US008377639B2 (12) United States Patent (10) Patent No.: US 8,377,639 B2 Ryder (45) Date of Patent: Feb. 19, 2013 (54) COMPOUNDS FOR MODULATING RNA (56) References Cited BINDING PROTEINS AND USES THEREFOR |U.S. PATENT DOCUMENTS (75) Inventor: Sean Ryder, West Boylston, MA (US) 3,953,492 A * 4/1976 Mrozik ............................. 558/6 (73) Assignee: University of Massachusetts, Boston, FOREIGN PATENT DOCUMENTS WO WO86/03941 A1 7/1986 MA (US) WO WO02/083629 A1 10/2002 WO WO2004/046095 A1 6/2004 (*) Notice: Subject to any disclaimer, the term of this WO WO2006/110762 A2 10/2006 patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 29 days. Massacret et al., Palladium(0)-Catalyzed Asymmetric Synthesis of (21) Appl. No.: 12/823,902 1,2,3,4-Tetrahydro-2-vinylquinoxalines, Eur, J. Org. Chem. 1999, 129-134.” Seftel et al., Comparison of Piperazine and Tetramisole in Treatment (22) Filed: Jun. 25, 2010 of Ascariasis, Brit. med. J., 1968, 4, 93-95.” International Search Report and Written Opinion issued in PCT/ (65) Prior Publication Data US2010/040035 on Jun. 29, 2011. |US 2011/0065704 A1 Mar 17, 2011 Mueller, Joachim et al., “Thioureides of 2-(phenoxymethyl)benzoic acid 4-R substituted: A novel class of anti-parasitic compounds”, Parasitology International, 2009, 58(2), pp. 128-135. (Available online Dec. 25, 2008). Related U.S. Application Data (60) Provisional application No. 61/220,985, filed on Jun. * cited by examiner 26, 2009. Primary Examiner – Jim Ketter Assistant Examiner – Reza Ghafoorian (51) Int. Cl. (74) Attorney, Agent, or Firm – McCarter & English, LLP; CI2O I/68 (2006.01) Elizabeth A. Hanley, Esq.; Jill Mello A ().IN 4 I./06 (2006.01) A0IN 43/653 (2006.01) (57) ABSTRACT A6 IK 31/18 (2006.01) The invention relates to compositions and methods for inhib A6 IK 31/41.96 (2006.01) iting RNA binding proteins (e.g., MEX-3, MEX-5 and POS (52) U.S. Cl. ...... 435/6.1: 514/383: 514/604: 548/263.6; 1), as well as methods for treating and preventing disorders 548/264.8: 564/89; 56.4/92; 564/152; 564/191 associated with parasitic infections and inflammatory disor (58) Field of Classification Search ........................ None ders. See application file for complete search history. 28 Claims, No Drawings US 8,377,639 B2 1 2 COMPOUNDS FOR MODULATING RNA pounds that inhibit the RNA-binding activity of MEX-3, BINDING PROTEINS AND USES THEREFOR MEX-5 and/or POS-1, RNA binding proteins which are required for early embryogenesis in parasitic worms. The RELATED APPLICATIONS identified compounds represent a novel class of anti-parasitic agents that specifically target parasitic worm embryos. This application claims priority to U.S. Provisional Patent Application No. 61/220,985, filed Jun. 26, 2009. The entire Accordingly, in one aspect, the invention pertains, at least contents of the foregoing application are hereby incorporated in part, to method for treating or preventing a parasitic asso in their entirety. ciated state in a subject comprising administering to the sub ject an effective amount of an RNA binding modulatory com GOVERNMENT INTERESTS 10 pound (e.g., a compound of formula I, Ia, Ib, II, IIa, IIb, IIc, III, IV, V, VI, VIa, VIb, VII, VIIa, VIIb, VIIc, VIId, VIIe, VIIf This invention was made with government support under or a compound of Table 1 or 2), such that the parasitic asso grant nos. 1R21NS059380 and 3R21NS059380-01S1 ciated state is treated or prevented. In one embodiment, the awarded by the National Institutes of Health. The government 15 parasitic associated state is a parasitic infestation or re-infes has certain rights in the invention. tation. In another embodiment, the parasitic associated state SUBMISSION ON COMPACT DISC is a disease caused by a parasitic infestation. In one embodiment, the invention pertains, at least in part, This application incorporates by reference the ASCII text to a method for treating or preventing a parasitic infestation in file identified by the name SequenceListing.txt, containing 20 a subject infested with or at risk for infestation with parasites 1.49 KB of data, created on Nov. 12, 2010 and filed in com by administering to the subject a therapeutically or pesticid puter-readable format (CRF). ally effective amount of an RNA binding modulatory com pound, e.g., a compound of formula I, Ia, Ib, II, IIa, IIb, IIc, BACKGROUND OF THE INVENTION III, IV, V, VI, VIa, VIb, VII, VIIa, VIIb, VIIc, VIId, VIIe, VIIf According to the World Health Organization (WHO), more 25 or a compound of Table 1 or 2, such that the parasitic infes than one-third of the world’s population, approximately 2 tation is treated or prevented. billion people, is infested with helminths. In 1999, the WHO In another embodiment, the invention pertains, at least in estimated that schistosomiasis and soil-based helminths rep part, to a method for protection of plants from a parasitic resented more than 40% of the disease burden due to all infestation by administering to the plants a pesticidally effec tropical disease, excluding malaria. While most parasitic 30 tive amount of an RNA binding modulatory compound, e.g., infestations are preventable and treatable, the effects of an a compound of formula I, Ia, Ib, II, IIa, IIb, IIc, III, IV, V, VI, infestation can be chronic and long-term and may eventually VIa, VIb, VII, VIIa, VIIb, VIIc, VIId, VIIe, VIIf or a com cause death. For example, a person who has endured persis pound of Table 1 or 2, such that the plants are protected. tent and heavy infestations is likely to suffer from anemia, In yet another embodiment, the invention pertains, at least malnutrition and chronic irreversible diseases, such as liver 35 in part, to a method for inhibiting parasitic embryogenesis in fibrosis, cancer of the bladder and kidney failure. These para a parasite or in a subject suffering from a parasitic infection sites also affect livestock, which can facilitate infestation in by administering to the parasite or subject suffering from the humans by causing contamination via soil or food supplies. parasitic infection a therapeutically or pesticidally effective In addition to the health risk posed to humans by parasites, amount of an RNA binding modulatory compound, e.g., a plants are highly susceptible to parasitic infestations. Effects 40 compound of formula I, Ia, Ib, II, IIa, IIb, IIc, III, IV, V, VI, of nematode damage to plants include stunting, chlorosis, VIa, VIb, VII, VIIa, VIIb, VIIc, VIId, VIIe, VIIf or a com nutrient deficiencies, wilting, root abnormalities and reduced pound of Table 1 or 2, such that embryogenesis is inhibited. yield. In a further embodiment, the invention pertains, at least in While there are a number of antihelminthic treatments part, to a method for reducing parasitic burden in soil, in currently available, some scientists are concerned that the 45 plants or in an animal suffering from a parasitic infection by parasites will develop resistance to these treatments, espe administering to the soil, plants or animal atherapeutically or cially in developing countries where people are repeatedly pesticidally effective amount of an RNA binding modulatory infected with helminths and receive multiple doses of anti compound, e.g., a compound of formula I, Ia, Ib, II, IIa, IIb, helminthic drugs. In fact, resistance to antihelminthic drugs IIc, III, IV, V, VI, VIa, VIb, VII, VIIa, VIIb, VIIc, VIId, VIIe, has been observed in livestock due to frequent and repeated 50 VIIf or a compound of Table 1 or 2, such that the parasitic treatments. Moreover, rates of re-infection by helminths are burden is reduced. very high due to the number and the durability of infective In another embodiment, the invention pertains, at least in eggs on surfaces and in soil. While infection is active, some part, to a method for treating or preventing a disease caused parasitic nematode species (e.g., Ascaris lumbricoides) by a parasitic infestation in a subject by administering to the release an estimated 100,000 new embryos per adult female 55 subject a therapeutically effective amount of an RNA binding per day. Currently available anti-helminthics work by para modulatory compound, e.g., a compound of formula I, Ia, Ib, lyzing the infectious nematode through blocking ion channels II, IIa, IIb, IIc, III, IV, V, VI, VIa, VIb, VII, VIIa, VIIb, VIIc, and receptors and do not inactivate the embryos that cause VIId, VIIe, VIIf or a compound of Table 1 or 2, such that the re-infection. Therefore, it is advantageous to develop new disease is treated or prevented. therapies for the treatment and prevention of parasitic infes 60 In one embodiment, the invention pertains, at least in part, tations and, in particular, therapies that limit the possibility of to a method for treating or preventing an inflammatory disor parasitic re-infection, in both plants and animals, der in a subject by administering to the subject a therapeuti cally effective amount of an RNA binding modulatory com SUMMARY OF THE INVENTION pound, e.g., a compound of formula I, Ia, Ib, II, IIa, IIb, IIc, 65 III, IV, V, VI, VIa, VIb, VII, VIIa, VIIb, VIIc, VIId, VIIe, VIIf The present invention is based, at least in part, on the or a compound of Table 1 or 2, such that the inflammatory development and use of screening assays to identify com disorder is treated. US 8,377,639 B2 3 4 In one embodiment, the subject is a plant. In one embodi In one aspect, the present invention provides methods of ment, the subject is an animal. In one embodiment, the subject identifying a compound useful in modulating embryogenesis.