Tetrahydrobenzo thiophenes

Tetrahydrobenzo[ ]thiophene behaves like thiophene in electrophilic substitution reactions. Thus, it is formylated with a mixture of vV-methylformanilide and phosphorus oxychloride,436 iodinated in the presence of mercuric oxide,193 and brominated by V-bromosuccinimide,193 all in the 2-position in Friedel-Crafts reactions with acetyl chloride,194-436 propionyl chloride,436 succinic... 

The oximes of 4,5,6,7-tetrahydrobenzo[6]thiophen-4-one and -7-one undergo the Beckmann rearrangement to give 146 354 451 and 147 (R = H),362 respectively. Compound 147 (R=C1) may be prepared similarly and by treating 2-chloro-4,5,6,7-tetrahydrobenzo[ ]thio-phen-7-one with ammonia in the presence of PPA.356 The oxime of 4,5,6,7 -tetrahydrobenzo [6]thiophene- 4-one affords 4-aminobenzo [6]-thiophene in a modified Leuckart reaction.241,355 The same oxime may be converted into 4-amino-4,5,6,7-tetrahydrobenzo[ ]thiophene by reduction with aluminum amalgam in methanol.452 The parent ketone also affords 4-amino-4,5,6,7-tetrahydrobenzo[6]thiophene on reaction with formamide at 165°, followed by acidic hydrolysis of the resulting 4-formylamino compound.355... 

The pyrimidine derivative (177 R = Me) is obtained by dehydrogenation of 2-acetamido-4,5,6,7-tetrahydrobenzo[ ]thiophene-3-carb-oxamide.114 The related compound (177 R = H) is obtained by treatment of ethyl 2-aminobenzo[6]thiophene-3-carboxylate with formamide.114... 

In conclusion, bioisosteric replacement of a phenol by a thiophene moiety gave dopamine receptor agonists with a lower affinity than the corresponding 2-aminotetralins. This loss in affinity is, however, partly compensated by a relative higher oral bioavailability of the tetrahydrobenzo[ ]thiophenes 34 and 35. 

In a series of tetrahydrobenzo[ ]thiophene analogues, we have identified novel selective dopamine D3 receptor agents, one of which displays a 100-fold selectivity over dopamine D2 receptors. These results provide information for the development of pharmacophoric models of the dopamine D2 and D3 receptor subtypes that can be used for the future development of selective agonists at these receptor subtypes. 

Hydroxylated 2-aminotetralins are potent dopamine receptor agonists. Examples of such are 5-hydroxy-2-(N,N-di- -propylamino)tetralin (5-OH-DPAT, 9)98,100,205 and 7-hydroxy-2-(N,N-di-w-propylamino)tetralin (7-OH-DPAT, 10) 79,213 These compounds have no clinical utility because of their low oral bioavailability and their short duration of action, due to glucuronidation in the liver and gut.161 We have synthesised and tested 6-(N,N-di-//-propyl)amino-4,5,6,7-tetrahydrobenzo[ ]thiophene (34) and 5-(N,N-di-/ -propyl )ami no-4,5,6,7-tetrahydrobenzo[/i]thiophene (35), which are thiophene analogues of hydroxylated 2-aminotetralins. These tetrahydrobenzo[/)]thiophenes turned out to possess a higher relative oral bioavailability than 5-OH-DPAT (chapter 4 and ref. 215). However, the affinity for the dopamine receptors is diminished, as compared to 5-OH-DPAT (chapter 2, ref. 239). 

The synthesis of 5- and 6-(N,N-di- -propyl)amino-4,5,6,7-tetrahydrobenzo[ ]thiophene (34 and 35) has been described previously (Chapter 2). Using a Vilsmeier-Haack reaction, a formyl moiety was introduced on the 2-position of the thiophene ring.240 An excess of N-methylformanilide was used which could be easily removed by column chromatography. Reduction of the formaldehydes 65 and 68 with NaBFC yielded the hydroxymethyl compounds 66 and 69. From compound 65, the aldoxime 67 was synthesised, using hydroxylamine.HCl in ethanol and 5N NaOH-solution. 

The synthesis of the 2-substituted 6-(N,N-di- -propyl)aminomethyl-4,5,6,7-tetrahydrobenzo[/>]thiophenes is outlined in Scheme 3.2. First the two enantiomers of 6-(N,N-di-/7-propyl)aminomethyl-4,5,6,7-tetrahydrobenzo[/>]thiophene (36) were separated. Since the affinity resides in the (+)-enantiomer, only the (+)-enantiomer was used for further reactions. The same reaction procedures were used as for the 2-substituted 5- and 6-(N,N-di- -propyl)amino-4,5,6,7-tetrahydrobenzo 7>]thiophenes. 

N,N-di- -propyl)amino-4,5,6,7-tetrahydrobenzo[/>]thiophene (34) this has led to compounds (65, 66, 67) with moderate to high affinity for the dopamine D3 receptor. However, the affinity for the dopamine D2 receptor was dramatically decreased. Therefore, these compounds showed a high selectivity for the dopamine D3 receptor. The introduction of 2-substituents in 5-(N,N-di- -propyl)amino-4,5,6,7-tetrahydrobenzo[/>]thiophene (35) gave compounds with low to no affinity for the dopamine D2 and D3 receptors. Surprisingly, because the parent compounds 34 and 35 show a comparable affinity for the dopamine receptors. An explanation could be that compounds 65, 66 and 67 are structurally comparable with the dopamine D3-preferring agonist... 

Our results suggest that the thiophene moiety can act as a bioisostere for a phenol group in hydroxylated 2-aminotetralins. For the hexahydrothianaphthoxazines it was not possible to discriminate between bioisosterism for a phenyl or a phenol moiety. The tetrahydrobenzo[ ]thiophenes could be used as lead compounds for the development of novel dopamine receptor ligands with improved relative oral bioavailability. 

The relative oral bioavailabilities, as determined by comparing the AUC after s.c. and p.o. administration, of 6-(N,N-di- -propylamino)tetrahydrobenzo[/>]thiophene (34), 5-(N,N-di- -propylamino)tetrahydrobenzo[/>]thiophene (35) and 5-OH-DPAT (9) were calculated from Figures 4.1-4.3, and are shown in Table 4.2. For compounds 34 and 35 the relative oral bioavailabilities were > 10 %, while for the reference compound 5-OH-DPAT it was 1 %. In order to verify the fact that the decrease induced by a dose of 10 pmol/kg p.o. was not already induced by a lower dose, we have found that a dose of 1 pmol/kg p.o. of 5-OH-DPAT induced a decrease in the release of dopamine in the striatum of only 50-55 %. Furthermore, microdialysis experiments in our laboratory with the (-)-enantiomer of 5-OH-DPAT also showed that the relative oral bioavailability was about 1-3 % (Chapter 7). 

Table 4.3 Behaviour after s.c. administration of the tetrahydrobenzo[/>] thiophenes 34 and 35 represented as the number of animals which showed the behaviour of the total number of animals used in the experiment.

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