US 2003O181495A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0181495 A1 Lai et al. (43) Pub. Date: Sep. 25, 2003 (54) THERAPEUTIC METHODS EMPLOYING Division of application No. 09/565,665, filed on May DSULFIDE DERVATIVES OF 5, 2000, now Pat. No. 6,589,991. DTHIOCARBAMATES AND Division of application No. 09/103,639, filed on Jun. COMPOSITIONS USEFUL THEREFOR 23, 1998, now Pat. No. 6,093,743. (75) Inventors: Ching-San Lai, Carlsbad, CA (US); Publication Classification Vassil P. Vassilev, San Diego, CA (US) (51) Int. Cl." ..................... A61K 31/426; A61K 31/325; Correspondence Address: A61K 31/55; A61K 31/4545; FOLEY & LARDNER A61K 31/4025 P.O. BOX 80278 (52) U.S. Cl. .................... 514/369; 514/476; 514/217.03; SAN DIEGO, CA 92138-0278 (US) 514/316; 514/422 (57) ABSTRACT Assignee: Medinox, Inc. (73) The present invention provides novel combinations of (21) Appl. No.: 10/394,794 dithiocarbamate disulfide dimers with other active agents. In one method, the disulfide derivative of a dithiocarbamate is (22) Filed: Mar. 21, 2003 coadministered with a thiazolidinedione for the treatment of diabetes. In another embodiment, In another embodiment, invention combinations further comprise additional active Related U.S. Application Data agents Such as, for example, metformin, insulin, Sulfony lureas, and the like. In another embodiment, the present (60) Continuation-in-part of application No. 10/044,096, invention relates to compositions and formulations useful in filed on Jan. 11, 2002, now Pat. No. 6,596,770. Such therapeutic methods. Patent Application Publication Sep. 25, 2003 Sheet 1 of 6 US 2003/0181495 A1 90 Wavelength 340 - Fig. 1 2 340 Fig. 2 C ------- r Fig. 3 3: 19 () Way clength 40 Patent Application Publication Sep. 25, 2003 Sheet 2 of 6 US 2003/0181495 A1 1 OO Statistical: p<0.01 Product -Lillic Survival Atalysis Gcil cralized Savage (Mantel-Cux) s 60 - s L-PD (n=30) M 40 & O Uttracd (n=31) - O - 50 6 O 7 O 8 O 9 O OO O 12 O Animal Age Fig. 4 Patent Application Publication Sep. 25, 2003 Sheet 3 of 6 US 2003/0181495 A1 o aloos Állue AeS Patent Application Publication Sep. 25, 2003 Sheet 4 of 6 US 2003/0181495 A1 0.5 8 A l so -g Fig. 6 90 Wavelength 340 0.5 U r d l a -g O ----------- . 190 w 340 Fig. 7 . Wavelength 0.5 A. - la -g ... O Fig.8 190 Wavelength 340 Patent Application Publication Sep. 25, 2003 Sheet 5 of 6 US 2003/0181495 A1 1.5 w 90 Fig. 9 - Wavelength 1.5 Fig.10 Wavelength 0.35 Fig.11 Wavelength Patent Application Publication Sep. 25, 2003 Sheet 6 of 6 US 2003/0181495 A1 600 500 400 300 - 200 - O T - DO D 2 O 8 D 15 D 22 D 28 D 35 D 42 D 50 Time (days) Figure 12 600 500 400 3 OO 200 100 O D - 1 D 2 D 9 D 16 D 23 D 27 Time (days) Figure 13 US 2003/O181495 A1 Sep. 25, 2003 THERAPEUTIC METHODS EMPLOYING (1993). For example, in blood, NO produced by the endot DISULFIDE DERVATIVES OF helium diffuses isotropically in all directions into adjacent DTHOCARBAMATES AND COMPOSITIONS tissues. AS NO diffuses into the vascular Smooth muscle, it USEFUL THEREFOR binds to guanylate cyclase enzyme, which catalyzes the production of c(GMP, inducing vasodilation (see, for RELATED APPLICATIONS example, Ignarro, L. J., Ann. Rev. Toxicol. 30:535-560 (1990); Moncada, S., Acta Physiol. Scand. 145:201-227 0001. This application is a continuation-in-part of appli (1992); and Lowenstein and Snyder, Cell 70:705–707 cation Ser. No. 10/044,096, filed Jan. 11, 2002, now pend (1992)). The overproduction of nitric oxide causes an ing, which is in turn, a divisional of application Ser. No. extreme drop in blood preSSure, resulting in insufficient 09/565,665, filed May 5, 2000, now issued as U.S. Pat. No. tissue perfusion and organ failure, Syndromes that are asso 6,316,502, which is in turn, a divisional of application Ser. ciated with many diseases and/or conditions (e.g., Septic No. 09/103,639, filed Jun. 23, 1998, now issued as U.S. Pat. Shock, overexpression of cytokines, allograft rejection, and No. 6,093,743, each of which is hereby incorporated by the like). The overproduction of nitric oxide is triggered by reference herein in its entirety. a number of Stimuli, Such as, the overproduction of inflam matory cytokines (e.g., tumor necrosis factor (TNF), inter FIELD OF THE INVENTION leukin-1 (IL-1), interferons, endotoxin, and the like). Addi 0002 The present invention relates to therapeutic meth tionally, the overproduction of .NO has been discovered to ods employing dithiocarbamates to reduce the level of be one of the major Side-effects of a number of therapeutic Species associated with disease States in mammals. In one treatments, e.g., cytokine therapy (See, for example, Miles et aspect, the invention relates to compositions containing al., in Eur: J. Clin. Invest. 24:287-290 (1994) and Hibbs et disulfide derivatives of dithiocarbamates and to therapeutic al., in J. Clin. Invest. 89:867-877 (1992)), anti-diabetic methods employing Such compositions. therapy, and the like. Thus, abnormally elevated nitric oxide levels have been linked to many inflammatory and infectious BACKGROUND OF THE INVENTION diseases. 0007 Numerous therapeutic agents (e.g., inflammatory 0003) In 1987, nitric oxide (NO), a gaseous free-radical, cytokines (e.g., TNF, interleukins or interferons), anti-dia was discovered in humans (see, for example, Ignarro et al., betic agents, and infectious agents (e.g., endotoxin), and the in Proc. Natl. Acad. Sci., USA 84:9265-69 (1987) and like) induce nitric oxide overproduction by inducing tran Palmer et al., in Nature 327:524-26 (1987)). As an indication Scription of the inducible nitric oxide Synthase gene, leading of the significance of this discovery for the understanding of to the production of inducible nitric oxide Synthase, which human physiology and pathophysiology, Science magazine in turn results in the overproduction of nitric oxide. The selected nitric oxide as the molecule of the year in 1992. production of nitric oxide by the above-described pathway 0004 Nitric oxide is formed from the terminal guanidino can be disrupted in a variety of ways. Thus, for example, nitrogen atom of L-arginine by nitric oxide Synthase (NOS; there have been attempts to develop monoclonal antibodies see, for example, Rodeberg et al., in Am. J. Surg. 170:292 (e.g., anti-endotoxin antibodies, anti-cytokine antibodies, 303 (1995), and Bredt and Snyder in Ann. Rev. Biochem. anti-cytokine receptor antibodies, and the like) in efforts to 63:175-95 (1994)). Two major forms of nitric oxide syn block the NO production pathway at the transcriptional thase, constitutive and inducible enzymes, have been iden level. Unfortunately, however, such efforts have met with tified. very limited Success (see, for example, Glauser et al., in Clin. Infect. Dis. 18:S205-16 (1994) and St. John & Dorin 0005 Under physiological conditions, a low output of sky, in Chest 103:932-943 (1993)). At least one reason for .NO is produced by the constitutive, calcium-dependent the relative lack of SucceSS in the art is the fact that the NOS isoform (cNOS) present in numerous cells, including production of inflammatory cytokines is short-lived (see, for endothelium and neurons. This low level of nitric oxide is example, Wange & Steinsham in Eur. J. Haematol. 50:243 involved in a variety of regulatory processes, e.g., blood 249 (1993)), while overproduction of nitric oxide lasts vessel homeostasis, neuronal communication and immune Several days, causing Systemic hypotension, insufficient System function. On the other hand, under pathophysiologi cal conditions, a high output of NO is produced by the tissue perfusion and organ failure. inducible, calcium-independent NOS isoform (iNOS) which 0008 Thus, for example, during endotoxemia, TNF pro is expressed in numerous cell types, including endothelial duction peaks at about 1-2 hours. Therefore, in order to be cells, Smooth muscle cells and macrophages. These high effective, anti-TNF antibodies would have to be adminis levels of nitric oxide have been shown to be the etiology of tered at an early Stage after infection. Indeed, in many endotoxin shock. This high output of .NO further contributes clinical Settings, patients are likely to already have been to inflammation-related tissue damage, neuronal pathology, infected with bacteria prior to being admitted. Accordingly, N-nitrosamine-induced carcinogenesis and mutations in Such therapeutic methods have met with only limited Suc human cells and bacteria Via deamination reaction with CCSS. DNA. Nitric oxide can therefore be seen to be a mixed 0009 Currently, many pharmaceutical companies have blessing, being very desirable when present in Small turned their attention to the design and development of amounts, while potentially being highly detrimental when Substrate or product analogue inhibitors of the enzyme, produced in excessive quantities. NOS, in efforts to treat the overproduction of NO. However, 0006 Nitric oxide is a potent vasodilator (see, for recent data show that the inhibition of NOS is detrimental to example, Palmer in Arch. Surg. 128:396–401 (1993) and subjects. For example, rodent studies show that inhibition of Radomski & Moncada in Thromb. Haemos. 70:36-41 the production of nitric oxide causes intrauterine growth US 2003/O181495 A1 Sep. 25, 2003 retardation and hind-limb disruptions in rats (see, for 0013 The classic antidotal action for cyanide poisoning, example, Diket et al., in Am. J. Obstet. Gynecol. 171:1243– introduced by Chen et al. in 1933 (see, for example, Chen et 1250 (1994)).