CO2 laser vaporization for the treatment of vaginal intraepithelial neoplasia: effectiveness and predictive factors for recurrence.

OBJECTIVE: To evaluate the outcome of vaginal intraepithelial neoplasia (VaIN) treatment with CO2 laser vaporization in terms of local recurrence and progression to vaginal carcinoma. Additionally, the authors investigated the predictive factors for first recurrence. MATERIALS AND METHODS: The medical records of all patients treated for VaIN with CO2 laser vaporization at Sant'Anna Hospital in Turin (1995-2012), were retrospectively reviewed. A univariate logistic model was applied to evaluate selected clinical features as predictive factors for recurrence. A multivariate logistic regression analysis was then carried out including significant risk factors after univariate analysis (p < 0.05). RESULTS: The analysis included 285 out of 302 patients. Seventy-one (25%) women relapsed; of these 24 VaIN 1 (22%), 37 VaIN 2 (27%), and ten VaIN 3 (26%). The median time to the first recurrence was 5.2 months (1.4-127.8) for VaIN 1, 6.6 months (1-85.2) for VaIN 2, and 3.6 months (1.2-62) for VaIN 3. Sixty-one out of 71 patients were retreated with CO2 laser vaporization. At the last follow-up visit, 273 (96%) women were free from VaIN. No patients progressed to vaginal carcinoma. The multivariate model showed a higher risk of VaIN recurrence in the case of previous hysterectomy (HR 3.3, 95% CI 1.7-6.3, p < 0.001) and concomitant H-SIL on the Pap smear (HR 1.9, 95% CI 1.2-3.1, p = 0.008). CONCLUSION: CO2 laser vaporization is an effective low impact treatment for VaIN. Despite this, VaIN recur, in particular in cases of previous hysterectomy and concomitant H-SIL on the Pap smear. An intensive follow-up is proposed for women with a high risk of VaIN relapse.

Practical synthesis of a neuropeptide Y antagonist via stereoselective addition to a ketene.

[Reaction: see text]. The synthesis of neuropeptide Y antagonist 1, currently under clinical investigation for the treatment of obesity, is described. The convergent synthesis from trans-spirolactone carboxylic acid intermediate 2a and aminopyrazole 3 is predicated on a stereoselective route to the former. The coupling reaction of ethyl 4-oxocyclohexanecarboxylate (10a) with lithiated isonicotinamide 11 was investigated in detail, but even optimized conditions only provided a 45:55 ratio of trans:cis isomers (12a:12b). While selective crystallization schemes were developed to isolate the thermodynamically less stable trans isomer 2a, improved stereocontrol was subsequentially achieved by the application of ketene chemistry. The ketene formation and quench was investigated under a variety of conditions aimed at maximizing the trans:cis ratio. Reacting a mixture of carboxylic acids 2a and 2b with POCl3 in THF, followed by concomitant addition of tert-butyl alcohol in the presence of TMEDA at 35 degrees C provided a 4:1 ratio of trans:cis tert-butyl esters (18a:18b) via in situ ketene formation. Ester hydrolysis, followed by selective crystallization of undesired 2b as the HCl salt, led to isolation of 2a in 47% overall yield. Aminopyrazole intermediate 3 was synthesized via the condensation reaction of 2-fluorophenylhydrazine hydrochloride (4a) with acrylonitrile derivative 5 in 65-70% yield. Coupling of advanced intermediates 2a and 3b via activation with thionyl chloride gave a 92% yield of 1.

Palladium-catalyzed regioselective arylation of imidazo[1,2-b][1,2,4]triazine: synthesis of an alpha 2/3-selective GABA agonist.

A convergent, practical, and efficient synthesis of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (1), an orally active GABA(A) alpha(2/3)-selective agonist, is described. The seven-step, chromatography-free synthesis was demonstrated on a multi-kilogram scale and utilized biaryl bromide 6 and imidazotriazine 22 as key intermediates. Biaryl bromide 6 was prepared via a highly selective aromatic bromination. The regioselective condensation of aminotriazine 15 with chloroacetaldehyde provided the desired imidazotriazine intermediate 22. A highly regioselective palladium-catalyzed arylation in the final step highlights the efficiency of the route.

Impact of the introduction of organised screening for cervical cancer in Turin, Italy: cancer incidence by screening history 1992-98.

After an organised cervical screening programme was introduced in Turin in 1992, the age-adjusted cervical cancer incidence ratio in 1992-98 was 0.81 (95% confidence interval (CI) 0.59-1.09) for invited vs not invited women and 0.25 (95% CI 0.13-0.50) for attenders vs non attenders. An organised screening programme can further reduce cervical cancer incidence in an area where substantial spontaneous activity was previously present.

An efficient chemoenzymatic approach to (S)-gamma-fluoroleucine ethyl ester.

[reaction: see text] An asymmetric synthesis of (S)-gamma-fluoroleucine ethyl ester 1 is described. The key transformation involves a lipase-catalyzed dynamic ring-opening of 2-(3-butenyl)azlactone 7b with EtOH to give amide ester (S)-6b in 84% enantiomeric excess. Removal of the N-pentenoyl group with N,N'-dibromodimethylhydantoin in the presence of trifluoroacetic acid afforded the titled compound, which was isolated as its hydrogen sulfate salt in 75% yield and >97% ee.

Methods for the synthesis of 5,6,7,8-tetrahydro-1,8-naphthyridine fragments for alphaVbeta3 integrin antagonists.

The preparation of 3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propan-1-amine 2a and 3-[(7R)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl]propan-1-amine 2b, key intermediates in the synthesis of alpha(V)beta(3) antagonists, is described. The syntheses rely on the efficient double Sonogashira reactions of 2,5-dibromopyridine 3 with acetylenic alcohols 4a/4b and protected propargylamines 10a-e followed by Chichibabin cyclizations of 3,3'-pyridine-2,5-diyldipropan-1-amines 9a/9b.

Enantioselective preparation of ring-fused 1-fluorocyclopropane-1-carboxylate derivatives: en route to mGluR 2 receptor agonist MGS0028.

[reaction: see text] An approach to the densely functionalized fluorocyclopropane 14, a key framework toward the synthesis of mGluR 2 receptor agonist MGS0028 (1) is reported. The Trost AAA reaction enantioselectively introduced the key allylic stereogenic center and the alpha-fluoroester moiety. Stereoselective epoxidation followed by intramolecular epoxide ring opening efficiently constructed the 1-fluorocyclopropane-1-carboxylate matrix. This route can potentially be a general methodology for a concise, highly enantio- and stereoselective synthesis of 1-fluorocyclopropane-1-carboxylate derivatives.

Practical synthesis of a potent hepatitis C virus RNA replication inhibitor.

A practical, efficient synthesis of 1, a hepatitis C virus RNA replication inhibitor, is described. Starting with the inexpensive diacetone glucose, the 12-step synthesis features a novel stereoselective rearrangement to prepare the key crystalline furanose diol intermediate. This is followed by a highly selective glycosidation to couple the C-2 branched furanose epoxide with deazapurine.

An efficient asymmetric synthesis of an estrogen receptor modulator by sulfoxide-directed borane reduction.

An efficient asymmetric synthesis of a selective estrogen receptor modulator (SERM) that has a dihydrobenzoxathiin core structure bearing two stereogenic centers is reported. The stereogenic centers were established by an unprecedented chiral sulfoxide-directed stereospecific reduction of an alpha,beta-unsaturated sulfoxide to the saturated sulfide in one step. Studies to elucidate the mechanism for this reduction are reported. Highly efficient Cu(I)-mediated ether formation was used to install the ether side chain, and selective debenzylation conditions were developed to remove the benzyl protecting groups on the phenols.

Facile synthesis of 2-bromo-3-fluorobenzonitrile: an application and study of the halodeboronation of aryl boronic acids.

A scaleable synthesis of 2-bromo-3-fluorobenzonitrile via the NaOMe-catalyzed bromodeboronation of 2-cyano-6-fluorophenylboronic acid was developed. The generality of this transformation was demonstrated through the halodeboronation of a series of aryl boronic acids. Both aryl bromides and aryl chlorides were formed in good to excellent yields when the corresponding aryl boronic acid was treated with 1,3-dihalo-5,5-dimethylhydantoin and 5 mol % NaOMe.

A regioselective approach to 5-substituted-3-amino-1,2,4-triazines.

Nucleophilic displacement of readily available alpha,alpha-dibromoketones with excess morpholine gave the corresponding ketoaminals, which upon condensation with aminoguanidine in MeOH in the presence of AcOH afforded 5-substituted-3-amino-1,2,4-triazines in >95% regioselectivity and 45-76% isolated yield. [reaction: see text]

Highly regioselective Friedländer annulations with unmodified ketones employing novel amine catalysts: syntheses of 2-substituted quinolines, 1,8-naphthyridines, and related heterocycles.

Catalysts were evaluated on the preparation of 2-substituted quinolines, 1,8-naphthyridines, and chromone derivatives from unmodified methyl ketones and o-aminoaromatic aldehydes. While oxide catalysts yielded the 2,3-dialkyl substituted products, cyclic secondary amines provided the 2-alkylsubstutited products regioselectively. In particular, pyrrolidine derivatives provided the highest regioselectivity favoring the 2-substituted products. The most reactive and regioselective catalyst was the bicyclic pyrrolidine derivative, TABO (1,3,3-trimethyl-6-azabicyclo[3.2.1]octane), yielding 1,8-naphthyridines with as high as 96:4 regioselectivity. Regioselectivity increased with slow addition of the methyl ketone substrate to the reaction mixture, and was positively related to temperature. Isolated yields of single regioisomers were typically 65-84%, while observed regioselectivities were > or =90:10 for 1,8-naphthyridines and > or =84:16 for quinolines.

Ullmann diaryl ether synthesis: rate acceleration by 2,2,6,6-tetramethylheptane-3,5-dione.

[reaction: see text]. In the copper salt catalyzed ether formation from aryl bromides or iodides and phenols, 2,2,6,6-tetramethylheptane-3,5-dione (TMHD) was found to greatly accelerate the ordinarily difficult reaction, making it occur under more moderate temperatures and reaction times. A series of aryl halides and phenols were shown to form ethers in NMP as the solvent, cesium carbonate as the base, and CuCl and TMHD as the catalysts. The reaction was shown to tolerate electron-rich aryl bromides and electron-neutral phenols.

Crystallization-induced diastereoselection: asymmetric synthesis of substance P inhibitors.

A novel three-component condensation followed by a crystallization-induced asymmetric transformation is used to build this key substance P inhibitor intermediate in a short synthetic sequence.

Synthesis of 5-pyridyl-2-furaldehydes via palladium-catalyzed cross-coupling with triorganozincates.

5-Pyridyl- and 5-aryl-2-furaldehydes are prepared from furaldehyde diethyl acetal in a four-step, one-pot procedure:(i) deprotonation; (2) Li to Zn transmetalation; (3) Pd-mediated cross-coupling; (4) aldehyde deprotection. Triorganozincate 7 was found to transfer all three groups in the Pd-catalyzed cross-coupling reaction with haloaromatics.

Synthesis of a muscarinic receptor antagonist via a diastereoselective Michael reaction, selective deoxyfluorination and aromatic metal-halogen exchange reaction.

An efficient synthesis of a structurally unique, novel M(3) antagonist 1 is described. Compound 1 is conveniently disconnected retrosynthetically at the amide bond to reveal the acid portion 2 and the amine fragment 3. The synthesis of key intermediate 2 is highlighted by a ZnCl(2)-MAEP complex 19 catalyzed diastereoselective Michael reaction of dioxolane 7 with 2-cyclopenten-1-one (5) to establish the contiguous quaternary-tertiary chiral centers and a subsequent geminal difluorination of ketone 17 using Deoxofluor in the presence of catalytic BF(3).OEt(2). The synthesis of the amine moiety 3 is highlighted by the discovery of a novel n-Bu(3)MgLi magnesium-halogen exchange reaction for selective functionalization of 2,6-dibromopyridine. This new and practical metalation protocol obviated cryogenic conditions and upon quenching with DMF gave 6-bromo-2-formylpyridine (26) in excellent yield. Further transformations afforded the amine fragment 3 via reductive amination with 35, Pd-catalyzed aromatic amination, and deprotection. Finally, the highly convergent synthesis of 1 was accomplished by coupling of the two fragments. This synthesis has been used to prepare multi-kilogram quantities of the bulk drug.

Practical asymmetric synthesis of a selective endothelin A receptor (ETA) antagonist.

[structure: see text]. A practical, chromotography-free asymmetric synthesis was developed for the large scale preparation of an endothelin receptor antagonist 2. This synthesis includes a new efficient process for the preparation of 6-bromo-2,3-dihydrobenzofuran, a stereoselective conjugate addition of an aryllithium followed by stereospecific addition of the Grignard reagent of the top aryl bromide, and an aminophosphate-mediated sterospecific intramolecular enolate alkylation, which led to the formation of the five-membered ring bearing three contiguous asymmetric centers.

Interaction of spontaneous and organised screening for cervical cancer in Turin, Italy.

In a screening programme for cervical cancer, coverage of the target population is a major determinant of effectiveness and cost-effectiveness and is one of the parameters for programme monitoring recommended by the "European Guidelines for Quality Assurance". An organised screening programme was started in Turin, Italy, in 1992. Spontaneous screening was already largely present, but coverage (proportion of women who had at least a test within 3 years) was low (< 50%) and distribution of smears uneven. No comprehensive registration of spontaneous smears was available. All women were invited for the first round, independently of their previous test history. Coverage was estimated by integrating routine data from the organised programme with data on spontaneous screening obtained by interviews of a random sample of 268 non-compliers to invitation and 167 compliers. Overall (spontaneous + organised) coverage was estimated to be 74% (95% CI, 71-78%). The proportion of the target population covered as an effect of invitation was estimated to be 17% (95% CI, 15-20%). Invitations were successful in increasing coverage in previously poorly screened groups. Although 20-25% of compliers was estimated to have had further tests before the end of the round, we estimated that switching to a 3-year interval saved approximately 0.26 tests per complier. This suggests that invitations to an organised programme even to previously covered women, can be a cost-effective policy. Our method of estimating overall coverage can be useful in many other European areas where a comprehensive registration of smears is not available.