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A novel series of 4-piperidinopyridines and 4-piperidinopyrimidines showed potent and selective inhibition of rat 2,3-oxidosqualene cyclase-lanosterol synthase (OSC) (e.g. 26 IC(50) rat = 398 +/- 25 nM, human = 112 +/- 25 nM) and gave selective oral inhibition of rat cholesterol biosynthesis (26 ED(80) = 1.2 +/- 0.3 mg/kg, n = 5; HMGCoA reductase inhibitor simvastatin ED(80) = 1.2 +/- 0.3 mg/kg, n = 5). The piperidinopyrimidine OSC inhibitors have a significantly lower pK(a) than the corresponding pyridine or the previously reported quinuclidine OSC inhibitor series. This indicates that other novel OSC inhibitors may be found in analogues of this series across a broader pK(a) range (6.0-9.0). These series may yield novel hypocholesterolemic agents for the treatment of cardiovascular disease.

Substitution by amines of fluorobenzenes containing a meta-substituted electron withdrawing group (EWG), in DMSO at 100 °C over 60 h gave meta-substituted aniline derivatives in isolated yields of up to 98%. The scope of the reaction is explored in terms of reaction conditions and substrates. It is postulated that facile meta-substitutions are facilitated through field stabilisation of the intermediate anion by EWG substituents.

Morpholine substitution in fluorobenzenes containing a meta-substituted electron withdrawing group proceeds in DMSO at 100 °C over 60 h to give meta-substitution products (by fluoride ion displacement) in pure isolated yields of 19–98%.

The reaction of tartrate-derived silylketene acetals and benzaldehyde has been investigated and the yields and diastereoselectivities have been found to be dependent upon the nature of the tartrate ester. Utilising the di-tert-butyl tartrate derivatives, high yields were achieved using a variety of aldehyde substrates. The reactions all proceeded with excellent levels of stereoselectivity ( 82∶18); the sense of induction being dependent upon the choice of Lewis acid. BF3·OEt2 and TiCl3(OiPr) furnished complementary products in several cases and a model has been proposed to account for this observation.

X-Ray crystallography and dynamic 1H NMR spectroscopy have revealed that 1,4,5,8-tetramethyl-, 1-bromomethyl-4,5,8-trimethyl-, and 1,8-bis(bromomethyl)-4,5-dimethyl-2,3,6,7-tetrabromonaphthalene — 3, 4, and 5, respectively — have severely distorted naphthalene nuclei in the solid state that also correspond to the gross conformations that occupy appreciable (ΔG‡∼16 kcal mol−1) energy wells in the solution state.

Quinuclidines with a 3-biaryl substituent are a new class of potent, orally active squalene synthase (SQS) inhibitors. Variants around these rigid structures indicate key structural requirements for cationic SQS inhibitors. Thus the lower in vitro potency found for quinuclidines bearing 3-substituents, which did not overlay the biphenyl group of 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (2) (IC50 = 16 nM, rat microsomal SQS), implied a directional requirement for the 3-substituent. Similarly, the lower potency of the 3-terphenyl analogue 6 (IC50 = 370 nM) indicated size constraints for this substituent. In compounds with a linking group between the quinuclidine and biphenyl ring, linking groups of lower lipophilicity were less well tolerated (e.g., 17, CH2CH2, IC50 = 5 nM vs 19, NHCO, IC50 = 1.2 μM). Replacement of the distal phenyl ring of 2 with a more polar pyridine heterocycle caused a reduction in in vitro potency. In general, good in vivo activity in the rat was restricted to 3-hydroxy analogues, with...

The reaction of tartrate-derived silylketene acetals and benzaldehyde has been investigated and the yields and diastereoselectivities have been found to be dependent upon the nature of the tartrate ester. Utilising the di-tert-butyl tartrate derivatives, high yields were achieved using a variety of aldehyde substrates. The reactions all proceeded with excellent levels of stereoselectivity ( 82∶18); the sense of induction being dependent upon the choice of Lewis acid. BF3·OEt2 and TiCl3(OiPr) furnished complementary products in several cases and a model has been proposed to account for this observation.

Substitution by amines of fluorobenzenes containing a meta-substituted electron withdrawing group (EWG), in DMSO at 100 °C over 60 h gave meta-substituted aniline derivatives in isolated yields of up to 98%. The scope of the reaction is explored in terms of reaction conditions and substrates. It is postulated that facile meta-substitutions are facilitated through field stabilisation of the intermediate anion by EWG substituents.

Much higher yields were found after shorter reaction times for the meta -substituted amination of benzenes in DMPU with microwave heating in a sealed tube (180°C, 5 h), e.g. piperidine and m -fluorobenzonitrile 1 gave the m -substituted 3 in 92% yield. These modified reaction conditions also afforded a new synthesis of unsymmetrical diamines in >80% yield.

Potent inhibition of rat microsomal oxidosqualene cyclase-lanosterol synthase (OSC) was maintained after structural modification of the 4-piperidinopyridine OSC inhibitor series. These novel analogues with a much lower pKa range (5.8–6.7) gave potent oral inhibition of rat cholesterol biosynthesis (8 ED80 0.7 mg/kg), and diminished effects on rat feeding after a 100 mg/kg oral dose.

A novel p38 MAP kinase inhibitor structural class was discovered through selectivity screening. The rational analogue design, synthesis and structure-activity relationship of this series of bis-amide inhibitors is reported. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide-induced tumour necrosis factor-alpha release is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues.

Potent inhibition of rat microsomal oxidosqualene cyclase-lanosterol synthase (OSC) was maintained after structural modification of the 4-piperidinopyridine OSC inhibitor series. These novel analogues with a much lower pKa range (5.8–6.7) gave potent oral inhibition of rat cholesterol biosynthesis (8 ED80 0.7 mg/kg), and diminished effects on rat feeding after a 100 mg/kg oral dose.

Novel 3-substituted quinuclidine inhibitors of cholesterol biosynthesis are reported. Compounds were optimized against oxidosqualene cyclase-lanosterol synthase (OSC) inhibition in vivo, rather than by the conventional optimization of structure-activity relationship information based on in vitro OSC inhibition. Thus, examination of HPLC lipid profiles from orally dosed rats showed cholesterol biosynthetic intermediates and whether cholesterol levels were reduced. A new substituted quinuclidine pharmacophore 18a-c was rapidly found for the inhibition of OSC, and the most promising inhibitors were validated by the confirmation of potent OSC inhibition. Compound 16 gave an IC50 value of 83 +/- 11 nM for human and an IC50 value of 124 +/- 14 nM, for rat, coupled with oral and selective inhibition of cholesterol biosynthesis derived from OSC inhibition (rat, ED50 = 1.3 +/- 0.7 mg/kg, n = 5; marmoset, 15 mg/kg dose, n = 3, caused complete inhibition). These 3-substituted quinuclidines, which were derived from a quinuclidine series previously known to inhibit cholesterol biosynthesis at the squalene synthase step, may afford a novel series of hypocholesterolemic agents acting by the inhibition of OSC.

The synthesis of 2-benzylmorpholine from allylbenzene together with its resolution into its (+)-and (—)-enantiomers is reported. Oral dosing of the racemate to dogs caused appetite suppression with an ED50 of 3 and 5.5 rag kg−1 at I and 2 h, respectively, after access to a meat meal. No stimulant activity was observed in dogs given oral doses of 200 mg kg−1 but the appetite suppressant effect in dogs declined during 20 days of chronic oral dosing at 10 mg kg−1. Appetite suppression activity was shown to reside in the (+)-enantiomer.

Quinuclidines with a 3-biaryl substituent are a new class of potent, orally active squalene synthase (SQS) inhibitors. Variants around these rigid structures indicate key structural requirements for cationic SQS inhibitors. Thus the lower in vitro potency found for quinuclidines bearing 3-substituents, which did not overlay the biphenyl group of 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (2) (IC50 = 16 nM, rat microsomal SQS), implied a directional requirement for the 3-substituent. Similarly, the lower potency of the 3-terphenyl analogue 6 (IC50 = 370 nM) indicated size constraints for this substituent. In compounds with a linking group between the quinuclidine and biphenyl ring, linking groups of lower lipophilicity were less well tolerated (e.g., 17, CH2CH2, IC50 = 5 nM vs 19, NHCO, IC50 = 1.2 microM). Replacement of the distal phenyl ring of 2 with a more polar pyridine heterocycle caused a reduction in in vitro potency. In general, good in vivo activity in the rat was restricted to 3-hydroxy analogues, with the 3-[4-(pyrid-4-yl)phenyl] derivative 39 (IC50 = 161 nM) showing the best inhibition (following oral dosing) of cholesterol biosynthesis from mevalonate (ED50 = 2.7 mg/kg).

A new class of dual-acting racemic thromboxane receptor antagonist/thromboxane synthase inhibitors is reported, based on the novel approach of linking the known thromboxane synthase inhibitors (TXSI) dazoxiben (2) or isbogrel (11) (separately) to thromboxane receptor antagonists (TXRA) from the 1,3-dioxane series, such as ICI 192605 (10). Dual activity was observed in vitro with inhibition of human microsomal thromboxane synthase in the range IC50 = 0.01-1.0 microM and receptor antagonist activity by inhibition of U46619-induced human platelet aggregation in the range pA2 = 5.5-7.0. The in vitro results also showed that very large groups could be tolerated at the selected substitution positions of the TXRA and TXSI components. Oral activity was observed in ex vivo tests in both rats and dogs at a dose of 10 mg/kg. Thus, (E)-7-[4-[[4-[(2SR,4SR,5RS)-5-[(Z)-5-carboxypent -2-enyl]-4-(2- hydroxyphenyl)-1,3-dioxan-2-yl]-benzyl]oxy]phenyl]-7-(3-pyridyl)he pt-6- enoic acid (110) was both an antagonist (pA2 = 6.7) and a synthase inhibitor (IC50 = 0.02 microM). On oral dosing (10 mg/kg) to rats and dogs, 110 showed significant TXRA activity [concentration ratio > 64 (rat, 3 h) and > 59 +/- 11.3 (dog, 2 h) vs ex vivo U46619-induced platelet aggregation]. Inhibition of thromboxane synthase at the respective time points in these experiments was 81 +/- 4.4% (rat) and 69 +/- 4.8% (dog).

The X-ray crystal structure of a 1,3-dioxane thromboxane receptor antagonist (2) is reported, which shows the presence of both an inter- and an intra-molecular hydrogen bond in the molecule and unexpectedly reveals that the hexenoic acid side chain carboxy group lies over the plane of the 1,3-dioxane ring.

The X-ray crystal structure of a 1,3-dioxane thromboxane receptor antagonist (2) is reported, which shows the presence of both an inter- and an intra-molecular hydrogen bond in the molecule and unexpectedly reveals that the hexenoic acid side chain carboxy group lies over the plane of the 1,3-dioxane ring.

Anticoccidial activity in vitro against Eimeria tenella is reported for crown polyethers with ring sizes from 14 to 30 atoms. The most potent compounds, 4 and 9, were found active at 0.33 ppm, but none were active in vivo. Test results are discussed in terms of lipophilic shielding of complexed cations.

The preparation of a novel potent thromboxane receptor antagonist ICI 180080, 5(Z)-7-[2,2-dimethyl-4-(2-hydroxyphenyl)-1, 3-dioxan-cis-5-yl] heptenoic acid, is described together with its methyl ether and methyl ester. Thromboxane antagonist pA2 data against U 46619 is presented for rabbit thoracic aorta in-vitro (ICI 180080, pA2 = 7.5). The relative antagonist pA2 values obtained are discussed in terms of the chemical structure of the molecules. The potent activity of ICI 180080 is attributed to a specific orientation of the phenolic oxygen, due to an intramolecular hydrogen bond.

Synthesis of eight benzo-15-crown-5 derivatives I (R = H, CO2Me, CO2H, Me; R1 = H, CO2H, CO2Me, CHO, CH=CHCO2H, CH2CH2CO2H) designed as rigid cyclic analogues of the anticoccidial ionophores is described. No anticoccidial activity was observed in chickens, but moderate activity in tissue culture was found for I (R = Me, R1 = H; R = R1 = H) and dibenzo-18-crown-6.

Reaction of 4-benzyl-3-chloromethylmorpholine with phenoxide anions led not only to 4-benzyl-3-phenoxymethyl morpholines, but substantial amounts of 4-benzyl-6-phenoxy-1,4-oxazepanes. The ring expansion reaction is explained in terms of neighbouring group participation, leading to an ambident aziridinium cation intermediate.

The blood glucose level lowering activity of [(acylamino)ethyl]benzoic acids, such as p-[2-(5-chloro-2-methoxy-benzamido)ethyl]benzoic acid (HB699, 2), is discussed in terms of binding at putative insulin-releasing receptor sites of pancreatic beta cells. The hypoglycemic potencies found for synthetic analogues of 2 indicate that high hypoglycemic activity is only found when a carboxyl group or a group that is readily oxidized to carboxyl in vivo, such as methyl, is attached to the aromatic ring of the phenethyl group. It is proposed that this carboxyl group is able to bind at the same receptor site as the SO2NHCONH group of the sulfonylurea drugs, such as tolbutamide (3). The role of the benzamide group in 2 was attributed to protein binding.

The synthesis and appetite-suppressant activity of (S)-3-[(benzyloxy)methyl]morpholine hydrochloride in dogs are reported. The oral ED50 for appetite suppression in dogs of 3 was 12 mg/kg, and it was tolerated up to 200 mg/kg. 3 had no inhibitory effect on the release or uptake of noradrenaline, dopamine, or serotonin at 10(-5) M. The (R) enantiomer of 3 was not anorexiant.

Synthesis of eight benzo-15-crown-5 derivatives I (R = H, CO2Me, CO2H, Me; R1 = H, CO2H, CO2Me, CHO, CH=CHCO2H, CH2CH2CO2H) designed as rigid cyclic analogues of the anticoccidial ionophores is described. No anticoccidial activity was observed in chickens, but moderate activity in tissue culture was found for I (R = Me, R1 = H; R = R1 = H) and dibenzo-18-crown-6.

The synthesis and resolution of potential appetite suppressant 3-(2-aryloxyethyl)morpholines is described. Assignment of the absolute configuration of the resolved enantiomers is based on a chiral synthesis from O-phenylhomoserines of known configuration. Appetite suppressant effects in dogs are briefly reported.

Anticoccidial activity in vitro against Eimeria tenella is reported for crown polyethers with ring sizes from 14 to 30 atoms. The most potent compounds, 4 and 9, were found active at 0.33 ppm, but none were active in vivo. Test results are discussed in terms of lipophilic shielding of complexed cations.

The unambiguous synthesis of 3-naphthyloxymethylmorpholine hydrochloride appetite suppressants is reported. Chemoselective reduction of 4-benzyl-5-oxomorpholine-3-carboxylic acid and its derivatives is described under various metal hydride reducing conditions.

Reduction of pyridazin-3-ones (1a—d) with zinc dust in acetic acid affords selectively 4,5-dihydropyridazin-3-ones (2a—d), but N(2)-substituted (1) react further with excess of zinc to give equal amounts of pyrrolidin-2-ones (3) and 3-pyrrolin-2-ones (4).

The blood glucose level lowering activity of [(acylamino)ethyl]benzoic acids, such as p-[2-(5-chloro-2-methoxy-benzamido)ethyl]benzoic acid (HB699, 2), is discussed in terms of binding at putative insulin-releasing receptor sites of pancreatic beta cells. The hypoglycemic potencies found for synthetic analogues of 2 indicate that high hypoglycemic activity is only found when a carboxyl group or a group that is readily oxidized to carboxyl in vivo, such as methyl, is attached to the aromatic ring of the phenethyl group. It is proposed that this carboxyl group is able to bind at the same receptor site as the SO2NHCONH group of the sulfonylurea drugs, such as tolbutamide (3). The role of the benzamide group in 2 was attributed to protein binding.

Reduction of 2-Allyl-3-phenyl-β-ketoesters (1) with complex metal hydrides (LiBH4) gave mainly erythro glycols (2) when an ortho substituent larger than fluorine was present, but with 2,6-disubstitution (1i) the threo glycol (3i) was the main product.

The synthesis and resolution of potential appetite suppressant 3-(2-aryloxyethyl)morpholines is described. Assignment of the absolute configuration of the resolved enantiomers is based on a chiral synthesis from O-phenylhomoserines of known configuration. Appetite suppressant effects in dogs are briefly reported.

The unambiguous synthesis of 3-naphthyloxymethylmorpholine hydrochloride appetite suppressants is reported. Chemoselective reduction of 4-benzyl-5-oxomorpholine-3-carboxylic acid and its derivatives is described under various metal hydride reducing conditions.

The unambiguous synthesis of 6-phenoxy-1,4-oxazepane from diethyl phenoxymalonate via a modified Hellmann Haas β-amino acid synthesis is described.

Reaction of 4-benzyl-3-chloromethylmorpholine with phenoxide anions led not only to 4-benzyl-3-phenoxymethyl morpholines, but substantial amounts of 4-benzyl-6-phenoxy-1,4-oxazepanes. The ring expansion reaction is explained in terms of neighbouring group participation, leading to an ambident aziridinium cation intermediate.

The chiral synthesis of 3-hydroxymethyl- and 3-carboxy-morpholines from serine enantiomers is described. Chemoselective and total reductions of 5-oxomorpholine-3-carboxylates are key synthetic steps.