Studies on absorption, distribution and excretion of 14C labeled pivaloyloxymethyl (+)-(6R,7R)- 7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]- 3-[(5-methyl-2H-tetrazol-2-yl)methyl]-8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (14C-T-2588) in rats and mice

Absorption, distribution and excretion of T-2588 were studied in rats and mice using (aminothiazole-2-14C) T-2588 and (pivaloyloxymethyl-14C) T-2588. Results are summarized below. The binding rate of 14C-T-2525, an activated form of 14C-T-2588 in vivo, to serum protein was 90 approximately 100% in rats and mice after an oral administration of (aminothiazole-2-14C) T-2588. Blood levels of radioactivity reached to the highest concentration at 1 hour after an oral administration of (aminothiazole-2-14C) T-2588 to rats, and then gradually diminished. After an oral administration of (aminothiazole-2-14C) T-2588 to rats and mice, the highest radioactivity distribution was found in kidney among all the organs except stomach, intestine and bladder. Radioactivity was widely distributed into other organs such as adrenal, lung, liver, heart and pancreas. But little radioactivity was found in the brain. In new born rats, tissue levels of radioactivity were lower and diminished slower than those of adult rats. After an oral administration of (aminothiazole-2-14C) T-2588 to rats and mice, urinary excretion of radioactivity was about 26% and 35% of the dosed radioactivity in rats and mice, respectively, and fecal excretion was about 76% and 63% of the dosed radioactivity in rats and mice, respectively. Urinary and fecal excretion patterns of radioactivity after multiple oral administration of (aminothiazole-2-14C) T-2588 for 7 days to mice were similar to those after a single administration. This result suggests that T-2588 did not accumulate in the body. After an oral administration of (pivaloyloxymethyl-14C) T-2588 to rats and mice, urinary excretion was both about 8% of the dosed radioactivity, and fecal excretion was both about 6%. Then excretion of 14CO2 into respiratory air was about 55% and 66% of the dosed radioactivity in rats and mice, respectively. Biliary excretion was about 6.5% of the dosed radioactivity after an oral administration of (aminothiazole-2-14C) T-2588 to rats. Small amount of radioactivity was secreted to the milk after intravenous administration of (aminothiazole-2-14C) T-2525 to nursing rats. After an administration of (aminothiazole-2-14C) T-2588 to pregnant mice, radioactivity hardly transferred into the fetus.     

(6R,7R)-7-[2-呋喃基(甲氧亚氨基)乙酰氨基]-3-羟甲基-8-氧代-5-硫杂-1-氮杂二环[420]辛-2-烯-2-甲酸的合成研究

目的　制备(6R,7R) - 7-[2 -呋喃基(甲氧亚氨基)乙酰氨基] - 3-羟甲基- 8-氧代- 5 -硫杂- 1-氮杂二环[4 2 0]辛- 2 -烯- 2 -甲酸。方法　通过7-氨基头孢烷酸的水解,生成去乙酰基7-氨基头孢烷酸,再与2 - (2 -呋喃基)- 2 -甲氧亚胺基乙酸氯反应进行7位氨基的酰化制备上述医药中间体。结果及结论　适宜的反应条件为:7-氨基头孢烷酸在- 2 5℃水解,与2 - (2 -呋喃基) - 2 -甲氧亚胺基乙酰氯在- 10℃反应,二者的摩尔比为1 0∶1. 15,收率可达80 %。     

Diastereomeric 7-ureidoacetyl cephalosporins. II. 7beta [[[(Aminocarbonyl) amino]-2-thienylacetyl] amino]-7-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl) thio] methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

The synthesis and antibacterial activity in vitro of 7-methoxylated cephalosporins having a thienylureidoacetyl or a thienylglycyl C-7 side-chain are described. Acylation of 7 beta-amino-7-methoxycephems with a novel 2-aminooxazolone hydrochloride under neutral conditions gave the thienylureidoacetyl derivatives in good yield with retention of configuration. 7 beta-[[D-[(Aminocarbonyl)amino]-2-thienylacetyl]amino]-7-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio] methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (SQ 14,359) was found to have a broad-spectrum of antibacterial activity in vitro, particularly against beta-lactamase-producing organisms.     

Pseudopolymorphism and phase stability in four solid forms of (6R,7R)-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxy- iminoacetamid]-3- [(4-carbamoyl-1-quinuclidinio)methyl]-8-oxo-5-thia-1-azabicyclo - [4,2,0]oct-2-ene-2-carboxylate (E1040)

(6R,7R)-7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxy- iminoacetamid]-3- [(4-carbamoyl-1-quinuclidinio)methyl]-8-oxo-5-thia-1-azabicyclo [4,2,0]oct-2-ene-2-carboxylate (1; E1040) was isolated as alpha-(decahydrate), beta-(pentahydrate), and gamma-form (anhydrate) crystals and the X-ray amorphous form. The relationship between the pseudopolymorphic crystal forms of this compound and water content was studied by X-ray diffractometry, coulometric moisture analysis, thermal analysis, and hygroscopic and vacuum-freeze-drying experiments. The phase transition of crystalline 1 clearly indicated the effect of water content on dehydration. During dehydration, hydrated alpha-form (decahydrate) crystals and beta-form (pentahydrate) crystals became anhydrate gamma-form crystals, with the diffraction angle shifting toward shorter spacing accompanied by line broadening. These results indicate conversion of hydrate 1 crystals to the anhydrous form and contraction of the crystal lattice. It was estimated that the decahydrate (alpha-form) crystals contain 8 mol/mol crystal water and 2 mol/mol adhesion water, and that the pentahydrate (beta-form) crystals contain 4 mol/mol crystal water and 1 mol/mol adhesion water. These estimates were made by comparing the data from equilibrium hydration experiments and vacuum-freeze-drying experiments. It thus follows that gamma-form crystals are anhydrate and the X-ray amorphous form exists in either the hydrous or anhydrous form.     

(6R,7R)-7-苯甲酰胺基-3-氯甲基-7-甲氧基-8-氧代-5-氧杂-1- 氮杂二环[4.2.0]辛-2-烯-2-羧酸二苯甲酯的合成

6-APA经酰化、氧化和羧基保护“一锅法”得到[2S-（2α，5α，6α）]-6-苯甲酰胺基-3，3-二甲基-4，7-二氧代-4-硫杂-1-氮杂二环[3．2．0]庚烷-2-羧酸二苯甲酯，再经重排、氯代、水解得[1R-[1α，5α]]-3-羟甲基-2-（7-氧代-3-苯基-4-氧杂-2,6-二氮杂二环[3．2．0]庚-2-烯-6-基）-3-丁烯酸二苯甲酯，与BF3·Et2O闭环后经氯加成、消除和甲氧基化等反应制得目标化合物，总收率约30％。     

2-羟甲基-青霉烯-3-羧酸对硝基苄酯的制备

目的研究(5R,6S)-2-羟甲基-6-[(1R)-1-叔丁基-2-二甲基硅氧乙基]-青霉烯-3-羧酸对硝基苄酯的合成方法.方法以商品化的小四环为原料,经噻酸亲核取代、与对硝基苄基草酰氯反应、与亚磷酸三乙酯反应、加热环合、脱去保护基生成目标化合物1.结果与结论设计的合成路线经4步反应,总收率为23%,合成路线简便易行,适宜大规模生产.所合成的中间体及目标产物经核磁共振氢谱确证.     

Structural studies on H2-antagonists: crystal and molecular structure of N-cyano-N'-methyl-N"-(2-[(2-amino-5-thiazolyl)methylthio]ethyl) guanidine and N-cyano-3-[(2-guanidino-5-thiazolyl)methylthio]propionamidine.

The crystal and molecular structures of N-cyano-N'-methyl-N"-(2-[(2-amino-5-thiazolyl) methylthio] ethyl) guanidine and N-cyano-3-[(2-guanidino-5-thiazolyl)methylthio]propionamidine are reported. Both molecules are in an extended conformation. In all two crystals a system of hydrogen bonds links the molecules in a three-dimensional network. A comparison with the structure of cimetidine and famotidine is also included.     

Studies on beta-lactam antibiotics. X. Synthesis and structure-activity relationships of 7 beta-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino)acetamido] cephalosporin derivatives

The synthesis of 7 beta-([Z) -2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino) acetamido]-cephalosporins (2a-h) modified at the C-3 position of a cephem nucleus and the effect of the C-3 substituents on the antibacterial activity, oral absorptivity and therapeutic activity are discussed. The cephems (2a and 2b) having a C-3 substituent such as hydrogen or vinyl were more potent than other cephalosporins against Gram-negative bacteria. However, the cephalosporin (2f) having methylthio group at the 3-position showed the highest absorption rate in rats. These three cephalosporins (2a, b and f) exhibited equally good protective activities in mice infected. Furthermore, the serum levels of these cephalosporins (2a, b and f) were examined in dogs, and 2b and 2f showed outstanding high and prolonged serum levels.     

The autoradiographic studies on the distribution of 14C-labelled sodium 7-[D(-)-alpha-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-alpha-(4-hydroxyphenyl)-acetamido]-3-[(1-methyl -1 H-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxylate (14C-cefoperazone) in rats and mice

The distribution of cefoperazone (CPZ), a new semisynthetic cephalosporin antibiotic, was studied by macroautoradiography following a single intravenous or subcutaneous administration of 100 mg/kg 14C-CPZ to rats, mice, pregnant mice and experimental pyelonephritic mice. (1) In whole body autoradiograms of rats administered subcutaneously and mice administered subcutaneously and intravenously, their distribution patterns of the radioactivity were found to be similar to each case. The radioactivity was distributed at high concentration in liver, kidney, lung, tongue, salivary gland, skin, gastrointestinal tracts and retina. The radioactivity was rapidly excreted in urine and bile. And it was observed that the radioactivity excreted through bile was not reabsorbed from gastrointestinal tracts. (2) In pregnant mice administered intravenously, the radioactivity was observed the same level as whole blood level in placenta, while was hardly observed in fetuses. (3) In the experimental pyelonephritic mice administered intravenously, a considerable radioactivity was concentrated on the acute inflammatory area.     

Preparation and properties of (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl- (R)-(+)-alpha-hydroxy-alpha-(4-[125I]iodophenyl)-alpha-phenyl acetate and (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(S)-(-)-alpha-hydroxy-alpha- (4-[125I]iodophenyl)-alpha-phenyl acetate as potential radiopharmaceuticals

rac-4-Nitrobenzilic acid was synthesized and resolved with quinidine and quinine to give the corresponding (R)- and (S)-salts. The resolved diastereomeric salts were converted to (R)- and (S)-4-nitrobenzilic acids and subsequent esterification gave their corresponding ethyl esters. Transesterification with (R)-(-)-3-quinuclidinol afforded (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(R)-(+)-alpha-hydroxy-alpha- (4-nitrophenyl)-alpha-phenyl acetate and (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(S)-(-)-alpha-hydroxy- alpha-(4-nitrophenyl)-alpha-phenyl acetate. After hydrogenation, the (R,R)- and (R,S)-amines were converted to the respective triazene derivatives. The triazene derivatives reacted with sodium [125I]iodide to give (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(R)-(+)- alpha-hydroxy-alpha-(4-[125I]iodophenyl)-alpha-phenyl acetate and (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(S)-(-)-alpha-hydroxy- alpha-(4-[125I]iodophenyl)-alpha-phenyl acetate. The evaluation of their affinities to muscarinic acetylcholine receptors (MAcChR) shows that (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(S)-(-)-alpha-hydroxy-alpha-(4- [125I]iodophenyl)-alpha-phenyl acetate exhibits an affinity for the MAcChR from corpus striatum that is approximately threefold lower than that of (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(R)-(+)-alpha-hydroxy-alpha-(4- [125I]iodophenyl)-alpha-phenyl acetate.     

Metabolites of [(14)C]-5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3, 6-tetrahydropyridine in mice, rats, dogs, and humans.

The M1 muscarine agonist, 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2, 3,6-tetrahydropyridine (Lu 25-109), is extensively metabolized in mice, rats, dogs, and humans. The metabolite profile after an oral dose of [(14)C]Lu 25-109 was determined in plasma and in urine. Lu 25-109 was metabolized by N-demethylation (Lu 25-077), N-oxidation (Lu 32-181), and N-deethylation (Lu 31-126). In addition, combined N-demethylation and N-deethylation (Lu 31-190), and formation of a pyridine derivative took place (Lu 31-102). Lu 25-109 was also oxidized to pyridinium (Lu 29-297), 3-hydroxy-pyridinium (Lu 35-080), N-deethyl-2-pyridone (Lu 35-026), and a glucuronide of a 4, 6-dihydroxy-pyridinium ("m/z 398") compounds. A glucuronide of a dihydroxylated dihydro-pyridine compound ("m/z 400") was isolated from human urine, but not fully identified. In vitro studies were undertaken to elucidate the order of formation of the metabolites. In human plasma, the concentrations of Lu 25-109 and the pharmacologically active N-demethyl metabolite (Lu 25-077) were small compared with the N-oxide (Lu 32-181) and the N-deethyl-2-pyridone (Lu 35-026) at the first sample time (0.75 h). The N-deethyl metabolite (Lu 31-126) was the major component in human plasma between 3 and 10 h postdose. The major human metabolites in urine (Lu 32-181, Lu 35-026, and Lu 31-126) and the minor metabolites (Lu 25-077, Lu 35-080, Lu 31-190, and Lu 29-297) were all present in urine from rats, dogs, and mice, whereas m/z 398 was present in only mice and humans, and Lu 31-102 in only rats. The minor human metabolite m/z 400 was not detected in mice, rats, or dogs.     

一种简便合成桥环硫代吗啉化合物(1R,5S)-3-硫代-8-氮代双环[3.2.1]辛烷的方法（英文）

目的设计一条简便的桥环硫代吗啉化合物(1R,5S)-3-硫代-8-氮代双环[3.2.1]辛烷的合成方法。方法以内消旋的2,5-二溴己二酸二乙酯和苄胺为起始原料,一步构建在2,5位具有顺式二羧酸酯取代的四氢吡咯关键中间体,再经过还原、合环等多步反应合成目标化合物。结果与结论本工艺路线操作简单,以35%的总收率(以内消旋的2,5-二溴己二酸二乙酯计)得到桥环硫代吗啉化合物,新工艺克服了现有合成方法中反应条件苛刻、使用昂贵试剂等缺点,具有反应条件温和、操作简单、收率高等特点。     

Synthesis and antibacterial properties of 7-[2-(3-substituted-5-isoxazolyl)-2-methoxyiminoacetamido]cep halospora nic acid derivatives

The synthesis of new 2-(3-substituted-5-isoxazolyl)-2-methoxyiminoacetic acids and their condensation derivatives with a suitable cephalosporanic nucleus, is reported. Their antibacterial properties were tested in vivo and in vitro also against beta-lactamase producer microorganisms; particularly the oral bioavailability of some of these new derivatives was studied.     

7-[(1 S,4S )-3,3-二甲基-2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基]-喹诺酮化合物的合成与抗菌作用

以（4R）－羟基－L脯氨酸为起始原料，经8步反应合成了[(1S,4S)-3，3－二甲基－2－氧杂－5－氮杂二环[2.2.1]庚烷，以此化合物作为喹诺酮类的7－位侧链，合成了3个衍生物，并测定了它们对10株革兰阳性菌和6株革兰阴性菌的MIC值。结果表明，它们的体外抗菌活性均低于对照药加替沙星和环丙沙星。     

Synthesis of 2-(3-Substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo[3.2.1]octanes and 2α-(3-Substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-enes as Potential Muscarinic Agonists

Radioligand binding affinities of seven muscarinic receptor ligands which possess an oxadiazole ring side chain have been determined in rat heart, rat brain, and m₁- or m₃-transfected CHO cell membrane preparations to determine the selectivity for subtypes of muscarinic receptor. The ratios of binding constants in brain membranes were measured as an indicator of potential agonist activity against [³H]QNB and [³H]Oxo-M. These muscarinic ligands did not discriminate the subtypes of muscarinic receptors. Six muscarinic ligands which have a 3-amino- or 3-methyl-1,2,4-oxadiazol-5-yl groups attached to the 8-methyl-8-azabicyclo[3.2.1]oct-2-ene or 8-methyl-8-azabicyclo[3.2.1]octane head group show binding constants between 2.04 x 10^–6 and 1.79 x 10^–5 M in rat heart, rat brain, and m₁- or m₃-transfected CHO cell membrane preparations. 1-Methyl-2-[3-amino-1,2,4-oxadiazol-5-yl]piperidine shows low binding constants of approximately 10^–4 M in rat heart and rat brain. (1R,5S)-2-[3-Amino-1,2,4-oxadiazol-5-yl]-8-methyl-8-azabicyclo-[3.2.1]oct-2-ene [(1R,5S)-17] was the most active compound.     

Improved synthesis of an ester-type prodrug, 1-acetoxyethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-1- propenyl]-3-cephem-4-carboxylate (BMY-28271)

1-Acetoxyethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3- [(Z)-1-propenyl]-3-cephem-4-carboxylate (BMY-28271) is an ester-type prodrug of cephalosporin for oral use. Methods suitable for large scale preparation were investigated. The yield was improved by esterification of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]cep hem-4-carboxylic acid (11) followed by removal of the trityl group and, in addition, column chromatographic purification at each step was eliminated by optimization of the reaction conditions.