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A new manufacturing process for N-[[1-(methylamino)cyclopropyl]methyl]pyridine-3-amine hemigalactarate (1) has been developed. Herein we wish to report the development and optimization of the route using alternative reaction conditions for a reduction/oxidation/reductive amination/protecting group cleavage sequence. Improvement of the crystallization process enabled the production of multikilogram amounts of agonist 1under cGMP control with a purity of >99.5%. A telescoped process involving 5 steps is also described.

The novel, potential antipsychotic, S33138 (N-[4-[2-[(3 aS,9 bR)-8-cyano-1,3 a,4,9 b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3 H)-yl)-ethyl]phenylacetamide), displayed ∼25-fold higher affinity at human (h) dopamine D3versus hD2L(long isoform) and hD2S(short isoform) receptors (p Kivalues, 8.7, 7.1, and 7.3, respectively). Conversely, haloperidol, clozapine, olanzapine, and risperidone displayed similar affinities for hD3, hD2L, and hD2Ssites. In guanosine-5′-O-(3-[35S]thio)-triphosphate ([35S]-GTPγS) filtration assays, S33138 showed potent, pure, and competitive antagonist properties at hD3receptors, displaying p KBand p A2values of 8.9 and 8.7, respectively. Higher concentrations were required to block hD2Land hD2Sreceptors. Preferential antagonist properties of S33138 at hD3versus hD2Lreceptors were underpinned in antibody capture/scintillation proximity assays (SPAs) of Gαi3recruitment and in measures of extracellular-regulated kinase phosphorylation. In addition, in cells cotransfected with hD3and hD2Lreceptors that assemble into heterodimers, S33138 blocked (p KB, 8.5) the inhibitory influence of quinpirole upon forskolin-stimulated cAMP formation. S33138 had low affinity for hD4receptors (<5.0) but revealed weak antagonist activity at hD1receptors (Gαs/SPA, p KB, 6.3) and hD5sites (adenylyl cyclase, 6.5). Modest antagonist properties were also seen at human serotonin (5-HT)2Areceptors (Gαq/SPA, p KB, 6.8, and inositol formation, 6.9) and at 5-HT7receptors (adenylyl cyclase, p KB, 7.1). In addition, S33138 antagonized hα2Cadrenoceptors ([35S]GTPγS, 7.2; Gαi3/SPA, 6.9; Gαo/SPA, 7.3, and extracellular-regulated-kinase, 7.1) but not hα2Aor hα2Badrenoceptors (<5.0). Finally, in contrast to haloperidol, clozapine, olanzapine, and risperidone, S33138 displayed negligible affinities for multiple subtypes of α1-adrenoceptor, muscarinic, and histamine receptor. In conclusion, S33138 possesses a distinctive receptor-binding profile and behaves, in contrast to clinically available antipsychotics, as a preferential antagonist at hD3versus hD2receptors.

The novel, potential antipsychotic, S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide), displayed approximately 25-fold higher affinity at human (h) dopamine D(3) versus hD(2L) (long isoform) and hD(2S) (short isoform) receptors (pK(i) values, 8.7, 7.1, and 7.3, respectively). Conversely, haloperidol, clozapine, olanzapine, and risperidone displayed similar affinities for hD(3), hD(2L), and hD(2S) sites. In guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]-GTPgammaS) filtration assays, S33138 showed potent, pure, and competitive antagonist properties at hD(3) receptors, displaying pK(B) and pA(2) values of 8.9 and 8.7, respectively. Higher concentrations were required to block hD(2L) and hD(2S) receptors. Preferential antagonist properties of S33138 at hD(3) versus hD(2L) receptors were underpinned in antibody capture/scintillation proximity assays (SPAs) of Galpha(i3) recruitment and in measures of extracellular-regulated kinase phosphorylation. In addition, in cells cotransfected with hD(3) and hD(2L) receptors that assemble into heterodimers, S33138 blocked (pK(B), 8.5) the inhibitory influence of quinpirole upon forskolin-stimulated cAMP formation. S33138 had low affinity for hD(4) receptors (<5.0) but revealed weak antagonist activity at hD(1) receptors (Galphas/SPA, pK(B), 6.3) and hD(5) sites (adenylyl cyclase, 6.5). Modest antagonist properties were also seen at human serotonin (5-HT)(2A) receptors (Galpha(q)/SPA, pK(B), 6.8, and inositol formation, 6.9) and at 5-HT(7) receptors (adenylyl cyclase, pK(B), 7.1). In addition, S33138 antagonized halpha(2C) adrenoceptors ([(35)S]GTPgammaS, 7.2; Galpha(i3)/SPA, 6.9; Galpha(o)/SPA, 7.3, and extracellular-regulated-kinase, 7.1) but not halpha(2A) or halpha(2B) adrenoceptors (<5.0). Finally, in contrast to haloperidol, clozapine, olanzapine, and risperidone, S33138 displayed negligible affinities for multiple subtypes of alpha(1)-adrenoceptor, muscarinic, and histamine receptor. In conclusion, S33138 possesses a distinctive receptor-binding profile and behaves, in contrast to clinically available antipsychotics, as a preferential antagonist at hD(3) versus hD(2) receptors.

The selective dopamine D3-receptor antagonist S33084 dose dependently attenuated induction of hypothermia by 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT) and PD128,907. S33084 also dose dependently reduced 7-OH-DPAT-induced penile erections (PEs) but had little effect on 7-OH-DPAT-induced yawning and hypophagia, and it did not block contralateral rotation elicited by the preferential D3agonist quinpirole in unilateral substantia nigra-lesioned rats. In models of potential antipsychotic activity, S33084 had little effect on conditioned avoidance behavior and the locomotor response to amphetamine and cocaine in rats, and weakly inhibited apomorphine-induced climbing in mice. Moreover, S33084 was inactive in models of potential extrapyramidal activity in rats: induction of catalepsy and prolactin secretion and inhibition of methylphenidate-induced gnawing. Another selective D3antagonist, GR218,231, mimicked S33084 in inhibiting 7-OH-DPAT-induced PEs and hypothermia but neither hypophagia nor yawning behavior. Similarly, it was inactive in models of potential antipsychotic and extrapyramidal activity. In distinction to S33084 and GR218,231, the preferential D2antagonist L741,626 inhibited all responses elicited by 7-OH-DPAT. Furthermore, it displayed robust activity in models of antipsychotic and, at slightly higher doses, extrapyramidal activity. In summary, S33084 was inactive in models of potential antipsychotic and extrapyramidal activity and failed to modify spontaneous locomotor behavior. Furthermore, it did not affect hypophagia or yawns, but attenuated hypothermia and PEs, elicited by 7-OH-DPAT. This profile was shared by GR218,231, whereas L741,626 was effective in all models. Thus, D2-receptors are principally involved in these paradigms, although D3-receptors may contribute to induction of hypothermia and PEs. S33084 should comprise a useful tool for further exploration of the pathophysiological significance of D3- versus D2-receptors.

The benzopyranopyrrole S33084 displayed pronounced affinity (pKi= 9.6) for cloned human hD3-receptors, and >100-fold lower affinity for hD2and all other receptors (>30) examined. S33084 concentration dependently, potently, and competitively (pA2= 9.7) antagonized dopamine (DA)-induced [35S]guanosine-5′-O-(3-thio)triphosphate (GTPγS) binding at hD3-receptors. It also concentration dependently abolished stimulation by DA of hD3-receptor-coupled mitogen-activated protein kinase. Administered alone, S33084 did not modify dialysate levels of DA in the frontal cortex, nucleus accumbens, or striatum of freely moving rats, nor the firing rate of ventrotegmental dopaminergic cell bodies. Furthermore, it had minimal effect on DA turnover in mesocortical, mesolimbic, and nigrostriatal projection regions. However, S33084 dose dependently blocked the suppressive influence of the preferential D3-agonist PD128,907 on frontocortical release of DA. Furthermore, it likewise antagonized the inhibitory influence of PD128,907 on the electrical activity of ventrotegmental dopaminergic neurons. Although less potent than S33084, GR218,231 likewise behaved as a selective hD3- versus hD2-receptor antagonist and its neurochemical and electrophysiological profiles were similar. In contrast, L741,626 was a preferential antagonist at hD2versus hD3sites. In vivo, on administration alone, L741,626 increased frontocortical, mesolimbic, and (more potently) striatal DA release, enhanced the firing rate of dopaminergic perikarya, and accelerated cerebral DA synthesis. It also blocked the actions of PD128,907. In conclusion, S33084 is a novel, potent, selective, and competitive antagonist at hD3-receptors. Although GR218,231 behaves similarly, L741,626 is a preferential D2-receptor antagonist. DA D2- but not D3-(auto) receptors tonically inhibit ascending dopaminergic pathways, although the latter may contribute to phasic suppression of DA release in frontal cortex.

AbstractA simple procedure for the synthesis of 2H-pyran-2-ones 1 is described: selective Wittig olefination of keto aldehydes at the aldehyde group followed by a cyclization in acidic medium.

A pyridine group was linked to the tetrahydronaphthalene moiety of the derivatives described in the preceding paper, to afford new combined thromboxane receptor (TP-receptor) antagonists and synthase inhibitors. The most interesting compound 2finhibits TXA2 synthase with an IC50 value of 0.64 μM and the aggregation of human platelets with an IC50 value of 0.063 μM and shows a long duration of action in different species after oral administration.

New polysubstituted tetrahydronaphthalene derivatives were prepared as thromboxane receptor (TP-receptor) antagonists. Within this series of compounds S 18886has been identified as an orally active, highly potent antagonist with a very long duration of action in different species.

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