Richard Labaudiniere

Novel safety-catch linker and its application with a Ugi/De- BOC/cyclization (UDC) strategy to access carboxylic acids, 1,4- benzodiazepines, diketopiperazines, ketopiperazines and dihydroquinoxalinones

Abstract This communication reveals the synthesis and application of a novel resin bound isonitrile. The resin is an example of a novel safety-catch linker which upon BOC-activation can be resin cleaved with a variety of nucleophiles. Use of this polymer supported isonitrile in the Ugi multi-component reaction (MCR), followed by resin clipping and cyclization allows access to diverse arrays of 1,4-benzodiazepine-2,5-diones, diketopiperazines and ketopiperazines respectively. The methoxide safety-catch clipping strategy and subsequent solution phase cyclization offers similar advantages to a traceless linker.

Novel applications of carbon dioxide/MeOH for the synthesis of hydantoins and cyclic ureas via the Ugi reaction

Abstract This communication reveals novel applications of the CO 2 /MeOH reagent combination coupled with the UDC (Ugi/DeBOC/Cyclize) strategy. The Ugi five component condensation (5CC) affords carbamate protected amino-amides in good yield. When one of the supporting reagents employed in the Ugi reaction possesses a tethered amino-BOC protected functional group, subsequent acid treatment and proton scavenging results in rapid cyclization to cyclic ureas. Additionally, treatment of the 5CC product with base affords hydantoins in good yield, representing a novel and short approach to this class of molecule.

Novel applications of resin bound α-amino acids for the synthesis of benzodiazepines (via Wang resin) and ketopiperazines (via hydroxymethyl resin)

Abstract This communication reveals a novel application of resin bound α-amino acids coupled with the UDC (Ugi/DeBOC/cyclize) strategy. Reaction with either N -BOC-α-amino aldehydes or N -BOC anthranilic acids and subsequent acid treatment allows the preparation of highly pure and diverse arrays (approx. 10 000 in size) of 1,4-benzodiazepines (Wang resin) and ketopiperazines (hydroxymethyl resin), respectively. Notable for the benzodiazepine series of compounds are the five potential points of diversity available from this two-step protocol.

Novel applications of convertible isonitriles for the synthesis of mono and bicyclic γ-lactams via a UDC strategy

This communication reveals a novel application of the so-called convertible isonitriles for the solution/solid phase generation of γ-lactam analogues. Use of tethered N-BOC aldehydes in the Ugi multi-component reaction (MCR), followed by BOC removal and base treatment (a ‘3-step, 1-pot procedure’) affords γ-lactams in good yield. The UDC (Ugi/De-BOC/Cyclize) strategy, coupled with a convertible isonitrile, is now feasible from all three substitution sites of the Ugi product. A conceptually novel approach, combining a bi-functional precursor with a post-condensation modification to give fused lactam-ketopiperazines, is also revealed.

Novel solid-phase synthesis of 1,5-benzothiazepine-4-one derivatives

Abstract A new solid-phase efficient route to 1,5-benzothiazepine-4-one derivatives is reported. The synthesis exploits the variety of halo-nitrobenzene derivatives available and the facile substitution of the benzamide nitrogen. A wide range of derivatives can be obtained in excellent purity.

Orally active indole N-oxide PDE4 inhibitors.

This communication describes the synthesis and in vitro and in vivo evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. Several of the compounds presented possess low nanomolar IC50s for PDE4 inhibition and excellent in vivo activity for inhibition of TNF-alpha levels in LPS challenged mice (mouse endotoxemia model). Emesis studies (dog) and efficacy in a SCW arthritis model for the most potent PDE4 inhibitors are presented.

Synthesis of novel proline and ψ-lactam derivatives as non-peptide mimics of Somatostatin/Sandostatin®

Abstract Original proline or γ-lactam derivatives bearing either an aryl group such as a phenyl or a 3-indolyl in position 3 of the proline moiety or on the 3-methyl chain of the γ-lactam skeleton were prepared as non-peptide mimics of Somatostatin/Sandostatin®.

New indole derivatives as potent and selective serotonin uptake inhibitors

A series of new indole derivatives (2-28) has been prepared in the search for novel 5-HT uptake inhibitors. These compounds were obtained by the condensation of N-(chloroalkyl) naphthalenesultam derivatives with the appropriate amine in presence of a base, at reflux of DMF or THF. The yields were moderate (12-56%), except for the piperazine derivative 20 (85%). The affinity of the compounds for uptake site and 5-HT2, alpha 1, and D2 receptors was measured. Some compounds were studied in vivo by their potentiating effect of 5-HTP-induced symptomatology. The most potent and selective (uptake, 5-HT2 versus alpha 1, D2 sites) compounds contain a 3-[(4-piperidinyl)methyl]indole moiety. 5-Fluoro-3-[(4-piperidinyl)methyl]indole itself (compound 1) displayed a high affinity for the uptake site but was devoided of in vivo activity. N-Methylation of this compound abolished the affinity. In contrast N-substitution by a two-carbon chain linked to a naphthalenesultam or related heterocycle led to compounds exhibiting high affinity for the uptake site. One of them, 1-[2-[4-((5-fluoro-1H-indol-3-yl)methyl-1- piperidinyl]ethyl]-5,6-dihydro-1H,4H-1,2,5-thiadiazolo[4,3,2- ij]quinoline 2,2-dioxide (compound 24), was found as active as fluoxetine in vivo.

Quaternary substituted PDE IV inhibitors II: The synthesis and in vitro evaluation of a novel series of γ-lactams

This communication describes the synthesis and in vitro evaluation of a novel potent series of phosphodiesterase type (IV) (PDE IV) inhibitors. Several of the quaternary substituted lactams presented possess low nanomolar IC50s for PDE IV inhibition.

SYNTHESE VON INHIBITOREN FUR ZWEI FAMILIEN BIOLOGISCHER TARGETS IN EINER SEQUENZ : EIN NACHSTER SCHRITT BEIM AUFBAU KOMBINATORISCHER BIBLIOTHEKEN ?

Uber nureinen Syntheseweg lassen sich Bibliotheken aus niedermolekularen Verbindungen aufbauen, die auf zwei Targetfamilien mit unterschiedlichen Funktionalitaten ausgerichtet sind. Dies wurde anhand der Entdeckung des Strukturtemplats 1 deutlich, das voneinander unabhangige pharmakophore Muster enthalt, uber die Mitglieder aus einer von zwei Targetfamilien, den Matrix-Metalloproteinasen (MMPs) oder den Phosphodiesterasen (PDEs), inhibiert werden konnen. Durch den Einbau von Bausteinen, die gegen mehrere Targets gerichtet sind, in eine Verbindungsbibliothek kann man so moglicherweise das Auffinden pharmazeutischer Leitstrukuren beschleunigen. Z=OR′ (PDE4), H (MMPs).