5-羟基-5H-[1]-苯并吡喃[2,3-b]吡啶的制备

目的改进5-羟基-5H-[1]-苯并吡喃[2,3-b]吡啶的合成工艺。方法以2-氯烟酸为起始原料,经亲核取代、环合和还原制得目标化合物。结果总收率68.6%,产物经熔点和1HNMR确证。结论改进后的工艺具有操作简便,对环境友好,收率高等优点。     

Dissolution properties and bioavailability of ground mixture of N,N-dimethylcarbamoylmethyl alpha, 2-dimethyl-5H-[1]benzopyrano[2,3-b]-pyridine-7-acetate with various pharmaceutical ingredients

Ground mixture of N,N-dimethylcarbamoylmethyl alpha, 2-dimethyl-5H-[1]benzopyrano-[2,3-b]pyridine-7-acetate (1) with various pharmaceutical ingredients were prepared in order to investigate their dissolution behaviors and bioavailability. Taking into account the weakly basic property of 1, the dissolution rate was determined in the 2nd fluid (pH 6.8) of disintegration test, JP XI. Dissolution rates of the ground mixtures (1 : 1, w/w) of 1 with hydroxypropylcellulose-L (HPC-L), low substituted hydroxypropylcellulose (L-HPC) or lactose respectively, showed a significant increase compared with compound 1 alone. Three kinds of experimental fine granules were prepared; type A: produced from ground mixture of 1, HPC-L, L-HPC and lactose; type B: produced from physical mixture having the same composition as type A; type C: produced 1, L-HPC and lactose. In these fine granules, only type A exhibited pH-independent dissolution profiles. Bioavailability study was carried out in beagle dogs whose gastric acidity was controlled in advance to low levels by administration of omeprazole. The test was conducted in a cross over design. Reflecting their dissolution characteristics, type A granules showed better bioavailability than the others. These results suggest that grinding is useful for the improvement of the dissolution property and bioavailability of 1, a weakly basic compound.     

Studies on antianaphylactic agents. 7. Synthesis of antiallergic 5-oxo-5H-[1]benzopyrano[2,3-b]pyridines

5-Oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acids 23 and their tetrazole analogues 24 were synthesized from 4-oxo-4H-1-benzopyran-3-carbonitriles 3 or 2-amino-4-oxo-4H-1-benzopyran-3-carboxaldehydes 4. When administered intravenously, they exhibited antiallergic activity in a reaginic PCA test in rats. In the carboxylic acid series, the activity was influenced by the substituents at the 2-position and increased substantially in the following order: Me, OMe less than NH2 less than OH, H less than NHOMe. On the other hand, in the tetrazole series, 2-unsubstituted derivatives showed the highest activity. Regardless of the kinds of substituents at positions 2 and 3, compounds bearing an alkyl group, especially an isopropyl group at the 7-position, were superior in activity to the corresponding unsubstituted compounds. Among these alkyl derivatives, 3-carboxylic acid derivatives, i.e., 23c (7-ethyl), 23g (2-amino-7-isopropyl), 23r [2-(methoxyamino)-7-isopropyl], and a 3-tetrazole derivative 24c (7-isopropyl), were 41-184 times as potent as disodium cromoglycate. They also exhibited remarkable activity when administered orally; clinical studies on 23g (AA-673) are in progress.     

Anti-allergic activity of 7-acetyl-5-oxo-5H-[1] benzopyrano (2,3-b] pyridine (Y-9000) (author's transl)]

The IgE mediated reactions such as 48 hr homologous passive cutaneous anaphylaxis (PCA) and active anaphylactic bronchoconstriction in rats were inhibited in a dose dependent manner by treatment with 7-acetyl-5-oxo-5H-[1]benzopyranol[2,3-b] pyridine (Y-9000) and disodium cromoglycate (DSCG) given intraperitoneally. The inhibitory activity of Y-9000 was to the same extent as that seen with DSCG. The IgE mediated reactions were also inhibited by oral treatment with Y-9000 but not with DSCG. In addition, the treatment with Y-9000 resulted in inhibition of IgG mediated reaction such as anaphylactic asthma in the passively sensitized guinea pigs and 4 hr heterologous PCA in rats. However, DSCG failed to prevent these reactions. Y-9000 also inhibited the active systemic anaphylaxis of the mouse and non-immunological reactions in rats such as histamine release after an intraperitoneal injection of dextran, anaphylactoid reaction and paw edema induced by the dextran, egg white or carrageenin. This agent had a stimulating effect on the adrenals, and showed glucocorticoid like activity, but bronchodilator and antagonistic activities on chemical mediators were nil. These results suggest that the anti-allergic activities of Y-9000 are elicited by inhibiting the release of allergic mediators in a manner similar to DSCG, and are partially mediated by stressor activity.     

2H-[1]benzopyrano[3,4-b]pyridines: synthesis and activity at central monoamine receptors

Two general synthetic approaches to a novel series of 2H-[1]benzopyrano[3,4-b]pyridines are described together with their receptor binding profile at a variety of monoamine receptors in mammalian brain tissue. The biologically active members of this series fall into into one of two broad classes: 3,4,4a,5-tetrahydro-2H-[1]benzopyrano[3,4-b]pyridines or trans-1,3,4,4a,5,10b-hexahydro-2H-[1]benzopyrano[3,4-b]pyridines. By appropriate pharmacophoric modification potent selective ligands for D2, alpha-2, 5HT1A, and 5HT2 receptors may be obtained. The previously published in vivo data on certain key representatives of these series are also summarized.     

Synthesis and Antihypertensive Activity of 2-Imino-2,3-dihydro-5H-1,3,4-thiadiazolo[2,3-b]quinazolin-5-ones

Hydrolysis of isatoic anhydride (1) with hydrazine derivatives gave the o-aminobenzohydrazides 2a-c. Treatment of these compounds with carbon disulfide provided the 3-substituted amino-2-mercapto-quinazolin-4(3H)-ones 3a-c. Compounds 3a-c underwent cyclo-condensation with cyanogen bromide to produce th title compounds 5a-c in 56-87% yields. Preliminary pharmacological evaluation of these compounds for antihypertensive activity on anesthetized rats was accomplished.     

5-甲氧基-1H-吡咯并[3,2-b]吡啶-2-甲酸的合成

目的制备5-甲氧基-1H-吡咯并[3,2-b]吡啶-2-甲酸。方法以2-甲基-6-氯-3-硝基吡啶为原料,经Williamson合成法制得2-甲基-6-甲氧基-3-硝基吡啶,再经Reissert合成法制得终产物。结果反应总收率33%,产物结构由1H-NMR光谱确证。结论该方法简单、原料价廉易得,后处理容易,副产物较少,适于工业化生产。     

Synthesis and tuberculostatic activity of some derivatives of imidazo [4, 5-b]pyridine-1-carboxylic acid

Imidazo [4,5-b] pyridine-2-carboxylic acid 2, its methyl ester 5, amide 7, hydrazide 12, hydrazone 14, nitrile 16, thioamide 18, and amidoxime 20 were synthesized. By methylation of acid 2 with diazomethane N3-CH3 derivatives of the above mentioned compounds were obtained. The resulting compounds displayed low tuberculostatic activity.     

2H,5H-[1]benzothiopyrano [4,3-b]pyran derivatives with platelet antiaggregating activity

The synthesis of some N,N-disubstituted 4-amino-3-phenyl-2H,5H-[1]benzothiopyrano [4,3-b]pyran-2-ones by reaction of phenylchloroketene with a series of N,N-disubstituted 3-aminomethylene-2,3-dihydro-4H-1-benzothiopyran-4-ones, followed by dehydrochlorination of the primary adducts with DBN, is described. Some of these compounds showed a strong platelet antiaggregating activity in vitro, superior to that of acetylsalicylic acid.     

Synthesis and pharmacological properties of 13H-naphtho[1',2':7,6] [1,4] diazepino[2,3-b] pyridines

The synthesis and properties of 13H-naphtho[1',2':7,6] [1,4] diazepino[2,3-b] pyridines (7a--g) were described. New compounds were studied in rats and in mice in the tests used for preclinical assessment of antidepressant or anxiolytic activity. Compound 7c showed weak antagonism towards the reserpine-induced hypothermia and shortened immobility time in the despair test. None of the tested compounds had an anxiety-relieving action.     

Pharmacokinetic behaviour in polymorphonuclear leucocytes of N,N-dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]benzopyrano[2,3-b]-pyridine-7-acetate (Y-23023), a new prodrug type of antiinflammatory agent,and indomethacin after oral administrations in rats

Abstract— N,N-Dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]-benzopyrano[2,3-b]pyridine-7-acetate (Y-23023) is a prodrug developed as a new non-steroidal anti-inflammatory drug (NSAID). Y-23023 is rapidly hydrolysed to an active metabolite, α,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid (M₁) following its absorption and then exhibits a strong anti-inflammatory activity. We have examined the pharmacokinetic behaviour in polymorphonuclear leucocytes (PMNs) of M₁ and of indomethacin after oral administration to rats of Y-23023 and indomethacin, respectively. Y-23023 was rapidly absorbed, producing a mean C_max (1·13 μg mL^?1) of M₁ after 1 h in plasma. Indomethacin was less rapidly absorbed, producing a mean C_max (3·38 μg mL^?1) after 3 h in plasma. The mean AUC of M₁ and indomethacin in plasma were 5·45 μg h mL^?1 and 22·49 μg h mL^?1, respectively. The mean t_max, C_max and AUC of M1 in PMNs were 1 h, 11·1 ng (41 pmol)/10⁸ cells and 58·6 ng (164 pmol) h/10⁸ cells, respectively. The same parameters for indomethacin in the PMNs were 3 h, 15·4 ng (57 pmol)/10⁸ cells and 95·2 ng (266 pmol) h/10⁸ cells, respectively. The PMNs/plasma ratio of M₁ was about 2·8 times that of indomethacin. These results indicate that the association of M₁, an active metabolite of Y-23023, from blood to the PMNs is greater than that of indomethacin.     

Synthesis and pharmacological activity of 2-alkylthio substituted thieno[2,3-d]pyrimidine-4-one and 5H-pyrimido [5,4-b]indol-4-one

Quaternary salts of several 2-alkylthio substituted derivatives of thieno [2,3-d]pyrimidin-4-one and 5H-pyrimido [5,4-b]indol-4-one with a basic group in position 2 of the alkyl chain were synthesized and screened for potential spasmolytic activity. These substances were prepared by condensation of the corresponding mercapto compounds with a 2-chloroalkyltertiary amine. The tertiary bases were quaternized with methyl iodide. Among the assayed compounds, the thieno [2-3-d]pyrimidin-4-one derivatives displayed a potent spasmolytic activity in the in vitro and in vivo assays.