c2) United States Patent ‘Vepachedu et al. (61) TARGETED DRUG RESCUE WITH NOVEL TIONS, COMBINATIONS, AND ODS THEREOF Vernon imbt (71). Applicans:Sreenivasa (72) Inventors: Srecnivasarae Vepucheds, Vernon (1) Note: Subject to any disclaimer, the ter ofthis patent is extended or ajusted under 38 USC. 154(b) by 0 days. (21) Appl. Nos 161672517 (2) PCT Filo: May 3, 2018 (85) PCT No: PCT#US201N/030978 $371 CX), Daten Nov. 3, 2019, (81) PCT Pub, Nos Wo20is204713 PCT Pub, Date: Nov. 8 2018 6s) Prior Publication Data US 202010069674 AI Ma. $, 2020 Related Application Data (60) Provisional application No, 62163671 fild on Feb. 28, 2018, provisional application’ No. 62/636,099, filed on Feb. 27, 2018. provisional application No 621635554, filed on Feb. 27, 2018, provisional ‘pplication No, 62/501,696, fled on May 4, 2017 (0) Foreign Application Prlority Data Ang. 28,2017 (TW) 106129169 (sy) tm. AGIK 31/4748 (2006.01) AGIK 31/662 (2006.01) 61K 317222 (200601) ABIK 317228 (2006.01) (2) US.eL CPC i AGIK 31/8748 (2013.01); ABIK 31/222 (2013.01); 467K 31225 (2013.01), AGT 31/662 (2013.01) (8) Feld of Clasiiation Search CDC." ABIK 31/228; AGIK 31/222; AGIK 31/662; AsiK 31/4748 ‘See application file fr complete search history (5) References Cited US, PATENT DOCUMENTS, 4241065 4121980 Boewel 147846782 US 11,478,467 B2 Oct. 25, 2022 (10) Patent No. 4s) Date of Patent: 12002. Mako 12002. Mata 72003 Makita 72012 Yalan 92012 Vays asik 92077 10022385 B2 72018 Friedhott taiao9 82° 82021 Vepacheds Asi 2500 2002055008 2002 Maelo 92002 Malika (Continued) POREIGN PATENT DOCUMENTS Wo Wonomdn6I98 AL 12009 OTHER PUBLICATIONS 2000, Can.) Anaesth, 470) pp 38 BBFO3018982) (Year 2000) (Continued) 6. (DOE 11007 Primary Bxaminee —My-Chat T. Tran (74) Attorney, Agent, or Firm —Sreenivssama Vepachests on ABSTRACT. Compounds of Formal , pa ly acceptable salts thereof, enantiomers thereof, metabolites theref, deriva- tives thereof, prodrugs thereof, aid sition salts thereof, Pharmacetially acceptable sats therenf, oF N-oxide: thereof ora combination thereof; processes and intemedi- tes foe preparation therof, compositions thereof, and uses thereof; are provided. Phannacestical compositions com- prising 2 compoursd of Formals I, or enantiomers there, metabolites thereof, dexvatives therof, procnags thereof cid addition sats thereof, pharmaceutically acceptable salts thereof, oF Neoxides thers of combination thereof where. the compound is a double andlor triple agent oF ligand for CYP2D6, S-HT2A, andlor SHT2C reoeptors anidor acctycholinesterase are provided 1 Claims, 14 Drawing SheetsUS 11,478,467 B2 Pape 2 (66) References Cited US, PATENT DOCUMENTS, 20020156068 AL 102002 Badan oonbi7ss05 AL 112002 Skogyat Ioonoaees AL Satritots ooyori6%8 AL Gacy onennssas At Fekete Jono AL bese donronosess AL 7 Creer ovrionato2 At Goal oom 0136808 AL Cremer, dorones At Sina aorowon9ss AL Phan 2oiso1tt087 AL 9 Site Dunounto Aly 92020 Nepacheas ... A6IK 31222 ‘atingssos AL* 72020 Nepucheds ASIP 35 28 (OTHER PUBLICATIONS ‘Oba tal, “Amiocceeon in ra by supogrlt, a ssetve SHTT2A repr antagonis,isperpral™. 2000, Fuopsan Journ ‘of Phaomacoloy, 4041-2) pp. 95102, Year 2000) Taine eta, Elect ofthe novel anise drag derameielne on ‘jtecome PASO 2D6 actly ao measured by despeamine ‘Phasmacokintes", 2004. Eur J, Clin Phamacol, $912). Fe onson. (DOr 101007 s0022%-003-09144. Cen: 3000) Gupta, "als afThrapeute Ages: Chemical Phyicocheni= ‘i, tnd Biologia! Consideration". 2018, Molecules, 237. Fp Tots (do 103390 molecules? 3071719). (Yee 2018)* © cit by examinerU.S. Patent Oct, 25,2022 Sheet 1 of 14 US 11,478,467 B2 FIGURE 14 Pe Bs) situs gov) % tem 2 f 2 x Bo & ose} Ve & a g 3 a 5 comPounn 50 (uM) FIGURE 1B 7 oe g * iit g a g z & Ps COMPOUND 146 (uM) FIGURE 1¢ 22st Ss jar 7 tout =< WN A 2, 1V (pmotantavmg protein) * QUINIDINE (1M)U.S. Patent Oct. 25,2022 Sheet 2 of 14 FIGURE 24 STAGE 1 ANALYSIS * Mean Score(95% CO) Baseline ' ; Mean Score(95% CO) Baseline * ‘ ® FIGURE. 2€ STAGE 3(10 Wk) ANALYSIS har 4 | Decco Mean Scare(95% CO) ca z « US 11,478,467 B2US 11,478,467 B2 Sheet 3 of 14 Oct, 25, 2022 U.S. Patent os y 4 wemesordmay ddd VS: aso9s Aplaaas-fo) m aBueK ‘Study Day Study DayU.S. Patent Oct, 25, 2022 e ; L Katt. 5 a Sou 0 070 19 0y" FIGURE 48 C80 rs ogy #2uM sou amokeniniamot 480) VS My" FIGURE 4¢ cep # 8am aay m2 phd K= 242 oa i o3 YS duty 010 04 0s OF of control) = 8 g i é Residual activity (% of control) Residual activity (% of control) Sheet 4 of 14 US 11,478,467 B2 FIGURE 4D 1205 100 oh, 804 RA 60 Vy 40 \ 20 {| NN 6 5 Cannabinoids (Log M) FIGURE 4E 120 100 80 604 404 QA 204 . od 6 s 4 Cannabinolds (Log M) FIGURE 4F © seTHe 120 = CED = «CBN a0 6 40 20 Cannabinoids (Log M)U.S. Patent Oct, 25,2022 Sheet 5 of 14 US 11,478,467 B2 EFFECTS OF COMPOUNDS 147 AND 148 ON = 7) = 5 i a) al fell It ge 23 + p<0.001 28 41 ™ peoot 2 £ af x z b3m osm OS (Mt (aya eat00907 (mga) (gig) (gg) FIGURES EFFECTS OF COMPOUND 50 ON HYPERACTIVITY INDUCED BY OLFACTORY BULBECTOMY a mm SHAM 08x. * pe0.01 * p005 Total ambulation time over 1S:min test interval (sec) ° 7 3 0 COMPOUND 50 dose (matkg) FIGURE 6U.S. Patent Oct, 25,2022 Sheet 6 of 14 US 11,478,467 B2 Plasma concentration after intravenous administration = 10000 -o- COMPOEND 50 & 1000 “= compounn 14s 2 & 100- Eo ie 2 + oon. — i 7 7 3 ‘Te (hours) FIGURE? 10000 1000 | Ez E100 { ; i T =) & ~e-vshicie | Poe oe z ~~ {4} COMPOUND #t A é se.) COMPOEND SD 1 7 0. 0 fo sine) FIGURE 8U.S. Patent Oct, 25,2022 Sheet 7 of 14 US 11,478,467 B2 EFFECTS OF COMPOUND 50 AND DEXTROMETHORPHAN ON [MOTOR ACTIVATION IN PCP-TREATED RATS | | Avecageacivits pers min (meat SED | j FIGURE 9A Compennd'S0 dose (mphg) Compound SO dose (mari) Average activ pes nF, FIGURE 9B, perSain 7 caeane SEND (0) Compounds? devs rea) (yDeate 8 mete RPFECIS OF COMPOUNDS $042 AND DEXTRO ON BLOOD GLUCRRE CONCAFTRAHON — “petae 3 ig 23 ggU.S. Patent Oct, 25,2022 Sheet 8 of 14 US 11,478,467 B2 Plasma buspirone (ng/ml) Piasma 1-PP (ng/ml) FIGURE 114 28) 1B vs] | 14 i =~ Compound 829 424 +o» Placebo 9 2 4 6 8 10 12 14 16 18 20 2 24 Time (hours) FIGURE 11B —*~ Compound 829 +++ Placebo: 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (hours)U.S. Patent Oct, 25,2022 Sheet 9 of 14 US 11,478,467 B2 FIGURE 124 Day 7 2 ow = Derameiciane = S00 s+ Placebo £ 4004 3 ifs a 200, Eco, 1004 = | Oops meme ° 4 2 3 4 Hours FIGURE 12B Day8 600+ buspirone eo Derameiciane Ye Plasma prolactin (mIU/L)U.S. Patent Oct. 25,2022 Sheet 10 of 14 US 11,478,467 B2 FIGURE 13 R= FORRULAIORE wade A vd ghey he Ne ogy “fhe dye doen a — "lee i XN ‘ey / \ opel ods mb = wedewle ndiokU.S. Patent Oct, 25,2022 Sheet 11 of 14 US 11,478,467 B2 FIGURE 144 * = = 10 rl * 3 Ere DO vehicle 3 MM Deramciclane 3 3 $ * 9<0.05 2 25 6 x FIGURE 14B 3 2 1 vehicle 2 1 I Deramciclane 8 SB 0: = 6 z o. e ¢ 3 aeU.S. Patent Oct, 25,2022 Sheet 12 of 14 US 11,478,467 B2 FIGURE 15A I Vehicle MM Deramciclane Immobility time (s) * p<0.05 () p20.10 FIGURE 15B 2 * 2 1 vehicie 1 M Ritanserin : * p<0.05 © e s Re x heU.S. Patent Oct, 25,2022 Sheet 13 of 14 US 11,478,467 B2 FIGURE 16A * 1006 ae g a0 1 venice aoe I Deramciclane 8 e ] * p<0.05 fe 20 ce & ¥ FIGURE 16B 1001 g a0 1D vehicle Sco I Derameiciane 8 = 40 3 fe 20 Re &U.S. Patent Oct, 25,2022 Sheet 14 of 14 US 11,478,467 B2 FIGURE 17 s Co vehicle & I Memantine 2 * 0.05 5 43 FIGURE 18 3m “© Blood 2 100% => Brain 5 = 81 8 ot — 0 dj 2 3 4 Time (hours)US 11,478,467 B2 i ‘TARGETED DRUG RESCUE WITH NOVEL ‘COMPOSITIONS, COMBINATIONS, AND. METHODS THEREOF TECHNICAL FIELD ‘This disclosure relates to Tangstad Dag Rescue (TDR ™ ‘wi novel compositions, combinations, therapeutic formu lations, symptomatic and disease-modifying. treatments, torapies, kits thereof, and methods there BACKGROUND Excess weight changes the boty, ineeasing certain hor. ones and levels of illammation tat ean Tad to metabolic isorders, cancer, and brain disorders, including develon= syohatic and neunedegenerative discases, which represeat an enomous disease bunden, epanting human sullering and economic cst, and causing the rapid ise in Dalthcare spending. Diseases llecting the brain an ceatral nervous system represent one of the anes global healthcare challenges and greatest medial nosds dve to the devastating personal and economic consequences for patients, ereaiv= {rand socity. Aa estimated 55 milion people worldwise Suller from neuredegenerative diseases wih no currently approved disease-modi¥ing therapies available. As modern herpetic interventions increase life expecta; the m= bor of patients suffering fom these disenses fs expected to double every 20 years. Just nine of the most common, neurological diseases such as Ahwimer's disease and other dementias, low back pin, stoke, ccaumatie brain injury. ‘migraine, epilepsy, multiple sclewsis, spinal cord injury. and Parkinson's disease is staggering, totaling S789 billion ia 2014 dollars, cunently estimated at $818 billion, and est nated to be moe than SI tillion by 2030. Total Furopean 2010 cost of brain disorders was €798 billion, of which iret healthcare cost 37%, direct non-medical eost 23%, And indirect cost P% (Oleson etal, The eeonomie eost of brain disorders in Europe, EIN, 19,1, 155-162 (2012) Progress in specifically addressing therpeutic nds in dementia hs been slow in the past two decades, and all lovelopment projects in Abdimer’s Disease have failed Since the approval of memantine by the EMA (2002) and the FDA (2008) Rather than insisting on “treatment” indica- tions, regulators have addressed te persisting high medial noed by opening up the range of approvable medications therapies With syndromal indication labels. Such a syo- lites thereof, derivatives thereof, andlor prodrugs theref, ‘pharmaceutically acceptable salts theo; N-oxides threo, ‘ra combination there Anembodliment ia compound of Formula I wherein the substituted or unsubstituted Cy eyeloayl i eyelopropy], is, nuttionals, pharmaceuticals, Compo 8 ‘yelobuty, eyclopentyl, cyclohexyl, eyclohepyh, cycloae: ‘yl eyelononsl, ar eyclodeey! radical. In another embodi- ent the eyeloalkyl comprises one or more heteroatoms N, S06 0. Another embodiment is a compound of Formula 1 wherein the substiuted or unsubstituted C.bieyeoalky is bicyelobuyl, bieyelopentyl, bieyclohex, bicyelobepty, bieyelooetyl, bieyelononyl, or bieyelodeeyl radical, In ‘another embodiment, the bieycoalky comprises one or tore hcteroatoms N.S, or O. Another embodiment is a compound of Formula | Wherein the aryl is phenyl, naphiy, anthroceayl, or Pbeaantbreayl In another embodiment, the compound is a compound of Formula I wherein RS isan acyl radical solocted from the x0up consisting of mono, di, and ti carboxyl acd rai cals, In another embodiment, the compound is compound of Formula T wherein RS iss acyl radial selected from the troup consisting of acetate, acetyl salicylate, adipae Neseylasparte, aspartate, butyrate, eapeat, capri, ‘aprylte, enanote, formate, Kimara, Neaey-gharate, lutate, isophiallate, maleate, malonate, methiomte Nevcyl-methionate oxalate, pelargonate, pimelate, propi ‘nate, phthalate, slieylate,sebacate, succinate, teephthal Tate, tyrosinate, Neaeytyrosinate, typlopianste, Neaeyl- typtophanate, and valecate Another embodiment is compound of Formula I, By ve Re ‘wherein, Rand Ry are independently D.C, ,oalhyl, hala C,.,-alkyl wherein halogen is Cl. or Be; Ry etd Rye are independently Hi C, lg halo Cally wherein halogen is F, Cl, oF Bir OF: of R, and Ry together form a five-membered hotroeycle wherein the hetero aon is OS. oN. Another embodiment is a compound of Formula 1, wherein RS and R2 form a hetewoeyele selected from the radicals such as morpholine, dihydrooxazin, oxazine, pip- cerazine, dhydropipezine, and tetrahydropiazine. Com- pounds ofthis embodiment includ, but not limited to, the following compounds 10-24:os | - - —continued » / o- xtc US 11,478,467 B2 2 continued ¢ 5 °- 7 : Fla So . 0 x ue Enoner Another embodiment is a pure enantiomer of Pormla 1 so selected rom Formula Tao Tb Tn another embodiment, the compound of Formula 1, wherein R,. Ry and Ry are methyl, provided X is ol ety. Tn another embodiment the composition comprising For- mula lis sarpogrlate(SARPO), wherein 8, Rand R, are methyl, X is esl and Ry is succinoyl radical, having the following compounds SGL, SGL-E1, and SOLE. Tm another embodiment, the composition comprising for. mula Tis sarpogteate metabolite MI. wherein Ry, Ry and R, are mets, X seth], and Ris OH, having the fol 4, compounds Mi, MI-E1. and MI-E2. Ta another embodiment, the composition comprising for. mula Ti sarpogrelate metabolite MI, wherein R, ad Re together withthe nitrogen form a strated or unsaturated heterocycle having one oF more heteo atoms selected from 446 N,O,and S;andR, is methyl, X is ethyl, and RA is OF ln another embodiment, the heterocycle is a five-membered Fing. Another embodiment is where the hetereyele is @ ‘ixemembere rng, In another embodiment, the heeroevele is saturated, Another embodiment has the unsaturated het- so eroeyele. In ane embodiment the heterocyelehas one hetero ftom In another, the heterocycle as two hetero atoms. Ta another embodiment, the compound of forma I, Wherein the hetereyele formed from R, and Ry together With the nitrogen is select from the heteweyelesTisted 5 below . OO D Oo o o © o w (OE iUS 11,478,467 B2 13 06 60 O 0 OO O The tenn “DEX” represents compound of Formula Ml such as dextromethorphan, enantiomers thereof, metabolites therwo, derivatives thereof, andor prodeugs there, of & ‘combination thereof, Derivatives ined, bu nt limite to, leterated derivatives, eg, DEX-HS, DEX-D3, DO, and Do.Ds, The teem "SARPO,” represents one or more compounds selecied from the group consisting of sapogrelate (SCL), ‘enantiomers thereof, metabolite thereof, MI, SGI, SG2, SMG Thereof, and combination thereof, “The term SARPODEX™" represents s combination of DEX and a compound of Formula An embodiment ofthe inveaton i 2 composition comprising a compound of formula T and dextromethorpan, An embodiment of the invention is a composition comprising a compound of formula T and DEX-H3, DEX-D3, DO, or DO-D3. An ‘embodiment ofthe invention is « composition comprising: Mi, MI-EI, MI-F2, SGL, SGL-EI, or SGL-£2; and DEX- HB, DEX:D3, DO, or DO.DS, ‘The team DERADEX"™ or DERAPHAN™Y represents & ‘combination of DEX and a compound of Formula I, wherein the compound is a derivative of bieyel[2.2.1]heptanol ‘having the Formula ‘wherein Risa bieyelic system and the rest of the Formula Treprsented by R,: as shown in Formula If Fol ‘wherein, Ris H, substituted oe unsubstited —C, alkyl, Substituted or uxsubstiuted —C, cycloalkyl, substituted for unsubstituted —C,.yy ary, substituted oF unsubstituted ‘oso AMVC, yo ary,” substituted oF unsubstituted C2") heteroaryl oF substituted oF nasubstiited —C, alky Ea heteroaryl; Ry is SMG3, 2 derivative thoeol, a prodrug 9 14 f ' ou fe so Las —CayyephaglX— Oe 3 © Coie aX Woy ar ES g heterary-X—(Y)e: wherein X's @ bond, N, O, S.C, alkyl, —Cyrp exeloallyl, “Cag al, COC, 4g alg, COC, Sieloalkgl, COC. aryl, COC. heteroart, CO-NH—C,,19 alkyl, ~CONE—C.), cycloalkyl, CONC.) any, or CO NEC terry! Y is He C.ay allyl, Cyay eyeloalkyh, “Coie any = 60-9 ‘alkyl, COE, eysoalest, “COC, aryl, CONC; 4g heteroary), "CO NHC yyy alll, “co NnE?, eyeloalkyl, —CONHC.,() ary of CO_NH_ Cy, heteroaryl and m isan iteper toe 2:0r pharmaceutically aceptable salts oF Neoxides thereof: or prodnigs there The tem DERATINE' represents a combination of an NMDA receptor antagonist and and compound of Forma 1. as defined above Te tenn SARPOTINE™ represents combination of an NMDA reeopior antagonist and and a compound of Formula 1. as defined above. ‘An embodiment ofthe invention is a composition com- prising compound of Formula 1 and DEX-S, DEX-D3, BO, or DO-DS, Tn another embodiment, a compound of Formula 1 or logs can be made using the following carboxylic aids! Malic Acid HO,C—CH,-CH(OH) C,H (Compounds 25.20), Methionine H,C_S_-(CH,),- CH(NH,) COM (Compounds 30-34), Phthalic Acid C.H(CO.H), (Com- pounds 35-37), Malonie Aeid HO.C-CH,—CO.H (Com- Pounds 38-40), Tyrosine. HO CH&CHl, CHIN) CoH (Compounds 41-43), Trypiophan C,t,N—CHy HINH,)—CO,I (Compounds 44-16), “Maleic Acid HO.C“CH—CH—CO.H (Compounds 47-49), Succinie ‘Acid HO.C—(CH.),-CO.H1 (Compounds 50-52), Glare acid HOC {CH), CO. (Compounds 3-55), dipie ‘Acid HO,C_ (CH), -CO,E (Compounds $6.58), Pimelie cid HOC (CHL), COaiT (Compounds 59-61), Sebacie seid HO,C__(CH,),—CO.H {Compounds 62-64), Formic ‘acid HCO.H (Compounds 65-67), Aeetic acid CH,CO,H (Compounds 68-70}, Propionic aeid CH,CH,CO,H (Com- pounds 71-73), Butte aeid CH,(CH),CO,H (Compounds 74-76), Nari seid CH(CH,)sCO,H (Compounds 77-79), Caproic acid. CH(CH.)sCO US 11,478,467 B2 60 -sontinacd 4 In another embodiment, a compound of Formula I or analogs can be made using the following carboxylic aids iluorosuecnie acid, HO.C—CF;—CH,—CO.H (20. 206), wilworsuecinie aeid, HO,C_CF,—CHF-CO.H1 (207-212), tetrativrostocinie acid, 1H0,C—{(CF,),— CO, difhorosuecinie acid 213-215), HO,C—CHF— CHP—CO,HT 216-219), difuoroglutarie acid, 110,C (CHy)y-CFs-CO.H_ (219-221), dilvoroglutaic acd, HOC CP, (CH). COM 222-225}, diluoreacetic acid, HO,C—CFH (226-228), and willuroacetic acd, HO.C—CP, (229-231),US 11,478,467 B2 63 continued ae . a > 0 In another embodiment, a compound of Formula 1 is Formula I or Formula I, as defined above, and derivatives «s ‘thereof eomprising aid addition salts elected from: acetate, acetyl siliylae, aipate, aspartate, butyrate, eapate, 64 ‘aproate, capeylate enanthate, formate fumarate, glutamate litte, isopallste, maleate, malonate, methionse, ‘oxalate, "pelargonate, pimlate, propionate, phhallate, Salicylate, sebecate, succinate, Terephtallat, tyrosine, luyptophanate, valerate, N-acy/-aspartate, Neacyl-hutamate, Naacyl-yrosinte, Neacyl-typtophanaie, Naacyl-methion- ate, ciate, galaetonate,glucarie aed (saccarie wei), man honate, mieate, chamnonate, an tartrate Tn another embodiment, 2 compound of Formula Tis Formula Te Formula 1,8 defined above, and derivatives thereof comprising acid adlition salts fone rom cand ‘carboxylic acids selected from: adipic acid, anparic acid Nesey aspartic aed, circ ack, Humane ack, galctonic sci, glutaric acid, glutamic acid, Neacyl glutamic acid, tlvcarie acid (Saccaric acid), malic acid, male aid onic acid, mucic acid oxalic ac, pmelic ci, pal lic ci, isphthali ci, trephiallie acid rhamnonie aid sebocic sci, stocinic aid, apd tartare eid Another embodiment is composition comprising derivative of componnd af Form Te o Form 1 sad a derivative of a compound of Formula Th, wherein the ‘derivative of Formula fe, Forma Id, snd Formula I threat is independently an acid addition salt: Bydrogen acetate, hydrogen aces] salicylate, hydrogen adipae, hydrogen spar, hydrogen butyrate, hydrogen eaprae, hydrogen ‘aproat, hydrogen eapeyate, hydrogen enanthate,byzogen, formate, hydrogen fumarate, hydeogen glutamate, hydrogen llarte hydrogen isoplhallte, hydrvgen maleate ydeo- pen malonate, ydrogen methionate. hydrogen oxalate hhydrogen pelargonate, hydrogen pimelte, hydrogen propi= ‘onate, hydrogen phiballste, hydengen salicylate, hydrogen Sebacate, Iydrogen suevinate, hydrogen. terephthalate, hydrogen tyrosinate, hydrogen typlophanate, hydrogen valerate, hydrogen N-acyL-aspariate, hydrogen N20) tamate, hydrogen N-aeyityrsinae, hydrogen N-ayl-tryp- tophinate, hydrogen Neacyl-methionste, hydrogen citrate, hydrogen palactonite, lydrogen glucarie acid (saecharic seid) hydrogen mannonate, hydrogen mocate, hydrogen ‘hamnonae, and hydengen treat ‘Another embodiment i composition comprising an aid sition salt of dextromethorphan and MI selected from: dlexicomethorphan and ML ditydrogen adipate, dex tromethorphan and MI dihydrogen aspartate, dextrometo- ‘phan and MI diydrogen fumarate, dextromethorphan and IMI diiydrogen glutamate, dexwomeorphan and M1 diy- drogen glutarate, dextromethoephan and. MI dibydmgen isophthaliate, dextromethorphan “and M1 diydrogen makate, dexomethorphan and MI dibydrogen mons exiomethorphan and MI dinydrogen oxalate, dex: teomethorpian and MI dihydrogen pimelae, dextrometho- ‘phan and M1 dihydrogen phthalate, dexteomethorphan and IMI dinyeogen scbocate, dextrometboan and MI diby~ drogen succinate, dextrometborphan and MI dibydrogea terepaallate, dextromethorphan and M1 diydropen Neseylaspartate, dextromethorpian and MI dihydrogen Nescylatutamate, dexttomethorphan and M1 dihydrogen ccirte, dextromettorphan and MI dibydrogen galactonate, ‘doxtromthorpban and MI ditydrogen lucarste, dex: tromethorpnan and MI dihydrogen saccharate, dex- tromethorphan and MI dihydrogen mannonate, dex- tromethorpian and MI dihydrogen musa, ‘dexteomethorpban and MI dibydrogen hamaonste, and ‘dexromethorphan and MI dibydogen tara Tn another embodiment, a compound of Formula 1 is Formula le or Formula Id, 28 defined above, and fo derivatives there. Ia snother embodiment, compound of Formula T is 2 compound of Formula Teor Formula Ki,US 11,478,467 B2 65 66 ‘wherein the compound is laore Derivative PD) of Formula coated Je (Pe) or Formula Id (FDIA} selected from compounds 221-269, an dextromethorphan oF a compound of Fema 11a dened above » Asetbercntodinentisacompostoncumpeinganacid © y_X _xkltion sat of dexromethorphan and FDIe seleted fom: ‘dexiromethorphan ann) Die diydrogen alipate, dex ‘womethorphan and FDIe dihydrogen asparate, dex > tromethorphan and FDIe_ hydrogen fumarate, dex- tromethoephaa and Fle diiyerogen glutamate, 5 0 dexiromethorphan and FDIe dihydrogen phiarate, dex Compount2835 tromethorphan and FDIc dibydrogen isoplihallate, dex- ‘romethorphan and FDIe dihydrogen maleate dextrometho- rphan and De ditydogen malonate, dextomethorphan and FDI dikydrogea oxalate, dextromethorphan and FDIC US 11,478,467 B2compos 29041 35 US 11,478,467 B2 congo 384336US 11,478,467 B2 B Another embodiment i composition comprising an acid addition salt of dextromethorphan and FD selected from: ‘extzomethorphan and DUD dihydrogen adipate, dex tromethorphan and FDId dihydrogen aspartate, dex- ‘womethorphan and FDId_ dihydrogen fumarate, dex tromethoephan and FDI diyeogen ghitamate, dextromethorphan and FDKE dihydrogen ghiarate, dex- ‘wometborphan and FOIA dihydrogen isophthallte, dex !nomethoephan and FDI liydrogen maleate, dextrometo- rphan and FDId dihydrogen malonate, dextromeorpan and FDIddikydrogen oxalate, dextrmethorphan and FDIS litydrogen pimelate, dextromethorphan and FDIC dihydo- ‘zen phihallate, dextromethoephan and FDIG dihydrogen Sebscate, dextromethorphan and FDIC dihydrogen succi e, deximmethorphan and FDIA dikydrogen terephthal- dextromethorphan and FDId_ dihydrogen Neaeyl- slutamate, dextomethorphan and FDI dihydrogen citrate, ‘extromethorphan and FDId dihydrogen galatenate, dex= tromethorphan and PDId. dihydrogen -gluearate, dex- tromethogphan and FDId dihydrogen stocharat, dex- tromethomphaa and FDI dihydrogen» mannona dextromethorphan and FDId dihydrogen mucate, dex tromethoepian and FDI dihydrogen eumnonate, and dex- tromethorpiaa and EDId dikydrogentertate, In nother aspost of the iaventions, the compound is 3 ‘compound of Formula I derivatives include the following, ‘compounds ots tor one 4 continued aaeae DONO aoe. .US 11,478,467 B2 7 8 continued continued Lan : : oO oy "~ 0 baer An otUS 11,478,467 B26508aseUS 11,478,467 B2 e 90 -sontinssd “i i 0, On oe ~ Ay rs . or i . om o : aA Sy in Co v N mam (Rss 20 i Qa - a gs 820-meospeactyDpteacny) XN " ASO Sepesu : In some embodiments, the compound of Formula Tis co Formal Teor Fort Td (815-2.6.netonteuty tpi Tn some embodiments, the compound of Formula le oF ‘NNstineash Formula Id is MI. wherein, ¥ is CH; RA is OH. Ia some «8 (eiorntinypep-amine ‘embodiments, the compound of Form le or Formula 1d, ‘8 defined above is anor derivative wherein Ré is OCFUS 11,478,467 B2 1 In an embodiment of the invention is a composition ‘comprising compound having a Foemul I herein R, is. bieyelie ystem and the rest ofthe Formula T represented by Ry: as shown in Formula If wherein, Rs H, substituted or unsubstnted —C, Bk, subsite or unsubstituted —C,, 9 eyclally) stituted for unsubstituted —C,,yy ary, substituted oF unsubstituted Cog alk gay substituted or unsubsttted — C1 beteroaryi, or substituted or unsubstituted C15 ky Ey heteroaryl; Ry is — Mw C0 aX (Vp. oF Cy hetroaryl-X(V)qi wherein X12 bond, N, O'S, Cy, alkyl, C3, eyeleallyl, Ca, CO-C.y5 alkyl, —CO"C 49 eyeballs, COC. 0) ary COC yyy heteroaeyh, CONE Cyug allyl, —CO_NH Cig eyeloalkyl, CO NHC. ary, of Cy ypallg Cp exeoalkyl C9 ab CO NHC, yg heteroaryl ¥ is H, COC, oak —"GO—C, 4, cycloalkyl, COC, aryl, COC gets ‘erway, CONH—C,5_ alkyl, —-CO-NH=C, CONE Cop aryl or —CONH-Ceg, ind m isan integer 1-02; oF pharmaceutically ts or Neoxides therefor prodrugs threo compound ta compound of Formula If wherein isan ary, and R, is substituted or unsubstiued Cp alkyl-X(Y)y, In certain embod rents, Ry i substiuted oF unsubsttted Cup alky-C, fyl and R, is substtted or unsubstituted ""C,_ allt X--(V}qIncersin embodiments, Ry is phenyl yt —C, roalkylN— (Cy gal In an embodtinent, the compound of Formula I includes, but no mite to, the following examples: RS4.((4(dim- cthylamino)1-(--methoryphenethyphenoxyutan-2- oxy} 3edifuoro-f-oxobataaoie acide S444 dime. ‘amino}-1-02-(3-methoxyphenethyjphenexyJoutan-2-y) foxy)-3difhiom-Foxobutancic acid RAC (Gimetiylamino)-1-(2-G-methoxsphenethyl) phenoxy) ‘utan-2-yDoxy)-3-iluoro-oxobutanoe aids RSH 92 (dimethylamino)1-(2-3-methoxyphenethypbenoxy) butan-2-yoxy}-2.2-difinon-t-oxabutanoic ac S4(4- {Gimetiy lamino-i-(2--methoxyphenethyphenoxy bu- tan-yDoxy)-22-diluorosd-oxobutanoic ack, RAC ‘methylamino)-1-@3-methoxyphenethy)) phenoxy utan- Dyijeny}2.2-ioro-Soxobutaapie acide RSC {Gimetiylamino)-1-(2-G-mothoxsphenethy!) _ phonox) butan-2-yoxy)-2.2,-tuoro-deoxobutanoie acid: SAAC (dimethyamin-i-(2-3-methoxsphenethsphenoxy) butan-2-yoxy)-2.2tnflono-toxobutanoie acids R&-(A- (Gimetiylamian)-i-(2-(-methoxyphenethy) phenoxy b= ‘an2-yDoxy)-2,2tiluoro-boxobutanoie act; RSAC (Gimeibylamine)-1-(2-C-methoxyphenethy!) phenoxy) butan-2-l)oxy)-23.3-tnfluore-4-oxobutanoie aid: S44 (Gimethylamian)-i-(2-C-methoxyphenethy!) phenoxy) butan-2-yoxy)-233-tuoro-deoxobutanoie acid, RAM {Gimets lino -i-(2-3-methoxsphenethsphenoxy) butan-2-yoxy)-233-inuore-4-oxobutanoxe acid; RS4- ((4-imethylamio)-1-(2G-methoxyphesethy) phenoxy) butan-2-yDoxy}-2eifion-t-oxabutanoie ack. Ste (Gimeth lamino-i-(2-G-methoxsphenethyphenoxy)- tan-2-yDoxy)-2,Sailluoro-oxobutanoie act RAN methylamino)-1-(243-methoxyphenethy?) phenoxy utan- Dyleny}2-Scifuoro-soxobutansie acd. RSAC {cimetislamino)-1-Q-G-methoxsphenethsl) phenoxy) butan-2-l)oxy)-2,2.8.3tetrafluor-oxoburanoe ae; S4- ((4-Gimethylamino -i-(2-3-methoxyphenetiy?phencxs) butan-2-soxy)-22.3,3teralluoro-oxobutanoe aid: RA ((4-Glimethy lamin i-(2G-metboxyphenethy phenoxy) hutan-2-1) oxy)2.28,setaluorotoxobutanoie acids SS.((4(dimetislamino)--2-C-methoxyphenetsl)phe- oxy butan-2yboxy)-4,¢ailuore-Soxopentanoic acid '5o(4-(dimetylamino)-1-2-@ametboxyphenethyD) —phe- roxy uta-2-4Toxy)-44difnoro-S-exopentanoic. aids R54(4-(cimethylamino}-1-(2-(S-methoxyphiencthy?)phe- oxy) butan->ylhoxy)4.4abiloore-Soxopentanoic_ acid RS5.(4-(dimetlivlamino)-1-2-CametboxypienethyTphe- roxy outa-2-sTioxy)-44difvoro-seexopentanoie aids $54(4-(dimethylamino)-142-Gumethonyplinetiyl) —phe- oxy) butan--yljoxy)4 4abiluore--oxopentanoic acid RS4(4-(dimethylamino)-1-(2-Cemetboxyphenethy})—phe- roxy) butan--yljoxy)4.4biluore-S-oxopentanoic acid: RSS.(4-(dimethylamino)-142-C-methoxyphenetiyl) phe- roxy) ban2-91joxy }2.2ilooro-soxopentancic ids (4-(dimethylamino)-1-2-Cumethosyphenetby}) phe 2edilvoro-S-oxopentanie acids R54(4-(dmethylaming}1-(2-C-mnethoxypenethy1) phe= oxy) butan-2-yl) oxy)-22-diluore-S-oxopeatanoie acid: St (dimethylmino}-1-2-G-methoxgphieneiyl) ——phe- roxy uta-2-y1 2 2-dillvorogeette; S4-(imethy lamin) {2-G-methoxyphenethyl) phenoxy butan-2-yh 22iooe- 'R&-(Gimetylamino)-I-(2Smetoxyphenety}) Phenoxyjbutan-2-yl 22difuoroacetate; RSA dimethyl Smino)-I-(2-(-methonyplienthy) phenoxy butan--+1 22, 2nfuoroaceate; St-(cimethylaming)-1-2-Cemethox phenethyl) phenoxy)butan-2-yl 2.2,2tifuoroaeetate, RA- (Gimethylamioo)-1-2-G-methoxsphenethsl) phenoxy) hutan-2-1222-trifluoracetate, RS4-(iuoromeths!) {wiuorometiy}mine)1-(2-3-(uiuoromethoxy) phenethyl )phenoxy) butan-2-ol, S4(dilooromethy!) (wif Fuoromethy}) ming)-1-2-C-(rioromethony pee!) phenoxy butan-2-o; R&4(lifuoromethy!) (siuorometbs!) smino}-1-2-((triluoromethoxy) phenety!) phenoxy Bu tan2-ol; RS4(Muoromethy) (ifworomethy) amino} 1- (2-G-(tittworometioxy) — phenethy)pienoxyutan-2-l Sé((lvorometiy!) (tnitorometby!) amino)-1-2-G-(ie Iuoromethoxy) phenethydjphenoxy) butan-2-al RAY (lve romethyD ilvoromethyamino)-1-2-8-v0- romethoxy) phenethyphenoxy)butan-2ol; RSA(methyTUS 11,478,467 B2 93 (idorometty}) amino)-142-(-(tilucromethoxy) phen- thy phenoxy) butan2-ol, St-methy? (iuoromethy) 'trilvorometboxy)phenety}jphenoxy)bur 'Rée(neyrfuoromety ano} 12-3 ‘phcacthyjphenoxyutan-?-1 {methyamino) tun2-ol, (iduorometboxy) {(dithaoromett) (tiuorometony) phenethy]) phenoxy) butan {(dithuoromes (nethy amino) 1-2-3 (wiuoromethony) phenethyl) phonoxy) butanol, RA- {(diftaromest) “nethy amino) 112-8 (wifuoromethoxy) phenethy!)phenoxy) butan-2-ol, RSA ((Guoromethy (eth! }amino-1-(23-4eilaoromethoxy) pphenethyt) phenoxy) butan-2-0f; S4-(uoromethy) {oethyamind1-(243-riMoorometioxy) phenethy}) phe- hoy )busan-2-ol, Re-(ThoromethyD (met amino} 2- (G-(riluorometioxy phenetyphenory) butan-2-f; RSA- (imetbylamine)-142-G-(witluoromethoxy) —pbeaety!) phenoxy) butan-2-ol; $4-(dimethslamino)-142434(eto- Fomethoxy) phenetiyD phenoxy) butan-2-l; R4dimeth Aino} 1-(24G-(ilvoromethoxy) —phenethy}) -phenoxs) bbutan-2-0l, R $1-(2-34iluoromethoxy) phenethyl) phe noxy)-4(imethylamine) butanol, S12-346ilao- romethoxy)phenethy}pbenexy)-4(dimethylamino)butan-2- ‘ok, RI-C2-G-(ifhioromethory phenethyl phenoxy} (cimethylamino butanol, RS4-(imethylamine 1-2-8. (Muoromethoxs) pheneths1) phenoxy) butan-2-0k (Gimethylamino)--@-GMuorometboxy) phenethyl) phenoxy)butan-2ol,-RéM(dimethyl amino} (uoromethoxyphencthy!)phenoxy)butan2-: (wiuoro- methoxy)-4-2-C-(lluorometboxy)_phenes1) phenoxy)-NIN-bisifvoromety)butan-I-amine: Sie Toromethoxy)-4-2-(tiluoromethoxy) —phenethsphe- noxs)-NN-bis (wifluoro methyl) butan-L-amine RBH Iuorometboxy)-4-2-3-(illuoromethoxy phenyl) pihenoxy)-N.N-bis(riuoromthy butan-I-ain; {ivoromethy)-3(tiflioromethoxy)-4-2-(-(rila ‘romethoxy phenethy)penoxy -N trifluoromethy] butan Teamine: SN-(iflcromety)-3eilceomethoxy oe(2- (G-(tiuoromethoxy phenetiyDphenoxy)-N- {widhorometiy)butan-laminc: RN (ifloromethy))-3- (iuorometnony)-4-2-(3-(lluoromethoxypaenethyl) phenoxy -N-ifluoromethy)butan-t-amine RSN- (Mvorometby))3-(rillvorometoxy 42-0 -(ifhuor> methoxy) phenethyphenoxy -N-(riluoromethybutan-t- amine; SN-(fuoromethy!)3-(iftuora methoxy 42-0 (wiluoromethony pene] phenoxy) -N-(siuoromethy) htan- amine, RN-(Htoro met) 3 (uiorometoxy) t= (2-G.(itloromethoxy)pheaethyiphenexy)-N(rifhoro Imethy) butan--amine; RSN-methiy]3+(iuoromethoxy)- 442-6.(eiMuoromethoxy) phenethy) phenoxy)-N-{eim- romethyDhutan-Lanine; SN-methyl-(iluoromethoxy 4-2-G4willuoromethoxy) Phenety])phenony)-N- (eifuorometny)butan-l-amine: N-methyl 3 (iuorometony)-4-2-C (rillvoromethoxy)pnnethyl) pheaoxy)-N-(tifuoromethyDbuan-L-amine,RSN- {cifaoromethy)-Nmety-3-(rfltoomethoxy) (2-2 (wiuoromethoxy) phenethy)phenoxy batan--amine: SN- (diluoromethy)-N-methy-3(tiuoromethoxy)--2-3- (iuoromethoxy pheney])phenoxybutan-Lamine;. RN- (diluoromethy)-N-methyl-3(infuore methoxy) --2-G- (tituoromettionypenethyphenoxy outa -amine; SN (fooromethyD-N-metiyl-3(trfuoromethoxy 4-(2- RSN- (iduorometbs {Muoromethy). 94 simethy-3-(rifluoromethoxy 442-3 -(llvoromethony) pheaethylpenoxy butan-l-amine; -SNN-dimethy3- {wituoromethoxy)-4(2-(-(ifluoromethoxy phenethyl) phenoxy butan-|-amin: RNNedimethyl3- {wiuoromethony)-4-2-(3-(illuoromethoxy pene!) Pheaoxyjbutn-l-amine: — RS4-(2-(3-(diuoromethoxy) Phen penx -NIN-dimeths-3-Criluoromethoxy) hutan-lamine; S4-(243+(dlluoromehoxy phenethyl) phenoxy)-NN-dimethy-34{tnromethoxy utan-I- mine: R4-(2-G-diluoromerboxy) phenty!)phonoxy)-N, Nelimethy!-3(iboremethoxy) butan-lamine: RS42- {G-(luorometioxy) — phenethybpieaoxy)NN-cimethy!-3- (rtuorometboxy) " butansl-amine; " S4-0-8- (Mooromethoxs)_phonethyphenaxy}N.N-timethy-3- (wituoromethoxy) " butanslamines REOG- (Ulvromethoxy pene )phenoxy)-N.N-dimethy1-3- (eidvoromethoxy)butan-L-amine; RS¥-(difvoromethony)- 44(2:G-(rilorometiony)_phensty) phenoxy -N.N-bis (ifvoromethybuian-Lamine: ~ S3-Giluoromethoxy 4. (2-G{ciftoro methoxy) _ phenethy)phenoxy)-NIN-bis (tivoromethyDbutan-lamine, - R3-(lifuorometboxy)-4- (2-64(withnoramethoxy)phonethy!)phenoxy)-NIN-bis (rifvoromethybutan-l-amine; RS3-(difloromethoxy)-N- (iloromethy!}-4-2-(-triloaromethoxy)phensty) pheaoxy}-N-(tiuoromethyl)butan-L-amine; S8-(iluo- romethoxy)-N-(diluoromethy}-4(2-3-(riuoromethoxs) ‘henethyl phenoxs)-Ntrilboromety but amine: R(-Gdiluoromethoxy)N-(diluoromethy) -42-C-(ifluo- romethoxy phencthyjpienoxy)-N-(riluorometis)butan- ‘amine; RS iluoromethoxy)-N-(Qvoromethy))-4-2-(- (ritluoromethony)phenethy)phenoxy)-N-(rifluoromethy) hutan-l-amine; 'S3-inoromethoxy)-N-(Mhxcrometyl) t= (2-6-(wiftoromethoxy phenethy!)phenoxy)-N= (eioromethybutan--amine: R3-(ileoramethony)-N- {ooromety!}-4-(2-8.4loromethoxy phenethy Pheaony)-N-(tiftnomety tan amin RSs. {Giluoromethoxy)-N-methy-4-(2-2-(eilvaromethoxy) heathy!) phonoxy)-N-(rifluoromethyl) —butan-I-amine: ‘Sh(diluromethoxs)-NsmethyT-42-34eilvoromethoxs) Phenetiyl)phenoxy)-N-(rillvoromethy!) bu 3 4lluoromethony-N-mety 14-(2-(3-(iloo- romethoxy phenethyjphenoxy)-N-(riuoromethyDbutan- Teamine; RS34iftueo methoxy) N-difuoromethsD-N- mmethy/4-(23.(eithoromethoxy phenethsiphenoxy) butan-aming; S3-{lthonomethony)-N-ilsoromethy)- [Nemethy-4-(2-(3(tiflioromethoxy) phenethyl) phenoxy) botan- amine; R3-(iflioromethony)-N-dilooromety)- [Nemethy-4-2-(3(rillioromethoxy)phenethy)piencny) hutan-lamine: _RS3}(dluoromethoxy)-N-(boremeth D> (rifluoromethoxy)phenethy!)phenoxy) 'S¥iftao methony)-N-(Hhoromethy-N- rilluorometioxy}phenciby})phencxy) 3iluoromethony)-N-(tonomethy))-N- methy1-4-2-G-(ciltuommettoxy) —phenetiyl) phenoxy) butan-I-amine; RS3-(dilvoromethoxy)-NN-Fimethy-4(2- {Gatriluoromethoxy phenethyl phenoxy uta Lame; ‘Sh diluoromethoxy)-NN-dimediyl-42-G-(wifuo romethoxy) phenetiy!phenoxy butan--amine; R3-(ilue- romethoxy -N N-imethy!-4-(23-(ridliomomethony phen ‘ethy)phenoxy)butan-I-amine, » RS3-(lifuoromethoxy {2-344ittuoromathoxy) ‘henethy}jphenory)-NN= ‘imedhytbutan-l-amine fiNuorometboxy 442-8 {diuoromethoxy phenetiyphenoxy)-N.N-dimetiylbatan amine; R3-(lifuoromesboxy)-4-(2-3-diluoromethexy) pheachyl)phenoxy)-NN-dimethylbutan-lamine: RS3-(l- uoromethoxy) 442-(-(fioromethoxy phenethyphie- roxy -N.Ndimeth Tbutan-1-amine; S¥(dtuoromeshony)-