Pharmacokinetics and bioequivalence of tofacitinib 5 mg in healthy Korean male subjects.

OBJECTIVE: Tofacitinib is an oral Janus kinase (JAK) inhibitor marketed as an immunomodulator that can effectively treat rheumatoid arthritis. This study aimed to compare the pharmacokinetics and evaluate the bioequivalence of tofacitinib free base (CKD-374) with those of tofacitinib citrate (Xeljanz). MATERIALS AND METHODS: A randomized, open-label, single-dose, 2-sequence, 2-period crossover study was conducted in healthy Korean male subjects. A total of 36 subjects were randomized into two sequence groups. At each period, subjects were administered the test formulation (tofacitinib free base, 5 mg) or the reference formulation (tofacitinib citrate, 8.078 mg; as tofacitinib, 5 mg). The plasma samples were collected up to 12 hours post dose and analyzed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (Cmax) and area under the plasma concentration vs. time curve from dosing to the last measurable concentration (AUC0-t), were determined by non-compartmental analysis. The 90% confidence intervals (CIs) of the geometric mean ratios for Cmax and AUC0-t were calculated to evaluate pharmacokinetic equivalence. RESULTS: The 90% CIs of the geometric mean ratios of Cmax and AUC0-t for tofacitinib free base to tofacitinib citrate were 0.9144 - 1.1230 and 1.0245 - 1.0932, respectively. All reported adverse events were of mild intensity, and there were no serious adverse events. CONCLUSION: In healthy Korean male adult subjects, the pharmacokinetic parameters of tofacitinib free base and tofacitinib citrate were evaluated and met the pharmacokinetic bioequivalent criteria. Both formulations were safe and well-tolerated.

Practical and Sustainable Synthesis of Optically Pure Levocabastine, a H1 Receptor Antagonist.

A practical and sustainable method for the synthesis of levocabastine hydrochloride (1), a H1 receptor antagonist for the treatment of allergic conjunctivitis, that can be applied to the industrial production of the compound has been developed. Substantial improvements over the previously reported procedure are achieved via efficient preparation of an optically active key intermediate (5) without chiral resolution and with a more effective detosylation, which complements the previous procedure. Notably, our process requires no chromatographic purification and provides levocabastine hydrochloride in greater than 99.5% purity in a 14.2% overall yield.

Isolation, characterization, and in silico, in vitro and in vivo antiulcer studies of isoimperatorin crystallized from Ostericum koreanum.

CONTEXT: Ostericum koreanum (Maxim.) Kitagawa (Apiaceae) roots are traditionally used as an analgesic and antiulcer agent. However, the antiulcer potential of isoimperatorin isolated from O. koreanum has not yet been explored. AIM: To evaluate the antiulcer activity of isoimperatorin isolated from the roots of O. koreanum. MATERIALS AND METHODS: Isoimperatorin was isolated as cubic crystals by repeated column chromatography of the ethyl acetate fraction and structure was verified with 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS-FAB). The crystals obtained were analyzed with the single crystal X-ray method. The MTT assay was used to determine its cytotoxicity against chondrocytes at different concentrations (0.0-737.74 µM, 24 h). The in vivo antiulcer activity of isoimperatorin (40 mg/kg) was determined against ethanol-, indomethacin- and pyloric ligation-induced ulcers in Sprague-Dawley rats. Furthermore, the effect of isoimperatorin (0.0-737.74 µM, 24 h) on the expression of type II collagen in chondrocytes was determined using western blot method. The in vitro urease inhibitory activity of isoimperatorin (0-80 µM) and molecular docking was also performed against urease. RESULTS AND DISCUSSION: Isoimperatorin demonstrated significant inhibitory activity (IC50 36.43 µM) against urease as compared to the standard drug thiourea (IC50 33.57 µM) without cytotoxic effects. It provided 70.9%, 67.65% and 54.25% protection in ulcer models induced by ethanol, indomethacin and pyloric ligation, respectively. Isoimperatorin showed the highest expression level of type II collagen at 368.87 µM. The docking results confirmed strong binding affinity with the target protein. CONCLUSION: Isoimperatorin may be used to develop antiulcer drugs with decreased side effects.

Crystal structure of a monoclinic polymorph of 5-amino-1,3,4-thia-diazol-2(3H)-one.

The title compound, C2H3N3OS, is a monoclinic (P21/c) polymorph of the previously reported triclinic structure [Kang et al. (2012 ▶). Acta Cryst. E68, o1198]. The asymmetric unit contains two independent mol-ecules which are essentially planar, with r.m.s. deviations of 0.001 and 0.032 Šfrom the mean plane defined by the seven non-H atoms. In the crystal, N-H⋯N and N-H⋯O hydrogen bonds link the mol-ecules into a sheet parallel to (111).

Crystal structure of phen-yl(pyridin-2-yl)methanol.

In the title compound, C12H11NO, the pyridine and phenyl rings are inclined to each other by 71.42 (10)°. In the crystal, O-H⋯N hydrogen bonds link the mol-ecules into helical chains extending along the c-axis direction.

Crystal structure of bis-(4-allyl-2-meth-oxy-phen-yl) terephthalate.

The asymmetric unit of the title compound, C28H26O6, contains one half-mol-ecule, with the complete molecule generated by a crystallographic inversion center. The central terephthalate and meth-oxy-benzene rings are approximately perpendicular, making a dihedral angle of 80.31 (5)°. No specific directional contacts are noted in the crystal packing. The terminal vinyl group is disordered over two orientations with an occupancy ratio of 0.796 (4):0.204 (4).

(5-Methyl-pyrazine-2-carboxyl-ato-κ(2) N (1),O)bis-[2-(4-methyl-pyridin-2-yl-κN)-3,5-bis-(tri-fluoro-meth-yl)phenyl-κC (1)]iridium(III) chloro-form hemisolvate.

In the title complex, [Ir(C14H8F6N)2(C6H5N2O2)]·0.5CHCl3, the Ir(III) atom adopts a distorted octa-hedral geometry, being coordinated by three N atoms (arranged meridionally), two C atoms and one O atom of three bidentate ligands. The complex mol-ecules pack with no specific inter-molecular inter-actions between them. The SQUEEZE procedure in PLATON [Spek (2009 ▶). Acta Cryst. D65, 148-155] was used to model a disordered chloro-form solvent mol-ecule; the calculated unit-cell data allow for the presence of half of this mol-ecule in the asymmetric unit.

Crystal structure of chlorido-penta-kis(dimethyl sulfoxide-κO)chromium(III) dichloride.

In the complex cation of the title salt, [CrCl(C2H6OS)5]Cl2, the Cr(III) ion is coordinated by one chloride ligand and five O atoms from dimethyl sulfoxide (DMSO) ligands, leading to a slightly distorted octa-hedral coordination environment [O-Cr-O angles range from 86.69 (16) to 92.87 (16)°]. In the crystal, complex cations are arranged in hexa-gonally packed rows parallel to [010], with the chloride counter-anions situated in between. The inter-actions between cations and anions are mainly ionic in nature.

Crystal structure of 2,6-bis-[(1H-pyrazol-1-yl)meth-yl]pyridine.

In the title compound, C13H13N5, the planes of the pyrazolyl groups are nearly perpendicular to that of the central pyridine ring, making dihedral angles of 87.77 (8) and 85.73 (7)°. In the crystal, weak C-H⋯N hydrogen bonds link the mol-ecules into layers extending parallel to (10-1).

Different Zn(II) cation coordination geometries in di-µ-acetato-bis{2-chloro-6-[(pyridine-2-ylmethylimino)methyl]phenol}dizinc(II) chloroform monosolvate.

In the title compound, di-µ-acetato-κ(2)O:O;κ(2)O:O'-bis[(6-chloro-2-{(E)-[(pyridin-2-yl)methylimino]methyl}phenolato-κ(3)N,N',O)zinc(II)], [Zn2(C13H10ClN2O)2(C2H3O2)2]·CHCl3, the Zn(II) cation adopts a five-coordinate geometry and is coordinated by two N atoms and one O atom of a tridentate 6-chloro-2-{(E)-[(pyridin-2-yl)methylimino]methyl}phenolate ligand and two O atoms of two bridging acetate groups, but their coordination geometries differ. One Zn(II) cation adopts a distorted trigonal bipyramidal geometry and the other a square-pyramidal geometry. The two acetate ligands bridge two Zn(II) cations with mono- and bidentate coordination modes. The title compound exhibits a strong emission at 460 nm upon excitation at 325 nm with a quantum yield of 23.1%.

1-Benzoyl-4-thio-biuret.

IN THE TITLE COMPOUND (SYSTEMATIC NAME: {[(phenyl-formamido)-carbon-yl]amino}-methane-thio-amide), C9H9N3O2S, both benzoyl and terminal thio-urea fragments adopt transoid conformations with respect to the central carbonyl O atom. The benzoyl and thio-biuret groups are almost coplanar, making a dihedral angle of 4.40 (8)°. The mol-ecular structure is stabilized by two intra-molecular N-H⋯O hydrogen bonds. In the crystal, N-H⋯O and N-H⋯S hydrogen bonds link the mol-ecules into a tape running along [101].

Bis[2-(1,3-benzo-thia-zol-2-yl)phenyl-κ(2) C (1),N][1,3-bis-(4-bromo-phen-yl)propane-1,3-dionato-κ(2) O,O']iridium(III).

The title complex, [Ir(C15H9Br2O2)(C13H8NS)2], lies about a crystallographic twofold rotation axis passing through the Ir(III) atom and the central C atom of the bis-(bromo-phen-yl)propane-1,3-dionate ligand. The Ir(III) atom adopts a distorted octa-hedral geometry coordinated by two N atoms in the axial positions, and two C and two O atoms in the equatorial plane. The dihedral angle between the two thia-zole ring systems in the complex is 77.45 (10)°.

A monoclinic polymorph of 1-benzoyl-4-thio-biuret.

The title compound, C9H9N3O2S, is a monoclinic (C2/c) polymorph of the previously reported triclinic structure [Kang (2013 ▶). Acta Cryst. E69, o1327]. The mol-ecule is almost planar with an r.m.s. deviation of 0.069 Šfrom the mean plane of all non-H atoms. The benzoyl and terminal thio-urea fragments adopt a transoid conformation with respect to the central carbonyl O atom. Two intra-molecular N-H⋯O hydrogen bonds are present. In the crystal, N-H⋯O and N-H⋯S inter-actions link the mol-ecules into zigzag chains extending along the c-axis direction.

[4-(2-tert-But-oxy-2-oxoeth-oxy)naph-thalen-1-yl]diphenyl-sulfonium trifluoro-methane-sulfonate.

In the cation of the title salt, C(28)H(27)O(3)S(+)·CF(3)O(3)S(-), the dihedral angle between the naphthalene ring system and the -C(=O)-O- plane is 80.39 (9)°. The three methyl groups of the tert-butyl group are each disordered over two orientations with an occupancy ratio of 0.712 (18):0.288 (18).

5,5'-[1,4-Phenyl-enebis(methyl-enesulfanedi-yl)]bis-[1,3,4-thia-diazol-2(3H)-one] dimethyl sulfoxide disolvate.

The asymmetric unit of the title compound, C(12)H(10)N(4)O(2)S(4)·2C(2)H(6)OS, contains one half of the p-xylene mol-ecule and one dimethyl sulfoxide mol-ecule. The p-xylene mol-ecule is located about a crystallographic inversion centre. In the mol-ecule, the thia-diazole and benzene rings are almost perpendicular to one another, with a dihedral angle of 88.95 (6)°. In the crystal, an N-H⋯O hydrogen bond is observed between the two components. The dimethyl sulfoxide mol-ecule is disordered over two orientations with an occupancy ratio of 0.879 (1):0.121 (1).

N-(5-Sulfanyl-idene-4,5-dihydro-1,3,4-thia-diazol-2-yl)acetamide dimethyl sulfoxide disolvate.

In the title compound, C(4)H(5)N(3)OS(2)·2C(2)H(6)OS, the five-membered heterocyclic ring and the N-(C=O)-C plane of the acetamide group are essentially co-planar, with a dihedral angle of 1.25 (3)°. Inter-molecular N-H⋯O hydrogen bonds between the acetamide compound and the dimethyl sulfoxide mol-ecules stabilize the crystal structure. The two dimethyl sulfoxide mol-ecules are each disordered over two positions with occupancy ratios of 0.605 (2):0.395 (2) and 0.8629 (18):0.1371 (18).

5-Amino-1,3,4-thia-diazol-2(3H)-one.

The asymmetric unit of the title compound, C(2)H(3)N(3)OS, contains three independent mol-ecules which are essentially planar, with r.m.s. deviations of 0.011 (2)-0.027 (2) Šfrom the mean plane defined by the seven non-H atoms. In the crystal, N-H⋯N and N-H⋯O hydrogen bonds link the mol-ecules into a sheet parallel to the (111) plane.

5-({3-[(5-Amino-1,3,4-thia-diazol-2-yl)sulfanylmeth-yl]benz-yl}sulfan-yl)-1,3,4-thia-diazol-2-amine.

In the title compound, C(12)H(12)N(6)S(4), the two terminal thia-diazole rings are twisted with respect to the central benzene ring, making dihedral angles of 54.28 (4) and 76.56 (3)°. The dihedral angle between the two thia-diazole rings is 27.77 (4)°. Inter-molecular N-H⋯N hydrogen bonds stabilize the crystal packing, linking the mol-ecules into a tape along the b axis.

Bis(2-amino-1,3-benzothia-zole-κN)dichloridozinc(II) ethanol hemisolvate.

In the title compound, [ZnCl(2)(C(7)H(6)N(2)S)(2)]·0.5CH(3)CH(2)OH, the Zn(II) atom is coordinated by two N atoms of two 2-amino-benzothia-zole ligands and two Cl atoms within a distorted tetra-hedral geometry. The dihedral angle between the N/Zn/N and Cl/Zn/Cl planes is 86.22 (7)°. The benzothia-zole mol-ecules are almost perpendicular to each other, forming a dihedral angle of 80.20 (8)°. The mol-ecular structure is stabilized by intra-molecular N-H⋯Cl hydrogen bonds. In the crystal, inter-molecular N-H⋯Cl hydrogen bonds link the mol-ecules into a three-dimensional network. The SQUEEZE procedure in PLATON [Spek (2009 ▶). Acta Cryst. D65, 148-155] was used to model a disordered ethanol solvent mol-ecule; the calculated unit-cell data allow for the presence of half of this mol-ecule in the asymmetric unit.

Ethyl N-[(benz-yloxy)thio-carbon-yl]carbamate.

In the title compound, C(11)H(13)NO(3)S, the dihedral angle between the benzyl and carbamate groups is 12.67 (10)°. The S atom and the carbonyl O atom are positioned anti to each other. In the crystal, pairs of N-H⋯S hydrogen bonds link mol-ecules into inversion dimers.