Dehydrogenation of indanol by rabbit liver 3-hydroxyhexobarbital dehydrogenase.

1. Among the several enzyme activities in rabbit liver cytosol able to dehydrogenate 1-indanol, only the main activity was not separable from 3-hydroxyhexobarbital dehydrogenase during purification including polyacrylamide gel disc electrophoresis. 2. Results of mixed substrate method indicated that the same enzyme catalyses the dehydrogenation of 1-indanol and 3-hydroxyhexobarbital. The ratio between the two dehydrogenation activities was almost constant as the enzyme underwent thermal inactivation. The Ki values of p-chloromercuribenzoate, the Km values for NAD+, and the Km values for NADP+ were very similar for the two dehydrogenations. These results lead to the conclusion that the same enzyme catalyses the dehydrogenation of 3-hydroxyhexobarbital and 1-indanol. 3. 1-Tetralol, 1-acenaphthenol, 9-fluorenol, thiochroman-4-ol and 4-chromanol also served as substrate of the enzyme, but 2-indanol, 2-tetralol, and trans- and cis-indan-1,2-diol were not oxidized. 4. Reversibility of the reaction was also confirmed using 1-indanone as substrate.     

Zur Synthese des Phaeantharins, 3. Mitt.1) Untersuchungen zur Diphenylether-Synthese nach Ullmann

On the Synthesis of Phaeantharine, III: Investigation of the Ullmann Synthesis of Diaryl Ethers The Ullmann synthesis of diaryl ethers was examined using the bromobenzene derivatives 1–6 and the phenols 7–10. It was found that the yield of diphenyl ether increases with increasing electron density at the phenolic oxygen and with decreasing electron density at the carbon atom to which the halogen atom is attached. These results indicate a reaction course analogous to that of a nucleophilic aromatic substitution. The pyridine method turns out to be more successful than the classical method.     

Antituberculosis agents II. Evaluation of in vitro antituberculosis activity and cytotoxicity of some 2-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole derivatives

Using the radiometric BACTEC 460-TB methodology, the minimum inhibitory concentration (MIC) of a series of 2-(1-methyl-5-nitro-2-imidazolyl-1,3,4-thiadiazole-5-alkylsulfides, alkylsulfoxides and alkylsulfones which had been reported previously as antifungal agents, were determined. Active compounds were also screened by serial dilution to assess toxicity to a VERO cell line. The results indicate that compounds bearing a primary alkylthio substitution displayed good antituberculosis activity (MIC = 3.13-6.25 microg/ml). Oxidation to sulfone abolished the antituberculosis activity in methyl and propyl derivatives while the ethylsulfonyl analogue was active (MIC = 1.56 microg/ml). The cytotoxic effects indicate that 2-(1-methyl-5-nitro-2-imidazolyl)-5-methylthio-1,3,4-thiadiazole was the least toxic compound (IC50 > 10 microg/ml). Generally, all compounds showed a low selectivity index.     

Potentielle Antiöstrogene vom Typ des 1,2-Diphenyl-1-pyridyl-but-1-ens Teil 1: Synthese

1,2-Diphenyl-1-pyridyl-but-1-enes - Potential Antiestrogens Part 1: Synthesis The synthesis of the potentially antiestrogenic 1,2-diphenyl-1-pyridyl-but-1-enes is reported. The key compounds 1-(4-methoxyphenyl)-1-(4- resp. 3-pyridyl)-2-phenyl-but-1-ene (E/Z-1c resp. E/Z-2c) were prepared by coupling of the corresponding 4-methoxyphenylpyridylketone with propiophenone using TCl₄/Zn as the reducing agent. Ether cleavage yielded the phenols 1 and 2 , which were either reacted with 2-dimethylamino-ethylchloride to give the Tam-analogues 1b,o and 2b,o or transformed into the derivatives 1a and 2a by acetylation.     

Synthese und Hofmann-Abbau des 1-Hydroxymethyl-2,2-dimethyl-1,2,3,4-tetrahydroisochinolinium-Ions

Synthesis and Hofmann-Degradation of 1-Hydroxymethyl-2,2-dimethyl-1,2,3,4-tetrahydroisoqinolinium-Ion Analogous to the derivatives of the 1-α-hydroxybenzyl-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium-ion, N,N-dimethyl-2-vinyl-benzylamine and formate arise from the I-hydroxymethyl-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium-ion under the conditions of Hofmann-degradation.     

Synthesis of 1-,2-, and 3-(aminoacetyl)indoles and 1-(aminoacetyl)indolines (author's transl)

Synthesis of 1-, 2-, and 3-(Aminoacetyl)indoles and 1-(Aminoacetyl)indolines The chloroacetyl derivatives of various indoles and indolines, prepared by the reaction of the parent compounds with derivatives of chloroacetic acid derivatives, were reacted with amines to yield the title compounds.     

Zur Synthese von Tiliacora-Alkaloiden, 2. Mitt.: Darstellung des unsymmetrischen Biphenyl-Schwanzteils

On the Synthesis of Tiliacora Alkaloids, II: Synthesis of the Asymmetrical Biphenyl Derivative The biphenyl derivatives S-1 and S-3 were obtained by mixed Ullmann reaction of the phenylacetic esters 3, 4 and 5 . Because they contain selectively removable protective groups for the carboxyl functions, S-1 and S-3 are proper intermediates for the constitution selective reaction with the former described asymmetrical dibenzo-1,4-dioxin derivative K ¹⁾.     

Untersuchungen über Nitrothiophen- und Nitrofuranderivate. 2. Mitt.: Iminocarbonsäureester und Amidine des 5-Nitrothiophens und 5-Nitrofurans

By reaction of 5-nitro-2-thiophene- and 5-nitro-2-furonitrile with aliphatic alcohols we prepared the corresponding imido ethers. Ethyl-5-nitro-2-thiophene- and ethyl-5-nitro-2-furimidate respectively were converted with primary amines into amidines. To a great extent these compounds showed good to very good bacteriostatic and fungistatic activity and proved active against worms. Imido ethers exhibited the highest activity, a clear dependence existing on the length of the aliphatic chain of carbon atoms. In contrast to the lower activity of the nitrothiophene derivatives compared to the nitrofuran derivatives, as often described in the literature the nitrothiophenes tested for this paper, often possessed a higher activity.     

Derivatives of 2-mercaptobenzenesulphonamide. X. Synthesis of 1-dialkylaminoalkyl-2-(2-mercaptobenzenesulphonyl)guanidines with potential pharmacological activity

Synthesis of 2-(4-R(1)-5-R(2)-2-mercaptobenzenesulphonyl)derivatives of 1-(dialkylaminoalkyl)-3-isobutylguanidine (III b-l) and 1,3-di(2-dialkylaminoethyl)guanidine (IV-V) as well as subsequent S-2-aminoethylation reaction VI a-h, VII a-b have been described.     

Novel 5-substituted 3-(2-naphthalenyl)-3-(1H-imidazol-l-ylmethy)-2-methylisoxazolidine derivatives

The synthesis and antifungal activity of a series of novel 5-substituted 3-(2-naphthalenyl)-3-(1H-imidazol-1-ylmethyl)-2- methylisoxazolidine derivatives are described. When tested in vitro in solid agar assays, some of the compounds demonstrated moderate to potent activity against Trichophyton rubrum and Candida albicans.     

5-( [aryl or aryloxy (or thio)]methyl)-3-(1H-imidazol-1-ylmethyl)-3- (2-thienyl)-2-methylisoxazolidine derivatives as novel antifungal agents

The in vitro antifungal activity of a novel series of cis- and trans-5-([aryl or aryloxy (or thio)]methyl)-3-(1H-imidazol-1-ylmethyl)-3- (2-thienyl)-2-methylisoxazolidines (13-24) was evaluated and compared with ketoconazole. The title series of compounds was prepared via a 1,3-dipolar cycloaddition reaction of 1-(2-thienyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxides with appropriate styrenes, allyl phenyl ethers, or allyl phenyl thioether precursors. The resulting products were mixtures of the corresponding cis- and trans-diastereomers which were readily separated by flash chromatography on neutral silica gel. The majority of compounds 13-24, when tested in solid agar cultures, exhibited moderate to potent activity against Trichophyton rubrum, Aspergillus fumigatus, and Candida albicans at concentrations ranging between less than or equal to 2.0 and 70.0 micrograms/mL.     

Synthesis of aminoalkaloids derived from 8-hydroxy-7-methoxy-2H-1-benzopyran-2-one with expected beta-adrenolytic action

Synthesis of 8-hydroxy-7-methoxy-2H-1-benzopyran-2-one and syntheses of several 8-(3-amino-2-hydroxypropoxy)-7-methoxy-2H-1-benzopyran-2-one derivatives with antiarrhythmic activity is described.     

Transformation of 5,6-dimethoxy-2-amino-1-tetralol hydrochloride into 5,6-dimethoxy-2-tetralone

The reduction procedure of 5,6-dimethoxy-2-amino-1-tetralone with sodium bis-(2-methoxy)-aluminum hydride, followed by palladium on charcoal in the presence of HClO₄ gave a major reduction product of 5,6-dimethoxy-2-amino-tetralin, along with a small amount of a transformed 5,6-dimethoxy-2-tetralone. The isolated intermediate, 5,6-dimethoxy-2-amino-1-tetralol hydrochloride yielded exclusively 5,6-dimethoxy-2-tetralone under catalytic acidic conditions (acid treatment). The unusual rearangement was verified on the basis of IR, NMR and the result of elemental analysis. A plausible mechanism for the rearrangement is discussed.     

Synthesis of 4'- and 5'-hydroxyoxprenolol:pharmacologically active ring-hydroxylated metabolites of oxprenolol

Synthesis and preliminary pharmacological activity data for 4'- and 5'-hydroxyoxprenolol (2 and 3) are reported. The synthetic routes make use of the isomeric 2-pyranyl monoether derivatives of 4-hydroxysalicylaldehyde and 2,5-dihydroxyacetophenone. The corresponding O-allyl ethers were converted to substituted phenols by Baeyer-Villiger oxidation and the propanolamine side chain elaborated using epichlorohydrin, followed by oxirane ring opening with isopropylamine. Each of the hydroxylated metabolites is about ten times less potent than oxprenolol as an antagonist to the isoproterenol-induced relaxation of guinea pig tracheal strips.     

N-(6,6-二甲基-2-庚烯-4-炔基)-N-甲基-α-取代-1-(4-取代)萘甲胺类的合成及抗真菌活性

根据氮唑类和烯丙胺类抗真菌化合物的构效关系、作用机理。设计合成了30个N-(6,6-二甲基-2-庚烯-4-炔基)-N-甲基-α-取代-1-(4-取代)萘甲胺类化合物。初步体外抑菌试验结果表明,大多数目标化合物对八种试验菌株都有不同程度的抗真菌活性。化合物Ⅰ_1a的真菌活性大致与克霉唑相当,对白念珠菌的活性明显高于naftifine和terbinafine,但对其它七种菌株的活性均不及naftifine和terbinafine;化合物Ⅲ_1a对八种试验菌株的活性均与terbinafine相当。     

Synthesis of 1-(4-pyridyl)-2-amino-alkanoles

Synthesis of 1-(4-Pyridyl)-2-amino-alkanols The preparation of N-substituted derivatives of 1-(4-pyridyl)-2-amino-alkanols is described. In a preliminary pharmacological screening the compounds 3c, 3d, 3e, 3f showed β-receptor-blocking activity.     

Design and synthesis of a series of (2R)-N(4)-hydroxy-2-(3-hydroxybenzyl)-N(1)- [(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]butanediamide derivatives as potent, selective, and orally bioavailable aggrecanase inhibitors

A pharmacophore model of the P1' site, specific for aggrecanase, was defined using the specificity studies of the matrix metalloproteinases and the similar biological activity of aggrecanase and MMP-8. Incorporation of the side chain of a tyrosine residue into compound 1 as the P1' group provided modest selectivity for aggrecanase over MMP-1, -2, and -9. A cis-(1S)(2R)-amino-2-indanol scaffold was incorporated as a tyrosine mimic (P2') to conformationally constrain 2. Further optimization resulted in compound 11, a potent, selective, and orally bioavailable inhibitor of aggrecanase.     

Derivate des 2-Amino-1,2,3,4-Tetrahydronaphthalins,II. Synthese und pharmakologische Untersuchung von N-substituierten trans-2-Amino-3-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalinen

Derivatives of 2-Amino-1,2,3,4-Tetrahydronaphthalene, II: Synthesis and Pharmacological Investigation of N-Substituted trans-2-Amino-3-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalenes By epoxydation of 5,8-dimethoxy-1,4-dihydronaphthalene the epoxide I was obtained. Reactions with certain aminoalcohols and primary or secondary amines led to the N-substituted derivatives of trans-2-amino-3-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene 1--14 . On pharmacological testing the hydrochlorides of the new compounds showed significant biological activity.     

Synthesis of 4-hydroxy-1-thiocoumarin derivatives-1: An efficient synthesis of thioflocoumafen

An efficient procedure for the preparation of 4-hydroxy-3-{1,2,3,4-tetra-hydro-3-[4-(4-triflu-oromethylbenzyl oxy)phenyl]-1-naphthyl}thiocoumarin (thioflocoumafen, 1a and 1b) is described. The key step in the synthesis involves the condensation reaction of 3-(4-methoxyphenyl)-1-tetralol (2) with 4-hydroxy-1-thiocoumarin (3).     

Metabolism and nephrotoxicity of indan in male Fischer 344 rats

Indan, a component of fuels, solvents, and varnishes, is metabolized in male Fischer 344 rats to 1-indanol, 2-indanol, 5-indanol, 1-indanone, 2-indanone, 2-hydroxy-1-indanone, cis-1,2-indandiol, and trans-1,2-indandiol. The metabolites were identified using the techniques of gas chromatography (GC) and gas chromatography/mass spectrometry (GC/MS). The rats treated with indan demonstrated the classic lesions of hydrocarbon-induced nephropathy. The kidney damage produced was less than that found for tetralin and other branched-chain acyclic hydrocarbons.