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PubMed2003

Preparation of enantiopure 1-azabicyclo[3.2.2]nonanes functionalized at carbon C3, from cinchonine and cinchonidine. stereoselective solvolysis and an easily enolizable ketone.

Solvolysis of C9 mesylated cinchonidine 1-OMs and cinchonine 2-OMs in solvent MeOH, EtOH, and CF(3)CH(2)OH affords ring-expanded 1-azabicyclo[3.2.2]nonanes oxygenated at carbon C3 ("second Cinchona rearrangement"). The newly introduced substituents at C3 and the neighboring quinolyl group Q' at C2 adopt quasiequatorial positions. The derived 1-azabicyclo[3.2.2]nonan-3-ones 5 and 6 are easily equilibrated. On contact with MeOD uptake of deuterium takes place at room temperature.

Alkanes↗
PubMed2006

64Cu-azabicyclo[3.2.2]nonane thiosemicarbazone complexes: radiopharmaceuticals for PET of topoisomerase II expression in tumors.

UNLABELLED: Topoisomerase II (Topo-II) is an essential enzyme in the DNA replication process and is the primary cellular target for many of the most widely used and effective anticancer agents. It has been reported that thiosemicarbazones (TSCs) are potent antitumor agents that inhibit Topo-II. The aim of this study was to investigate the relationship between the in vitro and in vivo behavior of novel (64)Cu-TSC complexes and the expression of Topo-II activity. METHODS: Four (4)N-azabicyclo[3.2.2]nonane TSC derivatives (EPH142, EPH143, EPH144, and EPH270) were successfully radiolabeled with (64)Cu, to form lipophilic cations of the general formula [(64)Cu(L)]Cl, and the partition coefficient (logP) values were determined. One agent [(64)Cu-EPH270](+) was observed in vitro in cultured cell studies. The kinetics of 2 compounds, [(64)Cu-EPH144](+) and [(64)Cu-EPH270](+), were examined in mice bearing L1210 tumors and small-animal PET was conducted in mice bearing L1210 and PC-3 tumors, which expressed high and low levels of Topo-II, respectively. All data were compared with the activity and levels of Topo-II, as determined by a commercially available assay kit and western blot analysis. RESULTS: The 4 complexes were radiolabeled by incubation of (64)CuCl(2) with the ligand in ethanolic solution. The complexes were isolated in high radiochemical purity, as determined by radio-thin-layer chromatography and radio-high-performance liquid chromatography. The compounds were shown to be lipophilic with logP values ranging from 1.34 to 1.92. In biodistribution studies, good L1210 tumor uptake was noted ([(64)Cu-EPH144](+) at 1 h, 4.70 %ID/g [percentage injected dose per gram]; 4 h, 8.80 %ID/g; 24 h, 6.64 %ID/g; and [(64)Cu-EPH270](+) at 1 h, 2.58 %ID/g; 4 h, 6.00 %ID/g; 24 h, 4.80 %ID/g). Small-animal PET of animals with L1210 tumors (high Topo-II expressing) showed excellent tumor accumulation compared with that of animals with PC-3 tumors (low Topo-II expressing), and the L1210 tumor uptake was significantly reduced by coadministration of a Topo-II poison. CONCLUSION: Here we describe the characterization of a new class of copper-radiolabeled TSC analogs. We demonstrate that the accumulation of the (64)Cu-compounds is related to the expression levels of Topo-II in tumor tissue.

Animals↗
PubMed1988

The comparative stability of different types of penicillin and cephalosporin N-pyrryl derivatives.

The kinetics of the decomposition of potassium salts of 4-thia-1-azabicyclo[3.2.0.]heptane-3,3-dimethyl-6-amino-7-oxo-N- [2(1H-pyrrolyl)acetyl] -2-carboxylic acid (6R, trans), 4-thia-1-azabicyclo[3.2.0]heptane-3,3-dimethyl-6-amino-7-oxo-N-[2-phenyl - 2(1H-pyrrolyl)acetyl]-2-carboxylic acid (6R, trans), 5-thia-1-azabicyclo[4.2.0.]oct-2-ene-3- [(acetyloxy)methyl]-7-amino-8-oxo-N-[2(1H-pyrrolyl)acetyl]-2-ca rbo xylic acid (6R, trans), 5-thia-1-azabicyclo[4.2.0.]oct-2-ene-3- [(acetyloxy)methyl]-7-amino-8-oxo-N-[2-phenyl-2(1H-pyrrolyl)acetyl ]- 2-carboxylic acid (6R, trans), 5-thia-1-azabicyclo[4.2.0.]oct-2-ene-7-amino-3-methyl-8-oxo-N- [2(1H-pyrrolyl)-acetyl]-2-carboxylic acid (6R, trans) and 5-thia-1-azabicyclo[4.2.0.]oct-2-ene-7-amino-3-methyl-8-oxo- N-[2-phenyl-2(1H-pyrrolyl)acetyl]-2-carboxylic acid (6R, trans), in aqueous solution at 37 degrees C and at ionic strength of 0.5 mol.l-1 have been studied over the 2.3-11.5 pH range. In all cases, the hydrolysis of these compounds is subject to acid-base catalysis and, in some instances, to a general catalysis by various species present in the buffer solutions. The experimental results have been analyzed and discussed in relation to the hydrolytic mechanisms.

Cephalosporins↗
PubMed1999

Synthesis and stereochemical assignment of exo- and endo-7-methyl-7-azabicyclo[2.2.1]heptan-2-ol.

[formula: see text] The syntheses of both exo and endo stereoisomers of 7-methyl-7-azabicyclo[2.2.1]heptan-2-ol were achieved in straightforward fashion. Alternatively, the intramolecular cyclization of syn-4-N-methylaminocyclohexane 1,2-epoxide was found to give exo-7-methyl-7-azabicyclo-[2.2.1]heptan-2-ol as the sole product. The stereochemistry of the exo isomer was unequivocally confirmed by X-ray crystallography.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed1984

Synthesis of a highly active angiotensin converting enzyme inhibitor: 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498).

The convergent, diastereoselective synthesis of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe acid (Hoe 498), a new ACE-inhibitor with improved bioavailability and pharmacokinetics, is described.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Synthesis and pharmacology of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives, a new class of potent serotonin-3 (5-HT3) receptor antagonists.

A series of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activity assessed by their ability to antagonize the von Bezold-Jarish (BJ) effect in rats. Derivatives bearing 1-azabicyclo[2.2.2]oct-3-yl moiety as a basic function attached to the carboxamide at position 8 showed more potent antagonistic activity than those bearing the other three basic moieties. Structure-activity relationships of this series showed that methyl and chloro groups were more effective as substituents at positions 4 and 6, respectively. The representative compound 15 (Y-25130) in this series showed potent antagonistic activity on the BJ effect (ED50 = 1.3 micrograms/kg i.v.), high affinity for 5-HT3 receptor (Ki = 2.9 nM) and complete protection against cisplatin-induced emesis in dogs at a dose of 0.1 mg/kg i.v.

Animals↗
PubMed2003

2-azabicyclo[2.2.2]octa-3,5-dione via a nitrile Diels-Alder reaction.

The hetero-Diels-Alder reaction of an electron-deficient nitrile, p-toluenesulfonyl cyanide, with the silyl enol ether of cyclohexenone produced a hydrolytically sensitive [4 + 2] adduct in good yield. Use of Mander's reagent, ethyl cyanoformate, with the same diene, produced an unstable adduct. Hydrolysis of the tosyl cyanide adduct resulted in the isoquinuclidinone 2-aza[2.2.2]octa-3,5-dione as a crystalline compound in excellent yield from the nitrile.

Journal Article↗
PubMed1996

Asymmetric Synthesis and DNA Intercalation of (-)-6-[[(Aminoalkyl)oxy]methyl]-4-demethoxy-6,7- dideoxydaunomycinones(1)(,).

The BF(3).Et(2)O-promoted Diels-Alder addition of 1-acetylvinyl RADO(Et)-ate (RADO(Et)-ate = 3-ethyl-2-oxo-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylate) to 1-(dimethoxymethyl)-2,3,5,6-tetramethylidene-7-oxabicyclo[2.2.1]heptane led to one major monoadduct that added to 1,2-didehydrobenzene and was converted into (-)-4-demethoxy-7-deoxydaunomycinone and (2R)-12-acetoxy-2-acetyl-5-(bromomethyl)-1,2,3,4-tetrahydronaphthacen-2-yl RADO(Et)-ate. The latter compound was used to construct (8R)-8-acetyl-6,8-dihydroxy-11-[[(3'-[(aminopropyl)oxy]-, -4'-[(aminobutyl)oxy], and -5'-[(aminopentyl)oxy]methyl]-7,8,9,10-tetrahydronaphthacene-5,12-dione hydrochloride (-)-8, (-)-9, (-)-10, respectively, as well as (8R)-8-acetyl-6,8-dihydroxy-11- [[[2'-[(3"-aminopropyl)amino]ethyl]oxy]- ((-)-11) and -[[3'-[(3"-aminopropyl)amino]propyl]oxy]methyl]-7,8,9, 10-tetrahydronaphthacene-5,12-dione hydrochloride ((-)-12). (8R)-8-Acetyl-6,8-dihydroxy-11-[[(alpha-L-daunosaminyl)oxy]methyl]-7,8,9,10-tetrahydronaphthacene-5,12-dione hydrochloride ((-)-13), a mimic of idarubicin, was also prepared. Absorbance and fluorescence titration experiments showed (-)-8, (-)-9, and (-)-10 to intercalate calf thymus DNA whereas (-)-11, (-)-12, and (-)-13 did not. The best intercalator was (-)-9 (K(b) = (1.1 +/- 0.1) x 10(5) M(-)(1)) with the [(4'-aminobutyl)oxy]methyl chain. Inhibition of topoisomerase II-induced DNA strand religation was observed for (-)-8 at a concentration of 50 &mgr;M.

Journal Article↗
PubMed1995

PET imaging studies of dopamine D2 receptors: comparison of [18F]N-methylspiperone and the benzamide analogues [18F]MABN and [18F]MBP in baboon brain.

A series of positron emission tomography (PET) imaging studies was conducted in a baboon with the benzamide derivatives [18F]2,3-dimethoxy-N-[9-(4-fluorobenzyl)-9-azabicyclo[3.3.1]non an-3 beta-yl]benzamide ([18F]MABN) and [18F]2,3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin-4-yl]be nza mide ([18F]MBP). Studies were also conducted with the butyrophenone [18F]N-methylspiperone (NMSP) for comparison. Tissue-time activity curves of [18F]MABN are similar to those of [18F]NMSP since both compounds displayed approximately the same uptake in the basal ganglia and displayed irreversible binding kinetics in vivo. However, the rapid rate of clearance from the cerebellum and high basal ganglia:cerebellum ratio of [18F]MABN indicate that this compound has a much lower amount of nonspecific binding than [18F]NMSP. [18F]MBP displayed a higher uptake in the basal ganglia relative to [18F]NMSP and [18F]MABN and exhibited reversible binding kinetics in vivo. This property of [18F]MBP is desirable since the uptake of radioactivity in D2-rich ligands is less likely to be influenced by changes in cerebral blood flow. The current data suggest that both [18F]MABN and [18F]MBP are promising ligands for studying dopamine D2 receptors with PET.

Animals↗
PubMed2003

Synthesis and pharmacology of site specific cocaine abuse treatment agents: 8-substituted isotropane (3-azabicyclo[3.2.1]octane) dopamine uptake inhibitors.

A series of 8-substituted-3-azabicyclo[3.2.1]octanes (isotropanes) were synthesized and tested for inhibitor potency using [(3)H]WIN 35,428 binding at the dopamine (DA) transporter, [(3)H]citalopram binding at the serotonin (5-HT) transporter, and [(3)H]DA uptake assays. The synthesis started with a Mannich condensation of cyclopentanone, benzylamine, and fomaldehyde to afford N-benzyl-3-azabicyclo[3.2.1]octan-8-one (6). The 8-phenyl group was introduced by Grignard addition to ketone 6 or nucleophilic displacement via a triflate of the corresponding alcohol 7a. The 8beta-phenyl-8alpha-alcohols from Grignard addition generally have low affinity for the two transporters and do not effectively inhibit the uptake of [(3)H]DA. The 8beta-phenyl compound (14) without the hydroxyl group at C-8 was much more potent (22-fold) for [(3)H]WIN 35,428 binding inhibition than the corresponding 8beta-phenyl-8alpha-hydroxy compound (7a). The 8alpha-phenyl compound 8a was almost as potent as cocaine in binding to the DA transporter (IC(50) = 234 nM vs 159 nM for cocaine), whereas the C-8 epimer, compound 14, was somewhat less potent (IC(50) = 785 nM). The lower potency of 14 (beta-orientation of 8-phenyl group) as compared to 8a (alpha-orientation) was unexpected, based on modeling studies comparing the new compounds to WIN 35,065-2, an analogue of cocaine. The benzhydryl ethers at C-8 (17), analogous to the benztropines, had better selectivity than the corresponding phenyl compounds, 8a and 14, for the DA transporter as compared to the 5-HT transporter. The isotropane and benzisotropine analogues seem to bind in a manner that is more similar to that of the benztropine compounds 5 rather than those of cocaine and WIN 35,065-2.

Animals↗
PubMed2001

Synthesis of n-heteroaryl-7-azabicyclo[2.2.1]heptane derivatives via palladium-bisimidazol-2-ylidene complex catalyzed amination reactions.

[reaction in text] A one-step approach to novel N-heteroaryl-substituted-7-azabicyclo[2.2.1]heptanes from readily available heteroaryl halides and 7-azabicyclo[2.2.1]heptane has been achieved. The cross-coupling amination reaction employs palladium-bisimidazol-2-ylidene complexes as catalysts to give good to moderate yields over a wide variety of substrates.

Amination↗
PubMed1993

Stereo (C7)-dependent topoisomerase II inhibition and tumor growth suppression by a new quinolone, BO-2367.

A new antimicrobial quinolone (-)BO-2367, (-)-7-[(1R*, 2R*, 6R*)-2-amino-8-azabicyclo[4.3.0.]-non-3-en-8-yl]-1- cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, strongly inhibited both mammalian and bacterial topoisomerase II. The IC50 values of (-)BO-2367 against the DNA relaxation activity of L1210 topoisomerase II and the supercoiling activities of Escherichia coli gyrase and Micrococcus luteus gyrase were 3.8, 0.5, and 1 microM, respectively. This compound enhanced double-stranded DNA cleavage mediated by topoisomerase II not only with purified enzyme, but also with intact L1210 cells. All these activities of (-)BO-2367 were more than 2-fold stronger than those of VP-16. Intriguingly, (+)BO-2367, which has an enantiomeric substituent at the C7 position of (-)BO-2367, did not affect the activity of the mammalian topoisomerase II, while it inhibited E. coli gyrase. Intraperitoneal injection of (-)BO-2367 at 0.08 mg/kg increased the lifespan of CDF1 female mice bearing ascitic L1210 leukemia by 2.4 times, and subcutaneous injection at 1.25 mg/kg completely inhibited the growth of colon 26 carcinoma implanted subcutaneously. These results suggest that (-)BO-2367 is a potent antitumor agent which targets topoisomerase II. These enantiomers should be a useful tool for studying drug-topoisomerase II interactions.

Animals↗
PubMed1991

Synthesis of 3-carbamoylecgonine methyl ester analogues as inhibitors of cocaine binding and dopamine uptake.

Five (1R-2-exo-3-exo)-3-(N-phenylcarbamoyl)ecgonine methyl ester analogues were synthesized and characterized by 1H and 13C NMR, IR, and thermospray MS. The compounds were synthesized in two or three steps as (-)-stereoisomers from (-)-ecgonine in good yield (56% overall). These cocaine derivatives were assessed for their ability to inhibit [3H]cocaine binding to rat striatal tissue and to inhibit [3H]dopamine uptake into synaptosomes prepared from the same tissue. The most potent of the analogues was (1R-2-exo-3-exo)-2-(carbomethoxy)-8-methyl-8-azabicyclo[3.2.1]octyl 3-N-(3'-nitrophenyl)carbamate. IC50 values for inhibition of cocaine binding and dopamine uptake were 37 and 178 nM, respectively. Amino derivatives were less active than the nitro and (1R-2-exo-3-exo)-2-(carbomethoxy)-8-methyl-8-azabicyclo [3.2.1]octyl 3-N-(4'-aminophenyl)carbamate had the lowest affinity for the receptor with IC50 values of 63 and greater than 100 microM in the aforementioned assays, respectively.

Animals↗
PubMed1998

Synthesis and structure-activity relationship of 3-Substituted benzamide, benzo [b]furan-7-carboxamide, 2,3-dihydrobenzo[b]furan-77-carboxamide, and indole-5-carboxamide derivatives as selective serotonin 5-HT4 receptor agonists.

The title compounds (6-9) were prepared and evaluated for serotonin 5-HT4 agonistic activity in in vitro tests. Introducing a propyl or allyl group at the 3-position of benzamide caused only a slight enhancement of agonistic activity. Construction of the benzo[b]furan skeleton and 2,3-dihydrobenzo[b]furan skeleton caused a significant enhancement of the activity. 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2-methylbenzo[b]furan-7-carboxamide (7b) hemifumarate was as potent as cisapride. 4-Amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2,3-dihydro-2-methylbenzo[b]furan-7-carboxamide (8a) hemifumarate, 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2,3-dihydro-2-ethylbenzo[b]furan-7-carboxamide (8c) hemifumarate, and 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2,3-dimethylbenzo[b]furan-7-carboxamide (8d) hemifumarate were more potent than cisapride. Furthermore, 8a hemifumarate was free from dopamine D1, D2, serotonin 5-HT1, 5-HT2 and muscarine M1, M2 receptor binding activity in the in in vitro tests. On the other hand, construction of the indole skeleton caused a remarkable decrease in activity.

Animals↗
PubMed1984

Tolerance and pharmacodynamics of the angiotensin converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) in healthy volunteers.

In healthy volunteers a single oral dose of 5 mg 2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) was well tolerated. Following 5 mg Hoe 498 plasma angiotensin converting enzyme (ACE) activity was inhibited by almost 100% up to 8 h. A marked effect on plasma ACE was observed for more than 8 days. Plasma renin activity increased whereas aldosterone plasma levels decreased only slightly. Sodium and potassium excretion was not influenced by the compound. Systolic and diastolic blood pressure was slightly lowered by Hoe 498, whereas no relevant changes in pulse rate were observed.

Adult↗