15196-02-8

A simple and efficient method to obtain α-xanthylmethyl ketones from α-diazo ketones is described. The reaction proceeds through a protonation/nucleophilic substitution sequence in the presence of p -toluenesulfonic acid and potassium ethyl xanthogenate as the nucleophile. As α-diazo ketones can be readily synthesized from ubiquitous carboxylic acids, a broad variety of xanthates can be obtained, including examples from naturally occurring substrates.

A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methyl-piperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.

The present invention relates to a compound of formula I wherein R1 is hydrogen, methoxy or fluoro; R2/R2' are independently from each other hydrogen, methoxy or fluoro; R3/R4 are independently from each other hydrogen or halogen; R is hydrogen or fluoro; L1 is -CH2-, -NR'-, -0-, -S-, CF2- or CH=; R' is hydrogen or lower alkyl; L2 is a bond, -C(0)NH-, -NH-, -CH2NHC(O)-, -NHC(O)- or -NHC(0)NH-; R is hydrogen, halogen, lower alkoxy, cyano or is phenyl optionally substituted by one or more substituents, selected from halogen, lower alkyl substituted by halogen or lower alkoxy, or is a five or six membered heteroaryl, selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or pyrazolyl, which heteroaryls are optionally substituted by one or more substituents, selected from halogen, lower alkyl, lower alkoxy, cyano, cycloalkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or by phenyl substituted by halogen; N is a ring nitrogen atom in position 1 or 2; or to a pharmaceutically suitable acid addition salt thereof. The compounds of formulas I have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1 and may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Enantiopure N-benzyloxycarbonyl-protected and free 3-substituted homotaurines were synthesized from naturally occurring amino acids via N-benzyloxycarbonyl protection, Arndt-Eistert homologation, reduction, esterification with thioacetic acid, and oxidation with performic acid. The current method is a convenient, practical, and salt-free method for the synthesis of enantiopure 3-substituted homotaurine with moderate to good yields.

The development of a continuous flow process for the multistep synthesis of α-halo ketones starting from N-protected amino acids is described. The obtained α-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor. The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber. The α-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide. This method eliminates the need to store, transport, or handle diazomethane and produces α-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of α-chloro ketone from the respective N-protected amino acid within ～4.5 h (87% yield).

Enantiopure N-benzyloxycarbonyl-protected and free 3-substituted homotaurines were synthesized from naturally occurring amino acids via N-benzyloxycarbonyl protection, Arndt-Eistert homologation, reduction, esterification with thioacetic acid, and oxidation with performic acid. The current method is a convenient, practical, and salt-free method for the synthesis of enantiopure 3-substituted homotaurine with moderate to good yields.

A fully continuous four step process for the preparation of β-amino acids from their corresponding α-amino acids utilizing the Arndt-Eistert homologation approach is described. the Partner Organisations 2014.

A simple and efficient protocol for the synthesis of selenazole containing dipeptidomimetics using Nα-amino selenocarboxamides and α-bromomethyl ketones is described. All the compounds made were isolated in good yields and fully characterized.

Eighteen new hydrazino-1,3-thiazole derivatives were evaluated against 8 strains of multi-resistant Candida spp. Introduction of an indolyl moiety linked to the hydrazone function enhanced the in vitro anti-Candida activity, with an activity spectrum towards Candida albicans strains. Introduction of a (S)-2-aminoethyl chain on the thiazole nucleus largely enhanced the in vitro antifungal activity, with a selectivity oriented towards non-C. albicans species.

The enantiospecific syntheses of pyridinones from amino acids via a gold-catalyzed strategy are reported. Excellent stereocontrol was observed during the cyclization. This approach provides a straightforward tool for further synthetic applications toward

A simple and efficient one-pot synthesis of Fmoc/Boc/Z-amino acid derived 2-amino-1,3-selenazoles by the condensation of Nα-urethane protected amino acid derived bromomethyl ketones with selenourea under the influence of ultrasound has been described. Insertion of 2-amino-1,3-selenazole moiety in the side chains of Asp and Glu has also been achieved following the similar protocol. ARKAT USA, Inc.

A series of novel HIV-1 protease inhibitors based on the (hydroxyethylamino)-sulfonamide isostere incorporating substituted phenyls and benzheterocycle derivatives bearing rich hydrogen bonding acceptors as P 2 ligands were synthesized. Prolonged chain linking the benzhereocycle to the carbonyl group resulted in partial loss of binding affinities. Introduction of a small alkyl substituent with appropriate size to the -CH2- of P1-P2 linkage as a side chain resulted in improved inhibitory potency, and in this study, isopropyl was the best side chain. Replacement of the isobutyl substituent at P 1′group with phenyl substituent decreased the inhibitory potency. One of the most potent inhibitor, compound 23 showing high affinity to HIV-1 protease with an IC50 value of 5 nm, also exhibited good anti-SIV activity (EC50 = 0.8 μm) with low toxicity (TC 50 > 100 μm). The flexible docking of inhibitor 23 to HIV-1 protease active site rationalized the interactions with protease.

Five optically active imidazole derivatives have been synthesized via a facile 4-step reaction sequence starting from commercially available and inexpensive N-Cbz amino acids. While microwave assisted condensation was unsuccessful, the condensation of the

N-Methyl β-amino acids are generally required for application in the synthesis of potentially bioactive modified peptides and other oligomers. Previous work highlighted the reductive cleavage of 1,3-oxazolidin-5-ones to synthesise N-methyl α-amino acids. Starting from α-amino acids, two approaches were used to prepare the corresponding N-methyl β-amino acids. First, α-amino acids were converted to N-methyl α-amino acids by the so-called '1,3-oxazolidin-5-one strategy', and these were then homologated by the Arndt-Eistert procedure to afford N-protected N-methyl β-amino acids derived from the 20 common α-amino acids. These compounds were prepared in yields of 23-57% (relative to N-methyl α-amino acid). In a second approach, twelve N-protected α-amino acids could be directly homologated by the Arndt-Eistert procedure, and the resulting β-amino acids were converted to the 1,3-oxazinan-6-ones in 30-45% yield. Finally, reductive cleavage afforded the desired N-methyl β-amino acids in 41-63% yield. One sterically congested β-amino acid, 3-methyl-3-aminobutanoic acid, did give a high yield (95%) of the 1,3-oxazinan-6-one (65), and subsequent reductive cleavage gave the corresponding AIBN-derived N-methyl β-amino acid 61 in 71% yield (Scheme 2). Thus, our protocols allow the ready preparation of all N-methyl β-amino acids derived from the 20 proteinogenic α-amino acids.

A route to the preparation of enantiopure ligands based on a 2-phenylimidazol ring is described. The stereogenic centre is placed into the chain bonded to the fourth carbon of the imidazole ring. The synthesis starts from inexpensive and readily available

An efficient and stereospecific homologation of urethane-protected α-amino acids to β-amino acids by Arndt-Eistert approach using an equimolar mixture of Fmoc-/Boc-/Z-α-amino acid and 9-fluorenylmethyl chloroformate for the acylation of diazomethane synth

A simple and efficient protocol for Arndt-Eistert chain homologation of Fmoc-/Boc-/Z-α-amino acids using BOP or PyBOP as a coupling agent to the corresponding β-amino acids, synthesizing the key intermediate α-diazoketones as crystalline solids in good yield is described.

A new and efficient method for the homologation of urethane protected α-amino acids to its β-homomers by the Arndt-Eistert method using TBTU as a coupling agent is described. Several Fmoc-/Boc-/Z-protected α-amino diazoketone derivatives have been obtaine

The use of Boc2O as a coupling agent in the homologation of N-urethane protected-α-amino acid to its β-homomers by the Arndt-Eistert method is described. The homologation gives good yields without racemization. The use of Boc2O as a

A simple method for the synthesis of Z-/Boc-/Fmoc-protected β-amino acids by the Arndt-Eistert approach employing p-toluenesulphonyl chloride for the activation of the carboxyl group of Nα-protected amino acid is described. The method is rapid and gave good yields with opitical purity.

The Wolff rearrangement of α-aminodiazoketones derived from Nα-urethane protected α-amino acids in presence of o-nitrophenol catalyzed by silver acetate at low temperature is described. The potential utility of the well-known ketene intermediat

(Equation presented) Methodology has been developed for the general synthesis of optically active β-amino acid N-carboxyanhydrides (β-NCAs) through cyclization of Nβ-Boc or Nβ-Cbz β-amino acids using phosphorus tribromide. The format

N-Z-γ-amino alcohols derived from nonracemic β-amino acids are smoothly oxidised by manganese dioxide in acetonitrile to afford aldehydes which can be trapped in situ in Wittig reactions with carbonyl-substituted phosphoranes. The application of this methodology to the synthesis of the alkaloids (S)-(+)-N-BOC-coniine, (S)-(-)-coniceine and a pipecoline precursor is described.

The development of novel monobactam inhibitors of HCMV protease incorporating a carbon side chain at C-4 and a urea function at N-1 is described. Substitution with small groups at the C-3 position of the β- lactam ring gave an increase in enzymatic activity and in stability; however, a lack of selectivity against other serine proteases was noted. The use of both triand tetrasubstituted urea functionalities gave effective inhibitors of HCMV protease. Benzyl substitution of the urea moiety was beneficial, especially when strong electron-withdrawing groups where attached at the para position. Modest antiviral activity was found in a plaque reduction assay.

We report here the synthesis and activity of HIV protease inhibitors. In the first stage hydrophobic compounds incorporating a 'carba' bond surrogate or a beta-homologated residue were synthesized. Secondly, we synthesized cyclic compounds in which we incorporated 2-quinoline carboxylic acid in the P3 position and the amino-hydroxyindane moiety in the P'3. The last part of this work was dedicated to a structure/activity study of a peptide substrate. These modifications allowed us to work up the synthesis of new pseudopeptide bonds: amino-amide and hydroxy-amide. Compounds with activity in the micromolar range were actually a starting point for the synthesis of new protease inhibitors.

The Arndt-Eistert homologation of α-amino acids was studied to determine the stereoselectivity in this reaction by chromatographic up-to-date analytical methods.While carbamate-protected phenylglycine was transformed to the corresponding β-amino acid methyl ester with a stereoselectivity of only 9:1, all other tested amino acid derivatives (Ala, Phe, Ser, Orn, tert-Leu and perhydro-azepine-2-carboxylic acid, suitably protected) were homologated with full retention of configuration (products 9-17).The intermediate diazo ketones 1-8 were purified and characterized by their NMR spectra.When nucleophiles derived from partially protected sugars were present during decomposition of the diazo ketones (derived from amino acids or dipeptides), a strong dependence of the yield (products 21-24) on the degree of steric hindrance of the nucleophilic OH group was observed.Two of the β-amino acids obtained from the homologation reaction were transformed to α-substituted (25-27, 31, 32) and α,α-disubstituted β-amino acid derivatives (28, 29) with excellent selctivities (in most cases, a single diastereoisomer was obtained). - Key Words: β-Amino acids, α-branched/Glycopeptides

The synthesis of erythro-isomers of N-α-t-Boc, N-α-Fmoc- and N-α-Cbz-L-phenylalanylepoxides from the appropriate N-α-protected L-phenylalanines via bromomethyl-ketone intermediates is described.

N-protected α-amino epoxides of erythro configuration, derived from α-amino acids, were synthesized in a stereoselective manner. The erythro (2S,3S), configuration was achieved by the synthetic sequence: amino acid -> haloketone -> halohydrin -> epoxide. A mechanistic explanation for the observed stereoselectivity is presented. This stereoselective synthetic approach was applied to the synthesis of a variety of short peptidyl epoxides, bearing a predefined absolute configuration of the chiral epoxide moiety.

A series of HIV protease inhibitors containing a novel C2 symmetrical "aminodiol" core structure were prepared from amino acid starting materials.The ability of the aminodiols to inhibit HIV replication in cell culture is comparable to their ability to inhibit the isolated enzyme, a result compatible with good cell membrane penetration by this class of compounds.Optimization of the structure-activity in this series led to aminodiol 9a (Ki = 100 nM; ED50(HIV-1) = 80 nM) containing P1/P1' benzyl and P2/P2' Boc substituents.Compound 9a is a selective inhibito r of HIV protease versus other aspartyl proteases such as human renin, human cathepsin D, and porcine pepsin.In addition, 9a is equipotent against HIV-1 and HIV-2 in cell culture and demonstrates similar activity in infected T-lymphocytes and PBMCs.After iv and oral administration in rats, 9a displayed significant oral bioavailability (ca. 40percent) and a promising plasma elimination half-life (4 h).

Renin inhibitors having 13 different isosteres connecting the P3 and P2 positions have been prepared. Synthetic routes and in vitro activity exhibited by these compounds are discussed. The two most potent compounds, 47 and 48, contai

A series of analogues of Boc-Trp-Leu-Asp-Phe-NH2, a potent gastrin agonist, were synthesized by introducing a β-homo residue in the sequence. These compounds were tested in vivo on acid secretion, in the anesthetized rat, and for their ability

Optimum conditions of synthesis of eight diazoketones derived from optically active N-(t-butyloxycarbonyl)- and N-benzyloxycarbonylamino acids have been described.The problem of formation of by-products during Arndt-Eistert synthesis of β-homoamino acids at the stage of reaction of mixed anhydride with a weak nucleophile-diazomethane - has been discussed.

Amino thiol substituted dipeptides of the formula STR1 are disclosed. These compounds are useful as hypotensive agents due to their angiotensin converting enzyme inhibition activity and depending upon the definition of X may also be useful as analgesics due to their enkephalinase inhibition activity.

Affinity-labeling reagents are useful for the inactivation of proteases in vivo but are apparently limited in application by the possibility of side reactions. In addition, increased specificity would be desirable. Substrate-derived chloromethyl ketones, one class of protease inhibitors, have been examined with the hope that replacement of the departing group halogen by other substituents might lead to improved inhibitor characteristics. Analogues of Z-Phe-Ch2X were synthesized in which X is a sulfonate or carboxylate substituent and examined as inactivators of chymotrypsin. The sulfonate esters were found to be more reactive than the previously studied halogen derivatives.