Michael-Additionen mit N-Acylaminosäureestern, 5. Mitt. Synthese von 3-Bicycloaryl-2-carboxy-pyrrolidonen-5 als Bausteine für 17-Azasteroide

Michael-Additions with Esters of N-acylamino Acids, V: Synthesis of 3-Aryl-5-oxopyrrolidine-2-carboxylates as Key Intermediates for 17-Azasteroids 3-Aryl-5-oxopyrrolidine-2-carboxylates were prepared by Michael-addition from esters of N-acylamino acids and ethyl 2-arylacrylates.     

3-NITRO-2-PYRIDINESULFENYL (Npys) GROUP

The novel 3-nitro-2-pyridinesulfenyl (Npys) group, which is useful for the protection and the activation of amino and hydroxyl groups for peptide synthesis, is reported. The Npys group is readily introduced by treatment of amino acids with 3-nitro-2-pyridinesulfenyl chloride. The Npys group is easily removed by treatment with very dilute HCl, e.g. 0.1-0.2 N HCl in dioxane, but it is resistant to trifluoroacetic acid and 88% formic acid. Npys is also selectively removed under neutral conditions using triphenylphosphine or 2-pyridinethiol 1-oxide without affecting benzyloxycarbonyl (Z), tert-butyloxycarbonyl (Boc), 2-(4-biphenylyl) propyl(2) oxycarbonyl (Bpoc), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyl (Bzl) or tert-butyl (tBu) protecting groups. The N-Npys and O-Npys groups when activated in the presence of RCOOH by the addition of tertiary phosphine form peptide or ester bonds via oxidation-reduction condensation. The important features of the Npys group are demonstrated through the synthesis of peptides in solution and by solid phase methodology without a formal deprotection procedure. In solid phase synthesis, 4-(Npys-oxymethyl) phenylacetic acid is used as the key intermediate for the introduction of the trifluoroacetic acid resistant 4-(oxymethyl) phenylacetamido linking group to the resin.     

Identification of Four New Metabolic Products of Metoclopramide using Mass Spectrometry

1. N-(Diethylaminoethyl)-4-amino-5-chloro-2-methoxybenzamide (metoclo-pramide, I), N-(ethylaminoethyl)-4-amino-5-chloro-2-methoxybenzamide (II), N-(aminoethyl)-4-amino-5-chloro-2-methoxybenzamide (III), N-(2′-hydroxy-ethyl)-4-amino-5-chloro-2-methoxybenzamide (IV), N-(diethylaminoethyl)-4-amino-5-chloro-2-hydroxybenzamide (V), and N-(ethylaminoethyl)-4-amino-5-chloro-2-hydroxybenzamide (VI) were obtained from chloroform extracts of incubation mixtures of I or II (HC1 salts) with 9000 g liver microsomal preparations from male rabbits.

2. Mass spectrometry (electron impact, chemical ionization and high resolution) was used to identify low concentrations of these products.     

LDA-Katalysierte Diastereoselektive Michael-Additionen Mit Glycinderivaten: Synthese von 4-Substituierten 3-Aryl-2-N(Diphenyl-Methylen)-glutaminsäureestern und Ihre Umwandlung in 4-Substituierte 3-Aryl-2-Ethoxycarbonyl-5-Oxo-Pyrrolidine

LDA-catalyzed Diastereoselectlve Michael -Additions with Glycine Derivatives: Synthesis of 4-Substituted 3-Aryl-N(diphenylmethylene)glutamates Followed by Cyclization to 4-Substituted 3-Aryl-2-ethoxycarbonyl-5-oxo-pyrrolidines Synthesis and stereochemistry of 4-substituted diethyl 3-aryl-N(diphenylme-thylene)glutamate 3 by LDA-catalyzed Michael addition of ethyl-N(diphe-nylmethylene)glycinate with diethylbenzylidene-malonate or ethyl-2-cyano-cinnamates, respectively, are reported. Deprotection yields diethyl-3-aryl-glutamates 4 which are easily cyclized to 4-substituted 3-aryl-2-ethoxycarbnyl-5-oxo-pyrrolidines 5.     

Nitramine, 8. Mitt.: Zur Umsetzung von Alkylnitraminen mit 2-Chloralkyl-dialkylaminen

The Reaction of Alkylnitramines with Dialkl-(2-chloroalky) amines Sodium methylnitramide ( 1a ) reacts with dialkyl-(2-chloroalkyl) amines ( 4a - c ) to yield N,N-dialkylnitramines ( 5a - c ) and thus differs from sodium ethylnitramide ( 1b ). The reaction of 2-chloroethyl(cycloalkyl) amines ( 4d - f ) with 1a or 1b leads to N,N-dialkylnitramines and 2-alkyloxy-1-alkyldiazene 2-oxides. From ( 1a ) und 2-chloro-1 (dimethylamino) propane ( 4g ) a mixture of three products is formed, which could be separated.     

Design and synthesis of novel N-substituted-3-chloro-2-azetidinone derivatives as potential anticonvulsant agents

Abstract  

A new series of N-[3-chloro-2-(substitutedphenyl)-4-oxo-azetidin-1-yl]isonicotinamide (2a–l) were synthesized through condensation reaction of isoniazide with substituted aldehyde. The newly synthesized compounds were characterized by spectral data (IR, ¹H NMR, mass spectra) and elemental analysis. Compound 2e exhibited excellent anticonvulsant activity and no neurotoxicity in comparison to reference drug phenytoin.     

Reaktionen von N-Alkoxycycliminiumsalzen, 11. Mitt.1) Reaktionen von 2-Chlor-N-methoxy-3-(-4)-nitropyridinium-(perchlorat) mit Aminen

Reactions of N-Alkoxycycliminium Salts, XI: Reactions of 2-Chloro-N-methoxy-3-or-4-nitropyridinium Perchlorate with Amines Reactions of 3-, 4- and 5-nitro-2-chloro-N-methoxypyridinium salts with aromatic and aliphatic amines show a remarkable dependence with regard to reactivity and pathway on the position of the nitro group. While reactions of the 3-nitro derivative 1a are characterized by attack at position 6 of the pyridine ring followed by ring cleavage yielding stable 1-methoxyimino-2,4-pentadiene derivatives, reactions of the 4-nitro compound 1b are more complex and the reactivity is remarkably decreased.     

Synthese und Eigenschaften des 3-Hydroxy-1,10-dioxo-5,10-dihydro-1H-pyrido[2,1-b]chinazolin-2-carbonitrils

Synthesis and Properties of 3-Hydroxy-1,10-dioxo-5,10-dihydro-1H-pyrido[2,1-b]quinazoline-2-carbonitrile Anthranilic acid reacts with 2-chloro-5-cyano-4-hydroxypyrid-6-one (3) in glacial acetic acid to yield 3-hydroxy-1,10-dioxo-5,10-dihydro-1H-pyrido[2,1-b]quinazoline-2-carbonitrile (4) . When the reaction is carried out in DMF under Ullmann conditions, 2-(dimethylamino)-5-cyano-4-hydroxypyrid-6-one (5) forms as a by-product. The methylation of 3 with diazomethane affords 2-chloro-5-cyano-2-methoxy-N-methylpyrid-6-one (9) and 2-chloro-5-cynao-4,6-dimethoxypyridine (10) . Under similar conditions compound 4 undergoes an esterifying ring cleavage to furnish methyl 2-(5-cyano-4,6-dimethoxypyrid-2-ylamino)benzoate (7) .     

Zur Umsetzung von Trialkylsulfonyldiamiden mit 2-Chlor-1-dimethylaminopropan und 3-Chlor-1-ethylpiperidin

Reactions of N,N,N′-Trialkylsulfonyldiamides with 2-Chloro-N,N-dimethylpropanamine and 3-Chloro-1-ethylpiperidine Sodium N,N,N′-trimethylsulfonyldiamide (1) was reacted with 2-chloro-N,N-dimethylpropanamine to yield the isomers 2 and 3 which were separated by column chromatography. The reactions of 1 and 4 with 3-chloro-1-ethylpiperidine gave only one isomer each, namely 6a and 6b .     

Metabolism of 6-Chloro-5-cyclohexylindane-1-carboxylic Acid (TAI-284), a New Non-steroidal Anti-inflammatory Agent. II. Isolation and Identification of Metabolites in the Perfusate of the Isolated Liver Perfusion in Rats

Abstract

1. Biotransformation of 6-chloro-5-cyclohexylindane-1-carboxylic acid labelled with tritium and deuterium was studied in isolated perfused rat liver. Five metabolites were isolated by column and thin-layer chromatography.

2. The metabolites and their methyl esters were characterized by mass and proton magnetic resonance spectrometry with aid of a shift reagent, tris(dipivalomethanato)europium. The following metabolites were identified : 6-chloro-5-(4′-oxocyclohexyl)indane-1-carboxylic acid(metabolite I),6-chloro-5-(cis-4′-hydroxycyclohexyl)indane-1-carboxylic acid (metabolite IIa), 6-chloro-5-(trans-4′-hydroxycyclohexyl)indane-1-carboxylic acid (metabolite III), 6-chloro-5-(cis-3′-hydroxycyclohexyl)indane-1-carboxylic acid (metabolite IV or IIb). Metabolites IV and IIb are diastereoisomers.

3. The compound was metabolized primarily by hydroxylation producing metabolites IIa (cis-4′-ol), IIb (cis-3′-ol), III (trans-4′-ol) and IV (cis-3′-ol). Metabolites IIa and III seemed to be further metabolized to I (4′-oxo).     

Metabolism of clebopride in vitro Identification of N-oxidized products

1. N-(1′-Benzyl-4′-piperidyl-N-oxide)-4-amino-5-chloro-2-methoxybenzamide,N-(4′-(N-hydroxylpiperidyl))-4-amino-5-chloro-2-methoxybenzamide and N-(4′-(Δ1′-piperidyl-N-oxide))-4-amino-5-chloro-2-methoxybenzamide were obtained from chloro- form extracts of incubation mixtures of clebopride or desbenzyl clebopride with 9000g supernatant of liver homogenates of male NZW rabbits.

2. These metabolites were identified using electron impact (low and high resolution) and field desorption mass spectrometry, and computer averaged time proton magnetic resonance spectroscopy.     

Synthesis of 5-imino-5H-dipyrido[1,2-a; 2',3'-d]pyrimidines as potential antiallergy agents (1)

A novel route to 5-imino-5H-dipyrido[1,2-a; 2',3'-d]pyrimidines is described. The method is based on the Ullmann condensation of 2-chloro-3-cyano-5-nitropyridine with 2-amino-pyridine 1-oxides, followed by intramolecular cyclization of the resulting 2-(3-cyano-5-nitro-2-pyridylamino)pyridine 1-oxides with phosphorous trichloride.     

Tumorhemmende Wirkstoffe, 12. Mitt. 2-Ureido-4(3H)-pyrimidinone

Tumor Inhibitory Agents, XII: 2-Ureido-4(3H)-pyrimidinones The condensation of guanidinecarboxylic amide ( 1 ) with the β-ketocarboxylates 2a - h leads to the 2-ureido-4(3H)-pyrimidinones 3a – h . The applicability of this reactin to cyclic ketocarboxylates is demonstrated by the condensation of 1 with ethyl 2-oxocyclohexanecarboxylate ( 2i ) which yields 2-ureido-5,6,7,8-tetrahydro-4(3H)-quinazolone( 3i ). Compound 3h exhibits tumor inhibitory activity.     

Eine bequeme Synthese von 2-Aryl-2-vinyl-[1,3]-dioxolanen und -dioxanen

A Convenient Synthesis of 2-Aryl-2-vinyl-[1,3]-dioxolanes and -dioxanes Cyclocondensation of γ-aryl-γ-oxosulfones 1 with 1,2- or 1,3-dioles 2 and 3 leads to 2-aryl-2-sulfonylethyl-[1,3]-dioxolanes 4 , and -dioxanes 5 , respectively. In the presence of potassium tert-butoxid 4 and 5 eliminate sulfinic acid yielding the title compounds 6 and 7 .     

Acetylenchemie, 3. Mitt. Ein einfacher Zugang zum Flindersin via Phasen-Transfer-Reaktion

Acetylene Chemistry, III: A Simple Approach to Flindersine by Phase-Transfer Reaction Reaction of 4-hydroxyquinolin-2-one (4) with 3-chloro-3-methylbut-1-yne by phase-transfer catalysis affords flindersine (3) and 2,3-dihydro-3,3-dimethyl-2-methylenefuro[3,2-c]quinolin-4-one (5) , whereas indolin-2-one (4g) yields N-(1′,1′-dimethylprop-2-yn-1-yl)indolin-2-one (19) . The reaction mechanism is discussed and studied by varying the reaction conditions.     

Synthesis and Antimicrobial Activity of Some New 5-Nitrofuran Derivatives

Starting from 5-nitro-2-furoyl azide (1) , some new 5-nitro-2-furamides 2a–d , O-alkyl N-(5-nitro-2-furyl)carbamates 3a,b and 5-nitro-2-ureidofurans 4a,b were synthesized and tested for in vitro antimicrobial activity. Compounds 2c and 2d exhibited appreciable activity against S. pyogenes and S. aureus.     

2-Aminobenzo[b]thiophencarbonsäureester aus 3-Hydroxy-2-nitro-1-thiochromon

2-Aminobenzo[b]thiophenecarboxylic esters from 3-Hydroxy-2-nitro-1-thiochromone 3-Hydroxy-2-nitro-1-thiochromone (1b) , when mixed with bases in alcoholic solution, yields the 2-nitro-benzothiophene-3-carboxylates 4a and 4b as well as the 2-amino-3-benzothiophene-3-carboxylates 11a and 11b . Under the same conditions, 3-methoxy-2-nitro-1-thiochromone (1c) yields 3-amino-2-nitro-1-thiochromone (12) . Compound 1b reacts with morpholine in dioxane to give 2-nitro-benzothiophene-3-carboxamide (10) .     

The Biotransformation of 8-Chloro-6-phenyl-4H-s-triazolo[4, 3-a][1,4] benzodiazepine (D-40TA), a New Central Depressant,in Man,Dog and Rat

1. Metabolic studies of 8-chloro-6-phenyl-4H-^s-triazolo [4,3-a] [1,4] benzodiazepine (D—40TA) in man, dog and rat led to identification of the following metabolites: six hydroxylation products; 8-chloro-2,4-dihydro-6-phenyl-1H-s-triazolo[4,3-a] [1,4]benzodiazepin-1-one (I), 8-chloro-6-(4-hydroxyphenyl)-4H-s -triazolo[4,3-a][1,4]benzodiazepine (II), 8-chloro-6- (3-hydroxyphenyl)-4H-s-triazolo[4,3-a] [1,4] benzodiazepine (III), 8-chloro-4-hydroxy-6-phenyl-4H-s- triazolo[4,3-a][1,4]benzodiazepine (IV), 8-chloro-2,4-dihydro-6- (4-hydroxy-phenyl)-1H-s-triazolo[4,3-a] [1,4] benzodiazepin-1-one (V) and 8-chloro-2,4-dihydro-6-(3-hydroxyphenyl)- 1H-s- triazolo[4,3-a][1,4]benzodiazepin-1-one (VI); five ring-opened metabolites; 5-chloro-2-(4H-1,2,4-triazol-4-yl) -benzophenone (VII), 5-chloro-2- (2,3-dihydro-3-oxo- 4H -1,2,4- triazol-4-yl)benzophenone (VIII), 5-chloro-2- (2,3-dihydro-3-oxo-4H - 1,2,4-triazol-4-yl)-2-hydroxybenzophenone (IX), 5-chloro-2- (2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl)-4'-hydroxybenzophenone (X) and 5-chloro-2-(3,5-dioxo-2,3,4,5-tetrahydro-1H-1,2,4-triazol-4-yl) benzophenone(XI).

2. In man, metabolites I, IV, VII and VIII are present as the free form in the urine, and I, II, IV and VIII are present as conjugates. In the dog, all the metabolites are present. The rat transforms the compound mainly to metabolites I, II, IV and V. None of the ring-opened metabolites are observed in the rat.     

N-Hydroxy-N-arylacetamides. III: Mechanism of haemoglobin oxidation by N-hydroxy-4-chloroacetanilide in erythrocytes in vitro

1. N-Hydroxy-4-chloroacetanilide(N-hydroxy-4ClAA) was the most active, and N-hydroxy-2-acetylaminofluorene(N-hydroxy-2AAF) the least active compound among six N-hydroxy-N-arylacetamides, in forming ferrihaemoglobin(HbFe³⁺) in bovine erythrocytes in the presence of 11 mM glucose.

2. N-Hydroxy-4ClAA oxidized 25 equiv. of HbFe²⁺, both in the presence and absence of glucose or lactate. Therefore, its catalytic properties did not depend on metabolic regeneration by the NADPH- or NADH-dependent erythrocyte reductases.

3. In contrast, N-hydroxy-4-chloroaniline(N-hydroxy-4ClA) oxidized 760 equiv. of HbFe²⁺ in the presence of glucose, but only 81 equiv. of HbFe²⁺ in the presence of lactate. These results indicate that the catalytic activity depended on the metabolic regeneration from 4-chloronitrosobenzene(4-CINOB) by NADPH-dependent erythrocyte reductases.

4. A relationship was established between HbFe³⁺ concn. and the concn. of N-hydroxy-4ClA and 4-CINOB(determined together), 4-chloroacetanilide(4-ClAA) and 4-chloroaniline(4-CIA), indicating co-oxidation of N-hydroxy-4ClAA and oxyhaemoglobin in erythrocytes and partial reduction of the newly formed 4-CINOB to 4-CIA.

5. In rat blood in vitro incubated with N-hydroxy-4CIAA, 4-CINOB concn. increased with increasing HbFe³⁺ concn., indicating that 4-CINOB was formed by co-oxidation of oxyhaemoglobin and N-hydroxy-4CIAA, and not by enzymic N-deacetylation.