Combination of structural elements from a potent Y5 antagonist (2) with thiazole fragments that exhibit weak Y5 affinities followed by lead optimisation led to the discovery of (5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino and (4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino derivatives. Both classes of compounds are capable of delivering potent and selective orally and centrally bioavailable NPY Y5 receptor antagonists.

Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, and heart failure, the leading causes of death in the Western world. Inhibitors of the renin-angiotensin system (RAS) have proven to be successful treatments for hypertension. As renin specifically catalyses the rate-limiting step of the RAS, it represents the optimal target for RAS inhibition. Several peptide-like renin inhibitors have been synthesized previously, but poor pharmacokinetic properties meant that these compounds were not clinically useful. We employed a combination of molecular modelling and crystallographic structure analysis to design renin inhibitors lacking the extended peptide-like backbone of earlier inhibitors, for improved pharmacokinetic properties. This led to the discovery of aliskiren, a highly potent and selective inhibitor of human renin in vitro, and in vivo; once-daily oral doses of aliskiren inhibit renin and lower blood pressure in sodium-depleted marmosets and hypertensive human patients. Aliskiren represents the first in a novel class of renin inhibitors with the potential for treatment of hypertension and related cardiovascular diseases.

The design of a novel series of NPY-Y5 receptor antagonists is described. Key elements for the design were the identification of weak Y5 hits from a Y1 program, results from a combinatorial approach and database mining. This led to the discovery of the quinazoline 4 and the aryl-sulphonamide moiety as major components of the pharmacophore for Y5 affinity. The synthesis and SAR towards CGP71683A is described.

The β-azido functionalization reaction provides a mechanistically different enone synthesis that involves treatment of 2 with fluoride anion to effect desilylation and concomitant β-elimination to give 3. Table 1 lists a number of examples of the direct conversion of a TIPS enol ether into the corresponding α,β-enone via a β-azido TIPS enol ether. The β-azido group can be ionized with Me3Al or Me2AlCl and the intermediate enonium ion trapped by a variety of nucleophiles such as an allylstannane, electron-rich aromatics, TMS enol ethers, Et2AlCN, Me2AlCCR, Me4AlLi, and vinylaluminum reagents to give the products listed in Table 2. The diastereoselectivity of the reaction of a 4-substituted enonium ion with indole shows an unusual increase of selectivity with increasing temperature. Reduction of the azide 2 provides access to β-amino TIPS enol ethers 5, which, for example, can be converted into a cinnamide derivative and cyclized via a putative "ene" process into a γ-lactam.

The new neuropeptide Y (NPY) Y-5 receptor antagonist CGP 71683A displayed high affinity for the cloned rat NPY Y-5 subtype, but > 1,000-fold lower affinity for the cloned rat NPY Y-1, Y-2, and Y-4 subtypes, In LMTK cells transfected with the human NPY Y-5 receptor, CGP 71683A was without intrinsic activity and antagonized NPY-induced Ca2+ transients. CGP 71683A was given intraperitoneally (dose range 1-100 mg/kg) to a series of animal models of high hypothalamic NPY levels. In lean satiated rats CGP 71683A significantly antagonized the increase in food intake induced by intracerebroventricular injection of NPY. In 24-h fasted and streptozotocin diabetic rats CGP 71683A dose-dependently inhibited food intake. During the dark phase, CGP 71683A dose-dependently inhibited food intake in free-feeding lean rats without affecting the normal pattern of food intake or inducing taste aversion. In free-feeding lean rats, intraperitoneal administration of CGP 71683A for 28 d inhibited food intake dose-dependently with a maximum reduction observed on days 3 and 4, Despite the return of food intake to control levels, body weight and the peripheral fat mass remained significantly reduced. The data demonstrate that the NPY Y-5 receptor subtype plays a role in NPY-induced food intake, but also suggest that, with chronic blockade, counterregulatory mechanisms are induced to restore appetite.

The P-azido functionalization reaction provides a mechanistically different enone synthesis that involves treatment of 2 with fluoride anion to effect desilylation and concomitant beta-elimination to give 3. Table 1 lists a number of examples of the direct conversion of a TIPS enol ether into the corresponding alpha,beta-enone via a beta-azido TIPS enol ether. The beta-azido group can be ionized with Me3Al or Me2AlCl and the intermediate enonium ion trapped by a variety of nucleophiles such as an allylstannane, electron-rich aromatics, TMS enol ethers, Et2AlCN, Me2AlCCR, Me4AlLi, and vinylaluminum reagents to give the products listed in Table 2. The diastereoselectivity of the reaction of a 4-substituted enonium ion with indole shows an unusual increase of selectivity with increasing temperature. Reduction of the azide 2 provides access to beta-amino TIPS enol ethers 5, which, for example, can be converted into a cinnamide derivative and cyclized via a putative "ene" process into a gamma-lactam.

The invention relates to DE - AMINO - GA - HYDROXY {OE} - ARYL - alkane acid amide of formula I wherein R Sub.1 {} is hydrogen, hydroxy, lower alkoxy, cycloalkoxy, lower alkoxy or lower alkoxy optionally esterified amidated carboxy or lower alkoxy, R} {SUB.2 is hydrogen, lower alkyl, cycloalkyl, lower alkoxy lower alkyl, lower alkoxy lower alkyl lower alkoxy, cycloalkoxy lower alkyl, hydroxy, hydroxy lower halogenated or sulphonated, optionally substituted lower alkyl , lower alkyl substituted amino loweralkanoyl AND / OR CARBONYL lower alkoxy, lower alkyl HETEROARYL EVENTUALLY HYDROGENATED, lower alkoxy substituted amino possibly by lower alkyl, loweralkanoyl and / or lower alkoxycarbonyl, ALCOXIOXO BOTTOM, lower alkoxy, cycloalkoxy, lower alkenyloxy, alkoxy BOTTOM cycloalkoxy, lower alkoxy lower alkoxy, lower alkoxy lower alkenyl, lower alkoxy LOWER alkenyl, alkoxy BOTTOM, lower alkyl alkenyl BOTTOM, lower alkoxy loweralkanoyl, loweralkanoyl (hydroxy) lower alkylthio optionally substituted by lower alkoxy lower alkylthio S - OXIDIZED, lower alkoxy ANIL, lower alkoxy HETEROARYL HYDROGENATED EVENTUALLY, lower alkoxy cyano, lower alkoxy amidated carboxy or optionally esterified or lower alkyl or amidated carboxy optionally esterified, R} {SUB.3 is lower alkyl optionally halogenated, lower alkyl lower alkoxy, cycloalkoxy lower alkyl, hydroxy lower alkyl, lower alkylthio lower alkyl EVENTUALLY S - oXIDIZED, lower alkyl heteroalkylthio EVENTUALLY HYDROGENATED lower alkyl HETEROARYL EVENTUALLY HYDROGENATED lower alkylene ALQUILADO N - MONO ON, N - ALQUILDO DI LOWER, N - ALCANOILADO LOWER, N, sulfonylated lower alkane or rented LOWER THROUGH lower alkylene, optionally N '' - ALQUILADO BOTTOM O N ' - ALCANOILADO LOWER ALKYL OR Amino lower N, N - disubstituted, lower alkylene TIANO S - substituted lower alkyl cyano, lower alkyl CARBOXI optionally esterified or amidated, cycloalkyl, aryl, hydroxy, lower alkoxy, cycloalkoxy, lower alkoxy lower alkoxy, lower alkoxy cycloalkoxy, lower alkoxy hydroxy, aryl lower alkoxy, lower alkylthio LOWER S - OXIDIZED EVENTUALLY, lower alkoxy optionally halogenated, alkoxy, lower alkoxy, lower alkoxy HETEROARYL HYDROGENATED EVENTUALLY, lower alkoxy HETEROARYL halogenated lower alkylene AZA N '' - lower alkoxylated or optionally N ' ALQUILADO LOWER, N - sulfonylated lower alkane or lower alkylene, optionally N - ALCANOILADO LOWER, N - MONO ON, N ALQUILADO LOWER or alkylene TIANIDADO S - OXIDIZED LOW, lower alkoxy AMINO N, N disubstituted, lower alkoxy cyano or lower alkoxy CARBOXI amidated or esterified or together with R {} SUB.4 dioxyalkylene FORM A RING OR LESS CICLOE Xeno BENZOEXENOCONDENSADO O, R} {SUB.4 CONJUNCTION WITH R REPRESENTS} {SUB.3 dioxyalkylene INFERIOR, hydroxy, lower alkoxy, cycloalkoxy, X is methylene or hydroxymethylene, R {} is lower alkyl SUB.5 CILCOALQUIL O, R {SUB 6} AMINO EVENTUALLY ALQUILADO MEAN N - MONO ON, N - ALQUILADO INFERIOR INFERIOR ON ALCANOILADO, R} {SUB.7 is lower alkyl, alkenyl LOWER ALKYL CILCOALQUIL aryl lower YR O SUB.8 {} is lower alkyl, CILCOALQUIL, lower alkyl hydroxy optionally esterified OF aliphatically, lower alkylene lower alkanoyloxy or lower alkoxy, lower alkylene AZA N '' ALCANOILIZADO BOTTOM O N '' - INFERIOR alkylated, or lower alkyl substituted amino N, N '' or alkylene TIANO LOWER S oXIDIZED, LOWER aLKYL EVENTUALLY CARBOXI esterified or amidated, lower alkyl EVENTUALLY dicarboxy esterified or amidated, lower alkyl (hydroxy) CARBOXI esterified or amidated, lower alkoxy EVENTUALLY aLKYL amidated carboxy or esterified, Lower alkyl thiocarbamoyl N - MONO ON, N ALQUILADO DI INFERIOR, lower alkyl sulfamoyl optionally N - MONO ON, N - ALQUILADO DI LOWER OR OTHER HETEROARYL LINKING ATOM CY optionally substituted OXO AND / OR HYDROGENATED radical or substituted heteroaryl OXO A COMPOUND THROUGH LINKED WITH HYDROGENATED and eventually carbon atom, representing lower alkyl and salts thereof, which possess inhibiting renin and can be used as anti-depressant ACTIVE SUBSTANCES MEDICATION.

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Treatment of trimethylsilyl enol ethers with the adduct 1, derived from chloramine-T and (PhS)2, gave good yields of α-phenylthioketones. The selenium version of this reagent 2 gave α-phenylselenoketones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.