US010751310B2 ( 12 ) United States Patent ( 10 ) Patent No .: US 10,751,310 B2 Freeman et al . ( 45 ) Date of Patent : Aug. 25 , 2020 ( 54 ) PREVENTION , TREATMENT AND ( 56 ) References Cited REVERSAL OF DISEASE USING THERAPEUTICALLY EFFECTIVE U.S. PATENT DOCUMENTS AMOUNTS OF DICARBOXYLIC ACID 3,527,789 A 9/1970 Payne COMPOUNDS 4,166,913 A 9/1979 Kesling , Jr. et al . 6,528,499 B1 * 3/2003 Kozikowski C07C 59/347 ( 71 ) Applicant: UNIVERSITY OF 514/574 8,324,277 B2 12/2012 Freeman PITTSBURGH — OF THE 8,735,449 B2 5/2014 Freeman COMMONWEALTH SYSTEM OF 9,066,902 B2 6/2015 Freeman et al . HIGHER EDUCATION , Pittsburgh , 9,186,408 B2 11/2015 Freeman et al . PA (US ) 9,700,534 B2 7/2017 Freeman et al . 9,750,725 B2 9/2017 Freeman et al . 10,213,417 B2 2/2019 Freeman et al . ( 72 ) Inventors : Bruce A. Freeman , Pittsburgh , PA 10,258,589 B2 4/2019 Freeman et al . ( US ) ; Francisco J. Schopfer , 2015/0018417 Al 1/2015 Freeman et al . Pittsburgh , PA ( US ) FOREIGN PATENT DOCUMENTS ( 73 ) Assignee : University of Pittsburgh — of the CN 103705499 4/2014 Commonwealth System of Higher DE 102011118462 5/2013 Education , Pittsburgh , PA ( US ) GB 1153464 5/1969 WO WO 2002/022627 3/2002 WO WO 2009/017802 2/2009 ( * ) Notice : Subject to any disclaimer , the term of this WO WO 2009/112455 9/2009 patent is extended or adjusted under 35 WO WO 2010/005521 1/2010 U.S.C. 154 ( b ) by 0 days . WO WO 2010/014889 2/2010 WO WO 2011/014261 2/2011 WO WO 2013/116753 8/2013 ( 21 ) Appl. No .: 16 / 081,791 WO WO 2013/142206 9/2013 WO WO 2013/162924 10/2013 ( 22 ) PCT Filed : Mar. 2 , 2017 WO WO 2015/012367 1/2015 ( 86 ) PCT No .: PCT / US2017 / 020477 OTHER PUBLICATIONS $ 371 ( c ) ( 1 ) , CAS Abstract of e -EROS Encyclopedia of Reagents for Organic ( 2 ) Date : Aug. 31 , 2018 Synthesis ( 2007 ) , No pp . given . John Wiley & Sons , Ltd .: Chichester, UK . ( Year : 2007 ) . * Alessandro Palmieri et al . , Green Chemistry Group , School of ( 87 ) PCT Pub . No .: WO2017 / 151938 Science and Technology, Chemistry Division, University of Camerino , PCT Pub . Date : Sep. 8 , 2017 Camerino , 62032 , Italy .Green Chemistry ( 2013 ) , 15 ( 9 ) , 2344-2348 . “ Low impact synthesis of B - nitroacrylates under fully heteroge neous conditions ” ( Year: 2013 ) . * ( 65 ) Prior Publication Data Mohammad Rafiee et al. , Studies in Basic Sciences ( IASBS ) , Zanjan , Iran ., “ CEC mechanism in electrochemical oxidation of US 2019/0091186 A1 Mar. 28 , 2019 nitrocatechol - boric acid complexes ” , Electrochimica Acta ( 2011 ) , 56 ( 27 ) , 9946-9952 CODEN : ELCAAV ; ISSN : 0013-4686 . ( Year: 2011 ) . * Related U.S. Application Data Roberto Ballini et al . , Stereoselective preparation of ( E ) -. vepsiln. nitro - B , y -unsaturated methyl esters : Amberlyst A 27 , using micro ( 60 ) Provisional application No. 62 / 303,960 , filed on Mar. wave, as superior catalyst for the 1,6 - conjugate addition of nitroalkanes 4 , 2016 . to methyl 1,3 -butadiene - 1 - carboxylate. ( Year: 2001 ) . * ( Continued ) ( 51 ) Int . Cl . Primary Examiner Alexander R Pagano A61K 31/194 ( 2006.01 ) Assistant Examiner Ebenezer O Sackey A61K 9/00 ( 2006.01 ) ( 74 ) Attorney, Agent, or Firm — Klarquist Sparkman , C07C 323/52 ( 2006.01 ) LLP A61K 31/225 ( 2006.01 ) ( 52 ) U.S. CI . ( 57 ) ABSTRACT CPC A61K 31/194 ( 2013.01 ) ; A61K 9/0073 Various embodiments of this invention are directed to phar ( 2013.01 ) ; C07C 323/52 ( 2013.01 ) ; AIK maceutical compositions and methods for treating disease . 9/0019 ( 2013.01 ) ; A61K 9/0034 ( 2013.01 ) ; The compositions of such embodiments include dicarbox A61K 9/0053 ( 2013.01 ) ; A61K 31/225 ylic acid compounds containing electron withdrawing ( 2013.01 ) groups, alkyl esters of dicarboxylic acids containing electron ( 58 ) Field of Classification Search withdrawing groups , or compounds of Formulae I to X. The CPC .. C07C 323/52 , A61K 9/0019 ; A61K 9/0034 ; methods of various embodiments include administering an A61K 31/225 , A61K 9/0073 ; A61K effective amount of any of these pharmaceutical composi 31/194 ; A61K 9/0053 tions to a patient in need of treatment . See application file for complete search history . 37 Claims , No Drawings US 10,751,310 B2 Page 2 ( 56 ) References Cited Tsai et al . , “ A novel synthesis of 1,21 -heneicosanedioic acid , ” The Journal of Organic Chemistry, 45 ( 23 ) : 4785-4786 , Nov. 30 , 1980 . U.S. Appl. No. 16 / 239,425 , filed Jan. 3 , 2019 . OTHER PUBLICATIONS U.S. Appl. No. 16 / 280,704 , filed Feb. 20 , 2019 . Baker et al. , “ Anodic syntheses. Part XIV . The use of acetylenic Akone et al . , “ 2 -pentenedioic acid derivatives from a soil - derived components . A new synthesis of oleic acid , ” Journal of the Chemi fungus Gongorella butleri, ” Phytochemistry Letters, vol . 10 , pp . cal Society, pp . 2218-2227 , Dec. 30 , 1955 . 184-188 , Sep. 19 , 2014 . Cantet et al . , “ A new synthesis of trifluorinated compounds via Hon et al . , “ Syntheses of bifunctional compounds from cycloalkenes 1,1 - dichloro - 1 - alkenes in superacid ,” Tetrahedron Letters, 48 ( 30 ) : via ozonide intermediates , ” Tetrahedron , 53 ( 14 ) : 5217-5232 , Apr. 7 , 5255-5260 , Jul. 23 , 2007 . 1997 . Effenberger et al . , “ Selective hydrolysis of aliphatic dinitriles to Supplemental Partial European Search Report issued for EPC monocarboxylic acids by a nitrilase from Arabidopsis thaliana , " Application No. 17760831.2 dated Dec. 10 , 2019 . Synthesis, No. 12 , pp . 1866-1872 , Sep. 25 , 2001 . Eliasson et al . , “ Aliphatic medium chain tricarboxylic acids in rat Xu et al . , “ A simple and highly efficient procedure for construction urine , ” Journal of Lipid Research , vol . 17 , pp . 637-646 , Nov. 30 , of quaternary carbons centers by tributylphosphine catalyzed bis 1976 . Michael addition ,” Tetrahedron , vol . 70 , pp . 176-180 , Dec. 4 , 2013 . International Search Report and Written Opinion issued for Inter Zurcher et al ., “ The oxidation of 3-( 1 -Nitro - 2 -oxocycloalkyl ) propanal, " national Application No. PCT US2017/ / 010477 dated Jun . 20 , 2017 . elvetica Chimica Acta , 70 ( 7 ) : 1937-1943 , Nov. 1987 ( in German Linforth et al ., “ 2,7 - dimethyl - octa -2,4 -dienedioic acid a possible with English abstract ). by - product of abscisic acid biosynthesis in the tomato ,” Phytochemistry, 26 ( 6 ) : 1631-1634 , Dec. 30 , 1987 . * cited by examiner US 10,751,310 B2 1 2 PREVENTION , TREATMENT AND tetradecyl, hexadecyl , eicosyl , tetracosyl and the like . A REVERSAL OF DISEASE USING “ lower alkyl” group is an alkyl group containing from one THERAPEUTICALLY EFFECTIVE to six carbon atoms. AMOUNTS OF DICARBOXYLIC ACID An “ alkenyl group ” is as a branched or unbranched COMPOUNDS 5 hydrocarbon group of 2 to 24 carbon atoms and structural formula containing at least one carbon -carbon double bond . CROSS REFERENCE TO RELATED The phrase “ alkynyl group ” as employed here refers to a APPLICATION branched or unbranched hydrocarbon group of 2 to 24 carbon atoms and containing at least one carbon - carbon This is the U.S. National Stage of International Applica 10 triple bond . tion No. PCT /US2017 /020477 , filed Mar. 2 , 2017 , which As used herein , “ aryl ” refers to a monocyclic or polycy was published in English under PCT Article 21 ( 2 ) , which in clic aromatic group , preferably a monocyclic or bicyclic turn claims the benefit of U.S. Provisional Application No. aromatic group , e.g. , phenyl or naphthyl. Unless otherwise 62 / 303,960 , filed Mar. 4 , 2016 , which is incorporated by 15 indicated , an aryl group can be unsubstituted or substituted reference herein . with one or more , and in particular one to four groups independently selected from , for example , halo , alkyl , alk ACKNOWLEDGMENT OF GOVERNMENT enyl, OCF3 , NO2 , CN , NC , OH , alkoxy, amino , CO2H , SUPPORT COzalkyl, aryl, and heteroaryl. Exemplary aryl groups 20 include but are not limited to phenyl, naphthyl, tetrahy This invention was made with government support under dronaphthyl, chlorophenyl, methylphenyl, methoxyphenyl, grant number HL058115 awarded by the National Institutes trifluoromethylphenyl, nitrophenyl, and 2,4 -methoxychloro of Health . The government has certain rights in the inven phenyl. tion. The term “ halogen ” and “ halo ” refers to —F , C1 , —Br 25 or — I. SUMMARY The term " heteroatom ” is meant to include oxygen ( 0 ) , nitrogen ( N ) , and sulfur ( S ) . In some embodiments, a method of treating a disease The term “ hydroxyalkyl , ” refers to an alkyl group having comprises administering a therapeutically effective amount the indicated number of carbon atoms wherein one or more of a dicarboxylic acid compound containing an electron 30 of the alkyl group's hydrogen atoms is replaced with an withdrawing group , an alkyl ester of dicarboxylic acid OH group . Examples of hydroxyalkyl groups include, but containing an electron withdrawing group , or a compound of are not limited to , CH2OH , CH2CH2OH , Formulae I to X , to a subject in need thereof. In some CH , CH , CH , OH , -CH , CH , CH , CH , OH , embodiments , pharmaceutical composition comprises a CH , CH , CH , CH , CH , OH , therapeutically effective amount of a dicarboxylic acid com- 35 CH CH CH CH CH.CH , OH , and branched versions pound , an alkyl ester of dicarboxylic acid , of a compound of thereof. Formulae I to X , and a pharmaceutically acceptable excipi The term “ haloalkoyl , ” refers to an ( C7 - C3 ) alkyl group ent . Various embodiments of the invention are directed to wherein one or more hydrogen atoms in the C , -C , alkyl dicarboxylic acid compounds containing electron withdraw group is replaced with a halogen atom , which can be the ing groups, and in some embodiments such compounds may 40 same or different. Examples of haloalkyl groups include , but further contain alkenes associated with the electron with are not limited to , difluoromethyl, trifluoromethyl, 2,2,2 drawing groups. Various embodiments of the invention are trifluoroethyl, 4 - chlorobutyl, 3 - bromopropylyl, pentachloro directed to alkyl esters of dicarboxylic acid compounds ethyl, and 1,1,1 - trifluoro - 2 - bromo - 2 - chloroethyl.