A Convenient 3-Step Synthesis of 3-Acetamido-6-arylpyridazines Directed to Novel Y5 Receptor Antagonist.

Abstract

Obesity is a common disorder in the industrialized world. The major environmental factor associated with the rising prevalence of obesity is an increasingly sedentary lifestyle, compounded by greater levels of caloric intake. Recent studies [1][2][3][4][5][6][7][8][9][10][11][12] have shown that in the central nervous system (CNS), neuropeptide Y (NPY) has been implicated in obesity and feeding, anxiety and depression, endocrine function and metabolism.1) More particularly it was observed that food intake was inhibited by antisense oligodeoxynucleotides to the NPY 5 receptors. 4)Therefore there is a great interest in the synthesis of NPY receptor antagonists acting as antagonists on NPY 5 receptors. Some potent and selective NPY 5 receptor antagonists have been described in the literature [13][14][15][16][17][18] and their affinities were assessed through in vitro data over transfected CHO cells. However for most of them no in vivo data were published, 19) this is the case for compound 1 (Fig. 1) which is active in vitro (IC 50 ϭ8.3 nM) but inactive in vivo. We hypothetized that the exchange of the pyrazole ring by a pyridazine ring, in abolishing an intramolecular hydrogen bond between oxygen from amide function and the heterocyclic nitrogen, could lead a better central biodisponibility: in addition, pyridazines are known to have a good central bioavailability.20) Hereafter we report the synthesis and biological evaluation of a series of pyridazine analogues of compound 1 (Fig. 1).To acceed to these compounds, we propose a 3-step synthesis of a series of 3-acetamido-6-arylpyridazines 5a-k.The first strategy we envisaged for the synthesis of 3-N-(2-naphtylacetamido)-6-phenylpyridazine 5b was based on a the sequence shown in route a (Chart 1): treatment of commercially available 3,6-dichloropyridazine 2 with aqueous ammonia 21) to yield the 3-amino-6-chloropyridazine 3, coupling reaction between 3-amino-6-chloropyridazine 3 and 2-naphtylacetic acid in the presence of benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (BOP) 22) produced the 3-N-(2-naphtylacetamido)-3-chloropyridazine 4. Finally we proceeded to a palladium-catalyzed Suzuki cross-coupling reaction between acetamidopyridazine derivative 4 and a commercially available arylboronic acid. However, none of the several literature conditions 23,24) allowed us to obtain 5b with satisfying yields (see Table 1).The key difficulty in preparing compound 5b lies in the cross-coupling reaction at last step. It can be explained by a stacking effect of the naphtyl ring with the pyridazine ring hindering the catalyst approach and by the electron withdrawing effect of amide function on pyridazine ring. To overcome this difficulty, the 3-N-(2-naphtylacetamido)-6-arylpyridazines 5a-k (Table 2) were synthesized as outlined in route b of Chart 1. First a Suzuki cross-coupling reaction of available arylboronic acids with 3-amino-6-chloropyridazine 3 described previously 25) was used to prepare 3-amino-6-arylpyridazine 6 with 12-60% yields. The acetamid...

The use of IRES-based bicistronic vectors allows the stable expression of recombinant G-protein coupled receptors such as NPY5 and histamine 4

“…Among several possible explanations, we hypothesized that the IRES may influence the mRNA stability, or that IRES activity may differ in stable versus transient transfections. Using the present system, we also showed the functionality of the NYP5 receptor, since the pharmacological data gathered with this system compare well with those reported on the other stable system available in the literature [15] or with our own data obtained, painfully, with the transiently expressed cells [4,27,30,31].…”

Palladium-Catalyzed Reactions on 1,2-Diazines

“…Both substrates can be easily obtained from 15 by a selective substitution of one chlorine atom, and their 3-aryl derivatives are useful intermediates in the pyridazine chemistry and are often themselves interesting due to their biological activities. In an attempt to develop novel neuropeptide Y5 receptor antagonists, Suzuki reaction of N-(6-chloropyridazin-3-yl)-2-(2-naphthyl)acetamide (43) with arylboronic acids was studied in the presence of Pd(PPh 3 ) 4 catalyst and aqueous Na 2 CO 3 solution [15]. 4-Carboxyphenylboronic acid could also be used on this substrate but in this case, 50% aqueous acetonitrile was used as the solvent [12].…”