Synthesis of aminopyrrolo[1,2-a ]thieno[3,2-e ]pyrazine derivatives as serotoninergic 5-HT 7 ligands

A series of piperazinopyrrolo[1,2-a ]thieno[3,2-e ]pyrazine derivatives were prepared and evaluated to determine their affinity for the 5-HT 7 receptor. Various substitutions on piperazine were explored as well as replacement of the piperazine by other amines


Introduction
2][3] The 5-HT7R displays a low degree of homology (40%) with other serotonin Gprotein-coupled receptors (GPCRs).Recent distribution studies in brain have revealed a high abundance of the 5-HT7R proteins in hippocampus, thalamus, hypothalamus and cerebral cortex. 4Their distribution in the central nervous system is highly associated with their implication in psychiatric disorders, 5,6 depression, anxiety and mood, [7][8][9] learning and memory, 10,11 and epilepsy. 12The 5-HT7 subtype has also been found in smooth muscle cells and in blood vessels of the skull and of other peripheral tissues 13,14 so it is suggested as a putative target for migraine 15 and irritable bowel syndrome 16 treatments.Therefore, this receptor has become an attractive target for drug discovery.1][22] We found that two of them (5-MeO-DPAC and S 20244) displayed significant affinity for 5-HT7R.Subsequently, we planned some structural modifications on such structures by varying systematically the nature of the substituent at the 5-position of the 2H-benzopyran ring to cover further hydrophobic, aromatic ring and H-bond acceptor capacities.The highest affinities in both series were obtained when R = 5-acetyl (S 23751).However, none of the new compounds showed any selectivity for the 5-HT7 over 5-HT1A receptors.This lack of selectivity has led us to translate the knowledge acquired in the benzopyran series, to aminopyrrolothienopyrazine series, which has been described recently as being the possible support of new 5-HT7 ligands. 24o, in this paper, we report the synthesis of a series of tricyclic aminopyrrolothienopyrazine 25 analogues of benzopyran having the structure key elements previously mentioned.
The chloride 1 26 was triturated with piperazine and then heated at 180°C for 4h to lead to amine 2 25 in 80% yield (Scheme 1).The bromo derivatives 3 could be easily generated by nucleophilic substitution of amides and imides on appropriate dibromoalkanes (Scheme 2).Starting from piperidin-2-one, addition of sodium hydride and 1,4-dibromobutane in DMF gave expected compound 3a in 46% yield (method A, Table 1).Starting from piperidine-2,6-dione, 3,3-dimethylglutarimide and 3,3tetramethyleneglutarimide, action of potassium carbonate and 1,4-dibromobutane with a catalytic amount of potassium iodide in refluxing acetonitrile led to compounds 3b-d in moderate yields (method B).The homologous 3e was generated in 47% yield starting from 1,3-dibromopropane and 3,3-tetramethyleneglutarimide following method B.   The piperidine derivative 4g could be easily generated in 84% yield by reduction of its corresponding compound 4a with lithium aluminium hydride in diethyl ether (Scheme 4).Starting from the piperazine derivative 4f, addition of hydrazine hydrate in refluxing methanol afforded the expected compound 4h in 96% yield (Scheme 5).As described in Scheme 6, sulfonamides 5a and 5b were easily obtained by addition of 4methylbenzenesulfonyl chloride or 4-bromobenzenesulfonyl chloride on amine 2 in 92 and 80% yields, respectively.The reaction was performed in methylene chloride in the presence of triethylamine.Amines 7 were obtained in a two steps procedure (Scheme 7).3-Bromopropionitrile or 4bromobutyronitrile was added on 3,3-tetramethyleneglutarimide in acetonitrile at 60°C in the presence of potassium carbonate and a catalytic amount of potassium iodide.This reaction furnished compounds 6a and 6b in 87 and 93% yield, respectively.Nitrile functions were reduced in their corresponding amines by hydrogenation using platinum oxide in ethanol at 30 psi.Amines 7a and 7b were obtained in 78 and 86% yield, respectively.Due to a low stability of such compounds, they were isolated as their corresponding hydrochloride salts.In literature, 29 a successful technique of cross coupling between the chloride 1 and some amines was already reported using palladium-catalyzed amination.Also, treatment of chloride 1 with several amines (7a, 7b and N,N-dimethylpropane-1,3-diamine 7c) in the presence of dibenzylidenacetone palladium II, racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphtyl and sodium tert-butoxide in toluene at reflux provided derivatives 8a-c in 69 to 73% yield (Scheme 8).

Conclusions
We have reported the successful synthesis of aminopyrrolothienopyrazine derivatives.In vitro binding studies show that the compounds 4a-d have a certain affinity for the 5-HT7 receptor.However, this affinity is still lower than that observed for the 5-HT1A receptor.Thus, for the interesting compound 4d, values obtained are the following: 5-HT1A Ki = 15 nM; 5-HT7 Ki = 165 nM.Further chemical modifications are currently been performed in order to determine the structure activity relationships required for good affinity and good selectivity for the 5HT7 receptor over the 5HT1A receptor in the light of recent progress in this improvement of selectivity. 30

General procedure for the synthesis of compounds 4
Under an argon atmosphere, to a solution of amine 2 in dry DMF, triethylamine (3 eq.), bromoderivatives 3 or N-(4-bromobutyl)phthalimide (1.1 eq.) and KI (cat.) were added.The mixture warmed at 60°C for 6 h, hydrolyzed and the crude product was extracted with AcOEt.The organic layers were dried over MgSO4 and concentrated.

General procedure for the synthesis of compounds 5
Under an argon atmosphere, to a solution of amine 2 in CH2Cl2, Et3N (3 eq.) and 4methylbenzenesulfonyl chloride or 4-bromobenzenesulfonyl chloride (1.5 eq.) were added at room temperature.The mixture was stirred for 5 h then hydrolyzed and extracted with CH2Cl2.The organic layers were dried over MgSO4 and concentrated under reduced pressure.The purification was performed by flash chromatography (SiO2; CH2Cl2/MeOH: 98/2) to give sulfonamides 5 as a white foam.

General procedure for the synthesis of compounds 6
Under an argon atmosphere, to a solution of 3,3-tetramethyleneglutarimide in dry acetonitrile, 3bromopropionitrile or 4-bromobutyronitrile (1.1 eq.), K2CO3 (3 eq.) and a catalytic amount of KI were added at room temperature.The solution was warmed to 60°C and stirred for 20 h.The mixture was concentrated under reduced pressure, hydrolyzed and extracted with CH2Cl2.The organic layers were dried over MgSO4, concentrated under reduced pressure and purified by flash chromatography (SiO2; CH2Cl2) to give nitrile derivatives 6.

General procedure for the synthesis of compounds 8
Under an argon atmosphere, to a mixture of chloride 1, Pd2dba3 (0.25 eq.), rac-BINAP (0.75 eq.) and primary amine 7 (1.2 eq.) in degazed toluene was added tBuONa (1.4 eq.).The solution was stirred for 18 h at reflux and concentrated under reduced pressure.

Table 1
Entry Methods n

Table 3
13 and13C NMR spectra were obtained with a Bruker instrument Advance DPX250 at 250.131 and 62.9 MHz, respectively.Chemical shifts ( values) were reported in parts per million and coupling constants (J values) in Hz. Cabon multiplicities have been assigned by distortion-less enhancement by polarization transfer (DEPT) experiments.Infrared spectra were recorded using NaCl film or KBr pellets techniques on a Perkin-Elmer spectrometer FT PARAGON 1000PC.Mass spectra (MS) were recorded on a Perkin-Elmer mass spectrometer SCIEX API 300 by ion spray (IS).Melting points (mp) were determined in open capillary tube and are uncorrected.Analytical thin-layer chromatography was performed on Merck 60F254 silica gel precoated plates.Flash chromatography was performed using silica gel Merck 40-70 m ARKIVOC 2010 (x) 116-131 ISSN 1551-7012 Page 123  ARKAT USA, Inc.