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A simple one-pot, two-step process for the conversion of 2-acylbenzoic acids to phthalazin-1(2H)-ones was developed. A robust process was required that delivered the final isolated solid with consistently low levels of residual hydrazine, for further processing to the final drug substance. An in situ formed intermediate was critical to control reactivity and allowed for the controlled crystallization that prevented entrainment of hydrazine. Leveraging Process Analytical Technology (PAT), we investigated the reaction profile with in situ IR and Power Compensation Calorimetry (PCC) to aid development prior to a successful scale-up.

A simple one-pot, two-step process for the conversion of 2-acylbenzoic acids to phthalazin-1(2H)-ones was developed. A robust process was required that delivered the final isolated solid with consistently low levels of residual hydrazine, for further processing to the final drug substance. An in situ formed intermediate was critical to control reactivity and allowed for the controlled crystallization that prevented entrainment of hydrazine. Leveraging Process Analytical Technology (PAT), we investigated the reaction profile with in situ IR and Power Compensation Calorimetry (PCC) to aid development prior to a successful scale-up.

Compound 1, (7-methoxy-N-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine) is a potent, selective inhibitor of c-Met (mesenchymal-epithelial transition factor), a receptor tyrosine kinase that is often deregulated in cancer. Compound 1 displayed desirable pharmacokinetic properties in multiple preclinical species. Glutathione trapping studies in liver microsomes resulted in the NADPH-dependent formation of a glutathione conjugate. Compound 1 also exhibited very high in vitro NADPH-dependent covalent binding to microsomal proteins. Species differences in covalent binding were observed, with the highest binding in rats, mice, and monkeys (1100-1300 pmol/mg/h), followed by dogs (400 pmol/mg/h) and humans (144 pmol/mg/h). This covalent binding to protein was abolished by coincubation with glutathione. Together, these in vitro data suggest that covalent binding and glutathione conjugation proceed via bioactivation to a chemically reactive intermediate. The cytochrome (CYP) P450 enzymes responsible for this bioactivation were identified as cytochrome P450 3A4, 1A2, and 2D6 in human and cytochrome P450 2A2, 3A1, and 3A2 in rats. The glutathione metabolite was detected in the bile of rats and mice, thus demonstrating bioactivation occurring in vivo. Efforts to elucidate the structure of the glutathione adduct led to the isolation and characterization of the metabolite by NMR and mass spectrometry. The analytical data confirmed conclusively that the glutathione conjugation was on the 4-C position of the isothiazole ring. Such P450-mediated bioactivation of an isothiazole or thiazole group has not been previously reported. We propose a mechanism of bioactivation via sulfur oxidation followed by glutathione attack at the 4-position with subsequent loss of water resulting in the formation of the glutathione conjugate. Efforts to reduce bioactivation without compromising potency and pharmacokinetics were undertaken in order to minimize the potential risk of toxicity. Because of the exemplary pharmacokinetic/pharmacodynamic (PK/PD) properties of the isothiazole group, initial attempts were focused on introducing alternative metabolic soft spots into the molecule. These efforts resulted in the discovery of 7-(2-methoxyethoxy)-N-((6-(3-methyl-5-isothiazolyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine (compound 2), with the major metabolic transformation occurring on the naphthyridine ring alkoxy substituent. However, a glutathione conjugate of compound 2 was produced in vitro and in vivo in a manner similar to that observed for compound 1. Furthermore, the covalent binding was high across species (360, 300, 529, 208, and 98 pmol/mg/h in rats, mice, dogs, monkeys, and humans, respectively), but coincubation with glutathione reduced the extent of covalent binding. The second viable alternative in reducing bioactivation involved replacing the isothiazole ring with bioisosteric heterocycles. Replacement of the isothiazole ring with an isoxazole or a pyrazole reduced the bioactivation while retaining the desirable PK/PD characteristics of compounds 1 and 2.

AMG 458 {1-(2-hydroxy-2-methylpropyl)-N-[5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl]-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide} is a potent, selective inhibitor of c-Met, a receptor tyrosine kinase that is often deregulated in cancer. AMG 458 was observed to bind covalently to liver microsomal proteins from rats and humans in the absence of NADPH. When [(14)C]AMG 458 was incubated with liver microsomes in the presence of glutathione and N-acetyl cysteine, thioether adducts were detected by radiochromatography and LC/MS/MS analysis. These adducts were also formed upon incubation of AMG 458 with glutathione and N-acetyl cysteine in buffers at pH 7.4. In vivo, the thioether adducts were detected in bile and urine of bile duct-cannulated rats dosed with [(14)C]AMG 458. The two adducts were isolated, and their structures were determined by MS/MS and NMR analysis. The identified structures resulted from a thiol displacement reaction to yield a quinoline thioether structure and the corresponding hydroxyaryl moiety. The insights gained from elucidating the mechanism of adduct formation led to the design of AMG 458 analogues that exhibited eliminated or reduced glutathione adduct formation in vitro and in vivo.

A stereoselective synthesis of the hydroxyethylene dipeptide isostere 1 is described. The route employs a substrate-directed kinetic protonation of an alpha/gamma-substituted lactone to afford the desired stereochemistry. A method for converting the diastereomerically enriched intermediate lactone to the ring-open form with retention of stereochemistry is demonstrated. A novel procedure for utilizing N,N-dibromo-5,5-dimethylhydantoin in Hofmann rearrangements is disclosed. This route was used to prepare amino alcohol 1, the core portion of the HIV protease inhibitor A-792611, in 46% yield from phenylalanine-derived epoxide 2.

Oritavancin is a semi-synthetic glycopeptide antibiotic which is structurally related to vancomycin. When oritavancin bisphosphate is dried in vacuo with heat, a new compound forms. This new compound is stable only in the solid state and reverts to oritavancin in solution. Highly enriched samples of this compound were obtained by preparative HPLC and the structure of this compound was elucidated by using one and two-dimensional ( 1 H and 13 C) NMR spectroscopy in conjunction with computer-assisted molecular modeling. It has been determined that oritavancin adopts a conformation similar to that of vancomycin in solution, while the new compound is the unnatural R -AB-biaryl atropisomer of oritavancin. This is the first observation and isolation of an AB-biaryl atropisomer in an intact member of the vancomycin family of glycopeptide antibiotics.

AMG 900 is an orally available small molecule that is highly potent and selective as a pan-aurora kinase inhibitor. AMG 900 is currently undergoing phase 1 clinical evaluation in patients with advanced solid tumors. The metabolism of AMG 900 was investigated in both male and female rats. We conducted studies in bile-duct catheterized (BDC) rats where bile, urine and plasma were analyzed to obtain metabolism profiles for each gender. These studies identified gender differences in the metabolism profiles in bile. Bile contained the majority of the drug related material and contained little unchanged AMG 900 which indicated that metabolism was the prominent process in drug elimination. Although bile contained the same metabolites for both genders, the amount of specific metabolites differed. Male rats metabolized AMG 900 primarily through hydroxylation with subsequent sulfate conjugation on the pyrimidinyl-pyridine side-chain whereas female rats favored a different oxidation site on the thiophene ring's methyl group, which is then metabolized to a carboxylic acid with subsequent conjugation to an acyl glucuronide. CYP phenotyping identified the prominent isoforms as being gender specific or biased in the oxidative metabolism of AMG 900. The metabolism in male rats favored both CYP2C11 and CYP2A2 whereas females favored the CYP2C12. The prominent sulfate conjugate identified in the male rat bile could also be due to male biased metabolism since it has been reported that sulfate conjugation is more prevalent in male rats. All the prominent rat metabolism routes for AMG 900 either have male or female bias. These differences in the rat AMG 900 metabolism profiles in bile can be explained by gender specific P450CYP isoforms.

Two new, air-stable BINAP complexes of ruthenium(II), (RCp)Ru(S-(−)-BINAP)Cl (R=1cr; H, CH3) have been prepared in good yield from the reaction of (RCp)Ru(PPh3)2Cl with S-(−)-BINAP in refluxing toluene. The structure of the methylcyclopentadienyl analog has been determined by X-ray crystallography. Both complexes have been found to be effective homogeneous catalysts for the enantioselective hydrogenation of β-ketoesters.

In the manufacturing process for Biaxin® (clarithromycin), erythromycin-A oxime, an intermediate, is obtained in high yield, when erythromycin-A is treated with hydroxylamine/isopropyl alcohol in the presence of acetic acid. An unusual impurity, the desosamine hydrazinium salt, is generated in this step of the synthetic pathway, and has been isolated and characterized by using one and two-dimensional NMR spectroscopy in conjunction with MS and EDS.

A new reaction of erythronolides, an intramolecular hetero-Diels-Alder, has been discovered. Heated aqueous alcoholic solutions of ABT-773 (1) and its cis isomer (3) convert slowly to cycloadducts 2 and 4, respectively. Optimal reaction conditions, mechanistic studies supported by molecular modeling, and biological activity data are reported. Single-crystal X-ray structures for both adducts 2 and 4 have been obtained.

In the years since the discovery of cisplatin, the search for new platinum-based antitumor agents has grown at a staggering rate. Several thousand platinum complexes have been prepared and screened in laboratories throughout the world in an effort to develop new platinum drugs with improved therapeutic properties. In many respects these efforts have been rewarded, as second generation analogs such as carboplatin are now proving to be successful clinical agents.1 However, the majority of the new compounds2 that have been identified from these studies are close relatives of cisplatin from a structural point of view and, by virtue of this fact, these agents are similar in terms of their mechanism of action.3 Consequently, clinical expectations for new platinum antitumor agents remain somewhat tempered by the narrow class of compounds that have been identified from drug discovery efforts. While basic improvements in pharmacology and toxicology have been made by altering the reactivity and lipophilicity of the cisplatin analogs, little progress has been made in altering the spectrum of activity displayed by these complexes. One approach to solving this problem is to look beyond the structural relatives of cisplatin by identifying novel materials that can be utilized as building blocks for new classes of platinum antitumor agents.

Cristallisation dans le groupe P2 1 /c avec a=12,169, b=10,860 et c=17,282 A, β=103,11°, Z=4. Affinement jusqu'a R=0,033. Formation d'un dimere de dimeres a l'etat solide comme son analogue cis-diammine platine(II). Augmentation des distances Pt-Pt dans le complexe etudie par rapport a son analogue due a des repulsions steriques entre les coordinats adjacents dans le plan

Les deux complexes de platine(II) presentent une coordination plan carree autour des atomes Pt tandis que le complexe de platine(IV) presente une coordination octaedrique autour de l'atome Pt. Orientation des coordinats hydroxy-2 pyridine dans le premier compose du titre, selon une conformation antirotationnelle

Preparation et etude RMN de 195 Pt et 13 C des complexes cis-[Pt(RNH 2 ) 2 (ascorbato-C 2 )(L)] +/0 (L=coordinat anionique ou neutre: Cl − , ascorbate, DMSO)

Explication d'apres les resultats de spectroscopie optique polarisee sur monocristal et par analyse par la methode d'onde Xα de la couleur bleue et des interactions Pt-Pt pour le bleu de cis-diamminoplatine α-pyridone; cis [Pt(NH 3 ) 2 (C 5 H 4 NO)] 4 (NO 3 ) 5 •H 2 O

trans-[Pt(NH 3 ) 2 (Me 2 SO)Cl](ClO 4 ) 0,8 Cl 0,2 cristallise dans le systeme orthorhombique avec le groupe d'espace Pnma. Affinement de la structure jusqu'a 0,0395. La geometrie du platine est plan carre

Preparation du dimere [(NO 3 )(NH 3 ) 2 Pt(C 5 H 4 NO) 2 Pt(NH 3 ) 2 (H 2 O)] (NO 3 ) 3 •2H 2 O par oxydation chimique du cis-diammineplatine α-pyridone avec l'acide nitrique. L'isomere tete a queue de [(NO 3 )(NH 3 ) 2 Pt (C 5 H 4 NO) 2 Pt(NH 3 ) 2 (NO 3 )](NO 3 ) 2 •1/2H 2 O est prepare par oxydation avec l'acide nitrique du dimere analogue de platine(II) [(NH 3 ) 2 Pt(C 5 N 4 NO) 2 Pt(NH 3 ) 2 ] (NO 3 ) 2 •2H 2 O. Structure cristalline des deux complexes formes. Etude par voltammetrie differentielle et cyclique