The autoradiographic studies on the distribution of 14C-labeled pivaloyloxymethyl (+)-(6R,7R)- 7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]- 3-[(5-methyl-2H-tetrazol-2-yl)methyl]-8-o xo-5-thia- 1-azabicyclo [4.2.0]oct-2-ene-2-carboxylate (14C-T-2588) in mice

The distribution of T-2588 was studied with whole body autoradiography in normal male mice and pregnant mice using two radioactive T-2588 labeled at the aminothiazole or pivaloyloxymethyl moieties. When (aminothiazole-2-14C) T-2588 was orally administered, the radioactivity was distributed widely to whole tissues except central nervous systems such as brain and spinal cord. In pregnant mice, no detectable radioactivity was present in the fetus. These results suggested that T-2588 was well absorbed and hardly crossed the blood-brain barrier and placenta. At 4 hours after administration, radioactivity was only observed in gastrointestinal tract implying rapid excretion of T-2588. When (pivaloyloxymethyl-14C) T-2588 was orally administered, radioactivity was accumulated to all tissues and fetus. From these results we speculated that formaldehyde formed by hydrolysis at the pivaloyloxymethyl ester and entered the C1-metabolic pathway.     

(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 %。     

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.     

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.     

(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％。     

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.     

3-酮-2硫杂-5-氮杂双环[2.2.1]庚烷-5-酸4-硝基苄酯在不同溶剂中溶解度测定与关联

采用平衡法测定了283.15~353.15K范围内美罗培南中间体(3-酮-2硫杂-5-氮杂双环[2.2.1]庚烷-5-酸 4-硝基苄酯)在乙酸乙酯、乙酸甲酯、正丙醇和丙酮溶液中的溶解度，并用Apelblat模型、经验多项式模型、λ-h模型对实验数据进行关联。结果证明：3-酮-2硫杂-5-氮杂双环[2.2.1]庚烷-5-酸4-硝基苄酯溶解度随着温度的升高而增加。Apelblat模型平均相对误差小于8%，经验模型平均相对误差小于10%，λ-h方程拟合平均相对误差小于2%，效果最佳。应用单晶衍射仪首次确定了晶体属正交晶系，空间群P21，晶胞参数a=7.1630nm、b=9.1713nm、c=20.998nm、α=90°、β=90°和γ=90°。     

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。     

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.     

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.     

A selective human H(4)-receptor agonist: (-)-2-cyano-1-methyl-3-[(2R,5R)-5- [1H-imidazol-4(5)-yl]tetrahydrofuran-2-y] methylguanidine

A series of 16 compounds related to chiral 4(5)-(5-aminomethyltetrahydrofuran-2-yl)imidazoles (1) have been designed, synthesized, and examined in vitro by radioligand displacement studies and functional assays for both the human H(3)- and H(4)-receptors expressed in SK-N-MC cells. Among them, the (2S,5S)-isomer 1d of amino compounds showed approximately 300-fold higher selectivity at the H(3)-receptor than the H(4)-receptor. On the other hand, (2R,5S)- and (2R,5R)-cyanoguanidines 3b and 3c, in which the amino group of the compounds 1b and 1c was substituted by the cyanoguanidino moiety, bound to the H(4)-receptor with a pEC(50) value of 6.65 and 7.11, respectively, and had >40-fold selectivities over the H(3)-receptor. As such, 3b and 3c are the first selective H(4) receptor agonists.     

4-［2-(2-氨基-4，7-二氢-4-氧-1H-吡咯［2，3-d］嘧啶-5-基)乙基］苯甲酸的中试生产

目的:研究培美曲塞二钠的关键中间体4-[2-(2-氨基-4,7-二氢-4-氧-1H-吡咯[2,3-d]嘧啶-5-基)乙基]苯甲酸的放大生产.方法: 以对碘苯甲酸甲酯为起始原料,经缩合、溴代、环合、水解等反应得到制备培美曲塞二钠的关键中间体.结果:总收率约36.8%,本方法操作简单,收率稳定,适合工业化生产.     

Studies on absorption, distribution and excretion of 14C labeled (+-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluene-sulfonate hydrate (14C-T-3262) in rats and mice

Absorption, distribution and excretion of T-3262 were studied in rats and mice after oral administration of 14C-T-3262. The obtained results are summarized as follows. 1. 14C-T-3262 was absorbed from the upper small intestine such as duodenum in rats. 2. Serum levels of radioactivity in rats reached the highest concentration at 1 hour after an oral administration, then gradually diminished. 3. Urinary excretion was 35% and 42% of the dosed radioactivity in rats and mice, respectively, and fecal excretion was about 65% and 56% of the dosed radioactivity in rats and mice, respectively. 4. Biliary excretion in rats was about 27% of the dosed radioactivity after an oral administration of 14C-T-3262, and a half amount of excreted radioactivity was reabsorbed from the intestine. 5. Radioactivity was distributed the most into the kidney and the liver among all organs other the stomach and the intestine. Radioactivity was widely distributed into other organs such as spleen, adrenal, pancreas, lung, heart and thymus. But the distribution of radioactivity into the brain was little. 6. The distribution of 14C-T-3262 was also studied with whole body autoradiography in normal male mice and pregnant mice. The radioactivity was distributed widely to whole tissues except brain, spinal cord and eye ball. In pregnant mice, radioactivity levels in the fetuses were the same as the blood level of the mother mice. 7. The binding rate of 14C-T-3262 to rats and mice serum proteins was 63-66%. 8. Urinary and fecal excretion patterns of radioactivity in mice after multiple oral administration of 14C-T-3262 for 10 days were similar to those after a single administration. This result suggests that T-3262 did not accumulate in body. 9. After oral administration of 14C-T-3262 to nursing rats, the secreted radioactivity level in the milk was higher than the blood level.     

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.     

1-(7-Chloroquinolin-4-yl)-2-[(1H-pyrrol-2-yl)methylene]hydrazine: a potent compound against cancer

Heteroaromatic derivatives (3a–f) have been synthesized and evaluated for their activity against four cancer cell lines. Among the studied compounds, 1-(7-Chloroquinolin-4-yl)-2-[(1H-pyrrol-2-yl)methylene]hydrazine (3e) exhibited an excellent cytotoxic activity against the referred lines, and especially on melanoma cells (MDAMB-435). In this case, compound 3e is four times more active than the standard substance Doxorubicin. Together with other results from our group, 7-chloro-4-quinolinylhydrazones derived from chloroquine could be considered a relevant finding toward the rational design of new leads for antitumor compounds.     

Antiallergic agents. 3. N-(1H-tetrazol-5-yl)-2-pyridinecarboxamides

A series of N-tetrazolylpyridinecarboxamides was prepared and evaluated for antiallergic activity by the passive cutaneous anaphylaxis (PCA) assay. From the structure-activity relationships (SAR) of this class of compounds, it was revealed that the N-tetrazolylcarbamoyl group as an acidic functionality is required to be at the 2-position of the pyridine nucleus and that the phenyl group as a subtituent is not necessarily required for activity. 6-Methyl-N-(1H-tetrazol-5-yl)-2-pyridinecarboxamide (36) showed good oral activity and low toxicity.