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US 2010/0056617 A1 Spect at Corports Coecio US 2010.00566.17A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0056617 A1 Steiner et al. (43) Pub. Date: Mar. 4, 2010 (54) ROLE OF LIMONOID COMPOUNDS AS Related U.S. Application Data NEUROPROTECTIVE AGENTS (62) Division of application No. 1 1/893,100, filed on Aug. 13, 2007. (75) Inventors: Joseph(US): Avindra P. Steiner, Nath, Baltimore, Ellicott City, MD (60) Pygal application No. 60/837.365, filed on Aug. MD (US); Norman Haughey, s Baltimore, MD (US) Publication Classification (51) Int. Cl. Correspondence Address: A63L/35 (2006.01) EDWARDS ANGELL PALMER & DODGE LLP A6IP 25/18 (2006.01) P.O. BOX SS874 A6IP 25/28 (2006.01) BOSTON, MA 02205 (US) (52) U.S. Cl. ........................................................ S14/453 (57) ABSTRACT (73) Assignee: The Johns Hopkins University, Disclosed herein are neuroprotective compounds. Methods Baltimore, MD (US) for the preparation of Such compounds are disclosed. Also disclosed are pharmaceutical compositions that include the (21) Appl. No.: 12/590,270 compounds. Methods of using the compounds disclosed, alone or in combination with other therapeutic agents, for the (22) Filed: Nov. 5, 2009 treatment of neurodegenerative conditions are provided. spect at Corports Coecio: w 3.x toxicity Scree : {{8 x 8.8 Patent Application Publication Mar. 4, 2010 Sheet 1 of 9 US 2010/00566.17 A1 Spect in Copaic Coirection. 3. Nir toxicity Scree :::::: 88:38:8: Patent Application Publication Mar. 4, 2010 Sheet 2 of 9 US 2010/00566.17 A1 Fig. 2 KhivOrin Odoratone Angolensic Acid, methyl ester Limonin Patent Application Publication Mar. 4, 2010 Sheet 3 of 9 US 2010/00566.17 A1 xxx...a..., xxx x * , sea sa & & & & % Patent Application Publication Mar. 4, 2010 Sheet 4 of 9 US 2010/00566.17 A1 f k Patent Application Publication Mar. 4, 2010 Sheet 5 of 9 US 2010/00566.17 A1 a Kixxi.; : s 8. : s : Patent Application Publication Mar. 4, 2010 Sheet 6 of 9 US 2010/00566.17 A1 $*:;$.?;;;)(&,** wa Patent Application Publication Mar. 4, 2010 Sheet 7 of 9 US 2010/00566.17 A1 : x 88: & ::: 3. & & : & : : : x: & & ax:: k x Patent Application Publication Mar. 4, 2010 Sheet 8 of 9 US 2010/00566.17 A1 Patent Application Publication Mar. 4, 2010 Sheet 9 of 9 US 2010/00566.17 A1 8:... 8 A. iroi; iv. US 2010/00566.17 A1 Mar. 4, 2010 ROLE OF LIMONOID COMPOUNDSAS 0005. In a further embodiment, the at least one compound NEUROPROTECTIVE AGENTS of Formula I has a structure selected from: RELATED APPLICATIONS 0001. This application claims the benefit of U.S. Provi sional Patent Application No. 60/837.365, entitled “Role of Liminoid Compounds as Neuroprotective Agents.” filed Aug. 11, 2006, the contents of which are incorporated by reference in their entirety. BACKGROUND OF THE INVENTION 0002 Neurodegenerative conditions such as Alzheimer's Disease, multiple sclerosis, AIDS-related dementia, Hunting ton's Disease, stroke, and spinal cord trauma are character ized by extensive loss of neurons or glia. SUMMARY OF THE INVENTION 0003. Described herein are neuroprotective compounds. Also described herein are pharmaceutical formulations com prising Such neuroprotective compounds, and methods for 0006. In a further embodiment, the at least one compound using Such neuroprotective compounds in the prophylaxis of Formula I has the structure: and treatment of neurodegenerative conditions. 0004. Accordingly, in one aspect provided herein is a pharmaceutical composition comprising at least one com pound having the structure of Formula I: wherein R and Rs together form a Substituted cycloalkyl or cycloalkenyl group. wherein each compound of Formula I is in a substantially 0007. In a further embodiment, the at least one compound purified form; and of Formula I has the structure: Y is O and Y, is OH, O-alkyl, O-(hydroxyalkyl) or O-(alkoxyalkyl); or Y and Y together form a furan group; RandR together form a substituted cycloalkyl or cycloalk enyl group; and / O is selected from s CH O , or s CH R6 \7 / O, O wherein X and R together form a substituted heteroalicyclic R X group provided that R is H; or pharmaceutically acceptable salts, esters, prodrugs, or metabolites thereof; wherein R and R, together form a substituted cycloalkyl or or ester derivatives, saccharide derivatives, or—(CH2CH2O) cycloalkenyl group; and CH derivatives thereof, where n is 1 to 100: X is selected from H, oxo, OH, O-alkyl, O-(hydroxyalkyl). and a pharmaceutically acceptable excipient O-(alkoxyalkyl), or O—C(O)-alkyl. US 2010/00566.17 A1 Mar. 4, 2010 0008. In a further embodiment, the at least one compound 0010. In a further embodiment, the at least one compound of Formula I has a structure selected from: of Formula I has the structure: wherein R and R, together form a substituted cycloalkyl or cycloalkenyl group; and X is selected from H, oxo, OH, O-alkyl, O-(hydroxyalkyl). O-(alkoxyalkyl), or O—C(O)-alkyl. 0011. In a further embodiment, the at least one compound of Formula I has a structure selected from: Ro Rs wherein Rs and R are independently H or alkyl: X and X are independently selected from H, oxo, OH, O-alkyl, O-(hydroxyalkyl), O-(alkoxyalkyl), or O C(O)- alkyl; and is selected from O V7 O 0009. In a further embodiment, the at least one compound of Formula I has the structure: wherein R and Rs together form a Substituted cycloalkyl or cycloalkenyl group. US 2010/00566.17 A1 Mar. 4, 2010 wherein Rs and R are independently H or alkyl: 0015. In another aspect provided herein is a pharmaceuti X and X are independently selected from H, oxo, OH, cal composition comprising at least one compound having the O-alkyl, O-(hydroxyalkyl), O-(alkoxyalkyl), or O C(O)- structure of Formula II: alkyl; and is selected from O V7 O 0012. In a further embodiment, the at least one compound of Formula I has the structure: wherein Het is a Substituted or unsubstituted oxygen-con taining aromatic or non-aromatic heterocycle; L is a bond or an alkylene group; each ------ is independently selected from s R10 O, O s / \ s X and Rio togetherform a substituted heteroalicyclic group. V/ X24 R20 0013. In a further embodiment, the at least one compound of Formula I has the structure: provided that no two adjacent ------ groups are adjacent O V7O groups: each X2, X, X2, X, and X is independently selected from H, oxo, OH, OC(O)-alkyl, O-(hydroxyalkyl). O-(alkoxyalkyl), or O-alkyl: wherein RandR togetherform a Substituted cycloalkyl or cycloalkenyl group. each Ro R and R is selected from Horalkyl, or any two 0014. In a further embodiment, the at least one compound of X20, X2, X22, X2: X24, R20 R2, or R22 can form an of Formula I has the structure: optionally substituted oxygen-containing heterocycle; or pharmaceutically acceptable salts, esters, prodrugs, or metabolites thereof; or ester derivatives, saccharide derivatives, or—(CH2CH2O) CH derivatives thereof, where n is 1 to 100; and a pharmaceutically acceptable excipient. I0016. In a further embodiment, the Het is an unsubsti tuted furanyl group. In a further or alternative embodiment, L is a bond. I0017. In a further or alternative embodiment, RandR are CH. In a further embodiment at least one of groups is a . Inafurther or alternative embodi ment, at least one of ------ groups is a R13 R14 wherein R and Ra are independently H or alkyl, V7 X is selected from H, oxo, OH, O-alkyl, O-(hydroxyalkyl). O O-(alkoxyalkyl), or O—C(O)-alkyl; and Rs is alkyl-C(O)O-alkyl. US 2010/00566.17 A1 Mar. 4, 2010 In a further or alternative embodiment, at least one of maceutically acceptable excipients. In a further or alternative groups is a embodiment, the pharmaceutical composition has atherapeu tically effective amount of a compound isolated from the plant families of order Rutales, including in Maliaceae and Rutaceae. In a further or alternative embodiment, the phar maceutical composition has a therapeutically effective amount of a compound derived from a 4.4.8-trimethyl-17 In a further or alternative embodiment, X is an oxo group. In furanylsteroid skeleton. In a further or alternative embodi a further or alternative embodiment, the compound of For ment, the pharmaceutical composition has a therapeutically mula II is selected from: effective amount of a compound is a tetranortriterpenoid. 0019. In another aspect provided herein is a method for treating or reducing the risk of a neurodegenerative condition in a Subject in need thereof by administering to the Subject a therapeutically effective amount of any of the above-de scribed neuroprotective compound compositions. In some embodiments, the sole active ingredient in the pharmaceuti cal composition administered to the Subject is a neuroprotec tive compound disclosed herein. In some embodiments, the composition to be administered to the Subject comprises a neuroprotective compound that at a concentration of 10 LM provides at least 6% (e.g., at least 20%, 50%, or 70%) pro tection against 3 mM 3-nitropropionic acid to rat mixed hip pocampal cultures. In some embodiments, the Subject is diag nosed as Suffering from the neurodegenerative condition prior to administration of the composition. In some embodi ments, administration of the composition to the Subject is parenteral, intravenous, Subcutaneous, intra-muscular, trans nasal, intra-arterial, transdermal, or respiratory. In some embodiments, the subject to be treated is administered, in addition to one of the above-described compositions, a com position comprising a therapeutically effective amount of a polyphenol (e.g., resveratrol or epigallocatechin 3-gallate) or an antioxidant compound (e.g., Vitamin C or Vitamin E). 0020. In a related aspect, the subject to be treated is suf fering from a chronic neurodegenerative condition.
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