Benzimidazoliumsalze durch nucleophile aromatische Substitution

Benzimidazolium Salts by Nucleophilic Aromatic Substitution Condensation of the N,N′-dimethylbenzamidines 5 or their lithium salts 6 with o-nitrophenyl substituted aryl fluorides leads to the benzamidines 7 . These cyclise on heating up to 100–150° by nucleophilic aromatic substitution to form the benzimidazolium nitrites 9 . The 1,3-dimethyl-2-phenyl-5-nitrobenzimidazolium nitrite 9a is hydrolysed by methanolic potassium hydroxide to yield N-methyl-N-(2-methylamino-5-nitrophenyl)benzamide ( 11 ). The sodium salt of 11 reforms 9a on treatment with nitrosyl tetrafluoroborate. The ring closure 7 → 9 is also deduced from the ¹H-NMR and ¹³C-NMR spectra. The successful cyclisation of the benzamidines 7 depends on two N,N′-alkyl groups and one N-(2-nitrophenyl) group. With N-ethyl-N′-methylbenzamidine it has been shown that the reversible 1,3-shift of an N-(2,4-dinitrophenyl) group is more rapid than the irreversible ring closure to form a benzimidazolium salt (e. g. 19 ? 20 ); with an N-(2-nitrophenyl) group the rates of the 1,3-shift and of the ring closure are of a comparable order of magnitude (e. g. 23?24 → 25).     

In vitro studies on the microsomal N-oxidation of N-substituted benzamidines

Studies of the Microsomal N-Oxidation of N-Substituted Benzamidines in Vitro The metabolism of the N-mono- and N,N-disubstituted benzamidines 4 and 7 was studied employing 9000 g supernatant fractions of rabbit liver homogenates as enzyme sources. The potential metabolites, i. e. the amidoximes 5 and 8 and the N-hydroxyamidine 6b , were synthesized and used as reference products. Among the N-substituted derivatives only N-phenylbenzamidine (4a) is metabolized with detectable yields (t.l.c./m.s.) to the amidoxime 5a. Considering this finding and the metabolism of other nitrogen-containing functional groups, it is assumed that the cytochrome P-450 system preferentially oxidizes NH₂ groups.     

Synthesis of N3-fumaramoyl-L-2,3-diaminopropanoic acid analogues,the irreversible inhibitors of glucosamine synthetase

Several analogues of N³-fumaramoyl-L-2,3-diaminopropanoic acid were synthesized and evaluated for inhibition of glucosamine-6-phosphate synthetase activity. The syntheses were accomplished by acylation reaction of N²-tert.-butoxycarbonyl-L-2,3-diaminopropanoic acid (Boc-A₂pr) or N²-tert.-butoxy-carbonyl-L-2,4-diaminobutanoic acid (Boc-A₂-bu) with the N-succinimidoyl esters of several derivatives of α, β-unsaturated acids 2a-d followed by deprotection of the Boc groups. The obtained compounds were tested for inhibition of glucosamine synthetase isolated from Salmonella typhimurium and Saccharomyces cerevisiae. The results indicated that among the synthesized compounds, N³-4-methoxyfumaroyl-L-2,3-diaminopropanoic acid (FMDP) was the most powerful inhibitor of glucosamine synthetase.     

Syntheses and Selective Inhibitory Activities of Terphenyl-Bisamidines for Serine Proteases

Biphenyl nitriles 5a—c , terphenyl dinitriles 11a—d , and naphthalene-bis(benzonitrile) 11e were prepared by palladium-catalyzed cross coupling reactions and subsequently converted to biphenyl amidines 8a—c and bis(benzamidines) 4a—e. Among the biphenyl amidines 8 only the meta-derivative 8b inhibits factor Xa and trypsin (K_i = 10 μM). The terphenyl bisamidine 4c does not inhibit factor Xa, trypsin, thrombin, and plasmin, while 4a and 4d are almost equipotent inhibitors of theses enzymes (K_i 1–6 μM), and 4b and 4e are selective for trypsin (K_i = 0.2 and 0.3 μM; but K_i > 1 μM for factor Xa, thrombin, and plasmin). X-ray analysis of crystals of 4b complexed with bovine trypsin revealed a unique binding mode: one benzamidino group binds in the S1 site to the side chain carboxylate of Arg189. The central phenyl group is twisted away from the S2/S3 sites and the second amidino group contacts the Asn143 side chain.     

Synthese von 9-Fluorenalkanaminen, 3. Mitt. Stickstoffalkylierte und -acylierte 2-(9H-Fluoren-9-yl)-2-propanamine

Synthesis of (9-Fluorenylalkan)amines, III: N-Alkylated or N-Acylated 2-(9H-Fluoren-9-yl)-2-propanamines The synthesis of N-alkylated or N-acylated derivatives of the fluorene 3a is described. Compound 3b can be prepared via 1b and 2b , but 3c – 3f have to be synthesised by direct alkylation or acylation of 3a . The reaction of 8 with basic agents yields the stable derivative 9 .     

Molecular electrostatic potential energies and methylation of DNA bases: a molecular orbital-generated quantitative structure-activity relationship

1. The results of molecular orbital (MO) calculations, by the MINDO/3 method, on DNA bases, are reported; which point to a radical mechanism of alkylation.

2. Molecular electrostatic potential energy maps indicate propensity for alkylation by N-methyl-N-nitrosourea at key atoms on DNA bases.

3. A correlation between the MO-derived parameters net atomic charges on heteroatoms and superdelocalizability with percentage alkylation by N-methyl-N-nitrosourea is shown.     

Antimykotische Wirkstoffe, 7. Mitt. Kernsubstituierte N-(1-Adamantyl)-N′-phenylthioharnstoffe

Antimycotic Agents, VII: N-(1-Adamantyl)-N′-phenylthiourea Derivatives with Substituents on the Aromatic Nucleus N-(1-Adamantyl)-N′-phenylthiourea derivatives 3 carrying methylthio groups, fluorine atoms or a trifluoromethyl substituent on the aromatic nucleus may be obtained by nucleophilic addition of an appropriately substituted aniline derivative 2 to (1-adamantyl) isothiocyanate ( 1 ).     

N-(β-Cyanethyl)-N-nitrosoharnstoffe

N-(β-Cyanoethyl)-N-nitroso Ureas The N-(β-Cyanoethyl)-N-nitroso ureas 2a , b are prepared in a one-step nitrosation of 2-ureidoethylmalonic acids 1a , b .     

PRECISION NEUTRON DIFFRACTION STRUCTURE DETERMINATION OF PROTEIN AND NUCLEIC ACID COMPONENTS. IV. The Crystal and Molecular Structure of the Amino Acid L-Histidine

A neutron diffraction study of orthorhombic L-histidine, C₆H₉N₃O₂, has been carried out. The structure belongs to space group P2₁2₁2₁, with four molecules per unit cell. Cell parameters are: a = 5.175 (5) Å, b = 7.315 (8) Å and c = 18.75 (2) Å. A total of 618 unique reflections were used in the least-squares refinement leading to a final conventional R-value of 5.8%. The atomic coordinates found for the non-hydrogen atoms agree well with those from a previous X-ray study (1). The molecule is in the zwitterion form, and the molecular conformation is stabilized by an intramolecular hydrogen bond between an ammonium group hydrogen and the imidazole group and an electrostatic interaction between an ammonium group hydrogen and a carboxyl oxygen. The N-C^α-C-O₂group is found to be nonplanar. Distances between non-hydrogen atoms and the distances in the ammonium group have been corrected for rigid-body motion. The molecules are bonded together by hydrogen bonds to form chains in the c-axis direction of the crystal. There is no protonation of the imidazole ring.     

Chemical Studies on Drug Metabolism II. N-Demethylation and N-Oxidation of Some Alicyclic Amines by Ruthenium Tetroxide

Oxidation with ruthenium tetroxide of alicyclic N-methylamines such as pempidine (1a) , 9-methyl-9-azabicyclo[3.3.1]nonane (2a) , and 8-methyl-8-azabicyclo[3.2.1]octane (3a) , in which carbon atoms linked to nitrogen are sterically hindered, leads to the N-formyl and N-demethylated derivatives. The latter, when further oxidized, give the N-oxides in good yields.     

Cyclodehydrogenation of aniline derivatives carrying carboxamide or urea functions (author's transl)

Cyclodehydrogenation of Aniline Derivatives Carrying Carboxamide or Urea Functions The synthesis of o-tert. aminobenzamides is described. Dehydrogenation of these compounds with mercury(II)-EDTA yields condensed quinazolinones. The analogous reaction of o-tert. aminophenylureas leads to condensed benzimidazoles with simultaneous removal of the aminocarbonyl group.     

Caution in the use of 2‐iminothiolane (Traut's reagent) as a cross‐linking agent for peptides. The formation of N‐peptidyl‐2‐iminothiolanes with bombesin (BN) antagonist (d‐Trp6,Leu13‐ψ[CH2NH]‐Phe14)BN6−14 and d‐Trp‐Gln‐Trp‐NH2

Abstract: During a study aimed at generating a bispecific molecule between BN antagonist (d ‐Trp⁶,Leu¹³‐ψ[CH₂NH]‐Phe¹⁴)BN_6‐14 (Antag1) and mAb22 (anti‐FcγRI), we attempted to cross‐link the two molecules by introducing a thiol group into Antag1 via 2‐iminothiolane (2‐IT, Traut's reagent). We found that reaction of Antag1 with 2‐IT, when observed using HPLC, affords two products, but that the later eluting peptide is rapidly transformed into the earlier eluting peptide. To understand what was occurring we synthesized a model peptide, d ‐Trp‐Gln‐Trp‐NH₂ (TP1), the N‐terminal tripeptide of Antag1. Reaction of TP1 with 2‐IT for 5 min gave products 1a and 3a ; the concentration of 1a decreased with reaction time, whereas that of 3a increased. Thiol 1a , the expected Traut product, was identified by collecting it in a vial containing N‐methylmaleimide and then isolating the resultant Michael addition product 2a , which was confirmed by mass spectrometry. Thiol 1a is stable at acidic pH, but is unstable at pH 7.8, cyclizes and loses NH₃ to give N‐TP1‐2‐iminothiolane ( 3a ), ES‐MS (m/z) [602.1 (M+H)⁺], as well as regenerating TP1. Repeat reaction with Antag1 and 2‐IT allowed us to isolate N‐Antag1–2‐iminothiolane ( 3b ), FAB‐MS (m/z) [1212.8 (M+H)⁺] and trap the normal Traut product 1b as its N‐methylmaleimide Michael addition product 2b , ES‐MS (m/z) [1340.8 (M+H)⁺]. Thiol 1b is also stable at acidic pH, but when neutralized is unstable and cyclizes, forming 3b and Antag1.     

Expeditious syntheses of stable and radioactive isotope‐labeled anticonvulsant agent,JNJ‐26990990, and its metabolites

Syntheses of stable and radioactive isotope‐labeled anticonvulsant agent, JNJ‐26990990, that is, N‐(benzo[b]thien‐3‐ylmethyl)‐sulfamide and its metabolites are described. [¹³C¹⁵N]Benzo[b]thiophene‐3‐carbonitrile was first prepared by coupling of 3‐bromo‐benzo[b]thiophene with [¹³C¹⁵N]‐copper cyanide. The resultant [¹³C¹⁵N]benzo[b]thiophene‐3‐carbonitrile was reduced with lithium aluminum deuteride to give [¹³CD₂¹⁵N]benzo[b]thiophen‐3‐yl‐methylamine; which was then coupled with sulfamide to afford [¹³CD₂¹⁵N]‐N‐(benzo[b]thien‐3‐ylmethyl)‐sulfamide, the stable isotope‐labeled compound with four stable isotope atoms. Direct oxidation of [¹³CD₂¹⁵N]‐N‐(benzo[b]thien‐3‐ylmethyl)‐sulfamide with hydrogen peroxide and peracetic acid gave the stable isotope‐labeled sulfoxide and sulfone metabolites. On the other hand, radioactive ¹⁴C‐labeled N‐(benzo[b]thien‐3‐ylmethyl)‐sulfamide was prepared conveniently by sequential coupling of 3‐bromo‐benzo[b]thiophene with [¹⁴C]‐copper cyanide, reduction of the carbonitrile to carboxaldehyde, and reductive amination with sulfamide.     

Structure and conformation of a novel inhibitor of angiotensin I converting enzyme – a tripeptide containing phosphonic acid

A novel phosphotripeptide, (IR)-1-(N-(N-acetyl-l -isoleucyl)-l -tyrosyl)amino-2-(4-hydroxyphenyl)ethyl-phosphonic acid, is a potent inhibitor of angiotensin I converting enzyme (ACE). ACE inhibitory activity in vitro of the peptide is comparable to that of captopril. Its diethylester (C₂₉H₄₂N₃O₈P, molecular weight, 591.6) crystallizes in the monoclinic space group C2, with cell constants: a = 25.666(9), b = 9.590(8), c = 13.557(2)Å, β= 91.65(2)°, Z = 4, Dc = 1.17g/cm³. The structure was solved by MULTAN 11/82 and refined by full matrix least-squares methods to a final R-factor of 0.063 for 2123 unique reflections (F > 3σ(F)) measured on an Enraf-Nonius CAD-4 diffractometer (CuKα, λ= 1.541 8 Å, T = 295 K). The absolute configuration of the α-carbon where the phosphonic acid is attached was determined unequivocally by referring to the l -isoleucyl moiety whose absolute configuration is known. The conformation of the molecule is relatively rigid owing to the intramolecular requisites and the resultant relative disposition of hetero atoms, which are necessary to its biological activities, are confined to the corresponding disposition in captopril.     

Structure and Properties of Cyclic Polymethylene Ureas,III. Synthesis and Biological Activity of Some Mannich Bases of Tetrahydro-2-(1H)-Pyrimidinone

Some N-mono- 2a–e and N,N-bis(aminomethyl) derivatives 3a–b of tetrahydro-2-(1H)-pyrimidinone 1a and tetrahydro-2(1H)-pyrimidinethione 1e are obtained by the Mannich reaction of 1a or 1e with formaldehyde and secondary amines. The compounds show a marked antiviral activity.     

Antiviral agents, XI: Nucleophilic substitutions and additions with 2-aminoadamantane (author's transl)]

Antiviral Agents, XI: Nucleophilic Substitutions and Additions with 2-Aminoadamantane Derivatives of 2-aminoadamantane ( 1 ) were prepared and compared with derivatives of 1-aminoadamantane for antiviral activity. Reaction of 1 with the isothiocyanates 2a, 2b, 2c and 2d yields the N′-substituted N-(2-adamantyl) thiourea derivatives 3a, 3b, 3c and 3d . Reaction of 1 with the carboxylic acid chlorides 4a and 4b leads to the N-(2-adamantyl)carboxamides 6a and 6b .     

Synthesis of Phthalimido-Desmuramylpeptide Analogues as Potential Immunomodulating Agents

The preparation of immunologically active phthalimido desmuramylpeptide analogues 2e-h, 4c-d , and 7b is described. The N-acetylmuramic acid in the muramyl dipeptide has been replaced by a phthaloylated acyclic moiety such as N-phthaloylated amino acids 1a – c , 2-(2-phthalimidoethoxy)acetic acid 3 , or by the carbocyclic rac. trans-2-(2′-phthalimidocyclohexyloxy)acetic acid 6 .     

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.     

Mecamylamine, dihydro-β-erythroidine, and dextromethorphan block conditioned responding evoked by the conditional stimulus effects of nicotine

Current smokers express the desire to quit. However, the majority find it difficult to remain abstinent. As such, research efforts continually seek to develop more effective treatment. One such area of research involves the interoceptive stimulus effects of nicotine as either a discriminative stimulus in an operant drug discrimination task, or more recently as a conditional stimulus (CS) in a discriminated goal-tracking task. The present work investigated the potential role nicotinic acetylcholine receptors play in the CS effects of nicotine (0.4 mg/kg) using antagonists with differential selectivity for β2*, α7*, α6β2*, and α3β4* receptors. Methyllycaconitine (MLA) had no effect on nicotine-evoked conditioned responding. Mecamylamine and dihydro-β-erythroidine (DHβE) dose-dependently blocked responding evoked by the nicotine CS. In a time-course assessment of mecamylamine and DHβE, each blocked conditioned responding when given 5 min before testing and still blocked conditioned responding when administered 200 min before testing. Two novel bis-picolinium analogs (N, N′-(3, 3′-(dodecan-1,12-diyl)-bis-picolinium dibromide [bPiDDB], and N, N′-(decan-1,10-diyl)-bis-picolinium diiodide [bPiDI]) did not block nicotine-evoked conditioned responding. Finally, pretreatment with low dose combinations of mecamylamine, dextromethorphan, and/or bupropion was used to target α3β4* receptors. No combination blocked conditioned responding evoked by the training dose of nicotine. However, a combination of mecamylamine and dextromethorphan partially blocked nicotine-evoked conditioned responding to a lower dose of nicotine (0.1 mg/kg). These results indicate that β2* and potentially α3β4* nicotinic acetylcholine receptors play a role in the CS effects of nicotine and are potential targets for the development of nicotine cessation aids.     

Chemical and Electrochemical Synthesis of Some Substituted N,N′-Diacyl-p-phenylenediamines

Some N,N′-diacyl-p-phenylenediamines substituted with halogens ( 2a - c ) were prepared. Their polarographic reduction in N,N-dimethylformamide with Et₄NClO₄ was performed and discussed. The mechanism of the electrochemical reduction is stated. Large-scale electrolytic reductions of 2a - b to 3a - b were performed.