Lsd derivatives, synthesis & method for treatment of diseases and disorders

Abstract

LSD derivative compounds and polymorphs thereof, methods for their synthesis, compositions and treatment of diseases and disorders are described herein, the compounds having the structure of Formula I:including pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers, diastereomers, racemates, polymorphs or combinations thereof; wherein: R1 to R14 are each independently selected from H, or a substituted or unsubstituted hydrocarbon group and X is selected from a halo group.

1 .- 259 . (canceled) 
     
     
         260 . A compound having the structure of Formula I: 
       
         
           
           
               
               
           
         
         a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, diastereomer, racemate, polymorph or combination thereof; wherein: R 1  to R 14  are each independently selected from H, or a substituted or unsubstituted hydrocarbon group and X is selected from a halo group,
 wherein the compound is crystalline, optionally, an isolated crystalline form. 
 
       
     
     
         261 . The compound of  claim 260 , wherein the compound comprises polymorphs thereof, optionally, a single polymorph thereof and/or an isolated polymorph thereof. 
     
     
         262 . The compound of  claim 260 , wherein:
 (i) the compound is one or more polymorphs thereof;   (ii) the compound comprises one or more compounds, each having two stereocenters, independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S;   (iii) the compound comprises one or more compounds, each having two stereocenters, independently selected from 5R,8S; 5R,8R; or 5S,8R;   (iv) the compound comprises one or more compounds, each having two stereocenters, independently selected from 5R,8S or 5R,8R;   v) the compound has two stereocenters, which are 5R,8R;   vi) the compound has two stereocenters, which are 5R,8S; and   vii) any one or more of (i) to (vi).   
     
     
         263 . The compound of  claim 260 , wherein the compound has stereocenters selected from 5R,8S or 5R,8R. 
     
     
         264 . The compound of  claim 260 , wherein the compound is an acid salt, optionally, wherein:
 i) the acid of the acid salt is selected from hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydriodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluene sulfonic acid (e.g. monohydrate), p-toluene sulfonic acid (e.g. monohydrate), 10-camphorsulfonic acid (e.g. (−)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythraric acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof;   ii) the acid of the acid salt is selected from hydrochloric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythraric acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof; or   iii) the acid of the acid salt is selected from tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythraric acid), glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof.   
     
     
         265 . The compound of  claim 260 , wherein R 1  to R 14  are each independently selected from H, substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, or substituted or unsubstituted alkynyl group, optionally, wherein:
 i) R 1  to R 14  are each independently selected from H, substituted or unsubstituted C 1 -C 6  alkyl group, substituted or unsubstituted C 2 -C 6  alkenyl group, or substituted or unsubstituted C 2 -C 6  alkynyl group;   ii) R 1  to R 14  are each independently selected from H, or substituted or unsubstituted C 1 -C 6  alkyl group;   iii) R 1  to R 14  are each independently selected from H, a methyl group or an ethyl group;   iv) R 1  and R 2  are each independently selected from H, a methyl group or an ethyl group; R 3 , R 4 , and R 6  to R 14  are each H, and R 5  is a methyl group;   v) R 1  and R 2  are each independently selected from a methyl group or an ethyl group; R 3 , R 4 , and R 6  to R 14  are each H; and R 5  is a methyl group; or   vi) R 1  and R 2  are each ethyl groups; R 3 , R 4 , and R 6  to R 14  are each H; and R 5  is a methyl group.   
     
     
         266 . The compound of  claim 260 , wherein X is selected from bromo, chloro, fluoro or iodo, optionally, wherein:
 i) X is selected from bromo, chloro, or fluoro;   ii) X is selected from bromo or chloro; or   iii) X is bromo.   
     
     
         267 . The compound of  claim 260 , wherein the compound has the structure of Formula I′: 
       
         
           
           
               
               
           
         
         a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, diastereomer, racemate, polymorph, or combination thereof. 
       
     
     
         268 . The compound of  claim 260 , wherein the compound has the structure of Formula I′ selected from: 
       
         
           
           
               
               
           
         
         a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, diastereomer, racemate, polymorph, or combination thereof; wherein: R 1  and R 2  are each independently selected from H, or a substituted or unsubstituted hydrocarbon group. 
       
     
     
         269 . The compound of  claim 268 , wherein the compound comprises polymorphs thereof, optionally, a single polymorph thereof and/or an isolated polymorph thereof. 
     
     
         270 . The compound of  claim 268 , wherein Formula I′ is Formula Ib or Id. 
     
     
         271 . The compound of  claim 268 , wherein the compound is an acid salt, optionally, wherein:
 i) the acid of the acid salt is selected from hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydriodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluene sulfonic acid (e.g. monohydrate), p-toluene sulfonic acid (e.g. monohydrate), 10-camphorsulfonic acid (e.g. (−)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythraric acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof;   ii) the acid of the acid salt is selected from hydrochloric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythraric acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof; or   iii) the acid of the acid salt is selected from tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythraric acid), glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof.   
     
     
         272 . The compound of  claim 268 , wherein R 1  and R 2  are each independently selected from H, substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, or substituted or unsubstituted alkynyl group, optionally, wherein:
 i) R 1  and R 2  are each independently selected from H, substituted or unsubstituted C 1 -C 6  alkyl group, substituted or unsubstituted C 2 -C 6  alkenyl group, or substituted or unsubstituted C 2 -C 6  alkynyl group;   ii) R 1  and R 2  are each independently selected from H, or substituted or unsubstituted C 1 -C 6  alkyl group;   iii) R 1  and R 2  are each independently selected from H, a methyl group or an ethyl group;   iv) R 1  and R 2  are each independently selected from a methyl group or an ethyl group;   v) R 1  and R 2  are each ethyl groups.   
     
     
         273 . The compound of  claim 268 , wherein the compound has the structure of Formula I′ selected from: 
       
         
           
           
               
               
           
         
         a pharmaceutically acceptable salt, hydrate, solvate, tautomer, polymorph or combination thereof. 
       
     
     
         274 . The compound of  claim 273 , wherein the compound comprises polymorphs thereof, optionally, a single polymorph thereof and/or an isolated polymorph thereof. 
     
     
         275 . The compound of  claim 273 , wherein Formula I′ is Formula Ib′ or Id′. 
     
     
         276 . The compound of  claim 273 , wherein the compound is an acid salt, optionally, wherein:
 i) the acid of the acid salt is selected from hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydriodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluene sulfonic acid (e.g. monohydrate), p-toluene sulfonic acid (e.g. monohydrate), 10-camphorsulfonic acid (e.g. (−)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythraric acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof;   ii) the acid of the acid salt is selected from hydrochloric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythraric acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof;   iii) the acid of the acid salt is selected from tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythraric acid), glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof.   
     
     
         277 . The compound of  claim 273 , wherein the compound has the structure of Formula I′ selected from: 
       
         
           
           
               
               
           
         
         or combination thereof. 
       
     
     
         278 . The compound of  claim 277 , wherein the compound comprises polymorphs thereof, optionally, a single polymorph and/or an isolated polymorph thereof. 
     
     
         279 . The compound of  claim 277 , wherein Formula I′ is Formula Ib′ or Id′. 
     
     
         280 . The compound of  277 , wherein the compound is an acid salt, optionally, wherein:
 i) the acid of the acid salt is selected from hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydriodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluene sulfonic acid (e.g. monohydrate), p-toluene sulfonic acid (e.g. monohydrate), 10-camphorsulfonic acid (e.g. (−)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythraric acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof;   ii) the acid of the acid salt is selected from hydrochloric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythraric acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof; or   iii) the acid of the acid salt is selected from tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythraric acid), glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof.   
     
     
         281 . The compound of  claim 260 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or combination thereof. 
       
     
     
         282 . The compound of  claim 281 , wherein the compound comprises polymorphs thereof, optionally, a single polymorph thereof. 
     
     
         283 . The compound of  claim 281 , wherein the compound comprises 2-bromoLSD tartrate salt (about 1: about 0.5) and/or (about 1: about 1), i) the compound is one or more polymorphs thereof; and/or ii) the compound comprises one or more compounds, each having two stereocenters, independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S; iii) the compound comprises one or more compounds, each having two stereocenters, independently selected from 5R,8S; 5R,8R; or 5S,8R; iv) the compound comprises one or more compounds, each having two stereocenters, independently selected from 5R,8S or 5R,8R; v) the compound has two stereocenters, which are 5R,8R; or vi) the compound has two stereocenters, which are 5R,8S. 
     
     
         284 . The compound of  claim 281 , wherein the ratio of the compound to the acid is from about 0.5:1 to about 2:1. 
     
     
         285 . The compound of  claim 260 , wherein the compound is (5R,8R) 2-bromo-LSD hemi-D-tartrate salt, optionally, an isolated polymorph of (5R,8R) 2-bromo-LSD hemi-D-tartrate salt. 
     
     
         286 . The compound of  claim 260 , wherein the compound has:
 i) a Powder X-ray Diffraction (PXRD) pattern comprising a peak at about 10.3° (2θ);   ii) a PXRD pattern comprising a peak at about 4.7° (2θ), about 9.4° (2θ), and about 10.3° (2θ);   iii) a PXRD pattern comprising a peak at about 4.7° (2θ), about 9.4° (2θ), about 10.3° (2θ), and about 20.1° (2θ);   iv) a PXRD pattern comprising a peak at about 10.3° (2θ) and d value of about 8.6 Å;   v) a PXRD pattern comprising a peak at about 4.7° (2θ) and d value of about 18.8 Å, about 9.4° (2θ) and d value of about 9.4 Å, and about 10.3° (2θ) and d value of about 8.6 Å;   vi) a PXRD pattern comprising a peak at about 4.7° (2θ) and d value of about 18.8 Å, about 9.4° (2θ) and d value of about 9.4 Å, about 10.3° (2θ) and d value of about 8.6 Å, and about 20.1° (2θ) and d value of about 4.4 Å;   vii) a PXRD pattern comprising a peak at 10.3°±0.2° (2θ);   viii) a PXRD pattern comprising a peak at 4.7°±0.2° (2θ), 9.4°±0.2° (2θ), and 10.3°±0.2° (2θ); or   ix) a PXRD) pattern comprising a peak at 4.7°±0.2° (2θ), 9.4°±0.2° (2θ), 10.3°±0.2° (2θ), and 20.1°±0.2° (2θ).   
     
     
         287 . The compound of  claim 260 , wherein the optical rotation is about 0.30° to about 0.40°; optionally, about 0.30° to about 0.35°. 
     
     
         288 . The compound of  claim 260 , wherein at least one of:
 i) the compound or polymorph thereof is non-hallucinogenic, optionally, substantially non-hallucinogenic;   ii) the compound does not induce tolerance in a subject;   iii) the compound is a moderate to potent pan-agonist across all 5-HT1 receptor subtypes;   iv) the compound is a potent 5-HT6 receptor partial agonist;   v) the compound is a partial agonist at 5-HT2A and 5-HT1A receptor subtypes;   vi) the compound exhibits agonism at D2-like receptors including D2 and D4;   vii) the compound promotes neural plasticity in neurons, for example in cortical neurons.   
     
     
         289 . A composition comprising a compound of  claim 260 . 
     
     
         290 . A formulation comprising the composition of  claim 260 .