom, Acta Chemica Scandinavica, 23: (1969) 2888-2899 U.S.P. Dictionary. (US Pharmacopeia, Rockville, Maryland, 1996) "Entry for Methimazole". Suzuki, et al, ARVO Abstract, (1995) "Methimaxole (MMI) An Agent Capable Of Reducing MHC Class I Expression, Inhibits Experimental Melanin-Induced Uveitis (EMIU) And Experimental Autoimmune Uveoretinitis (EAU)". Guiliani, et al., The Endocrine Society, (1994) "Down-Regulation Of Major Histocompatibility Complex (MHC) Class I Gene Expression In FRTL-5 Thyroid Cells By Hydrocortisone Is Transcriptional And Mediated By The p50 Subunit Of NF-B". Napolitano, et al., The Endocrine Society, (1994) "Methimazole Regulation Of major Histocompatibility (MHC) Class I Gene Expression In Thyroid Cells Involves TSH-And Insulin-Activated Transcription Factors". Neumann, et al., Science 269, 549-522 (1995) "Induction of MHC Class I In Genes in Neurons". Sartoris, et al., International Journal of Clinical & Laboratory Research 25: 71-78 (1995) "Transcriptional Regulation of MHC Class II Genes". Volpe, Thyroid 4(2), 217-223, Evidence That the Immunosuppressive Effects of Antithyroid Drugs Are Mediated through Actions on the Thyroid Cell, Modulating Thyrocyte-Immunocyte Signaling: A Review (1990). Cooper, New England Journal of Medicine 311(21), 1353-1362 (1984) "Medical Progress, Antithyroid Drugs". Mozes, et al., Science 261, 91-93 (1993) "Resistance of MHC Class I-Deficient mice to Experimental Systemic Lupus Erythematosus". Cooper, "Treatment of Thyrotoxicosis" in Werner and Ingbar's The Thyroid, Seventh Edition, (1996) Lippincott-Raven, pp. 713-714. Chan, et al., Journal of Immunology, 154, 4830-4835 (1995) "Periocular Inflammation in Mice with Experimental Systemic Lupus Erythematosus". Krieg, Trends in Microbiology 4(2) 73-77 (1996) "Lymphocyte activation CpG dinucleotide motifs in prokaryotic DNA". Shimojo, et al., Proc. Natl. Acad. Sci. 93, 11074-11079 (1996) "Induction of Graves-like disease in mice by immunization with fibroblasts transfected with the thyrotropin receptor and a class II molecule". Wicker, et al., Diabetes, 35, 855-860 (1986) "Transfer of Autoimmune Diabetes Mellitus With Splenocytes From Nonobese Diabetic (NOD) Mice". Oren, et al., Aliment Pharmacol Ther 11(2) 341-345 (1997) "Anti-Thyroid Drugs Decrease Mucosal Damage in a Rat Model of Experimental Colitis". Montain, et al., Endocrinology, 139(1), 280-289 (1998) "Major Histocompatibility Class II HLA-Dra Gene Expression in Thyrocytes: Counter Regulation by the Class II Transactivator and the Thyroid Y Box Protein". Montain, et al., Endocrinology, 139(1), 290-302 (1998) "Regulation of Major Histocompatibility Class II Gene Expression in FRTL-5 thyrocytes: Opposite Effects of Interferon and Methimazole |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A pharmaceutical composition comprising a safe and effective amount of a compound selected from ##STR38## wherein Y is selected from the group consisting of H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 substituted alkyl, --NO.sub.2, and the phenyl moiety ##STR39## and wherein no more than one Y group in said active compound may be the phenyl moiety; R.sup.1 is selected from the group consisting of H, --OH, C.sub.1 -C.sub.4 alkyl, and C.sub.1 -C.sub.4 substituted alkyl; R.sup.2 is selected from the group consisting of H, C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 substituted alkyl; R.sup.3 is selected from the group consisting of H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 substituted alkyl, and --CH.sub.2 Ph; R.sup.4 is selected from the group consisting of H, C.sub.1 -C.sub.4 alkyl, and C.sub.1 -C.sub.4 substituted alkyl; X is selected from S and O; and Z is selected from --SR.sup.3 , --OR.sup.3 and C.sub.1 -C.sub.4 alkyl; and wherein at least two of the R.sup.2 and R.sup.3 groups in said compound are C.sub.1 -C.sub.4 alkyl when Y is not a phenyl moiety, and at least one Y is --NO.sub.2 when Z is alkyl; and a pharmaceutically-acceptable carrier. 2. A pharmaceutical composition according to claim 1 wherein Z is selected from --SR.sup.3 and OR.sup.3. 3. A pharmaceutical composition according to claim 2 wherein Z is --SR.sup.3 and X is S. 4. A pharmaceutical composition according to claim 3 wherein Y is H. 5. A pharmaceutical composition according to claim 4 wherein R.sup.3 is C.sub.1 -C.sub.4 alkyl. 6. A pharmaceutical composition according to claim 5 wherein R.sup.3 is methyl. 7. A pharmaceutical composition according to claim 6 wherein at least one of the R.sup.2 groups is methyl. 8. A pharmaceutical composition according to claim 4 wherein both R.sup.2 groups are methyl. 9. A pharmaceutical composition according to claim 6 wherein the active compound has the formula ##STR40## 10. A pharmaceutical composition according to claim 1 wherein the active compound has the formula ##STR41## 11. A pharmaceutical composition according to claim 4 wherein the active compound has the formula ##STR42## 12. A pharmaceutical composition according to claim 1 wherein the active compound has the formula ##STR43## 13. A pharmaceutical composition according to claim 1 wherein the active compound has the formula ##STR44## 14. A pharmaceutical composition according to claim 3 wherein one of the Y groups is the phenyl moiety. 15. A pharmaceutical composition according to claim 14 wherein R.sup.1 and R.sup.4 are H. 16. A pharmaceutical composition according to claim 15 wherein R.sup.3 is methyl and at least one of the R.sup.2 groups is methyl. 17. A pharmaceutical composition according to claim 16 wherein R.sup.3 is H. 18. A pharmaceutical composition according to claim 17 wherein both R.sup.2 groups are methyl. 19. A pharmaceutical composition according to claim 15 wherein the active compound is selected from the group consisting of ##STR45## 20. A pharmaceutical composition according to claim 1 in unit dosage form. 21. A pharmaceutical composition according to claim 1 which comprises from about 0.01% to about 25% of the active compound and from about 75% to about 99.99% of the pharmaceutically-acceptable carrier. 22. A pharmaceutical compound comprising a safe and effective amount of a compound selected from ##STR46## wherein R.sup.5 and R.sup.6 are selected from the following moiety pairs CH.sub.3, CH.sub.3 ; Ph, H and H, Ph; R.sup.7 is selected from H and CH.sub.3 ; and R.sup.8 is selected from O, S, NH and NCH.sub.3 ; and a pharmaceutically-acceptable carrier. 23. A method of treating autoimmune diseases in a patient in need of such treatment by administering to that patient a safe and effective amount of the pharmaceutical composition according to claim 1. 24. A method of treatment according to claim 23 wherein the pharmaceutical composition is administered intraperitoneally, intravenously, intramuscularly, orally, or topically. 25. A method of treatment according to claim 24 wherein the pharmaceutical composition is administered orally. 26. A method of treatment according to claim 25 wherein the pharmaceutical composition is in unit dosage form. 27. A method of treatment according to claim 24 wherein pharmaceutical composition is administered in an amount such that the active compound is dosed at from about 0.05 to about 50 milligrams per day. 28. A method of treating autoimmune diseases in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to claim 9. 29. A method of treating autoimmune diseases in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to claim 10. 30. A method of treating autoimmune diseases in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to claim 11. 31. A method of treating autoimmune diseases in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to claim 12. 32. A method of treating autoimmune diseases in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to claim 13. 33. A method of treating autoimmune diseases in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to claim 19. 34. A method of treating SLE in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to claim 1. 35. A method of treating diabetes in a patient in need of such treatment by administering to said patient a safe and effective amount of the pharmaceutical composition according to claim 1. 36. The compound having the formula ##STR47## wherein R.sup.2 is selected from the group consisting of H, C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 substituted alkyl. 37. The compound of claim 36 wherein R.sup.2 is selected from the group consisting of C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 substituted alkyl. 38. The compound of claim 37 wherein R.sup.2 is methyl. 39. A pharmaceutical composition comprising a safe and effective amount of a compound selected from ##STR48## wherein Y is selected form the group consisting of H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 substituted alkyl, --NO.sub.2, and the phenyl moiety ##STR49## and wherein no more than one Y group is said active compound may be the phenyl moiety; R.sup.1 is selected from the group consisting H, --OH, halogens, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 substituted alkyl, C.sub.1 -C.sub.4 ester and C.sub.1 -C.sub.4 substituted ester; R.sup.2 is selected from the group consisting of H, C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 substituted alkyl; R.sup.3 is selected from the group consisting of H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 substituted alkyl, and --CH.sub.2 Ph; R.sup.4 is selected from the group consisting of H, C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 substituted alkyl; X is selected from S and O; Z is selected from --SR.sup.3, --OR.sup.3, --S(O)R.sup.3, --SR.sup.3, and C.sub.1 -C.sub.4 alkyl; and wherein at least two of the R.sup.2 and R.sup.3 groups in said compound are C.sub.1 -C.sub.4 alkyl when Y is not a phenyl moiety, and at least one Y is --NO.sub.2, when Z is alkyl: and a pharmaceutically-acceptable carrier. 40. A pharmaceutical composition according to claim 39 wherein the active compound is selected from the group consisting of ##STR50## wherein R.sup.9 is selected from the group consisting of --OH, --M and --OOCCH.sub.2 M; wherein M is selected from F, Cl, Br and I. 41. A pharmaceutical composition according to claim 39 wherein the active compound is selected from the group consisting of ##STR51## wherein R.sup.10 is selected from the group consisting of H, --NO.sub.2, Ph, 4-HOPh and 4-MPh, wherein M is selected from F, Cl, Br and I. 42. A method of treating autoimmune diseases in a patient in need of such treatment by administering to that patient a safe and effective amount of the pharmaceutical composition accord to claim 39. 43. A method of treating autoimmune disease in a patient in need of such treatment by administering to that patient a safe and effective amount of the pharmaceutical composition according to claim 40. 44. A method of treating autoimmune diseases in a patient in need of such treatment by administering to that patient a safe and effective amount of the pharmaceutical composition according to claim 41. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
TECHNICAL FIELD This invention relates to the treatment of autoimmune diseases and transplantation rejection in mammals. More specifically, the present invention relates to the use of a narrowly-defined group of methimazole derivatives and tautomeric cyclic thiones for the purposes described herein. BACKGROUND OF THE INVENTION A primary function of immune response in mammals is to discriminate self from non-self antigens and to eliminate the latter. The immune response involves complex cell to cell interactions and depends primarily on three major types of immune cells: thymus derived (T) lymphocytes, bone marrow derived (B) lymphocytes, and macrophages. Immune response is mediated by molecules encoded by the major histocompatibility complex (MHC). The two principal classes of MHC molecules, Class I and Class II, each comprise a set of cell surface glycoproteins (see Stites, D. P. and Terr, A. I. (eds), "Basic and Clinical Immunology", Appelton and Lange, Norwalk, Conn./San Mateo, Calif., 1991). MHC Class I molecules are found on virtually all somatic cell types, although at different levels in different cell types. By contrast, MHC Class II molecules are normally expressed only on a few cell types, such as lymphocytes, macrophages and dendritic cells. Antigens are presented to the immune system by antigen presenting cells in the context of Class I or Class II cell surface molecules, for example, CD4.sup.+ helper T-lymphocytes recognize antigens in association with Class II MHC molecules, and CD8.sup.+ cytotoxic lymphocytes (CTL) recognize antigens in association with Class I gene products. It is currently believed that MHC Class I molecules function primarily as the targets of the cellular immune response, while Class II molecules regulate both the humoral and cellular immune response (Klein, J. and Gutze, E., "Major Histocompatibility Complex", Springer Verlag, New York, 1977; Unanue, E. R., Ann. Rev. Immunology, 2:295-428, (1984)). MHC Class I and Class II molecules have been the focus of much study with respect to research in autoimmune diseases because of their roles as mediators or initiators of immune response. MHC Class II antigens have been the primary focus of research in the etiology of autoimmune diseases, whereas MHC Class I antigens have historically been the focus of research in transplantation rejection. Numerous experimental animal models for human disease have linked aberrant expression and/or function of MHC Class I and MHC Class II antigens to the autoimmune disease process, for example, insulin-dependent diabetes mellitus (IDDM) (Tisch and McDevitt, Cell 85: 291-297 (1996)), systemic lupus erythematosus (SLE) (Kotzin, Cell 85: 303-306 (1996)), and uveoretinitis (Prendergast et al., Invest. Opthalmol. Vis. Sci. 39: 754-762 (1998)). The pathological link between MHC Class I and/or Class II expression and disease has been examined in many of these model systems using a variety of biochemical and genetic approaches. However, the strongest evidence for aberrant MHC gene function as a mediator of autoimmune disease stems from transgenic animal models in which the MHC genes have been inactivated. Using MHC Class I deficient animals resistance to the autoimmune disease process--and hence the dependence of autoimmunity upon MHC gene expression--can be directly demonstrated in animal models for IDDM (Serreze et al., Diabetes 43: 505-509 (1994)), and SLE (Mozes et al., Science 261: 91-93 (1993)). Moreover, the dependence of the progressive multifocal inflammatory autoimmune disease phenotype exhibited by TGF-betal deficient transgenic mice (Shull et al., Nature 359: 693-699 (1992); Kulkarni et al., Proc. Natl. Acad. Sci. 90: 770-774 (1993); Boivin et al., Am. J. Pathol. 146: 276-288 (1995)) on MHC Class II expression has recently been demonstrated using MHC Class II deficient animals. Specifically, TGF-betal deficient animals lacking MHC Class II expression are without evidence of inflammatory infiltrates, circulating antibodies, or glomerular immune complex deposits (Letterio et al., J. Clin. Invest. 98: 2109-2119 (1996)). In addition to the information supportive of MHC Class I and Class II antigens as critical for the development of autoimmunity in animal models there is equally strong evidence linking autoimmune processes with expression of MHC Class I and MCH Class II antigens in humans. Graves' disease is a relatively common autoimmune disorder of the thyroid. In Graves' disease, autoantibodies against thyroid antigens, particularly the thyrotropin receptor (TSHR), alter thyroid function and result in hyperthyroidism (Stites, D. P. and Terr, A. I. (eds), "Basic and Clinical Immunology", Appleton and Lang, Norwalk, Conn./San Mateo, Calif., 1991, pp. 469-470)). Thyrocytes from patients with Graves' disease have aberrant MHC Class II expression and elevated MHC Class I expression (Hanafusa et al., Lancet 2:1111-1115 (1983); Bottazzo et al., Lancet 2:1115-1119 (1983); Kohn, et al., in "International Reviews of Immunology," Vol. 912, pp. 135-165, (1992)). Aberrant expression of MHC Class II and TSHR on fibroblasts, but not either alone, has recently been shown to induce Graves' disease in mice, i.e., aberrant expression of Class II on target tissue can yield autoimmune disease in animals with normal immune systems. Thionamide therapy has historically been used to treat Graves' disease. The most commonly used thionamides are methimazole, carbimazole and propylthiouracil. These thionamides contain a thiourea group; the most potent are thioureylenes (W. L. Green, in Werner and Ingbar's "The Thyroid": A Fundamental Clinical Text, 6.sup.th Edition, L. Braverman and R. Utiger (eds), J. B. Lippincott Co., 1991, p. 324). The basis for thionamide therapy has, however, not focused on immune suppression. Rather, the basis has been suppression of thyroid hormone formation. Experiments suggesting an effect on immune cells, to inhibit antigen presentation or antibody formation, are largely discounted as nonphysiologic in vitro artifacts of high MMI concentration. MMI activity under those circumstances is suggested to be based on free-radical scavenger activity. See D. S. Cooper, in Werner E. Ingbar's "The Thyroid", op. cit., pp. 712-734. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that, like Graves' disease, has a relatively high rate of occurrence. SLE affects predominantly women, the incidence being 1 in 700 among women between the ages of 20 and 60 (Abbus, A. K., Lichtman, A. H., Pober, J. S. (eds), "Cellular and Molecular Immunology", W.B. Saunders Company, Philadelphia, 1991, pp. 360-370). SLE is characterized by the formation of a variety of autoantibodies and by 20 multiple organ system involvement (Stites and Terr, ibid, pp. 438-443). Current therapies for treating SLE involve the use of corticosteroids and cytotoxic drugs, such as cyclophosphamide. Immunosuppressive drugs, such as cyclosporin, FK506 or rapamycin suppress the immune system by reducing T cell numbers and function (Morris, P. J., Curr. Opin. in Immun., 3:748-751 (1991)). While these immunosuppressive therapies alleviate the symptoms of SLE and other autoimmune diseases, they have numerous severe side effects. In fact, extended therapy with these agents may cause greater morbidity than the underlying disease. A link between MHC Class I expression and SLE in animal models has been established. Thus, Class I deficient mice do not develop SLE in the 16/6 ID model (Mozes, et al., Science 261: 91-93 (1993)). Women suffering from SLE who have breast cancer face particular difficulties. These individuals are immunosuppressed as a result of corticosteroid and cytotoxic drug treatment for SLE; radiation therapy for the treatment of the cancer, a current treatment of choice, would additionally exacerbate the immunosuppressed state. Further, radiation therapy can exacerbate disease expression or induce severe radiation complications. For these individuals, alternative therapies that would allow for simultaneous treatment of SLE and cancer are greatly needed. Diabetes Mellitus is a disease characterized by relative or absolute insulin deficiency and relative or absolute glucagon excess (Foster, D. W., Diabetes Mellitus. In Stanbury, J. B., et al., The Metabolic Basis of Inherited Disease. Ch. 4, pp 99-117, 1960). Type I diabetes appears to require a permissive genetic background and environmental factors. Islet cell antibodies are common in the first months of the disease. They probably arise in part to .beta. cell injury with leakage cell antigens but also represent a primary autoimmune disease. The preeminent metabolic abnormality in Type I diabetes is hyperglycemia and glucosuria. Late complications of diabetes are numerous and include increased atherosclerosis with attendant stroke and heart complications, kidney disease and failure, and neuropathy which can be totally debilitating. The link to HLA antigens has been known since 1970. Certain HLA alleles are associated with increased frequency of disease, others with decreased frequency. Increased MHC class I and aberrant MHC class II expression in islet cells has been described (Bottazzo et al., NEJM 313: 353-360 (1985); Foulis and Farquharson, Diabetes 35: 1215-1224 (1986)). A definitive link to MHC class I has been made in a genetic animal model of the disease. Thus MHC class I deficiency results in resistance to the development of diabetes in the NOD mouse (Sereze et al., Diabetes 43: 505-509 (1994); Wicker et al., Diabetes 43: 500-504 (1994)). A wealth of genetic, biochemical and animal model data support a contributory role of inflammatory cytokines (e.g., IL-12, IL-18; and particularly IFN-gamma) in the autoimmune process (Sarvetnick, J Clin Invest 99: 371-372 (1997)). Studies using non-obese diabetic (NOD) mice, which spontaneously develop auto-immune diabetes reminiscent of Type I human IDDM, are particularly illustrative in demonstrating how IFN-gamma stimulated processes play critical roles in the development of autoimmunity; and how the actions of other pro-inflammatory cytokines are channeled through IFN-gamma stimulated processes--among which are the enhanced expression of MHC Class I and MHC Class II antigens. IL-12 and IL-18 (IFN-gamma inducing factor) are known to act synergistically in stimulating production of IFN-gamma in T cells (Micallef et al., Eur. J. Immunol. 26: 1647-1651 (1996)). In diabetic NOD mice the systemic expression of IL-18 (Rothe et al., J. Autoimmun. 10: 251-256 (1997)) and islet expression of IL-12 are increased (Rabinovitch et al., J. Autoimmun. 9: 645-651 (1996)). Moreover, additional IL-12 accelerates autoimmune diabetes in NOD mice (Trembleau et al., J. Exp. Med. 181: 817-821 (1995)). Genetic analysis has determined the IL-18 gene maps to a chromosomal region (Idd2) associated with a genetic susceptibility for autoimmune diabetes (Kothe et al., J. Clin. Invest. 99: 469-474 (1997)). These reports support help to define a critical role for IFN-gamma in the process of autoimmunity. The role of IFN-gamma in the autoimmune process is further substantiated by studies where IFN-gamma's signaling capacity was abrogated in some manner. For example, transgenic NOD mice deficient in the cellular receptor for IFN-gamma (Wang et al., Proc. Natl. Acad. Sci. 94: 13844-13849 (1997)) do not develop autoimmune diabetes. NOD mice treated with a neutralizing antibody for IFN-gamma (Debray-Sachs et al., J. Autoimmun. 4:237-248 (1991)) also do not develop autoimmune diabetes. While it is somewhat surprising that the onset of diabetes is only delayed in transgenic NOD mice deficient in IFN-gamma (Hultgren et al., Diabetes 45: 812-817 (1996)), this observation only further stresses the importance of blocking the IFN-gamma signal--and more importantly IFN-gamma stimulated downstream events--for the effective prevention of autoimmunity in NOD mice. Analogous observations have been made in animal models for SLE. Soluble IFN-gamma receptor blocks disease in the NZB/NZW F1 spontaneous autoimmune disease model for SLE (Ozmen et al., Eur. J. Immunol. 25: 6-12 (1995)); uveitis, where the targeted expression of IFN-gamma increases ocular inflammation (Geiger et al., Invest. Opthalmol. Vis. Sci. 35: 2667-2681 (1994)); and autoimmune gastritis, where neutralizing IFN-gamma antibody blocks disesase (Barret et al., Eur. J. Immunol. 26: 1652-1655 (1996)). Moreover, in humans treatment with IFN-gamma has been reported to be associated with the development of an SLE-like disease (Graninger et al., J. Rheumatol. 18: 1621-1622 (1991)). It is well recognized that .gamma.-IFN increases MHC class I and class II expression in many tissues and thus is linked to the action of a coregulatory molecule, the class II transactivator (Mach et al., Ann Rev Immunol 14: 301-331 (1996); Chang et al., Immunity 4: 167-178 (1996); Steimle et al., Science 265: 106-109 (1994); Chang et al., J Exp Med 180: 1367-1374 (1994); Chin et al. Immunity 1: 687-697 (1994); Montani, V. et al., Endocrinology 139: 280-289 (1998)). It is also known that MMI can inhibit IFN-increased class I and class II expression in thyroid (Saji et al., J. Clin. Endocrinology. Metab. 75: 871-878 (1992); Montani et al., Endocrinology. 139: 290-302 (1998)). Finally, it has been shown that MMI decreases expression of CIITA increased class II expression and this appears to be related to the action of MMI to enhance Y box protein gene expression; the Y box protein suppresses class II gene expression (Montani et al., Endocrinology 139: 280-289 (1998)). As is true for autoimmune diseases, there is a great need for new and different ways of treating or preventing transplantation rejection. Transplantation rejection occurs as a result of histoincompatibility between the host and the donor; it is the major obstacle in successful transplantation of tissues. Current treatment for transplantation rejection, as for autoimmune disease, involves the use of a variety of immunosuppressant drugs and corticosteroid treatment. Kjellin and Sandstrom, Acta Chemica Scandinavica, 23: 2879-2887 and 2888-2899 (1969), discloses a series of tautomeric cyclic thiones, i.e., oxazoline-, thiazoline-, and imidazoline-2-(3)-thiones, having methyl and phenyl groups in the 4 and 5 positions. The compounds were used for a study of thione-thiol equilibria. No pharmaceutical, or any other utility, is disclosed or suggested for these compounds. U.S. Pat. No. 3,641,049, Sandstrom et al., issued Feb. 8, 1972, discloses N,N'-dialkyl4-phenylimidazoline-2-thiones, particularly 1,3-dimethyl4-phenylimidazoline-2-thione, for use as an antidepressant agent. The dimethyl compound is also said to exhibit antiviral properties against herpes simplex and vaccinia viruses. U.S. Pat. No. Re. 24,505, Rimington et al., reissued Jul. 22, 1958, discloses a group of imidazole compounds useful as anti-thyroid compounds. U.S. Pat. No. 3,505,350, Doebel et al., issued Apr. 7, 1970, discloses a group of substituted 2-mercaptoimidazole derivatives which are said to be effective as anti-inflammatory agents. Illustrative compounds include 1-(4-fluorophenyl)-5-methyl-2-mercaptoimidazole and 1-methyl-5-phenyl-2-mercaptoimidazole. U.S. Pat. No. 3,390,150, Henry, issued Jun. 25, 1968, is representative of a group of patents which disclose nitroimidazole derivatives which possess antischistosomal and antitrichomonal activity. U.S. Pat. No. 5,051,441, Matsumoto et al., issued Sep. 24, 1991, discloses diphenyl imidazoline derivatives which are said to act as immunomodulators, showing efficiency in the treatment of rheumatoid arthritis, multiple sclerosis, systemic lupus, and rheumatic fever. U.S. Pat. No. 4,073,905, Kummer, et al., issued Feb. 14, 1978, discloses 2-amino4-phenyl-2-imidazolines, which are said to be useful for treating hypertension. U.S. Pat. No. 5,202,312, Matsumoto et al., issued Apr. 13, 1993, discloses imidazoline-containing peptides which are said to have immunomodulatory activity. PCT Application WO 92/04033, Faustman, et al., identifies a method for inhibiting rejection of transplanted tissue in a recipient animal by modifying, eliminating, or masking the antigens present on the surface of the transplanted tissue. Specifically, this application suggests modifying, masking or eliminating human leukocyte antigen (HLA) Class I antigens. The preferred masking or modifying drugs are F(ab)' fragments of antibodies directed against HLA-Class I antigens. However, the effectiveness of such a therapy will be limited by the hosts' immune response to the antibody serving as the masking or modifying agent. In addition, in organ transplantation, this treatment would not affect all of the cells because of the perfusion limitations of the masking antibodies. Faustman, et al. contends that fragments or whole viruses can be transfected into donor cells, prior to transplantation into the host, to suppress HLA Class I expression. However, use of whole or fragments of virus presents potential complications to the recipient of such transplanted tissue since some viruses, SV40 in particular, can increase Class I expression (Singer and Maguire, Crit. Rev. Immunol., 10:235-237 (1991), see particularly Table 2). British Patent 592,453, Durant, et al., identifies isothiourea compositions that may be useful in the treatment of autoimmune diseases in host versus graft (HVG) disease and assays for assessing the immunosuppressive capabilities of these compounds. However, this patent does not describe methimazole or the suppression of MHC Class I molecules in the treatment of autoimmune diseases. No tautomeric cyclic thiones are disclosed or discussed. Several autoimmune diseases have been treated with methimazole with potential success. In one study, MMI was deemed as good as cyclosporin in treating juvenile diabetes (W. Waldhausl, et al., Akt. Endokrin. Stoffw. 8:119 (1987), and psoriasis has also been treated with MMI. U.S. Pat. No. 5,556,754, Singer, et al. (which is equivalent to PCT Application WO 94/28897), issued Sep. 17, 1996, describes a method for treating autoimmune diseases using methimazole, methimazole derivatives and methinazole analogs. The terms "methimazole derivative" and "methimazole analog" are not defined or exemplified anywhere in the patent. U.S. Pat. No. 5,310,742, Elias, issued May 10, 1994, describes the use of thioureylene compounds to treat psoriasis and autoimmune diseases. Propylthiouracil, methimazole, and thiabendazole are the only specific compounds disclosed in the patent. Examples show the use of methimazole to treat psoriasis in humans and the use of thioureylene to treat rheumatoid arthritis, lupus and transplant rejection. No methimazole analogs or derivatives are disclosed or discussed. No tautomeric cyclic thiones are disclosed or discussed. U.S. Pat. No. 4,148,885, Renoux, et al., issued Apr. 10, 1979, describes the use of specific low molecular weight sulfur-containing compounds as immunostimulants. Methimazole, thioguanine and thiouracil are among the compounds specified. No methimazole analogs or derivatives are disclosed or discussed. No tautomeric cyclic thiones are disclosed or discussed. U.S. Pat. No. 5,010,092, Elfarra, issued Apr. 23, 1991, describes a method of reducing the nephrotoxicity of certain drugs via the coadministration of methimazole or carbimazole (which is taught to be the pro-drug of methimazole) together with the nephrotoxic drug. No methimazole analogs or derivatives are discussed in this patent. No tautomeric cyclic thiones are disclosed or discussed. U.S. Pat. No. 5,578,645, Askanazi, et al., issued Nov. 26, 1996, describes a method for minimizing the side effects associated with traditional analgesics. This is accomplished via the administration of a mixture of specific branched amino acids together with the analgesic compound. Methimazole is disclosed, in the background section of this patent, as a non-steroidal anti-inflammatory drug which may provide some of the side effects which this invention is said to address. No tautomeric cyclic thiones are disclosed or discussed. U.S. Pat. No. 5,587,369, Daynes, et al., issued Dec. 24, 1996, describes a method for preventing or reducing ischemia following injury. This is accomplished by introducing dehydroepiandrosterone (DHEA), DHEA derivatives or DHEA congeners to a patient as soon as possible after the injury. The background section of this patent teaches that methimazole is a thromboxane inhibitor which has been shown to prevent vascular changes in burn wounds. The U.S.P. Dictionary (US Pharmacopeia, Rockville, Md., 1996) includes methimazole (CAS-60-56-0) and describes it as a thyroid inhibitor. Methimazole, therefore, is known in the art for a variety of pharmaceutical utilities: for the treatment of psoriasis (Elias), as an immunostimulant (Renoux, et al.), for the reduction of nephrotoxicity of certain drugs (Elfarra), for the minimization of side effects found with certain analgesics (Oskinasi, et al), as a thyroid inhibitor (USP Dictionary), and as a thromboxane inhibitor (Daynes, et al.). It is also taught in the Singer, et al. patent as being useful in the treatment of autoimmune diseases, such as rheumatoid arthritis and systemic lupus. While the Singer, et al. patent contains general references to the use of methimazole analogs and derivatives for these therapeutic purposes, no definition of these compounds is given and no specific compounds are suggested. The pharmacological properties of tautomeric cyclic thiones are not discussed nor related to those of methimazole derivatives. It has now been found that a specific class of methimazole derivatives and tautomeric cyclic thiones are effective in treating autoimmune diseases and suppressing the rejection of transplanted organs, and that these compounds show clear and unexpected benefits over the use of methimazole itself. In particular, these compounds: (a) are more effective in inhibiting basal and IFN-induced Class I RNA expression and in inhibiting IFN-induced Class II RNA expression than methimazole; (b) inhibit the action of IFN by acting on the CIITA/Y-box regulatory system; (c) may be significantly more soluble than methimazole, leading to significant formulation flexibility and advantages; (d) have less adverse effects on thyroid function than methimazole; (e) have an enhanced ability to bind to targets affected by MMI; and (f) exhibit therapeutic activities in vivo. These properties are unexpected based on the known properties of methimazole and particularly the tautomeric cyclic thiones. Finally, the present invention relates to the method by which these agents inhibit interferon-gamma actions, specifically those related to increase MHC Class I and MHC Class II expression and mediation of pro-inflammatory processes, and more specifically those processes related to the induction of autoimmune disease and/or transplant rejection. SUMMARY OF THE INVENTION The present invention relates to pharmaceutical compositions comprising a safe and effective amount of an active compound selected from ##STR1## wherein Y is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 substituted alkyl, --NO.sub.2, or the phenyl moiety ##STR2## wherein no more than one Y group in said active compound may be the phenyl moiety; R.sup.1 is selected from H, --OH, halogens (F, Cl, Br or I), C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 substituted alkyl, C.sub.1 -C.sub.4 ester or C.sub.1 -C.sub.4 substituted ester; R.sup.2 is selected from H, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 substituted alkyl; R.sup.3 is selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 substituted alkyl or --CH.sub.2 Ph (wherein Ph is phenyl); R.sup.4 is selected from H, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 substituted alkyl; X is selected from S or O; Z is selected from --SR.sup.3, --OR.sup.3, S(O)R.sup.3 or C.sub.1 -C.sub.4 alkyl; and wherein at least two of the R.sup.2 and R.sup.3 groups on said compound are C.sub.1 -C.sub.4 alkyl when Y is not a phenyl moiety, and at least one Y is --NO.sub.2 when Z is alkyl; together with a pharmaceutically-acceptable carrier. Preferred compounds for use in these pharmaceutical compositions have the forumlae ##STR3## wherein Y is selected from H and C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 substituted alkyl; R.sup.1 is selected from H, --OH, halogens (F, Cl, Br, or I), or C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 substituted alkyl, C.sub.1 -C.sub.4 ester or C.sub.1 -C.sub.4 substituted ester; R.sup.2 is selected from H or C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 substituted alkyl; R.sup.3 is selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 substituted alkyl, or --CH.sub.2 Ph; R.sup.4 is selected from H, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 substituted alkyl; X is selected from S or O; and Z is selected from --SR.sup.3 or --OR.sup.3. Particularly preferred compounds are those which have the formulae ##STR4## Preferred compounds also include those of the formulae: ##STR5## wherein R.sup.9 is selected from --OH, --M and MCH.sub.2 COO--; and M is selected from F, Cl, Br and I. The present invention also relates to the method of treating autoimmune diseases or transplantation rejection in a patient in need of such treatment by the administration of a safe and effective amount of the active compounds and pharmaceutical compositions described above. The present invention also relates to in vivo assay methods which permit high efficiency screening of the effects of compounds on the expression of MHC Class I and Class II proteins. Finally, the present invention relates to the method by which the compounds defined herein inhibit gamma interferon actions to increase MHC class I or class II expression. Gamma interferon has been linked to expression of immune disease. As used herein, all ratios, fractions and percentages are "by weight", unless otherwise specified. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1. Diagrammatic representation of the upstream silencer/enhancer region of the MHC Class I PD1 gene (Panel A), the downstream silencer region of the Class I PD1 gene (Panel B), and the regulatory region of the HLA-DR.alpha. MHC Class II promoter (Panel C). FIG. 2. Effect of methimazole and several of the active compounds used herein on formation of protein/DNA silencer complexes with Fragment 140 (-770 to -636 bp) of the MHC (Class I) 5'-flanking region, which contains within it the upstream silencer/enhancer which controls constitutive MHC class I expression in different tissues. FIG. 3. Sequence of MHC Class I gene between -250 bp and the start of translation. FIG. 4. Effect of treating FRTL-5 cells with MMI or a representative compound studied herein, compound 8 (see Table 1), on the formation of protein/DNA complexes with radiolabeled Fragment 127 (see FIG. 1) of the MHC 5'-flanking region, -127 to +1 bp, as a function of time. FIG. 5. Nucleotide sequence of the 176 bp 5'-flanking region of the -176 bp HLA-DR.alpha.-CAT construct used in the experiments herein. FIG. 6. Electrophoretic mobility shift analysis (EMSA) of the ability of a .sup.32 P-radiolabeled DR.alpha.-5'-flanking region probe to form protein/DNA complexes with extracts from FRTL-5 cells maintained with and without TSH and treated or not with .gamma.-IFN. FIG. 7. Effect of MMI on the ability of .gamma.-IFN to increase the formation of protein/DNA complexes with the .sup.32 P-radiolabeled DR.alpha.-5'-flanking region probe. FIG. 8. Effect of 1 mM MMI or 1 mM concentrations of representative compounds studied herein on the ability of .gamma.-IFN to increase the formation of protein/DNA complexes with the .sup.32 P-radiolabeled DR.alpha.-5'-flanking region probe. FIG. 9. Effect of MMI and/or TSH on exogenous class I promoter activity in FRTL-5 cells. FIG. 10. Effect of MMI and TSH on the promoter activity of CAT chimeras of 5'-deletion mutants of the swine class I promoter in FRTL-5 cells. FIG. 11. Effect of .gamma.-interferon (IFN) on class II expression in FRTL-5 thyroid cells measured using the -176 bp HLA-DR.alpha.-CAT construct and 5'-deletions thereof (A) or the -176 bp DR.alpha.-CAT construct having mutations with the S, X.sub.1, X.sub.2, and Y boxes (B). FIG. 12. Effect of .gamma.-IFN and MMI on MHC class II antigen expression in FRTL-5 cells. FIG. 13. Effect of .gamma.-IFN on class II expression in FRTL-5 thyroid cells as a function of .gamma.-IFN concentration (A) and in the presence of MMI (B). FIG. 14. Effect of MMI on .gamma.-IFN-increased class II expression in FRTL-5 thyroid cells as a function of MMI concentration. FIG. 15. Effect of MMI, compound 10 (5-phenylmethimazole) and compound 3(2-mercaptoimidazole) on immune complexes in the kidneys of (NZBxNZW)F.sub.1 mice. FIG. 16. Ability of MMI or compounds 10 (5-phenylmethimazole), 7 (5-methylmethimazole), 8 (N-methylmethimazole) or 11 (1-methyl-2-thiomethyl-5(4) nitroimidazole) to reverse the ability of .gamma.-IFN to reduce Y box RNA levels. FIG. 17. Model of the development of autoimmune disease and the effect of the MMI, MMI derivatives or tautomeric cyclic thiones on the development process. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutical compositions which may be used to treat autoimmune diseases and to suppress the rejection of transplanted tissue. The methods of treating autoimmune diseases and of suppressing rejection of transplanted tissue utilizing these pharmaceutical compositions are also covered, as are specific methimazole derivatives and tautomeric cyclic thione compounds which may be used to make these pharmaceutical compositions. As used herein, the following terms shall have the definitions given below. The phrase "safe and effective amount" means a sufficient amount of pharmaceutically active compound to desirably affect the treatment of autoimmune diseases or to suppress the rejection of transplanted tissue, at a reasonable benefit/risk ratio attendant with any medical treatment. Within the scope of sound medical judgement, the required dosage of a pharmaceutically active agent or of the pharmaceutical composition containing that active agent will vary with the severity of the condition being treated, the duration of the treatment, the nature of adjunct treatment, the age and physical condition of the patient, the specific active compound employed, and like considerations discussed more fully hereinafter. In this regard it should be noted that the use of MMI at high doses can induce side effects, such as aplastic anemia, agranulocytosis, hepatic dysfunction and dermatitis, in certain patients. In arriving at the "safe and effective amount" for a particular compound, these risks must be taken into consideration, as well as the fact that the compounds described herein provide pharmaceutical activity at lower dosage levels than conventional methimazole compounds. "Pharmaceutically-acceptable" shall mean that the pharmaceutically active compound and other ingredients used in the pharmaceutical compositions and methods defined herein are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. The term "administration" of the pharmaceutically active compounds and the pharmaceutical compositions defined herein includes systemic use, as by injection (especially parenterally), intravenous infusion, suppositories and oral administration thereof, as well as topical application of the compounds and compositions. Oral administration is particularly preferred in the present invention. The term "comprising", as used herein, means that various other compatible drugs and medicaments, as well as inert ingredients, can be conjointly employed in the pharmaceutical compositions and methods of this invention, as long as the defined pharmaceutically active compounds and carriers are used in the manner disclosed. The term "comprising" thus encompasses and includes the more restrictive terms "consisting of" and "consisting essentially of". The term "patient", as used herein, is intended to encompass any mammal, animal or human, which may benefit from treatment with the compounds, compositions and methods of the present invention. By "compatible" herein is meant that the components of the compositions which comprise the present invention are capable of being comingled without interacting in a manner which would substantially decrease the efficacy of the pharmaceutically active compound under ordinary use conditions. The pharmaceutical compositions of the present invention comprise specifically-defined methimazole derivatives and tautomeric cyclic thiones, used in a safe and effective amount, together with a pharmaceutically-acceptable carrier. The methimazole derivatives used in the compositions of the present invention are those having the following structural formulae: ##STR6## In these formulae, Y is selected from H, C.sub.1 -C.sub.4 alkyl C.sub.1 -C.sub.4 substituted alkyl, --NO.sub.2, and the phenyl moiety ##STR7## Y is preferably H, the phenyl moiety or --NO.sub.2, and is most preferably H or the phenyl moiety ##STR8## In the defined compounds, no more than one Y group may be the phenyl moiety. R.sup.1 is selected from H, --OH, halogens (F, Cl, Br and I), C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 substituted alkyl, C.sub.1 -C.sub.4 ester and C.sub.1 -C.sub.4 substituted ester; preferably R.sup.1 is H, --OH, halogen, --OOC CH.sub.2 M (where M is H or a halogen); and is most preferably H. R.sup.2 is selected from H, C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 substituted alkyl; preferably one or both of the R.sup.2 groups is methyl. As used herein, "substituted alkyl" or "substituted ester" is intended to include alkyl, aryl or ester groups which are substituted in one or more places with hydroxyl or alkoxyl groups, carboxyl groups, halogens, nitro groups, amino or acylamino groups, and mixtures of those moieties. Preferred "substituted alkyl" groups are C.sub.1 -C.sub.4 hydroxyl or alkoxyl groups, as well as groups substituted with halogens. The R.sup.3 groups in the above formulae are selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 substituted alkyl and --CH.sub.2 Ph (wherein Ph is phenyl); in preferred compounds, R.sup.3 is H or C.sub.1 -C.sub.4 alkyl; most preferably R.sup.3 is C.sub.1 -C.sub.4 alkyl, particularly methyl. R.sup.4 is selected from H, C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 substituted alkyl, and preferably is H. X may be S or O, and is preferably S. Finally, Z is selected from C.sub.1 -C.sub.4 alkyl, --SR.sup.3, --S(O)R.sup.3 and --OR.sup.3, is preferably --SR.sup.3, --OR.sup.3, and --S(O)R.sup.3 ; most preferably --SR.sup.3 and --OR.sup.3 ; and particularly --SR.sup.3. In the above formulae, at least two of the R.sup.2 and R.sup.3 groups on the compound must be C.sub.1 -C.sub.4 alkyl when Y is not a phenyl moiety. Further, at least one of the Y groups should be --NO.sub.2, when Z is C.sub.1 -C.sub.4 alkyl. Compounds useful in the present invention include the tautomeric cyclic thiones, disclosed in Kjellin and Sandstrom, Acta Chemica Scandanavica 23: 2879-2887 (1969), incorporated herein by reference, having the formulae ##STR9## wherein R.sup.5, R.sup.6 =CH.sub.3, CH.sub.3 ; Ph, H; H, Ph R.sup.7 =H, CH.sub.3 R.sup.8 =O, S, NH, NCH.sub.3 Preferred compounds for use in the compositions of the present invention include those having the formulae: ##STR10## Another group of preferred compositions include those having the formulae: ##STR11## wherein R.sup.10 is selected from H. NO.sub.2, Ph, 4-HOPh and 4-m-Ph (wherein m is F, Cl, Br, or I). A particularly preferred subset of the pharmaceutical compounds defined herein are those wherein one of the Y groups is the phenyl moiety defined above. These compounds have the following formulae: ##STR12## In these compounds, Y is selected from H, C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 substituted alkyl, and is preferably H. R.sup.1 is selected from H, --OH, halogens (F, Cl, Br and I), C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 substituted alkyl, C.sub.1 -C.sub.4 ester, and C.sub.1 -C.sub.4 substituted ester, and is preferably H, --OH, halogen, --OOCCH.sub.2 M (where) M is H or a halogen), and is not preferably H. R.sup.2 is selected from H, C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 substituted alkyl, and it is preferred that at least one of the R.sup.2 groups be methyl. R.sup.3 is selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 substituted alkyl, and --CH.sub.2 Ph; preferred R.sup.3 moieties are H and methyl. R.sup.4 is selected from H, C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 substituted alkyl, and is preferably H. X is selected from S and O, and is preferably S. Finally, the Z moiety is selected from --SR.sup.3 and --OR.sup.3, and is preferably --SR.sup.3. Particularly preferred compounds are those having the structural formulae ##STR13## Other preferred compounds include: ##STR14## wherein R.sup.9 is selected from --OH, --M and --OOCCH.sub.2 M; and M is selected from F, Cl, Br and I. Most preferred is the compound having the structure given below. This compound has demonstrated an unexpectedly high activity in terms of suppressing the expression of MHC Class I and Class II proteins. Further, this compound has shown a different effect on thyroid gene expression, i.e., thyroglobin, when compared to MMI. This suggests that it may be used to treat autoimmune diseases and even Graves' Disease, without requiring thyroid hormone supplementation. ##STR15## Mixtures of the pharmaceutically active compounds defined herein may also be used. The methimazole derivatives and tautomeric cyclic thiones described above can be synthesized using techniques well known to those skilled in the art. For example, the synthesis of several tautomeric cyclic thiones is described in Kjellin and Sandstrom, Acta Chemica Scandanavica 23: 2879.congruent.2887 (1969), incorporated herein by reference. A representative methimazole derivative may be synthesized using the following procedure. Appropriately substituted analogs of acetaldehyde are brominated in the 2-position by treatment with bromine and UV light, followed by formation of the corresponding diethylacetal using absolute ethanol. The bromine is then displaced from this compound by treatment with anhydrous methylamine, or other suitable amine, in a sealed tube at about 120.degree. for up to about 16 hours. Reaction of the resulting aminoacetal with potassium thiocyanate in the presence of hydrochloric acid, at steam bath temperatures overnight, provides the methimazole analogs. The pharmaceutical compositions of the present invention comprise a safe and effective amount of one or more of the methimazole derivatives or tautomeric cyclic thione compounds (i.e., the active compounds). Preferred compositions contain from about 0.01 % to about 25 % of the active compounds, with most preferred compositions containing from about 0.1% to about 10% of the active compounds. The pharmaceutical compositions of the present invention may be administered in any way conventionally known, for example, intraperitoneally, intravenously, intramuscularly, or topically, although oral administration is preferred. Preferred compositions are in unit dosage form, i.e., pharmaceutical compositions which are available in a pre-measured form suitable for single dosage administration without requiring that the individual dosage be measured out by the user, for example, pills, tablets or ampules. The pharmaceutical compositions of the present invention additionally include a pharmaceutically-acceptable carrier compatible with the methimazole derivatives or tautomeric cyclic thiones described above. In addition to the pharmaceutically-acceptable carrier, the pharmaceutical compositions may contain, at their art accepted levels, additional compatible ingredients, such as additional pharmaceutical actives, excipients, formulational aids (e.g., tabletting aids), colorants, flavorants, preservatives, and other materials well known to those skilled in the art. As used herein, the term "pharmaceutical carrier" denotes a solid or liquid filler, diluent or encapsulating substance. These materials are well known to those skilled in the pharmaceutical arts. Some examples of the substances which can serve as pharmaceutical carriers are sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols, such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents and lubricants, such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, tableting agents, and preservatives, can also be present. Formulation of the components into pharmaceutical compositions is done using conventional techniques. The pharmaceutical carrier employed in conjunction with the pharmaceutical compositions of the present invention is used at a concentration sufficient to provide a practical size-to-dosage relationship. Preferably, the pharmaceutical carrier comprises from about 75% to about 99.99%, preferably from about 90% to about 99.9%, by weight of the total pharmaceutical composition. The methimazole derivatives or tautomeric cyclic thiones defined in the present application may surprisingly be more soluble than methimazole in conventional carrier materials. This provides significant benefits in allowing greater flexibility in the formulation of pharmaceutical compositions containing those methimazole derivatives, and may allow the use of significantly lower doses of the active compound. The present invention also provides a method for treating autoimmune diseases and for preventing or treating rejection of tissue in a transplant recipient. More specifically, this invention relates to methods for administering to a mammal in need of such treatment a drug or drugs, as defined herein, capable of suppressing expression of MHC Class I or Class II molecules. Examples of autoimmune diseases that can be treated using this method include, but are not limited to, rheumatoid arthritis, psoriasis, juvenile or type I diabetes, primary idiopathic myxedema, systemic lupus erythematosus, DeQuervains thyroiditis, thyroiditis, autoimmune asthma, myasthenia gravis, scleroderma, chronic hepatitis, Addison's disease, hypogonadism, pernicious anemia, vitiligo, alopecia areata, Coeliac disease, autoimmune enteropathy syndrome, idiopathic thrombocytic purpura, acquired splenic atrophy, idiopathic diabetes insipidus, infertility due to antispermatazoan antibodies, sudden hearing loss, sensoneural hearing loss, Sjogren's syndrome, polymyositis, autoimmune demyelinating diseases such as multiple sclerosis, transverse myelitis, ataxic sclerosis, pemphigus, progressive systemic sclerosis, dermatomyositis, polyarteritis nodosa, hemolytic anemia, glomerular nephritis and idiopathic facial paralysis. In its broadest aspects, methimazole derivatives of the present invention are administered in a dosage range of from about 0.001 to about 100 milligrams, preferably from about 0.05 to about 50 milligrams, per day. The pharmaceutical compositions of the present invention are administered such that appropriate levels of pharmaceutical active are achieved in the bloodstream. The precise dosage level required in a given case will depend upon, for example, the particular methimazole derivative used, the nature of the disease being treated, and the size, weight, age and physical condition of the patient. In a preferred embodiment, an active compound of the present invention, for example 5-phenylmethimazole, is administered to a mammal, preferably a human, afflicted with an autoimmune disease. Suitable therapeutic amounts of the methimazole derivatives are in the range of from about 0.05 to about 20 milligrams per day. A preferred dosage is from about 0.05 to about 10 milligrams per day. The dosage can be administered daily, in approximately equally divided amounts at 8 hour intervals or with breakfast, lunch and dinner. Therapy can be continuous, for example, for periods up to one year or longer. Alternatively, therapy can be tapered, for example, starting at a higher dosage level and tapering to a lower daily dosage level within four to ten weeks. Thyroid hormone (thyroxin T.sub.4 or triiodothyronine T.sub.3) or thyroid stimulating hormone (TSH) levels in the individual receiving such treatment may, for some compounds, be an index of therapeutic effectiveness. It is understood by one skilled in the art that the dosage administered to a mammal afflicted with an autoimmune disease may vary depending on the mammal's age, severity of the disease and response to the course of treatment. One skilled in the art will know the clinical parameters to evaluate to determine proper dosage for an afflicted mammal. In another preferred embodiment, an active compound described herein is administered to a mammal, preferably a human, afflicted with systemic lupus erythematosus (SLE). A preferred therapeutic amount is in the range of from about 0.05 to about 20 milligrams per day, administered over two to twelve months, but can be administered in discontinuous treatment periods of similar length over a five-year period or for as long as necessary. Alternatively, the compositions of the present invention may be administered in conjunction with the current therapies for SLE, hydrocortisone and cytotoxic drugs, to suppress the disease. SLE patients with breast cancer cannot be readily treated with radiation therapy since they are already immunosuppressed by the current conventional treatment for SLE. Also SLE may be associated with unusual sensitivity to radiation complications and therefore radiation therapy exacerbates the disease. It is anticipated, therefore, that the use of the methimazole derivatives and tautomeric cyclic thiones of the present invention to treat SLE individuals with breast cancer will allow radiation therapy to be administered to such individuals without radiation complications or exacerbation of their condition. In another embodiment, the methimazole derivatives, cyclic tautomeric thiones, and pharmaceutical compositions of the present invention are administered to a mammal, preferably a human, afflicted with type I or juvenile diabetes. In another embodiment, the methimazole derivatives, tautomeric cyclic thiones, and pharmaceutical compositions of the present invention are administered to a mammal, preferably a human, afflicted with an autoimmune disease associated with the development of thyroid autoantibodies in the sera of these animals. In yet another embodiment, the methimazole derivatives, tautomeric cyclic thiones, and pharmaceutical compositions of the present invention are administered to a mammal, preferably a human, afflicted with an autoimmune disease characterized by the development of receptor autoantibodies. For example, autoimmune asthma is associated with P-adrenergic receptor autoantibodies. Treatment with the compositions of the present invention will alleviate the disease. Another example of such an autoimmune disease is myasthenia gravis. Myasthenia gravis is associated with acetylcholine receptor autoantibodies. Individuals afflicted with myasthenia gravis have a higher frequency of thyroid autoimmunity. Because of the structural and functional relationship between the TSH and acetylcholine receptors, treatment of an animal, preferably a human, afflicted with myasthenia gravis with a drug able to suppress both MHC Class I and Class II, such as the methimazole derivatives or tautomeric cyclic thiones of the present invention, will help suppress the disease. The method of this invention is also suitable for preventing or treating rejection of a transplanted tissue in a recipient mammal, preferably a human. Examples of tissues which may be transplanted include, but are not limited to, heart, lung, kidney, bone marrow, skin, pancreatic islet cells, thyroid, liver and all endocrine tissues, neural tissue, muscle, fibroblast, and adipocytes. As an example of the prevention of rejection of transplanted tissue, pancreatic islet cells are isolated from a donor and treated with a methimazole derivative or tautomeric cyclic thione of the present invention prior to transplantation into a recipient suffering from diabetes. Diabetes is caused by loss of islet cells as a result of autoimmune disease. Transplantation of islet cells will correct such a deficiency. Islet cells may be treated with from about 0.05 to about 20 milligrams of active compound per day, for example, in the form of an aqueous solution for from about 24 to about 72 hours or longer as necessary to suppress expression of MHC Class I molecules on the islet cells. After transplantation, the recipient may be further treated with a methimazole derivative or tautomeric cyclic thione together with hydrocortisone and/or other immunosuppressive agents. The present invention also relates to an in vitro assay for assessing the ability of a drug to suppress expression of MHC Class I and MHC Class II proteins by measuring the activity of a reporter gene operably linked downstream of a MHC Class I and MHC Class II promoter and its regulatory sequences. The reporter gene operably linked to an MHC Class I and MHC Class II promoter and its regulator sequence is introduced into mammalian cells, said mammalian cells are treated with the candidate drug and the activity of the reporter gene in lysates from treated and untreated mammalian cells is measured. A decrease of activity of the reporter gene in cell lysates from treated versus nontreated cells is predictive of the usefulness of the candidate drug in suppressing MHC Class I and MHC Class II expression and, in turn, suppressing an autoimmune disease or preventing transplant rejection. Preferred regulatory sequences that may be operably linked to the reporter gene are sequences corresponding to the regulatory region of the class I gene, -1 Kb to +1 bp; upstream silencer/enhancer region of the MHC Class I, PD1 gene, -769 to -673 bp (FIG. 1A); the downstream regulatory region of the PD1 gene, -203 or -127 to -1 bp; the downstream silencer region of the PD1 gene, -127 to -80 bp (FIG. 1B); and the regulatory region of the MHC Class II gene containing the S,Y,X.sub.1 and X.sub.2 boxes, -137 to -50 bp (FIG. 1C). These sequences are shown in FIG. 1, with their cognate promoters. It will be understood by one skilled in the art that sequentially and functionally homologous regions found in the regulatory and promoter domains of other Class I and Class II genes may also be used. Examples of reporter genes include, but are not limited to, the chloramphenicol acetyltransferase (CAT) gene, the .beta.-galactosidase gene, the luciferase gene and human growth hormone (hGH) (Sambrook, J. et al., Molecular Cloning: A Laboratory Manual, Vol. 2, 2.sup.nd ed.; Cold Spring Harbor Press, NY (1989); Ausubel, F. et al. in "Current Protocols in Molecular Biology: Supplement 14, section 9.6 (1987); John Wiley and Sons, New York (1990)). Examples of mammalian cells that can be used in this in vitro assay include, but are not limited to, mammalian cell thyrocytes, hepatocytes, neural tissue, muscle, fibroblasts, adipocytes and HELA cells. The means by which the regulatory sequence operably linked to the reporter gene may be introduced into cells are the same as those described above. In a preferred embodiment the luciferase gene is operably linked to one of the above mentioned PD1 sequences and introduced into FRTL-5 cells. It is understood by one skilled in the art that the ability of a candidate drug to suppress expression of MHC Class I and MHC Class II molecules can also be assessed by comparing levels of cellular mRNA in mammalian cells treated with the candidate drug versus cells not treated with the candidate drug. Examples of methods for determing cellular MRNA levels include, but are not limited to, Northern blotting (Alwine, J. C. et al. Proc. Natl. Acad. Sci., 74:5350-5354 (1977)), dot and slot hybridization (Kafatos, F. C. et al. Nucleic Acids Res., 7:1541-1522 (1979)), filter hybridization (Hollander, M. C. et al. Biotechniques; 9:174-179 (1990)), RNase protection (Sambrook, J. et al. in "Molecular Cloning, A Laboratory Manual", Cold Spring Harbor Press, Plainview, N.Y. (1989)), polymerase chain reaction (Watson, J. D. et al.) in "Recombinant DNA" Second Edition, W.H. Freeman and Company, New York (1992)) and nuclear run-off assays (Ausubel, F. et al. in "Current Protocols in Molecular Biology" Supplement 9 (1990); John Wiley and Sons, New York (1990)). The following examples are intended to illustrate the pharmaceutically active compounds, pharmaceutical compositions and methods of treatment of the present invention, but are not intended to be limiting thereof. |
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