Herein we report the identification of two new fatty acid amide hydrolase (FAAH) inhibitor lead series with FAAH k inact /K i potency values greater than 1500M −1 s −1 . The two novel spirocyclic cores, 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane, clearl...
The intramolecular 1,3-dipolar cycloaddition of a cyclic nitrone, prepared by an asymmetric electrophilic enolate hydroxyamination using the (2R)-bornane-10,2-sultam chiral auxiliary, proceeds to give bridged and fused cycloadducts with total diastereocontrol. Reduction of the fused isoxazolidin...
The synthesis and biological activity of analogues containing spiro piperidinylpyridine and pyrrolidinylpyridine templates are described. The potent activity of these compounds as platelet aggregation inhibitors demonstrates the utility of the spiro structures as central template for nonpeptide ...
We identified 2,8-diazaspiro[4.5]decane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase (sEH) inhibitors and orally active agents for treating hypertension. Docking studies using human and murine sEH X-ray crystal structures revealed steric hindrance around the s...
Spiro[4.5]decane and spiro[4.4]nonane ring systems were synthesized by FeCl 3 -induced Nazarov cyclization of α-(trimethylsilylmethyl)divinyl ketone derivatives. It was found that the double bond position of the product is controlled by the presence/absence of α'-substituent, while tri...
A Tsuji-Trost variant of the Winstein-Masamune reaction has been investigated for the synthesis of the AC spirocyclic ring system 9 bearing a quaternary carbon found in the fawcettimine type Lycopodium alkaloids magellanine 1 and lycojaponicumin B 2 and cyclopiane diterpenes such as conidiogenon...
Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a highly selective and potent 5-HT 1A R ligand. In the present work we adopted an in-parallel synthetic strategy to rapidly explore a new set of arylpiperazine (7–32) that is structurally r...
Diols 2, easily prepared by a DTBB-catalysed lithiation of the dithioether 1 in the presence of different carbonyl compounds, react with ozone in dichloromethane at −78°C leading, after treatment with thiourea at 20°C, to the corresponding substituted 1,6-dioxaspiro[4.4]nonanes 3.
The asymmetric cyclization of 1-hydroxyoct-7-en-4-one, promoted by camphorselenenyl tetrafluoroborate, generated from camphor diselenide and silver tetrafluoroborate in dichloromethane at room temperature, afforded a mixture of two diastereoisomeric E- and two diastereoisomeric Z-2-[(camphorsele...
To continue our systematic SAR studies, two series of N-benzyl- (X=CH 2 ) and N-aminophenyl- (X=NH) derivatives of 2-azaspiro[4.4]nonane (1a–1j) and 2-azaspiro[4.5]decane-1,3-dione (2a–2j) were synthesized, and evaluated in maximum electroshock seizure (MES), subcutaneous pentylenetetr...
The synthesis, physicochemical and pharmacological properties of new N-phenylamino derivatives of 2-azaspiro[4.4]nonane-1,3-dione (8–10), 2-azaspiro[4.5]decane-1,3-dione (11–18) and 3-cyclohexyl-pyrrolidine-2,5-dione (19, 20) derivatives were described. The anticonvulsant properties of those c...
In continuation of the studies on weak H-bond formation in N-substituted-spiro-succinimides, the crystal structures of three derivatives from the series of N-methyl-arylpiperazine-spiro-succinimides were examined. Previously and newly studied species differ in the lengths of the distance between...
For the first time cycloalumination of methylenecyclobutane with the aid of Et 3 Al in the presence of Cp 2 ZrCl 2 leading to 6-ethyl-6-aluminaspiro[3.4]octane has been realized. The latter, without isolation, was converted into spiro[3.3]heptane, 6-thiaspiro[3.4]octane a...
Among a series of C-alkylated analogs of the weak μ opioid ligand spiro[benzofuran-3(2H),4 -1 -methylpiperidine-7-ol] (1), the 2-methyl, 2-ethyl, and cis 3 -methyl analogs, namely compounds (±)2, (±)-3, and (±)-4, showed much enhanced μ-affinities, with (±)-4 being almost as potent as (...
A new strategy for the synthesis of oxide-containing fragments of morphine has been developed. Thus, the tricyclic (ANO) morphine fragment spiro[7-methoxybenzofuran-3(2H),4 -1 -methylpiperidine] (1) was obtained as the sole product via an intramolecular radical cyclization of 4-[(2 -bromo-6 ...
As a better alternative to radical cyclization, 5-(2-bromo-6-methoxyphenoxy)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (2) and its 1-oxo analog 3 underwent Pd-catalyzed intramolecular cyclization to give the tetracyclic (ACNO) morphine fragments 5 and 6 respectively. 4-[(2 -Iodo-6 -methox...
A series of small molecules derived from MK-0677, a potent synthetic GHS, mimicking the N-terminal Gly-Ser-O-(n-octanoyl)-l-Ser-Phe segment of ghrelin was synthesized and tested in a binding and in a functional assay measuring intracellular calcium elevation in HEK-293 cells expressing hGHSR1a. ...
A simple synthetic route has been developed to prepare 1'-H-spiro(indoline-3,4'-piperidine) (1d). Dialkylation of 2-fluorophenylacetonitrile with N-(tert-butyloxycarbonyl)-bis(2-chloroethyl)amine (5) gave 6. Deprotection of Boc followed by cyclization resulted 1d in 67% overall yield. Selective ...
The reductions of 2-naphthaldehyde, (3), 9,9′-spirobi-(9H-fluorene)-2-carboxaldehyde, (2), and 2-fluorenecarboxaldehyde, (4), have been studied in N,N-dimethylformamide (DMF) and acetonitrile. Putative spiroconjugation was the source of interest in 2 and its formal potential for the neutral/rad...
A new spiro[fluorene-9,9′-xanthene]-based host material SFX-PF without possessing conventional hole- and electron-transporting units has been developed, via very simple two-step synthesis, for efficient and low voltage blue phosphorescent organic light-emitting device (PHOLED). The blue device ...