US 20160263257A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0263257 A1 Elmaleh et al. (43) Pub. Date: Sep. 15, 2016 (54) CROMOLYN DERVATIVES AND RELATED (52) U.S. Cl. METHODS OF IMAGING AND TREATMENT CPC ......... A61K 51/0421 (2013.01); A61K 9/4808 (2013.01); A61K 9/0075 (2013.01); A61 K (71) Applicants: David R. ELMALEH, Newton, MA 9/0053 (2013.01); A61K 31/192 (2013.01); (US); Timothy SHOUP, Waltham, MA A61K 31/352 (2013.01); A61K 9/0019 (US) (2013.01) (57) ABSTRACT (72) Inventors: David R. Elmaleh, Newton, MA (US); Novel cromolyn analogs useful as imaging agents for detect Timothy M. Shoup, Waltham, MA ing atherosclerotic plaques and for treating atherosclerosis (US) and Alzheimer's Disease, and methods of making the cro molyn analogs, are disclosed. The cromolyn analogs have (21) Appl. No.: 15/031,098 the general formula: (22) PCT Fed: Oct. 22, 2014 (I) (86) PCT No.: PCT/US1.4f61694 O S 371 (c)(1), (2) Date: Apr. 21, 2016 Related U.S. Application Data (II) (63) Continuation of application No. 14/059.924, filed on Oct. 22, 2013. Publication Classification COH: (51) Int. C. A6 IK 5L/04 (2006.01) wherein X is OH, C-C alkoxyl: Y and Z are independently A6 IK3I/352 (2006.01) selected from a C-C alkyl, C-C alkoxyl, halogen, mi A6 IK3I/92 (2006.01) substituted or C-C substituted amine, F, F, or H; and n A6 IK 9/48 (2006.01) is 1, 2, or 3; and wherein for structure (I), if n are both 1 and A6 IK 9/00 (2006.01) Y and Z are both H and X is OH. Patent Application Publication Sep. 15, 2016 Sheet 2 of 11 US 2016/0263257 A1 33 St SS Sis: s S. SCCs Siss w SCR $3S S. 588.svg 2, is givg 3,5s give Cronholy in Sodium ** st Figure 2A Patent Application Publication Sep. 15, 2016 Sheet 3 of 11 US 2016/0263257 A1 E. Figure 2B Patent Application Publication Sep. 15, 2016 Sheet 4 of 11 US 2016/0263257 A1 Croinoyr Socii in Figure 3A Patent Application Publication Sep. 15, 2016 Sheet 5 of 11 US 2016/0263257 A1 he difference between with and without Gd using AB WAKO ELISA siss SS ..{Sigisg 2. Sigisg 3.5g. &g {roinoiyn Sodium Figure 3B Patent Application Publication Sep. 15, 2016 Sheet 6 of 11 US 2016/0263257 A1 S. S {S$g;&g S.S. gig 3,5 gig Croinoiy Sociiuri Figure 3. arYi Patent Application Publication Sep. 15, 2016 Sheet 7 of 11 US 2016/0263257 A1 18.00000 16.00000 Šr 14.00000 12.00000 10.00000 Š Series Š Sees 8.00000 8 Seges 3 6.00000 4.00000 2.00000 S :8 {{ } { Š: 8 N Ba if Figure 4 Patent Application Publication Sep. 15, 2016 Sheet 8 of 11 US 2016/0263257 A1 At aggregatio test Assayed by triotawi forescent intensity kinetics Wntax is per sec) Ailitary sits {A} aggi'egates as "eadigs at K45f.3 in : O in eva 80 re-erecreer-recreer-recreer-recreer-recreer-recreer-recreer-rrerrerrers Figure 5 Patent Application Publication Sep. 15, 2016 Sheet 9 of 11 US 2016/0263257 A1 A aggregation wit agents at SO), 5, 58, 8: 5; it 50 oo: 8,000 X x - - - - - - - - - - - - - - - - - - - - - - - - 50 nM Attitrary units {Ai} aggregates S . : SC s :S.SSSa:::::::::::::::::: ; ::::::::::::::::::::::::::::::::::::::::: ife Cir irissy 3 for 9. in Figure 6 Patent Application Publication Sep. 15, 2016 Sheet 10 of 11 US 2016/0263257 A1 Figure 7 Patent Application Publication Sep. 15, 2016 Sheet 11 of 11 US 2016/0263257 A1 Figure 8 US 2016/0263257 A1 Sep. 15, 2016 CROMOLYN DERVATIVES AND RELATED mast cells thus stabilizing inflammatory cells. Prevention of METHODS OF IMAGING AND TREATMENT mediator release is thought to result from indirect blockade of the entry of calcium ions into the membrane of sensitized CROSS-REFERENCE TO RELATED mast cells. Cromolyn has also been shown to inhibit the APPLICATIONS movement of other inflammatory cells Such as neutrophils, 0001. This application claims benefit of U.S. application eosinophils, and monocytes (8). Ser. No. 14/059,924 filed Oct. 22, 2013, which is incorpo 0007 Recent studies in mice have demonstrated that rated by reference herein. systemic mast cell activation during atherogenesis leads to STATEMENT REGARDING FEDERALLY plaque formation (Bot, de Jager, et al., 2007). Furthermore, treatment of the animals with the mast cell stabilizer cro SPONSORED RESEARCH OR DEVELOPMENT molyn prevented dinitrophenyl-albumin-induced plaque 0002. Not Applicable. expansion. In another study, cardiac mast cell activation was studied in mice after stress-related coronary inflammation FIELD OF THE INVENTION (Huang, Pang, et al., 200). Activated mast cells were found 0003. The invention relates generally to medical imaging adjacent to atherosclerotic vessels. In cromolyn treated and disease treatment. In particular, the invention is directed mice, release of the pro-inflammatory cytokine interleukin-6 to cromolyn derivatives for use in positron emission tomog (IL-6) present in mast cells, was partially inhibited. raphy (PET) imaging and related methods of diagnosis and 0008. There is growing evidence that activated cardiac therapeutic treatment. mast cells are increased in association with coronary inflam mation, myocardial infarction, as well as ischemic cardio BACKGROUND OF THE INVENTION myopathy. Moreover, mast cells can promote the formation 0004 Coronary artery disease is the leading cause of of human atherosclerotic lesions by causing endothelial morbidity and mortality in the United States and in most dysfunction of the heart’s arteries that lead to plaque developed countries. Atherosclerosis and its complications buildup. Since cromolyn targets sensitize mast cells, a Such as myocardial infarction and stroke, is mainly respon labeled cromolyn analog potentially could serve as a diag sible for coronary artery disease. All together, atherosclero nostic probe for early detection of coronary artery disease. sis accounts for at least forty-three percent of all death in the 0009. As can be appreciated, it would be desirable to United States affecting over 60 million people (American obtain new imaging agents useful for detecting degenerative Heart Association, 2004). diseases in human Subjects. In particular, novel imaging 0005 Advances in basic science indicate coronary artery probes that associate with markers of inflammation Such as disease is an inflammatory process, characterized by a long mast cells would facilitate the early detection of inflamma cycle of irritation, injury, healing and re-injury to artery tory diseases such as atherosclerosis by utilizing sensitive endothelial cells. There is growing evidence that mast cells and non-invasive approaches Such as PET or MRI imaging. are found in the various stages of atherosclerosis, coronary Such new compounds may also provide unexpected thera inflammation and cardiac ischemia (Libby 2002; Fernex. peutic benefits for treatment of conditions including, but not 1968; Mor and Mekori, 2001; Kelly, Chi, et al., 2000; Sun, limited to, inflammation, infection, atherosclerosis and Sukhova, et al., 2007; Huang, Pang, et al., 2002). Mast cells, Alzheimer's Disease. located in connective tissue, play an important role in helping the immune system defend tissues from disease by activating the release of intracellular mediators (degranula SUMMARY OF THE INVENTION tion), as well as attracting other key players of the immune defense system to areas of the body where they are needed. 0010. The inventors show herein the synthesis and use of In response to vascular injury, cardiac mast cells interact new cromolyn derivatives. Accordingly, the invention pro with lipoproteins to deliver lipids to macrophages, and to vides imaging agents suitable for imaging sites of inflam release a large variety of cytokines that affect Smooth muscle matory activity, including atherosclerotic plaques in the cells and T lymphocytes. This process can develop into the heart, brain and carotid artery, and 3-amyloid plaques in the more advanced and complex occlusive lesions, termed brain. In addition, the invention provides compounds that fibrous plaques. Other pro-inflammatory mediators released provide therapeutic effects in the treatment of various con by mast cells are histamine, which can constrict the coro ditions including, but not limited to, inflammation, infection, naries, and cytokines IL-6 and IFN-gamma, which induce atherosclerotic plaque, and Alzheimer's Disease. degradation of the extracellular matrix and the death of 0011. In a first aspect, the invention provides a compound Smooth muscle cells in the wall of the aorta, weakening the having the formula: walls and allowing it to dilate. Thus, the inflammatory response stimulates endothelial dysfunction causing migra tion and proliferation of smooth muscle cells that become intermixed in the area of inflammation to form fibrous plaques and complicated lesions. O X O 0006 Disodium cromoglicate, termed “cromolyn,” is the HOCNA --- Y-CO2H, or disodium salt of cromoglicic acid. It is used as an anti O s pi Ye O inflammatory medication. Cromolyn is described in the literature as a mast cell stabilizer since it works by prevent \ h ing the release of mediators such as the vasoactive and Y Z pro-arrhythmogenic chemical histamine and cytokines from US 2016/0263257 A1 Sep. 15, 2016 -continued 0017. As can be appreciated, the compounds of the (II) invention are useful for imaging in other modalities in addition to PET imaging. Exemplary compounds may be O X O optionally isotopically labeled with isotopes such as the 'F HOCNZ isotope or "C isotope to facilitate nuclear magnetic reso O s ---," | N nance imaging (MRI). 0018. In yet another aspect of the invention, a method for \ 1 O COH, providing a positron emission tomography (PET) scan of a Y subject is provided. Such a method includes steps of: (a) or an ester or salt of (I) or (II); wherein: X is OH, C-C, administering to a subject a compound containing an 'F alkoxyl, Y and Z are independently selected from a C-C, label as described and claimed herein; and (b) imaging alkyl, C-C alkoxyl, halogen, un-substituted or C-C Sub gamma rays emitted due to the compound within the Subject stituted amine, F, F, or H; and n is 1, 2, or 3; and wherein in order to provide a PET scan of the compound contained for structure (I), if n are both 1 and Y and Z are both H.