Physicochemical characterization of a new crystal form and improvements in the pharmaceutical properties of the poorly water-soluble antiosteoporosis drug 3,9-bis(N,N-dimethylcarbamoy-loxy)-5H-benzofuro[3,2-c]quinoline-6-one (KCA-098) by solid dispersion with hydroxypropylcellulose

The present study was undertaken to improve the oral absorption of KCA-098, an antiosteoporosis drug. In this study, the form 2 of KCA-098 was used as a desirable crystal form for pharmaceutical formation among three kinds of crystal forms, 1, 2, and 3. Solid dispersions of KCA-098 with hydroxypropylcellulose (HPC) or poly(vinylpyrrolidone) (PVP) were prepared by the solvent method. The physicopharmaceutical properties of the solid dispersions were characterized by powder x-ray diffraction, FTIR spectroscopy, and differential scanning calorimetry (DSC). The powder x-ray diffractograms suggest that KCA-098 in the HPC-SL solid dispersion existed in a partial crystalline state as a new crystal form that could be produced by recrystallization from the solvent. Dissolution from the solid dispersions was markedly enhanced in comparison with that of the drug alone. The dissolution enhancement was observed to be greater for the solid dispersion with HPC-SL than for that with PVP. The KCA-098/HPC-SL (1:2) solid dispersion capsule showed a 3.5-fold increase in the initial concentration and 2.5-fold increase in initial concentration of dissolved drug after 60 min, compared with the values for a physical mixture of KCA-098 (form 2)/lactose (1:2). The in vivo absorption of the drug was investigated after oral administration of KCA-098 or its solid dispersion. The area under the plasma concentration curve of KCA-098 after oral administration of the KCA-098/HPC-SL (1:2) solid dispersion capsule was three-fold greater than that for the drug itself.     

Synthesis and pharmacological activities of some new 2-[1-(6-methoxy-2-naphthyl)ethyl]-6-(substituted)benzylidene thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one derivatives

In this study, thirteen new compounds having a 2-[1-(6-methoxy-2-naphthyl)ethyl]-6-(substituted)benzylidenethiazolo[3,2-b]- 1,2,4-triazole-5(6H)-one structure were synthesised using N-[2-(6-methoxy-2-naphthyl)propanoyloxysuccinimide, N-[2-(6-methoxy-2-naphthyl)propanoyl]thiosemicarbazide and 3-[1-(6-methoxy-2-naphthyl)ethyl]-5-mercapto-1,2,4-triazole. The structures and physical properties of the compounds were elucidated by IR, 1H NMR, mass spectroscopy and elemental analysis. The antiinflammatory activity and gastric ulceration potential of the compounds were tested using naproxen as a reference compound.     

Synthesis and biological evaluation of 6-amino-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (3,7-dideazaguanine)

The synthesis of 6-amino-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (3,7-dideazaguanine, 2) has been accomplished from 3-(ethoxycarbonyl)pyrrole-2-acetonitrile. In contrast to 3-deazaguanine, compound 2 did not show any antitumor, antiviral, or antibacterial properties. Furthermore, it was not a substrate for hypoxanthine-guanine phosphoribosyltransferase or purine nucleoside phosphorylase.     

Synthesis, cytotoxic activity, and mechanism of action of furo[2,3-c]acridin-6-one and benzo[b]furo[3,2-h]acridin-6-one analogues of psorospermin and acronycine

Compounds possessing the epoxyfuran system present in the natural cytotoxic dihydrofuroxanthone psorospermin (4) fused onto the acridone or benzo[b]acridone chromophores present in the antitumor acronycine (1) and S23906-1 (3) were prepared. The basic furoacridone and benzofuroacridone cores bearing an isopropenyl substituent at a convenient position were synthesized by condensation of 1,3-dihydroxyacridone (7) or 1,3-dihydroxybenz[b]acridin-12(5H)-one (9) with (E)-1,4-dibromo-2-methylbut-2-ene. In both series, the (2R*,1'S*) epoxides, with the same relative configuration as psorospermin, were the most active compounds, exhibiting cytotoxic properties with IC50 values in the 10-100 nM range. As in the acronycine and psorospermin series, the new compounds act through alkylation of the DNA guanine units. However, a strong difference was noted in the DNA alkylation site between the benzopyranoacridone S23906-1, which alkylates DNA guanine units at position N-2 in the minor groove, and the new 13H-benzo[b]furo[3,2-h]acridin-6-one derived epoxide 21, which alkylates DNA guanine units at position N-7 in the major groove.     

Anellierte Thiopyrone, 5. Mitt.1): Darstellung und Reaktionen von 3-Formyl-indeno[1,2-b]-, -[1]benzofuro[3,2-b]-, -[1]-benzothieno[3,2-b]thiopyronen und 3-Formyl-thiopyrono[3,2-b]indolen

Fused Thiopyrones, V: Syntheses and Reactions of 3-Formyl-indeno[1,2-b]-, -[1]benzofuro[3,2-b]-, -[2]benzothieno[3,2-b]thiopyrones, and 3-Formyl-thiopyrono[3,2-b]indoles Alternative syntheses of the title compounds are described. The configuration of the oximes, obtained from the aldehydes, is proved. Furthermore the syntheses of the nitriles and the carboxylic acids is presented.     

12-acyl-6,1 2-dihydro-6-phenyl-[1 ]benzofuro[2,3-c]- and -[1,5]benzothieno[2,3-c]-[1 ,5]-benzothiazepines--tetracyclic diltiazem derivatives

The reaction of the tetracycles 1 with chloroacetylchloride yields the amides 2. The structure of 2a was proven by X-ray analysis. The amides 2 exist as diastereomers in solution because of planar chirality. From the N-chloroacetyl compounds only 2a, b could be substituted with diethylamine to give 3a, b. Reduction experiments of 3a, b with DIBAH do not afford diltiazem analogues; instead, the starting compounds la, b are formed by hydrolysis.     

Synthesis of new thiazolo[3,2-b][1,2,4]triazole-6(5H)-one derivatives as potent analgesic and anti-inflammatory agents

A series of thiazolo[3,2-b][1,2,4]triazole-6(5H)-ones were synthesized and evaluated for their analgesic and anti-inflammatory activities. The structures of these compounds were supported by FT-IR, ¹HNMR, and Mass spectra. All of the final compounds showed potent analgesic activity and the best compound 9d was 2.4 times more potent than mefenamic acid as the reference drug. In addition, most of them showed comparable or better anti-inflammatory activity in comparison with mefenamic acid and indomethacin. Moreover, compounds 9d, 9e, 9g, 9h, 9i, 9k, 9n, and 9o did not exhibit any significant ulcerogenic activity.     

Anellierte Thiopyrone, 4. Mitt.1): Indeno[1,2-b]-, Indolo[3,2,-b]-, [1]Benzofuro[3,2-b]- und [1]Benzothieno[3,2-b]thiopyrone

Fused Thiopyrones, IV: Indeno[1,2-b]-, Indolo[3,2-b]-, [1]Benzofuro[3,2-b]-, and [1]Benzothieno[3,2-b]thiopyrones The thiopyrones 2 are obtained from the corresponding thiopyranones 1 by dehydration with tritylperchlorate or SeO₂. Treatment of the benzofurane 2d with m-chloroperbenzoic acid (mCPBA) yields the thiopyrone-S, S-dioxide 3d. Starting from the benzothienothiopyrone 2e only one product, the thiophene-sulfone 3e , can be isolated.     

6-aminopyrazolo[4,3-c]pyridin-4(5H)-one, a novel analogue of guanine.

Treatment of dimethyl alpha-ethoxymethylidineacetonedicarboxylate with hydrazine gave methyl 3-(methoxy-carbonylmethyl)pyrazole-4-carboxylate which, upon ammonolysis and dehydration, afforded methyl 3-(cyanomethyl)pyrazole-4-carboxylate. This compound, when heated with liquid ammonia, gave 6-aminopyrazolo[4,3-c]pyridin-4(5H)-one, a new guanine analogue, which did not possess any of the potent antiviral activity shown by 6-aminoimidazo[4,5-c]pyridin-4(5H)-one (3-deazaguanine).     

Dihydroisochinolinumlagerung, 29. Mitt. 4-Benzyl-5-methyl-4,5-dihydrofuro[3,2-c]pyridine

Dihydroisoquinoline Rearrangement, XXIX: 4-Benzyl-5-methyl-4,5-dihydrofuro[3,2-c]pyridines The synthesis of 4-benzyl-5-methyl-4,5-dihydrofuro[3,2-c]pyridine (7) is described. With diluted acids 7 does not undergo the dihydroisoquinoline rearrangement, and no reaction product can be isolated. Introduction of a methyl group at C-2 (compound 14 ) does not change this situation. The tetrahydro compound 10 is stable under the conditions of the dihydroisoquinoline rearrangement.     

Dihydroisochinolinumlagerung, 31. Mitt.1) 4-Allyl-5-methyl-4,5-dihydrothieno[3,2-c]pyridin+)

Dihydroisoquinoline Rearrangement, XXXI: 4-Allyl-5-methyl-4,5-dihydrothieno[3,2-c]pyridine The synthesis of 4-allyl-5-methyl-4,5-dihydrothieno[3,2-c]pyridine (4) is described. With 1N-HCl 4 rearranges with 23% yield to the 6-allyl compound 5. To a small extent 4 disproportionates to yield the compounds 3 and 7 .     

Synthesis and antifungal activity of new derivatives of 5-(4-halobenzoyl)-4-amino-3-(2-dialkylaminoethylthio)thieno [2,3-c] and [3,2-d] isothiazole

A new series of 5-(4-halobenzoyl)-4-amino-3-(2-dialkylamino-ethylthio)thieno [2,3-c] and [3,2-d] isothiazole derivatives has been synthetized. The compounds were evaluated for antifungal activity on yeast and dermatophytes. The compound (VI b) resulted about thirty times less potent than miconazole on dermatophytes.     

Synthesis of the antileukemic compound N,N(11)-[5-[bis(2-chloroethyl)amino]-1, 3-phenylene]bisurea.

Conversion of 5-nitro-1, 3-benzenedicarboxylic acid (1) to the diamide 2 followed by hypochlorite rearrangement to the idamine 3 and subsequent reaction with acetic anhydride gave the bisacetamide 4. Reduction to the amine 5 followed by treatment with ethylene oxide formed the diol 6. The latter was converted to the bistosylate 7, which undrewent facile displacement with lithium chloride in acetone to give the mustard 8. Removal of the acetyl groups with hydrochloric acid gave 9, which reacted with potassium cyanate to provide the bisurea 10. In an alternative, but less satisfactory synthesis of 10, the compound (5-nitro-1, 3-phenylene) biscarbamic acid diphenyl ester (11), or the corresponding diethyl ester 12, was converted by ammonolysis to 13. The nitrodiurea 13 was next reduced to the amine 14, the hydrochloride of which reacted with ethylene oxide to give the diol 15. Treatment of the latter in dimethylformamide with N-chlorosuccinimide in the presence of triphenylphosphine gave 10 in low yield. The nitrogen mustards 8, 9 and 10 showed significant antitumor activities against P388 lymphocytic leukemia in mice.     

Synthesis of derivatives of 4,9-dimethoxy-5-methyl-7H-furo-(3,2-g)-1-benzopyrano-6-carboxy-7-one]

Compounds of the 7H-furo-[3,2-g]-1-benzopyran system are prepared by condensation of kellinone with malonic acid derivatives. The 4,9-dimethoxy-5-methyl-7-H-furo-[3,2g]-1-benzopyran-7-one-6-carboxylic acid chloride reacts with aliphatic and heterocyclic amines and with aliphatic aminoalcohols giving amides that could have pharmacological interest.     

Synthesis of new derivatives of 5H-furo[3,2-g][1]benzopyran-5-one with potential beta-adrenolytic activity

With the purpose of obtaining new compounds with antiarrhythmic activity, nine novel aminoalkanol derivatives of 5H-furo[3,2-g] [1]benzopyran-5-one were synthetized. In pharmacological studies, compound IX proved to display strong antiarrhythmic action, which in chloroform-induced arrhythmia was stronger from that of propranolol at three times lower acute toxicity.     

Pharmacological properties of 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-c]thieno[2,3-e] [1,4]diazepine (Y-7131), a new anti-anxiety drug.

6-(o-Chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-c]thienol[2,3-e][1,4]diazepine (Y-7131), a new derivative of the thienodiazepines, had marked activities in antipentylenetetrazole effect in mice, attenuation of conflict behavior in rats, inhibition of aggressive behavior induced by hypothalamic stimulation in cats and muscle relaxant effects in normal and decerebrate cats. Y-7131 had weak activities in anti-MES effect in mice and loss of righting reflex in mice. The acute toxicity of Y-7131 was considerably lower than that of diazepam. No significant autonomic or neuroleptic effects were noted. Y-7131 appears to be a characteristic and potent anti-anxiety agent different from the benzodiazepines.