Substituted 2,3,4,5-tetrahydro-1H-3-benzazepine and 2,3,4,5-tetrahydro-1H-naphth[1,2-d] azepine derivatives

The multi-step synthetic procedures to prepare a number of 2,3,4,5-tetrahydro-1H-benzazepine derivatives 1 through a series of intermediates are described. The condensation of arylaldehydes 2 with 2-nitropropanes 3 gave nitroalcohols 4 which were reduced to alcohol amines 5 . The condensation of 5 with arylacetaldehydes 6 gave imino derivatives 7 which on reduction with borohydride gave secondary amines 8 . By employing different methods, alcohol amines 5 were condensed with arylacetic acids 9 to give amides 10 which were then reduced to amines 8 . On treatment with mineral acids, amines 8 were cyclized to the target compounds 1 . Biological activities of 1 are also briefly discussed.     

Aromatie-substituted derivatives of 2,3,4,5-tetrahydro-7,8-methylenedioxy-1H-3-benzazepine. Syntheses via chloromethylation

Chloromethylation of N-acetyl-2,3,4,5-tetrahydro-7,8-methylenedioxy-1H-3-benzazepine ( 4 ) proceeded, depending on reaction conditions, at the 6- or 6,9- positions. Subsequent transformation of these intermediates provided a series of mono and bis aromatic-substituted derivatives of the parent benzazepine 3 .     

The synthesis of some 7- and 7,8-substituted 2,3,4,5-tetrahydro-1H-3-benzazepines

The nitration of 2,3,4,5-tetrahydro-1H-3-benzazepine and its 3-methyl and 3-acetyl derivatives yields the corresponding 7-nitro derivatives which can be further transformed by classical procedures. The preparation of the ether cleavage products of the known 2,3,4,5-tetrahydro-7,8-dimethoxy-1H-3-benzazepine is also reported.     

Synthesis of some 4-acetyl-3,5-dioxo-2,3,4,5-tetrahydro[1]benzoxepine or benzothiepine and 6-acetyl-5,7-dioxo-6,7,8,9-tetrahydro-5H-benzocycloheptene derivatives

The title compounds were prepared from benzoxepino-, benzothiepino- or benzocycloheptaisoxazolones which in turn were synthetized from simple materials.     

Synthesis, photophysical, photochemical and biological properties of caged GABA, 4-[[(2H-1-benzopyran-2-one-7-amino-4-methoxy) carbonyl] amino] butanoic acid

The photorelease of a caged neurotransmitter can be used to investigate the function of neuronal circuits in tissues. We have designed and synthesized a stable, caged gamma-aminobutyric acid (GABA) derivative, 4-[[(2H-1-benzopyran-2-one-7-amino-4-methoxy)carbonyl]amino] butanoic acid (BC204), that releases the neurotransmitter in physiological medium when irradiated with UV light at 300-400 nm in PBS at pH 7.4. The release of GABA occurs with the formation of the major photoproduct, 7-amino-4-(hydroxymethyl)-2H-1-benzopyran-2-one, via a solvolytic photodegradation mechanism of the coumarin moiety and was confirmed by electrospray mass spectrometry/mass spectrometry (ESI MS/MS). BC204 is chemically stable and shows no intrinsic activity after many hours under physiological dark conditions. These properties suggest that BC204 is an excellent form of caged GABA that is well suited for long-term biological studies.     

Synthesis of 4,10-dihydro-4,10-dioxo-1H-[1]-benzopyrano[3,2-b]pyridine, 4,5-Dihydro-4,5-dioxo-1H-[1]-benzopyrano[2,3–6]pyridine and 1,5-Dihydro-1,5-dioxo-4H-[1]-benzopyrano[3,4-b]pyridine derivatives from aminobenzopyrones

3-Aminochromone and 3-aminocoumarin were condensed with diethyl ethoxymethylenemalonate and with dimethyl acetylenedicarboxylate to give intermediates, which were thermally cyclized to give 4,10-dihydro-4,10-dioxo-lH-[1]-benzopyrano[3,2-b]pyridinecarboxylates and 1,5-dihydro-1,5-dioxo-4H-[1]-benzopyrano-[3,4-b]pyridinecarboxylates. 2-Aminochromone was converted to 4,5-dihydro-4,5-dioxo-1H-[1]-benzopyrano-[2,3-b]pyridinecarboxylate via an intermediate condensation product with diethyl ethoxymethylenemalonate. These esters were hydrolyzed to the corresponding carboxylic acids (21, 30, 36, 50, and 60). Attempts to prepare 4,5-dihydro-4,5-dioxo-1H-[1]-benzopyrano[4,3-b]pyridinecarboxylates from 4-aminocoumarin were unsuccessful.     

Esters of 4-(3-Dialkylamino-2,5-dioxo-2,3,4,5-tetrahydro-1<Emphasis Type="Italic">H</Emphasis>-pyrrolyl)phenylacetic acids

Reaction of equivalent amounts of alkyl 4-aminophenylacetates with maleic anhydride gave rise to the corresponding alkyl 4-N-maleimidophenylacetates which with diethylamine, piperidine, and morpholine afforded esters of 4-(3-dialkylamino-2,5-dioxo-2,3,4,5-tetrahydro-1H-pyrrolyl)phenylacetic acids as stereoisomer mixtures.     

Complete 1H and 13C NMR spectral assignment of N-aralkylsulfonamides, N-sulfonyl-1,2,3,4-tetrahydroisoquinolines and N-sulfonyl-2,3,4,5-tetrahydro-1H-2-benzazepines. Conformational analysis of N-[((3',4'-dichlorophenyl)methyl)sulfonyl]-3-methyl-2,3,4,5-tetrahydro-1H-2-benzazepin

The complete and unambiguous assignment of the 1H NMR and 13C NMR spectra of 26 N-aralkylsulfonamides, N-sulfonyl-1,2,3,4-tetrahydroisoquinolines and N-sulfonylbenz[c]azepines was performed on the basis of APT, DEPT, homonuclear (gs-COSY) and 1H-detected heteronuclear one-bond (gs-HMQC) and long-range (gs-HMBC) correlation experiments. The methylated 2,3,4,5-tetrahydro-1H-2-benzazepine derivative 26 adopts a chair conformation as determined by 1H-1H coupling analysis and gamma-gauche effects. This is supported by a single-crystal X-ray structure analysis.     

Nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors: synthesis and pharmacological properties of 4'-[5-(substituted methylidene)-2,3,4,5-tetrahydro-1H-1-ben zoazepine-1-carbonyl]benzanilide and 4'-[5-(substituted methyl)-2,3-dihydro-1H-1-benzoazepine-1- carbonyl]benzanilide derivatives

Arginine vasopressin (AVP) has a dual action, i.e. vasoconstriction and water reabsorption via V1A and V2 receptors, and may play a role in a number of diseases, including congestive heart failure (CHF), hypertension, renal disease, edema, and hyponatremia. We have attempted to develop a new series of AVP antagonists for both V1A and V2 receptors based on the hypothesis that the blockade of both V1A and V2 receptors might be beneficial to CHF patients. In this report, a series of compounds structurally related to 4'-[5-(substituted methylidene)-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl ]benzanilide (exo-olefin isomer) and 4'-[5-(substituted methyl)-2,3-dihydro-1H-1-benzoazepine-1-carbonyl]benzanilide (endo-olefin isomer) were synthesized and examined to have AVP antagonist activity for both V1A and V2 receptors. As a result, it was found that the (E)-exo-olefin isomers showed more potent binding affinity compared with endo-olefin isomers. Among these (E)-exo-olefin isomers, (E)-N-methyl-{1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahyd ro-1H-1 -benzoazepin-5-ylidene}acetamide (14) exhibited the most potent binding affinity and (E)-N-methyl-(1-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-2,3,4,5- tetrahydro-1H-1-benzoazepin-5-ylidene)acetamide (20) exhibited a high AVP antagonist activity for both V1A and V2 receptors after intravenous administration. Details of the synthesis and pharmacological properties of this series are presented.     

Electron impact mass spectrometry of 3-hydroxy-3,4,5,6-tetrahydro-2H-[1]benzoxocines. A comparison with the behaviour of isomeric 2-hydroxymethyl-2,3,4,5-tetrahydro-[1]-benzoxepines and 1,2-epoxy-5-(2-hydroxyphenyl)pentane

The mass spectrometric behavior of 3-methyl-3-hydroxybenzoxocines has been studied in detail by means of linked scans and mass analyzed ion kinetic energy spectrometry. The structure of the molecular ion and the fragmentation processes are strictly related to the structure of the neutral moieties. The possible isomerization of 3-hydroxy-10-methoxy-3-methyl-3,4,5,6-tetrahydro-2H-[1]benzoxocine to 2-methyl-2-[3-(3′-methoxy-2′-hydroxy)phenyl]pentyloxirane and to 2-hydroxymethyl-9-methoxy-2-methyl-2,3,4,5-tetrahydro[1]benzoxepine is investigated.     

Highly potent and orally active non-peptide arginine vasopressin antagonists for both V1A and V2 receptors: synthesis and pharmacological properties of 4'-[(4,4-difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-y l)carbonyl]-2-phenylbenzanilide derivatives

A series of compounds structurally related to 4'-[(4,4-difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoaz epin-1-yl) carbonyl]-2-phenylbenzanilide were synthesized and evaluated for arginine vasopressin (AVP) antagonistic activity. Compounds with a (Z)-olefin geometry at the 5-position of benzoazepine possessed potent affinity for both the V1A and V2 receptors. Further study has shown that one of these derivatives, (Z)-4'-(?4,4-difluoro-5-[(4-dimethylaminopiperidino)carbonylmet hylene]-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yI?carbonyl)2- phenylbenzanilide monohydrochloride (29, YM-35471), exhibits exceptionally potent affinity for both of V1A and V2 receptors, even when administered orally. The synthesis and pharmacological properties of this compound are detailed in this paper.     

Single crystal X-ray structure of 2-[({[(4-methylphenyl)sulfonyl]methyl} amino)carbonyl]-1,3-dioxo-2,3-dihydro-1<Emphasis Type="Italic">H</Emphasis>-inden-2-yl 2-thiophenecarboxylate

The title compound 2-[({[(4-methylphenyl)sulfonyl]methyl}amino)carbonyl]-1,3-dioxo-2,3-dihydro-1H-inden-2-yl 2-thiophenecarboxylate is synthesized and studied by the single crystal X-ray diffraction method. The structure of the product is confirmed by IR, ¹H and ¹³C NMR spectroscopy, and mass spectrometry. The structure is solved in the C2/c monoclinic space group with a = 16.739(3) Å, b = 11.087(3) Å, c = 23.194(4) Å, β = 93.32(3)°, V = 4297.2(16) ų, Z = 8, R1 = 0.033 and wR2 = 0.088.     

Parallel solution-phase synthesis of 4H-benzo[1,4]thiazin-3-one and 1,1-dioxo-1,4-dihydro-2H-1lambda6-benzo[1,4]thiazin-3-one derivatives from 1,5-difluoro-2,4-dinitrobenzene

This paper discusses the synthesis of privileged structures 4H-benzo[1,4]thiazin-3-one and 1,1-dioxo-1,4-dihydro-2H-1lambda6-benzo[1,4]thiazin-3-one derivatives in a parallel solution-phase manner using 1,5-difluoro-2,4-dinitrobenzene. Each scaffold possesses four diversity points. A cheap and efficient oxidant, urea-hydrogen peroxide (UHP), was applied for the introduction of the sulfone group. The intramolecular cyclization to 1,1-dioxo-1,4-dihydro-2H-1lambda6-benzo[1,4]thiazin-3-one was achieved by microwave assistance or the use of an inorganic base.     

New heterocyclic derivatives of 1′- and 3′-amino-5′,6′,7′,8′-tetrahydro-2′-acetonaphthones

The preparation of 1′-and 3′-amino-5′,6′,7′,8′-tetrahydro-2′-acetonaphthones (IIIa and IIIb) is described, by reduction of the low temperature nitration products of 5′,6′,7′,8′-tetrahydro-2′-acetonaphtone (I). The structures of the nitro isomers (IIa and IIb), and the reduction products, IIIa and IIIb, were elucidated spectroscopically. By known reactions, a series of new heterocyclic compounds prepared from the o-aminoketones, IIIa and IIIb, resulted in two series of new heterocyclic compounds.     

1,1-Disubstituted-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolecarboxylic acid esters and ketones. The base catalyzed transformation of 1-(2′,3′,4′,9′-tetrahydrospiro[cyclohexane-1,1′-[1H]pyrido[3,4-b]indol]-2-yl)alkanones into 2-(4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)-1 -alkylcyclohexanols

Condensation of 1H-indole-3-ethanamines 1 with cyclic β-keto esters 2 under azeotropic conditions followed by acid-catalyzed ring closure of the resulting enamines 3 gave 2′,3′,4′,9′-tetrahydrospiro[piperidine-3,1′,-[1H]pyrido[3,4-b]indole] -4-carboxylic acid alkyl esters 4 . Condensation of 1 with 2-acylcycloalkanones 8 gave two types of enamines, 10 and 11 , respectively. Enamines 10 on treatment with acid gave 1-(2′,3′,4′,9′-tetrahydro-3H-pyrido[3,4-b]indol-1-yl)-1-alkylcyclohexanols 17 . Compounds 17 were further dehydrated to give cycloalkane derivatives 19.     

Novel synthesis and reactions of 5,7-dialkyl-4,6-dioxo-4,5,6,7-tetrahydro- isothiazolo[3,4,-d]pyrimidine-3-carbonitriles and 6-methyl-4-oxo-4H-1-aza-5-oxa-2- thiaindene-3-carbonitrile

[reaction: see text] 5,7-Dialkyl-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-carbonitriles 4, prepared from 6-amino-1,3-dialkyluracils 3 and 4,5-dichloro-5H-1,2,3-dithiazolium chloride (Appel's salt) 1, are utilized for the preparation of new derivatives of 4 bearing amino, alkylthio, amido, thioamido, tetrazolyl, and carboximidic acid ethyl ester groups at position 3. Similarly, the reactions of 6-methyl-4-oxo-4H-1-aza-5-oxa-2-thiaindene-3-carbonitrile 8, prepared from 4-amino-6-methyl-2-pyrone 6 and 1, with alkyl- and arylamines in DMF at 50 degrees C and reflux afforded different isothiazole derivatives 11 and 17, respectively. On the other hand, treatment of 8 with 1,3-diaminopropane in THF at room temperature, followed by chromatography on silica gel, gave 3-(2-oxopropyl)-6,7,8-trihydro-4H-1-thia-2,5,9-triazacyclopentacyclononene-4,10-dione 12 in 59% yield.