Design,Synthesis And Antidepressant Activity Of SIPI6116 Multi-Target Compounds

Depression is a common mental illness,a kind of affective disorder,chronic and recurrent.It has a serious impact on the lives,work,and society of patients.Since the 1950 s to the present,after decades of development,many important advances have been made in the development of new antidepressant drugs,but there is still room for improvement in terms of effectiveness,time of onset,and side effects.Studies have found that triple-reuptake inhibitors(TRIs)of 5-HT,NA,and DA may compensate deficiency of existing antidepressant drugs in terms of time of onset,effectiveness,etc.,and are important directions for the development of new antidepressant drugs.Our research group has been studying antidepressant drugs for more than 10 years.In the early stage,SIPI6116,a preferred TRIS compound,was found.In vitro target activity it is comparable to that of the clinical candidate drug DOV-21947.In vivo antidepressant experiment it is superior to that of the marketed drug Venlafaxin,and has good pharmacokinetic characteristics.However,in the sub-emergency experiment,the safety window is low,and the preliminary hypothesis may be related to the SIPI6116 chirality.In this paper,SIPIP6116 was firstly resolved to synthesize two chiral isomers.The isomers and SIPI6116 were simultaneously compared for in vitro and in vivo pharmacological activities and safety,and the preferred compound structure was determined.Secondly,using SIPI6116 as the lead compound to derivatize structures,design and synthesize three new structural types of compounds.Through in vitro and in vivo studies,it is expected to enrich the active compound library and establish an antidepressant active compound echelon.The research work mainly includes the following five aspects:1.Preparation and activity research of SIPI6116 isomersThe two chiral isomers SIPI6116-1 were synthesized by the resolution of the compound SIPI6116 intermediate N,N-dimethyl-3-hydroxy-3-(3,4-dichlorophenyl)propylamine racemate.SIPI6116-2,with an ee value of over 99%,optimizes the synthetic route and successfully prepares ten-gram samples.A comparison of the efficacy,pharmacokinetics,and safety of the SIPI 6116 racemate with two optical isomers revealed that the isomer SIPI6116-2 showed higher in vitro activity against 5-HT/NE/NA(IC50 value of 140 /250/720nM),higher bioavailability(blood brain transmissivity of around 10,bioavailability of 23.3%)and better safety(biweekly toxicity pre-test results show that SIPI6116-2 has a relatively small effect on weight gain in female rats.)2.Design and activity research of new compoundsOn the basis of the structure of the lead compound SIPI6116,the influence of the structure on the activity was investigated by introducing the hydroxypiperidine structure,changing the position of hydroxyl substitution,replacing the aryl moiety with benzothiophene,etc.Five A class compounds were designed.In vitro reuptake inhibition activity experiments showed that Class A compounds had no inhibitory activity against DA.Compounds SIPI8152,SIPI8153,and SIPI8154 showed certain inhibitory activity against 5-HT/NA reuptake and were SNRIs inhibitors.On the basis of the structure of compound A,the morpholino ring fragment in the active compound structure was replaced with a 4-hydroxypiperidine structure.At the same time,the straight-chain amine structure was changed to a different aliphatic amine structure,and seven B-type compounds were designed.In vitro reuptake inhibitory activity experiments showed that SIPI8157,SIPI8160-1,and SIPI8160-2 showed strong reuptake inhibitory activity against 5-HT(>94%)and DA(>103%),but they had weaker effects on DA.SIPI8163 showed strong reuptake inhibitory activity against NE(>103%)and DA(>93%),but the reuptake inhibitory rate against 5-HT was less than 90%;SIPI8158-1,SIPI8158-2,and SIPI8164 5-HT(>99%),NE(>103%),and DA(>93%)have strong reuptake inhibitory activity and have further research value.The forced swimming test in mice showed that compounds SIPI8157 and SIPI8164 showed antidepressant activity at a dose of 50 mg/kg.Combining with the structural characteristics of the marketed drugs,the aryl fragment of SIPI 8164,a preferred class B compound,was modified to design 7 compounds of class C.Among them,compound SIPI8175 showed a 5-HT/NE reuptake inhibiting activity with an inhibition rate of over 93%;compound SIPI8177 showed 5-HT/NE/NA reuptake inhibitory activity with an inhibition rate of over 90%,has further research value.The forced swimming test in mice showed that compound SIPI8171/8172/8177/8178 reduced the immobility time of the mice at a dose of 50 mg/kg,but there was no significant difference compared with the control group.3.Synthesis of new compoundsTwo synthetic routes were designed to prepare Group A compounds.According to the intermediate ketone 63,the Mannich reaction was performed on the compounds containing the benzothiophene fragment to give 63;for the compound containing the 3,4-dichloro fragment,the F-C reaction with the amine gives 63.63 is reduced to give the intermediate alcohol 64,after chloro substitution,a nucleophilic substitution reaction with hydroxypiperidine yields a class A compound.The synthesis of B and C compounds takes corresponding brominated aryl compounds as raw materials to prepare corresponding reagents,and then reacts with the corresponding WEB amides to obtain intermediates 69.After reduction,intermediates 70 are obtained.70 under the conditions of triphenylphosphine,a substitution reaction occurs with the carbon tetrabromide to obtain the bromine substituent 72,which is then reacted with 4-hydroxypiperidine to obtain the B and C compounds after removing the Boc.In summary,in this dissertation,the isomers SIPI6116-1 and SIPI6116-2 of the triple reuptake inhibitor SIPI6116 were resolved and synthesized,and SIPI6116-2 was found to be better by comparing the efficacy,pharmacokinetics,and safety of the experimental study.The antidepressant activity in vivo and in vitro,and the pharmacokinetic characteristics are ideal and safe,and it is worth further study.At the same time,a total of 19 new compounds A,B and C were devised based on the SIPI6116 structure.In vitro and in vivo pharmacological experiments revealed that SIPI 8164 has a strong triple reuptake inhibitory activity and exhibited some antidepressant activity,with further research value.