Nachweis der Inversion bei der Umsetzung optisch aktiver 1-(0-Hydroxymethyl-benzyl)-N-methyl-1,2,3,4-tetrahydroisochinoline zu 3-Phenylisochromanen

Conversion of 1-[2-(Hydroxymethyl)benzyl]-N-methyl-1,2,3,4-tetrahydroisoquinolines to 3-Phenylisochromans: Evidence of Inversion. Optically active 1-[2-(hydroxymethyl)benzyl]-N-methyl-1,2,3,4-tetrahydroisoquinolines react with ethyl chloroformate (CAE) to yield optically active 3-phenylisochromans. Oxidation to the 3-phenylisochroman-1-ones and degradation with ozone to malic acid demonstrate an inversion in the course of the CAE reaction.     

Preparation and analgesic activity of tetrahydroquinolines and tetrahydroisoquinolines

A series of 1,2,3,4-tetrahydroquinolines and of 1,2,3,4-tetrahydroisoquinolines were synthesised and evaluated for analgesic activity by both hot-plate and acetic acid writhing methods in rats. Te most potent compound was 2-methyl-1,2,3,4-tetrahydro-5-quinolinol (IV i) which was shown to be 1/8 and 1/50 as active as morphine according to the employed assay. The analgesic activity was shown to be associated to a not selective action on the CNS.     

Cer(IV)sulfat-Oxidationen: Intramolekulare Cyclisierung von N-Benzyl-β-aminoketonen zu 4-Benzoyl-1,2,3,4-tetrahydroisochinolinen

Oxidations with Cerium(IV) Sulfate: Intramolecular Cyclization of N-Benzyl-β-aminoketones Yielding 4-Benzoyl-1,2,3,4-tetrahydroisoquinolines Preparation and regiospecific cerium(IV) sulfate oxidation of the substituted N-benzyl-β-aminoketones 3 are described. 4-Benzoyl-1,2,3,4-tetrahydroisoquinolines 4 so obtained are reduced by sodium borohydride.     

Synthesis of C-13-alkylated 8-oxoberbines

C-13-alkylated methoxy-8H-dibenzo[a,g]quinolizin-8-ones 2a-e were synthesized by photocyclization of 1-alkylidene-N-benzoyl-1,2,3,4-tetrahydroisoquinolines 1 . Moreover, condensation of 1,2,3,4-tetrahydro-6,7-dirnethoxy-1-oxo-isoquinoline with homophthalic acid anhydrides 7a and b leads to the C-13-alkylated 8-oxoberbines 2b and c and improves the yields compared with those of the photocyclization method.     

Untersuchungen zur Reaktion cyclischer Imine mit Chinonmethiden

Investigations about the Reaction of Cyclic Imines with Quinone Methids Alkyl substituted Δ1-pyrrolines, 3H-indoles or 3,4-dihydroisoquinolines do not react with quinone methids to yield Diels-Alder adducts. Instead, the reactions afford by C-alkylation the hydroxybenzyl derivatives 2, 4, 5 and 9–12 . This constitutes a general approach to hydroxybenzyl derivatives of CH-acidic cyclic imines and is of interest in the synthesis of β-phenylethyl-1,2,3,4-tetrahydroisoquinolines.     

Synthesis and pharmacological evaluation of some new tetrahydroisoquinoline derivatives inhibiting dopamine uptake and/or possessing a dopaminomimetic property

As shown by structure-activity relationship studies in 8-(substituted-amino)-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines, the most important structural requirement for a marked antidepressant action is the presence of an ureido, (alkoxycarbonyl)amino, or [(alkylamino)acyl]amino group attached to the isoquinoline skeleton in position 8. In one of the biological tests a significant difference was found between 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (nomifensine) and the new compounds synthesized. Nearly all compounds substituted in the amino group either decrease the spontaneous motility in mice or exert no effect on it. Two syntheses have been elaborated for the preparation of the compounds represented by the general formulas II-V where R1 = hydrogen, halogen, or methyl; Y = CONHR, OCOR, or CO(CH2)nNHR, in which R = alkyl or aralkyl or NHR = cyclic amine and n = 1-2. The syntheses start either from the corresponding 8-amino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines or from the corresponding noncyclized amino alcohols. Of the compounds, 4-(p-chlorophenyl)-8-[(ethoxy-carbonyl)amino]-2-methyl-1,2,3,4- tetrahydroisoquinoline was found to possess the highest activity.     

Nanomolar inhibitors of CNS epinephrine biosynthesis: (R)-(+)-3-fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines as potent and highly selective inhibitors of phenylethanolamine N-methyltransferase1

A series of (R)-(+)-3-fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines has been synthesized and evaluated as inhibitors of PNMT and for their affinity for the alpha(2)-adrenoceptor. Compounds (R)-8 and (R)-9 are remarkably potent and selective inhibitors of PNMT and are predicted to penetrate the blood-brain barrier on the basis of their calculated log P values. Conformational analysis and docking studies were performed in order to examine why the (R)-enantiomer of these 3-fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines is more potent than the (S)-enantiomer and to determine the likely bound ring conformer of the (R)-enantiomer. It appears that the (R)-enantiomer participates in a water-mediated hydrogen bond in which the (S)-enantiomer cannot. The likely favored ring conformation for (R)-3-fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines in the PNMT active site is similar to the ring conformation of (R)-5a as determined by gas-phase ab initio calculations.     

Massenspektrometrische Untersuchungen an 4-Benzyl-1.2.3.4-tetrahydroisochinolinen

Mass-Spectrometric Studies on 4-Benzyl-1,2,3,4-tetrahydroisoquinolines The electron-impact induced decomposition of the 4-benzyl-1,2,3,4-tetrahydro-N-methylisoquinolines 1–3 proceeds mainly in three competing ways: 1. By retro-Diels-Alder reaction and successive fragmentations, 2. by loss of C₆H₅X with [1,3]H shift, and 3. by loss of C₇H₇X with [1,5]H shift. The unexpected explusion of the ortho substituent × from M^+· is highly specific as shown by comparison of the isomeric chlorobenzyl compounds 1f, 2 and 3 . In striking contrast to the behavior of the 1-isomers, simple fission of the benzylic bond is of minor importance.     

Removal of the Pyrrolidine Substituent by Dehydrogenation of 4-Pyrrolidin-2-yl-3,4-dihydro-and 1,2,3,4-tetrahydroisoquinolines

Pyrrolidin-2-yl-groups located at C-4 of 3,4-dihydro- or 1,2,3,4-tetrahydroisoquinolines, respectively, are lost in the course of dehydrogenation of these isoquinoline derivatives. However, acyclically substituted isoquinolines, hydrogenated in ring B, 2-benzyl-4-(l-dimethylaminoethyl)-1,2,3,4-tetrahydroisoquinoline, e.g., show loss of the amine group only by benzylic cleavage, affording 4-ethylisoquinoline. Scope and limitation of this reaction are determined using specifically substituted isoquinolines.     

Elektronenstoßinduzierter Verlust der Substituenten an C-5 und C-8 bei 1,2,3,4-Tetrahydroisochinolinen, 2. Mitt.1) Synthese C-8-substituierter 1,2,3,4-Tetrahydroisochinoline

Electron-Impact Induced Loss of C-5/C-8 Substituents in the Molecular Ions of 1,2,3,4-Tetrahydroisoquinolines, II: Synthesis of C-8 Substituted 1,2,3,4-Tetrahydroisoquinolines The synthesis of various C-8 substituted 1,2,3,4-tetrahydroisoquinolines is described.     

Elektronenstoßinduzierter Verlust der Substituenten an C-5 und C-8 bei 1,2,3,4-Tetrahydroisochinolinen, 3. Mitt.1) Synthese C-8-substituierter 5-Ethoxy-6-methoxy-1,2,3,4-tetrahydroisochinoline

Electron-Impact Induced Loss of C-5/C-8 Substituents in the Molecular Ions of 1,2,3,4-Tetrahydroisoquinolines, III: The Synthesis of C-8 Substituted 5-Ethoxy-6-methoxy-1,2,3,4-tetrahydroisoquinolines The synthesis of the title compounds is described.     

Evaluation of isomeric 4-(chlorohydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines as dopamine D-1 antagonists

The isomeric 4-(3-chloro-4-hydroxyphenyl)- and 4-(4-chloro-3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines, the N-methyl derivative of the 4-(4-chloro-3-hydroxyphenyl) isomer, and 4-(3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline were synthesized and evaluated for dopamine D-1 antagonist activity. The 4-(3-chloro-4-hydroxyphenyl) and the 4-(3-hydroxyphenyl) isomer possessed similar potencies as D-1 antagonists. Introduction of the N-methyl group enhanced potency about twofold. The "pharmacophore" for selective dopamine D-1 antagonist activity appears to be a tertiary 2-(3-hydroxyphenyl)-2-phenethylamine.     

Structure-Activity Relationship Studies of CNS Agents,Part 31[1]: Analogs of MP 3022 with a Different Number of Nitrogen Atoms in the Heteroaromatic Fragment — New 5-HT1A Receptor Ligands

Two series of new MP 3022 analogs, i.e. 1-(o-methoxyphenyl)-4-n-propylpiperazines ( 3, 4a, 4b, 6–9 , and 12–13 ) and 2-(n-propyl)-1,2,3,4-tetrahydroisoquinolines ( 5a, 5b, 11a , and 11b ) containing a terminal heteroaromatic system with a different number of nitrogen atoms, were synthesized and their 5-HT_1A/5-HT_2A and α₁ receptor affinity was assayed. The majority of investigated piperazines may be classified as non-selective 5-HT_1A/5-HT_2A/α₁ receptor ligands. Compounds 3, 4a, 4b, 7–9a with the highest affinity for 5-HT_1A receptors (K_i = 4–54 nM) were tested in vivo. Their functional activity was differentiated; while 3, 8 , and 9a behaved like weak antagonists of postsynaptic 5-HT_1A receptors, 4b and 7 may be classified as potential partial 5-HT_1A receptor agonists. Isomer 4a has characteristic features of a potential weak postsynaptic 5-HT_1A receptor agonist.     

Synthesis and antimicrobial evaluation of some 6-aryl-5-cyano-2-thiouracil derivatives

A series of 6-aryl-5-cyano-2-thiouracil derivatives (1a-d) was synthesized by the reaction of ethyl cyanoacetate with thiourea and aldehydes. These products were used as intermediate compounds for the synthesis of a number of thiouracil derivatives (2a-d to 10a-d). All compounds were screened for antibacterial and antifungal activities. Some of the prepared compounds, 6-(4-fluorophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (2a), 4-oxo-2-thioxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (2d), 6-(4-fluorophenyl)-4-hydrazino-2-thioxo-1,2-dihydropyrimidine-5-cabonitrile (7a) and 4-hydrazino-2-thioxo-6-(3,4,5-trimethoxyphenyl)-1,2-dihydropyrimidine-5-carbonitrile (7d) revealed promising antimicrobial activity.     

Novel potent anticonvulsant agent containing a tetrahydroisoquinoline skeleton

In our studies on the development of new anticonvulsants, we planned the synthesis of N-substituted 1,2,3,4-tetrahydroisoquinolines to explore the structure-activity relationships. All derivatives were evaluated against audiogenic seizures in DBA/2 mice, and the 1-(4'-bromophenyl)-6,7-dimethoxy-2-(piperidin-1-ylacetyl) derivative (26) showed the highest activity with a potency comparable to that of talampanel, the only noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist in clinical trials as an anticonvulsant agent. Electrophysiological experiments indicated that 26 acts as noncompetitive AMPA receptor modulator.     

Patent Evaluation: Novel GABA Autoreceptor Antagonists

Summary

Novelty: Novel 1-substituted-1,2,3,4-tetrahydroisoquinolines are claimed. A method of treating CNS disorders such as anxiety, depression or psychoses by the administration of such compounds is also claimed. The compounds are GABA autoreceptor antagonists which have little activity at the GABA_A receptor itself.

Biology: Compounds were tested for their ability to block agonist-induced inhibition of potassium-evoked GABA-release from rat cortex in vitro (a measure of GABA autoreceptor antagonism), and to antagonize agonist-induced depolarization of isolated rat vagus nerve (a measure of GABA_A antagonism). In the former test pA₂ values quoted range from 5.2 to 9.2.

Chemistry: Twenty-two compounds are exemplified by synthesis. [1RS,2'SR]-1-(2-Tetrahydrofuranyl)-1,2,3,4-tetrahydroisoquinoline is one of twelve specifically claimed compounds.

Structure:      

Selektive katalytische Hydrierungen und Hydrogenolysen, 5. Mitt. Ein einfacher Zugang zu 1-Benzyl-5,6,7,8-tetrahydroisochinolinen

Selective Catalytic Hydrogenations and Hydrogenolyses, V: Convenient Preparation of 1-Benzyl-5,6,7,8-tetrahydroisoquinolines 1-Benzylisoquinolines 1 can be hydrogenated selectively with Pt and Ru catalysts to yield the title compounds 2 . Using Pd/charcoal, the products 2 contain ca. 5% of the isomers 3 , which can be separated via the N-acetyl derivatives, e. g. 7d . Extended reaction times in the presence of platinum cause simultaneous hydrogenation of the unsubstituted aromatic nucleus of the benzyl group. At higher temperatures, the substituted benzyl nucleus is hydrogenated, too, involving C,O-hydrogenolysis, e. g. 1a → 4 or 1d → 4 . The structures of 2 were proved by ¹H-NMR spectroscopy. Compound 2a was prepared independently from 2c via 5 → 6 .     

Durch Cyanogruppen stabilisierte 2-Sulfonio-indenide

2-Sulfonioindenides stabilised by Cyano Groups 2-Hydroxyindene-3-carbonitrile (3) reacts with p-toluenesulfonyl chloride to form the p-toluenesulfonates 4 , which are substituted by thiolate to give the 2-alkylthio- or 2-arylthioiindene-3-carbonitriles 5. Methylation of 5 with trimethyloxonium tetrafluoroborate yields the sulfonium salts 6 , which can be deprotonated to the 1-cyano-2-(dialkylsulfonio)indenides 7 .     

Reaktionen mit Aziridinen (Aziranen), 25. Mitt. Amidoethylierung monosubstituierter Cyanessigester

Reactions with Aziridines (Aziranes), XXV:¹⁾ Amidoethylation of Monosubstituted Ethyl Cyanoacetates The amidoethyl derivatives of ethyl cyano(phenyl)acetate (1) , which are generated from N-(arylcarbamoyl)aziridines 2 in ethanolic ethanolate solution, cyclize to give high yields of 1-acyl-3-cyano-3-phenyl-2-pyrrolidones 4 . In the amidoethylation of ethyl 2-cyano-3-methyl-valerianate, however, the analogous N-acylpyrrolidone 7 is deacylated. Besides, a small amount of the primarily formed amidoethyl derivative 6 can be isolated by chromatography.     

Reaktionen ionisierter 4-Benzyl-2-methyl-1,2,3,4-tetrahydroisochinoline in der Gasphase

Reactions of Ionized 4-Benzyl-2-methyl-1,2,3,4-tetrahydroisoquinolines in the Gas Phase The M⁺* of 4-Benzyl-1,2,3,4-2-methyl-tetrahydroisoquinoline ( 1 ) decomposes by competing loss of H*- or H₃C*-radicals, of H₃C-NH₂, C₆H₆ and C₇H₈, respectively, or by RDA-fission. The fragmentation mechanisms are studied on the specifically deuterated analogues 2–8 . The elimination of C₆H₆ and C₇H₈ is preceded by extensive H/D-exchange, especially between the positions 1, 4, the benzylic methylene group, and the aromatic positions (pos. 5, 8, and phenyl).