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Inhibition of monoamine oxidase by isoquinoline derivatives. Qualitative and 3D-quantitative structure-activity relationships

A series of isoquinolines, N-methyl-1,2-dihydroisoquinolines, N-methyl-1,2,3,4-tetrahydroisoquinolines, 1,2,3,4-tetrahydroisoquinolines, and N-methylisoquinolinium ions were tested as inhibitors of monoamine oxidases A and B. All compounds were found to act as reversible and time-independent MAO inhibitors, often with a distinct selectivity towards MAO-A. As a class, the N-methylisoquinolinium ions were found to be the most active MAO-A inhibitors, with N-methyl-6-methoxyisoquinolinium ion emerging as a potent (IC50 = 0.81 muM) and competitive MAO-A inhibitor. Comparative molecular field analysis (CoMFA, a 3D-QSAR method) of MAO-A inhibition was performed using the data reported here and in the literature. Using the steric and lipophilic fields of the inhibitors, quantitative models with reasonable predictive power were obtained that point to the importance of steric, lipophilic, and polar interactions in modulating MAO-A inhibitory activity.

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Reference£º
Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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Inhibition of phenylethanolamine n-methyltransferase (PNMT) by aromatic hydroxy-substituted 1,2,3,4-tetrahydroisoquinolines: Further studies on the hydrophilic pocket of the aromatic ring binding region of the active site

In a continuation of studies directed toward characterizing the hydrophilic pocket within the aromatic ring binding region of the active site of phenylethanolamine N-methyltransferase (PNMT), 5-, 6-, 7-, and 8-hydroxy-1,2,3,4-tetrahydroisoquinoline were prepared and evaluated as substates and inhibitors of PNMT. In order to discern the necessity of an acidic hydrogen for interaction at this pocket the corresponding methyl ethers were also evaluated. The enhanced affinity of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline (16) versus tetrahydroisoquinoline (13) itself indicates that a hydrophilic pocket exists off of carbon C7 in bound tetrahydroisoquinolines. The diminished affinity of the corresponding methyl ether is consistent with a requirement for the acidic hydrogen of 16 for interaction of the aromatic hydroxyl at site. From the relative activities of the other regioisomeric aromatic hydroxyl-substituted tetrahydroisoquinolines, their corresponding methyl ethers, and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, it appears that the hydrophilic pocket is spatially compact with respect to bound tetrahydroisoquinolines and is surrounded by larger areas of lipophilic character. To allow a comparison of the results of this study with previous data on bound beta-phenylethylamines, the methyl ethers of 5-, 6-, 7-, and 8-hydroxy-exo-2-aminobenzonorbornene and of 5- and 6-hydroxy-anti-9-aminobenzonorbornene were also evaluated for their activity as substrates and inhibitors for PNMT. The results of this study are in agreement with previous findings for bound beta-phenylethylamines and support the conclusion that the natural substrate for PNMT, norepinephrine, has a different active site binding orientation than most known substrates and competitive inhibitors of the enzyme.

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Reference£º
Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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QUINAZOLINE DERIVATIVES

Compounds of the formula I in which R, X, L2 and A1-A6 have the meanings indicated in Claim 1, are PI3K inhibitors and can be employed, inter alia, for the treatment of autoimmune diseases, inflammation, cardiovascular diseases, neurodegenerative diseases and tumours.

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Reference£º
Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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Receptor Antagonists

The present invention provides an alpha2c-adrenoceptor antagonist comprising, as an active ingredient, a condensed-ring-pyrimidine derivative represented by general formula (I) below or a pharmaceutically acceptable salt thereof useful for treating and/or preventing various diseases induced by hyperactivity of alpha2c-adrenoceptor (for example, Parkinson”s disease, L-DOPA-induced dyskinesia, tardive dyskinesia and depression) and the like. 1 {wherein p represents an integer of 1 to 3; R1 represents a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, or the like;R2 represents ?N(?R4)(?R5) (wherein R4 and R5 are the same or different, and each represents a hydrogen atom, substituted or unsubstituted aralkyl, or the like, or R4 and R5 form a substituted or unsubstituted heterocyclic group together with the adjacent nitrogen atom) or the like; and-Q- represents ?N?C(?R7)? [wherein R7 represents ?N(?R9)(?R10) (wherein R9 and R10 are the same or different, and each represents substituted or unsubstituted aralkyl, or the like, or R9 and R10 form a substituted or unsubstituted heterocyclic group together with the adjacent nitrogen atom) or the like] or the like}

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Reference£º
Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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Synthesis and in vitro opioid receptor functional antagonism of analogues of the selective kappa opioid receptor antagonist (3R)-7-hydroxy-N-((1S)-1- {[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl) -1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic)

In previous structure-activity relationship (SAR) studies, we identified (3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1- piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3- isoquinolinecarboxamide (JDTic, 1) as the first potent and selective kappa opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine class of opioid antagonist. In the present study, we report the synthesis and in vitro opioid receptor functional antagonism of a number of analogues of 1 using a [35S]GTPgammaS binding assay. The results from the studies better define the pharmacophore for this class of kappa opioid receptor antagonist and has identified new potent and selective kappa antagonist. (3R)-7-Hydroxy-N-[(1S, 2S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4- dimethylpiperidin-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3- carboxamide (3) with a Ke value of 0.03 nM at the kappa receptor and 100- and 793-fold selectivity relative to the mu and delta receptors was the most potent and selective kappa opioid receptor antagonist identified.

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Reference£º
Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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Heterocyclic derivatives and their use as antithrombotic agents

The present invention relates to antithrombotic compounds comprising the group Q, Q having formula (I), wherein the substructure (i) is a structure selected from (a, b and c), wherein X is O or S; X? being independently CH or N; and m is 0, 1, 2 or 3; wherein the group Q is bound through an oxygen atom or an optionally substituted nitrogen or carbon atom, or a pharmaceutically acceptable salt thereof or a prodrug thereof. The compounds of the invention are therapeutically active and in particular are antithrombotic agents.

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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To a solution OF 7-METHOXY-3, 4-DIHYDRO-2H-ISOQUINOLIN-1-ONE (200mg) in THF (8mL) is added LiAIH4 (76mg) and stirred for 3hr under reflux, and diluted with THF. The reaction mixture is added sodium sulfate decahydrate and filtration through celite pad. The filtrate is concentrated in vacuo. The residue is dissolved in Et20, then HCI in EtOAc is added the Et20. White precipitate is collected. by filtration to provide the title compound; 1 H NMR (CDCI3, 6 (ppm) ); 2.92 (dd, 2H), 3.30-3. 35 (m, 2H), 3.72 (s, 3H), 4.18-4. 23 (m, 2H), 6.81- 6.86 (m, 2H), 7.12 (d, 1H), 9.45 (brs, 2H).

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Reference£º
Patent; NOVARTIS AG; NOVARTIS PHARMA GMBH; WO2004/69256; (2004); A1;,
Tetrahydroisoquinoline – Wikipedia
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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To a solution OF 7-METHOXY-3, 4-DIHYDRO-2H-ISOQUINOLIN-1-ONE (200mg) in THF (8mL) is added LiAIH4 (76mg) and stirred for 3hr under reflux, and diluted with THF. The reaction mixture is added sodium sulfate decahydrate and filtration through celite pad. The filtrate is concentrated in vacuo. The residue is dissolved in Et20, then HCI in EtOAc is added the Et20. White precipitate is collected. by filtration to provide the title compound; 1 H NMR (CDCI3, 6 (ppm) ); 2.92 (dd, 2H), 3.30-3. 35 (m, 2H), 3.72 (s, 3H), 4.18-4. 23 (m, 2H), 6.81- 6.86 (m, 2H), 7.12 (d, 1H), 9.45 (brs, 2H).

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Reference£º
Patent; NOVARTIS AG; NOVARTIS PHARMA GMBH; WO2004/69256; (2004); A1;,
Tetrahydroisoquinoline – Wikipedia
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.43207-78-9,7-Methoxy-1,2,3,4-tetrahydroisoquinoline,as a common compound, the synthetic route is as follows.

Lithium aluminium hydride, L. OM solution in THF (Aldrich, 21,277-6) (22mL, 22MMOL) was added drop wise to 7-METHOXY-3, 4-dihydro-2H-isoquinolin-l-one (3. 0g, 17MMOL) in THF (25mL) at RT. After addition the reaction was refluxed for 3HRS. THE reaction was cooled to 0C and quenched by the careful addition of deionised H20 (1ML), 10% OH solution (LML) and deionised H20 (3mL). The basic suspension was filtered through celite and extracted into EtOAc (3XL50ML). The combined extracts were dried over MGS04 and the solvent was removed in vacuo. The residue was purified via flash chromatography eluting with MEOH/CH2CL2 (10: 90) to AFFORD 7-METHOXY-1, 2, 3,4-tetrahydro-isoquinoline. This was dissolved in EtOAc (LOML) and hydrogen chloride, 2. 0m solution in Et2O (Aldrich, 45,518-0) (lOmL) was added drop wise, which formed a white ppte. The solid was filtered off and washed with Et20 to afford 7-methoxy-1,2, 3, 4-TETRALLYDRO- isoquinoline hydrochloride as a white solid. Yield 1.4g (42%). HPLC retention time, 3. 05min. Mass spectrum (ES+) m/z 164 (M + H).

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Reference£º
Patent; IONIX PHARMACEUTICALS LIMITED; WO2005/5392; (2005); A1;,
Tetrahydroisoquinoline – Wikipedia
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem