Biotransformation and pharmacokinetics of the nitrate trans-2-amino-2-methyl-N-(4-nitroxycyclohexyl)-propionamide in dogs.

The biotransformation and the pharmacokinetic behavior of the organic nitrate trans-2-Amino-2-methyl-N-(4-nitroxycyclohexyl)-propionamide (BM 12.1179, CAS 129795-96-6) were examined in dogs. BM 12.1179 was predominantly eliminated by urinary excretion, and the unchanged molecule prevailed in urine as well as in plasma. By means of various mass spectroscopic methods, the chemical structures of the metabolites were elucidated. As metabolites trans-2-amino-2-methyl-N-(4-hydroxycyclohexyl)-propionamide and trans-2-amino-2-methyl-N-(4-oxocyclohexyl)-propionamide were formed. Urine levels of the main metabolite were determined by high-pressure liquid chromatography; plasma and urine levels of BM 12.1179 were determined by capillary gas chromatography. The absolute bioavailability of BM 12.1179 was 80-100%. The plasma protein binding was about 34% which is high in comparison to other organic nitrates. BM 12.1179 represents a long-acting organic nitrate in that it shows a slow reductive denitration, and a long elimination half-life of about 10 h.     

Pethidin-Analoga mit eingeschränkter Konformation, 2. Mitt.: Stereoselektive Synthese von trans-4-Methyl-10b-carbethoxy-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)chinolin

Pethidine Analogs with Restricted Conformation, II¹⁾: Stereoselective Synthesis of trans-4-Methyl-10b-ethoxycarbonyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline Compound 6 , readily available from 4 , reacts with benzylamine to give trans- 9 . The reaction is thermodynamically controled. N-methylation of trans- 9 yields 11 . This can be alkylated by allyl bromide with inversion at C-1 to yield 12 . Subsequent hydroboration and iodation furnish the heterocycle trans- 14 which is catalytically debenzylated to yield the title compound 2a . The configuration of 2 is nmr-spectroscopically assigned with the aid of trans-methoiodide 15a , trans- 1 , and trans- 16 . Compound 12 is converted to the carbinol 13 by hydroboration. Halogenation of 13 causes cyclisation to 14 which, when prepared by this route, fails to undergo hydrogenolysis to 2a . The hydroxy esters 4 , accessible from 3 , can be alkylated to 7 which in turn is oxidized to 8 . Halogen nitrogen exchange or reductive amination fail to yield 2a . Compound 3 resists cyanoethylation, whereas under identical conditions 5 is transformed into 6 by elimination.     

氟他胺邻位硝基异构体的研究

氟他胺邻位硝基异构体的研究杨征宇，夏奕，郑筠青，夏鹏（上海医科大学药学院有机化学教研室上海２０００３２；中国科学院上海有机化学研究所上海２０００３２）氟他胺（ｆｌｕｔａｍｉｄｅ，Ｉ）是美国先灵药厂生产的一种非甾体抗雄激素药物，临床上用于治疗前列腺癌。...     

Metabolism of tetramethrin isomers in rat: IV. Tissues responsible for formation of reduced and hydrated metabolites

1. To identify the sites of formation of the reduced metabolites, 3-hydroxycyclohexane-1,2-dicarboximide (3-OH-HPI-1 and-2), 1,2-cyclohexanedicarboxylic acid (TCDA) and 1-hydroxy-1,2-cyclohexanedicarboxylic acid (1-OH-HPA), in rat treated with ¹⁴C-labelled (1 RS, trans)-tetramethrin, [3,4,5,6-tetrahydrophthalimidomethyl (1 RS, trans)-chrysanthemate], bile-duct cannulated animals were orally or intravenously administered ¹⁴C-labelled 3,4,5,6-tetrahydrophthalimide (TPI) or 3,4,5,6-tetrahydrophthalic acid (THPA), precursors of these metabolites, and bile, urine and faeces were collected for analysis. 2. 3-OH-HPI-1 and 3-OH-HPI-2, which are cis-form reduced metabolites, and 1- OH-HPA were detected in bile and urine samples of the bile-cannulated rat treated intravenously and orally with ¹⁴C-labelled TPI, indicating their formation in tissues or blood. TCDA, a trans-form reduced metabolite, was not detected in bile, urine or faeces of the bile-cannulated rat treated intravenously with ¹⁴C-THPA, but was found in the faeces after oral application, indicating formation in the gastrointestinal tract. 3. To clarify whether 1-OH-HPA is produced from THPA via TCDA (hydroxylation via reduction) or by direct addition of H₂O to its double bond (hydration), rats were orally administered ¹⁴C-labelled TCDA, and metabolites in urine and faeces were analysed. The observed lack of 1-OH-HPA indicated formation by direct addition of H₂O to the doublebond of THPA. 4. To specify whichtissues form reduced and hydratedmetabolites, in vitro metabolism studies were carried out. Reduction to the cis-form was found to take place in blood cells, reduction to the trans-form took place in the gastrointestinal tract contents, and hydration took place in the liver and the intestinal tract contents.     

Formation of a diazonium cation intermediate in the metabolism of sulphamethazine to desaminosulphamethazine in the rat

¹⁴C-Sulphamethazinediazonium tetrafluoroborate (¹⁴C-SDTFB) when orally administered to rats was converted primarily to ¹⁴C-labelled desaminosulphamethazine (desaminosulmet) and methanol-insoluble residues in the gastrointestinal tract (gut). ¹⁴C-labelled sulphamethazine (sulmet), N⁴-acetylsulmet, the N⁴-glucose conjugate of sulmet and other unidentified products were also observed in the tissues and urine of rats given ¹⁴C-SDTFB.

2. When ¹⁴C-sulmet, nitrite and dimethylaniline were simultaneously administered to a rat by the oral route, one of the ¹⁴C-labelled products formed in the stomach was isolated and identified as 4-dimethylaminophenyl[4-(N-4,6-dimethyl-2-pyrimidinyl)sulphamidophenyl]diazene, providing evidence that ¹⁴C-sulmet was diazotized in the stomach of the animal.

3. SDTFB was weakly mutagenic when evaluated by the Ames test.

4. The methanol-insoluble ¹⁴C-labelled residues in the gut of rats dosed orally with ¹⁴C-SDTFB and ¹⁴C-sulmet + nitrite were partially converted to ¹⁴C-labelled desaminosulmet, sulmet, N⁴-acetylsulmet and other unidentified products when fed to recipient rats.     

Zur Kenntnis einiger Hydroxamsäuren mit (s-trans)-Anordnung

Hydroxamic Acids with s-trans Structure Hydroxamic acids with sufficient steric hindrance (tert-butyl, 1-adamantyl) on N and C-2 are capable of forming a stable s-trans configuration (conformation). The N-standing group undergoes thermic elimination.     

Derivate des 2-Amino-1,2,3,4-tetrahydro-naphthalins, 5. Mitt. Synthese des trans-2-Amino-3,5,8-trihydroxy-1,2,3,4-tetrahydronaphthalins und seiner N-substituierten Derivate

Derivatives of 2-Amino-1,2,3,4-tetrahydronaphthalene, V: Syntheses of trans-2-Amino-3,5,8-trihydroxy-1,2,3,4-tetrahydronaphthalene and N-Substituted Derivatives. The trans-aminoalcohol 14 was synthesized by ammonolysis of 5,8-dimethoxy-2,3-epoxytetraline (I) . The hydrochloride of 14 was further demethylated and trans-2-amino-3,5,8-trihydroxy-tetraline hydrobromide (14a ) was obtained. Similarly the hydrobromides of the 3,5,8-trihydroxy-analogues 1a–13a were obtained from the N-substituted trans-2-amino-3-hydroxy-5,8-dimethoxytetraline hydrochlorides 1–13 .     

Synthesis and Authentication of Iodoazidophenpyramine,a Photoaffinity Reporter Ligand Previously used for Histamine H1-Receptor Labelling

The synthesis is described of aminophenpyramine ( 7 ) (N-{5-[2-(4-aminophenyl)ethananmido]pentanyl}-N′-(4-methoxybenzyl)-N-methyl-N′-(2-pyridinyl)-1,2-ethandiamine), its monoiodo- and diiodo-derivatives ( 8 and 9 ), and iodoazidophenpyramine ( 1 ). The last compound is synthesised by two different routes to confirm the identity of the [¹²⁵I]iodinated ligand previously made only in solution and used for characterisation of the histamine H₁-receptor protein. The procedures employ the novel intermediates 4-amino-3-iodo-phenylacetic acid ( 11 ) and 4-azido-3-iodo-phenylacetic acid ( 13 ). They have general applicability to the synthesis of non-radioactive iodinated photoaffinity receptor ligands which may be required for chemical authentication of the corresponding radiolabelled compounds.     

Metabolism of N-[4-chloro-2-fluoro-5-[(1-methyl-2-propynyl)oxy]phenyl]-3,4,5,6-tetrahydrophthalimide (S-23121) in the rat. II. Absorption,disposition, excretion and biotransformation

1. To examine the metabolic fate of N-[4-chloro-2-fluoro-5-[(1-methyl-2-propynyl)oxy]phenyl]-3,4,5,6-tetrahydrophthalimide (S-23121), rats were given a single oral dose of [phenyl-¹⁴C]S-23121 at 1 or 250mg/kg.

2. The radiocarbon was almost completely eliminated from the rat within 7 days after administration for both dose groups. Faecal ¹⁴C-excretion was major (71-86% of the dose) and urinary ¹⁴C-excretion was minor (18-30%).

3. ¹⁴C-tissue residues on the seventh day after administration were generally very low. Peak ¹⁴C-concentrations in the kidney and liver occurred 4h after administration and decreased rapidly thereafter. Amounts (percentage of dose) of the parent compound in faeces were 13-26% for low dose, and 22-35% for high dose.

4. The major metabolites in faeces were sulphonic acid conjugates (13-20% of the administered dose), formed by incorporation of a sulphonic acid group into the double bond of the tetrahydrophthalimide. The major metabolites in urine were sulphates and glucuronides of 4-chloro-2-fluoro-5-hydroxyaniline, amounting to 5-7 and 2-3% of the administered dose, respectively. Sulphonic acid conjugates were not detected in urine, blood, kidney or liver.     

Metabolic pathways of the contragestational agent, 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-lH-l, 2,4-triazole (DL 111-IT), in the rat

1. The metabolic pathways of the non-hormonal anti-fertility agent 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-lH-l,2,4-triazole (DL 111-IT) were studied in rats given the ¹⁴C-labelled compound intramuscularly.

2. The diaryltriazole, once absorbed, was metabolized rapidly by three phase I reactions: (a) hydroxylation at the C-4 of the methoxyphenyl ring, (b) hydroxylation at the α-C of the ethyl chain, and (c) demethylation of the methoxyl function.

3. Seven free metabolites and three conjugates have been isolated and characterized by u.v., i.r., n.m.r. and mass spectroscopy.

4. The products of the first step of metabolism of the diary ltriazole were tested for their pregnancy-terminating activity in the rat. They were only 5-9% as effective as the parent compound, indicating that the unchanged drug is the active molecule.     

Derivate des 2-Amino-1,2,3,4-tetrahydronaphthalins,III. Synthese einiger N'-substituierter N-(trans-3-Hydroxy-1,2,3,4-tetrahydro-2-naphthyl)-piperazine

Derivatives of 2-Amino-1,2,3,4-tetrahydronaphthalene, III: Synthesis of Some N'-Substituted N-(trans-3-Hydroxy-1,2,3,4-tetrahydro-2-naphthyl)piperazines The synthesis of the N'-substituted N-(trans-3-hydroxy-1,2,3,4-tetrahydro-2-naphthyl)piperazines 2 – 5 and of trans-2-morpholino-3-hydroxy-1,2,3,4-tetrahydronaphthalene ( 6 ), starting from 2,3-epoxytetralins 1 , is reported. The new Mannich bases 3 show hypotensive and antiarrhythmic activities.     

The preparation of tritiated E- and Z-4-aminobut-2-enoic acids,conformationally restricted analogues of the inhibitory neurotransmitter 4-aminobutanoic acid (GABA)

A synthesis of [³H]E- and [³H]Z-4-aminobut-2-enoic acids from methyl 4-N-phthalimidobut-2-ynoate by catalytic hydrogenation using tritium gas in the presence of a homogeneous catalyst, tris(triphenylphosphine)rhodium(I) chloride, is reported. HPLC separation of the E- and Z-isomers, and the saturated analogue, 4-aminobutanoic acid (GABA), is also described.     

Alkaloids from Erythroxylum vacciniifolium MARTIUS, II: The structures of catuabine A, B, and C (author's transl)

Alkaloids from Erythroxylum Vacciniifolium Martius, II: The Structures of Catuabine A, B, and C The alkaloids Catuabine A ( 1 ), B ( 2 ) and C ( 3 ) are the hitherto unknown diesters of tropane-3,7-diol. As shown by ¹H-NMR spectroscopy, all three esters have α-configuration at C-3. The configurations at C-7 are β, according to the ¹³C-NMR spectra. 3,4,5-Trimethoxybenzoic acid (A and B) and pyrrole-2-carboxylic acid (C) are bound at C-3. N-Methylpyrrole-2-carboxylic acid (A and C) and benzoic acid (B) are bound at C-7. A complete interpretation of the ¹³C-NMR-spectrum of Catuabine A is given.     

Reaktionsmechanismus der Hydantoinsynthese nach Biltz, 2. Mitt.: Einfluß der Substituenten auf die Umlagerungsrichtung

Concerning the Reaction Mechanism of the Hydantoin Synthesis According to Biltz, II: Influence of Substituents on the Direction of the Rearrangement From 1-¹³C-labelled 4-monosubstituted benzils 1a - c and the ureas 3a - d the 5-aryl-5-phenylhydantoines 6a - c and the 3-substituted 5-aryl-5-phenylhydantoines 9a - i were obtained as mixtures of isotopomeres. The distribution of ¹³C-labelling of C-4 and C-S was determined by mass- and ¹³C-nmr-spectroscopy. As in the case of benzilic acid rearrangement the 4-methylphenyl- and 4-methoxyphenyl-increment, respectively, migrate less easily than does the unsubstituted phenyl group, which in turn migrates less easily than the 4-chlorophenylrest. In the latter case the differences are small and in one example even slightly reversed. The characteristics of the rearrangement is explained by thermodynamic control of the reaction by preceding equilibria (Schemes 2 and 3).     

Pharmacokinetics of the organic nitrates trans-2-amino-2-methyl-N-(4- nitroxycyclohexylmethyl)-propionamide in dogs, and of 4-(2-nitroxyethyl)-piperidine in dogs and in monkeys.

The plasma concentrations of the organic nitrates (nitric acid esters) trans-2-amino-2-methyl-N-(4-nitroxycyclohexylmethyl)-propionamide (BM 12.1200) and of 4-(2-nitroxyethyl)-piperidine (BM 12.1173, CAS 129999-77-5) were determined in dog plasma by capillary gas chromatography with electron capture detection (GC-ECD). Intra- and interassay variation coefficients of the gas chromatographic analysis lay between 2.9 and 8.8%; recoveries amounted to 50-62%. Both nitric acid esters were absorbed quickly and attained maximum plasma levels within 1 h. The total bioavailability of BM 12.1200 is > 55%, and that of BM 12.1173 is 63%; their elimination half-lives are, respectively, 4.2 h and 1.3-1.4 h. Thus, BM 12.1173 and the reference substance IS-5-MN (isosorbide-5-mononitrate) show corresponding elimination half-lives. These results regarding the pharmacokinetic parameters of BM 12.1173 were confirmed by cross-over application of BM 12.1173 and IS-5-MN to Macaca Arctoides. In comparison to all species which have been treated with IS-5-MN thus far, the shortest elimination half-life (t1/2 = 0.6 h) is found in monkeys.     

The Metabolism of Tamoxifen (I.C.I. 46,474) Part I : In Laboratory Animals

Abstract

1. The metabolism and excretion of a non-steroidal oestrogen antagonist, tamoxifen (I.C.I. 46,474) [trans-1-(p-β-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene], has been studied in rat, mouse, rhesus monkey and dog using the ¹⁴C-labelled compound.

2. In all species the compound was well absorbed and extensively metabolized after oral administration. The ¹⁴C was slowly eliminated, largely in the faeces. No loss of ¹⁴C as carbon dioxide could be detected in expired air from small animals.

3. In most of the species levels in the blood were low and showed two maxima following oral dosing. Enterohepatic circulation was demonstrated in rat and dog.

4. Metabolic patterns were qualitatively similar in all the species examined. Metabolites were isolated from faecal extracts and bile. Most of the ¹⁴C-labelled material was present as glucuronides and other conjugates. Hydroxylation was a significant metabolic pathway in all species.

5. A novel metabolite formed by deamination of the side chain, hydroxylation of an aromatic ring and oxidation of the ethyl group was present in rat bile.     

An Exploration of the Structure-activity Relationships of 4−Aminoquinolines: Novel Antimalarials with Activity In-vivo

The structure-activity relationships of bisquinolines, a potentially important group of novel antimalarial drugs, were studied. The high-temperature (180?250°C) synthesis of 4?aminoquinolines, including bisquinolines, by nucleophilic displacement was both fast and efficient. Several bisquinolines including (±)-trans-N¹,N²-bis(7?trifluoroquin-olin-4?yl)cyclohexane-1,2?diamine and 1R,2R-(-)-, 1S,2S-(+)-, (±)-trans- and cis-N¹,N²-bis(7?chloroquin-olin-4?yl)cyclohexane-1,2?diamine exhibited potent activity against Plasmodium berghei in mice; (±)-trans-N¹,N²-bis(7?chloroquinolin-4?yl)cyclohexane-1,2?diamine was orally active. Our results indicate that these compounds conform to a putative receptor for quinoline antimalarials. In addition, a 7?haloquinoline linked by a heterocyclic bridge, at the 4?position, to another heterocycle (such as an acridine at the 9?position) maximally occupies the active site of our postulated target.     

1H- und 13C-NMR-spektroskopische Zuordnung der cis- und trans-Isomere einiger 1-Aryl-1,2,3,4-tetrahydro-β-carbolin-3-carbonsäuren bzw. deren Methylester

¹H- and ¹³C-NMR Spectroscopic Assigment to the cis and trans Isomers of Some 1-Aryl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic Acids and their Methyl Esters The cis and trans isomers of the tetrahydro-β-carbolines 3 and 4 were assigned on the basis of the shifts of the NMR signals of the proton at C-1 and of the carbon atoms C-1 and C-3.     

Synthesis of N-(4-aminobenzoyl)-γ-oligo (L-glutamic acid)s*

N-(4-aminobenzoyl)-γ-oligo (l -glutamic acid)s (6) containing from two to six glutamic residues have been prepared in solution using Nα-Boc-α-Bzl protections and isobutyl-chlorocarbonate activation. Key steps in the synthesis were the coupling of γ-oligo(α-benzyl l -glutamate) benzyl esters (1) with N-(4-benzyl-oxycarbonylaminobenzoyl)-l -glutamic acid α-benzyl ester (4) to blocked precursors of N-(4-aminobenzoyl)-γ-oligo (l -glutamic acid)s (5) and catalytic hydrogenolysis of 5 to 6. Elaboration of the required oligo γ-l -glutamate chains (1) was achieved step by step beginning with the coupling of glutamic acid dibenzylester with N-(t-butoxycarbonyl)-l -glutamic acid α-benzyl ester (2) to 3 followed by selective removal of the Boc from 3 with HCl-dioxane followed by coupling with 2.     

Metabolites of 2-(3-Trifluoromethylphenyl)Tetrahydro-1,4-Oxazine (Cerm 1841) in Rats and Dogs

1. In rats and dogs dosed with ¹⁴C-labelled 2-(3-trifluoromethylphenyl)tetrahydro-1,4-oxazine hydrochloride, the ¹⁴C was excreted mainly in the urine. The ¹⁴C eliminated in the faeces of dog was significantly higher than for rat.

2. Conjugated metabolites, mostly glucuronides, accounted for the greater part of the urinary radioactivity in both species.

3. Biotransformation products were predominantly acids in both species, followed by significant amounts of basic metabolites, with very little neutral substances.

4. The major urinary metabolite in rats was 3-trifluoromethylbenzoic acid and 3-trifluoromethylhippuric acid. In the dog it was 3-trifluoromethylmandelic acid in addition to the benzoic acid and its conjugate. The basic products identified in the urine of both species were unchanged drug and 1-amino-2-hydroxy-2-(3-trifluoromethylphenyl)ethane, with the first predominating.