There is a continuous search for therapeutics that have immunosuppressive activity, and therefore facilitate organ tissue transplants, as well as being beneficially applied to the treatment of autoimmune or graft versus host disease. The basis of organ tissue rejection is known and resides in the histocompatibility two locus (H-2) in the mouse, and the human leucocyte antigen (HLA) complex in the human. Klein, J., et al. Ann. Rev. Immunol. 1:119 (1983). Both systems code for cell surface molecules that are recognized as foreign in a recipient host. Only in those instances where the donor and recipient are genetically identical, that is when the donor and recipient are identical twins, is there little or no chance of rejection of the transplanted organ. However, since the donor and recipient are rarely genetically identical, some degree of histocompatibility antigenic mismatch is present, and hence the application of immunosuppressive drugs is required. This is true, even where donors and recipients are HLA matched, that is, matched with the antigens of the major histocompatibility complex loci, since rejection of the transplant can still arise as a result of mismatching of minor genetic loci that are also involved in rejection.
Immunosuppressive drugs are also widely used in the area of graft versus host rejection, particularly bone marrow transplants. The graft from a donor contains a significant number of immunocompetent lymphoid cells that can mount an effective destructive reaction against host cells. Bone marrow transplants are often employed to treat various malignant diseases, including leukemia. Generally this involves immunologically crippling the leukemic patient, and then transplanting bone marrow from a donor. Unless the lymphoid cells in the donor marrow are suppressed they can react against recipient tissue antigens, often with dire consequences. A variety of drugs, and antisera to lymphoid cells are used as immunosuppressives. Particularly useful drugs are corticosteroids, othiopirne, and cyclosporine. Various monoclonal antibodies, alone or when coupled to a cytotoxic agent, are available for eliminating lymphoid cells from the donor marrow. P. S. Russell et al., Annual Review Medicine 35:63 (1984). Not only are these immunosuppressive drugs used in the area of organ tissue transplantation and graft versus host disease, they are also widely sought after to treat autoimmune diseases.
Another drug that is useful in the above context is succinyl acetone (4, 6-dioxoheptanoic acid, hereinafter referred to as SA). For example, U.S. Pat. No. 4,670,467 claims SA as an immunosuppressive medicament and Clin. Imm. and Immunopath., 49:63-71 (1988) describes SA in the treatment of experimental autoimmune disease. Also, Hess et al., Jour. of Immunol. 139:2845-2849 (1987), discloses that graft versus host disease may be treated with SA. Against this background, it is evident that SA is a compound that is useful to treat disease. As a consequence, processes for making SA are also important.
In the prior art, SA has been made in a variety of ways. See U.S. patent application Ser. No. 324,360 which is hereby incorporated by reference in its entirety and Pendarvis et al., J. Org. Chem., 39:2289-2291 (1974). Also, SA can be prepared from simple esters, i.e. methyl (Battersby, et al., J. C. S. Perkin I, 1981:2786-2792) and ethyl (Treibs et al., Chem. Berichte, 87:1163-1166 (1954)). Generally, they can be complicated procedures that involve multiple steps, different reagents, and reaction conditions. Obviously, if a process is complex, then it can be expensive and provide more opportunities for mistakes. Consequently, there is always a need to simplify the process that is used to make a chemical compound such as SA. That need is satisfied by the invention that is described below.
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USPTO Backgrounds