- Enabling Synthesis of Triple Reuptake Inhibitor (+)-BMS-820836, a Potential Therapeutic Agent for the Treatment of Depression
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Herein, we describe the enabling synthesis of (+)-BMS-820836, a 4,7-disubstituted tetrahydroisoquinoline which was developed as a treatment for a range of neurological diseases, including depression and neurophatic pain. In order to advance the drug candi
- Lobben, Paul C.,Amin, Rasidul,Chen, Bang-Chi,Cui, Wenge,Hu, Min,Isherwood, Matthew,Liu, Shuang,Nacro, Kassoum,Miles, Brandon,Mobele, Bingidimi,Olson, Richard E.,Wang, Bei,Yang, Yuh-Lin,Zhao, Rulin
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- Tandem C(sp3)?H Arylation/Oxidation and Arylation/Allylic Substitution of Isoindolinones
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Isoindolinones comprise an important class of medicinally active compounds. Herein we report a straightforward functionalization of isoindolinones with aryl bromides (22 examples) using a palladium(II) acetate/NIXANTPHOS-based catalyst system. Additionally 3-aryl-3-hydroxyisoindolinone derivatives, which exhibit anti-tumor activity, can be accessed via a tandem reaction. Thus, when the arylation product is exposed to air under basic conditions, in situ oxidation takes place to install the 3-hydroxy group. Furthermore, a tandem arylation/allylic substitution reaction is advanced in which both the arylation and allylic substitution are catalyzed by the same palladium catalyst. Finally, a tandem arylation/alkylation procedure is presented. These tandem reactions enable the synthesis of a variety of structurally diverse isoindolinone derivatives from common starting materials. (Figure presented.).
- Jiménez, Jacqueline,Kim, Byeong-Seon,Walsh, Patrick J.
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supporting information
p. 2829 - 2837
(2016/09/13)
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- CRYSTALLINE FORM OF 6-[(4S)-2-METHYL-4-(2-NAPHTHYL)-1,2,3,4-TETRAHYDROISOQUINOLIN-7-YL]PYRIDAZIN-3-AMINE
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The present disclosure generally relates to a crystalline form of 6-[(4S)-2-methyl-4-(naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine. The present disclosure also generally relates to pharmaceutical compositions comprising the crystalline form, as well of methods of using a crystalline form in the treatment of depression and other conditions and methods for obtaining such crystalline form.
- -
-
Paragraph 0072; 0074; 0075
(2014/09/30)
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- Smooth isoindolinone formation from isopropyl carbamates via bischler-napieralski-type cyclization
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Isopropyl carbamates derived from benzylamines provide isoindolinones by treatment with phosphorus pentoxide at room temperature. Utility of this Bischler-Napieralski-type cyclization and a new mechanism involving a carbamoyl cation for rationalization of this smooth conversion are discussed.
- Adachi, Satoshi,Onozuka, Masao,Yoshida, Yuko,Ide, Mitsuaki,Saikawa, Yoko,Nakata, Masaya
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supporting information
p. 358 - 361
(2014/04/03)
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- Synthesis and biological evaluation of urea derivatives as highly potent and selective rho kinase inhibitors
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RhoA and its downstream effector ROCK mediate stress fiber formation and cell contraction through their effects on the phosphorylation of myosin light chain (MLC). Inhibition of the RhoA/ROCK pathway has proven to be a promising strategy for several indications such as cardiovascular disease, glaucoma, and inflammatory disease. In 2010, our group reported urea-based ROCK inhibitors as potential antiglaucoma agents. These compounds showed potent IC50 values in enzymatic and cell-based assays and significant intraocular pressure (IOP)-lowering effects in rats (～7 mmHg).(22) To develop more advanced ROCK inhibitors targeting various potential applications (such as myocardial infarction, erectile dysfunction, multiple sclerosis, etc.) in addition to glaucoma, a thorough SAR for this urea-based scaffold was studied. The detailed optimization process, counter-screening, and in vitro and in vivo DMPK studies are discussed. Potent and selective ROCK inhibitors with various in vivo pharmacokinetic properties were discovered.
- Yin, Yan,Lin, Li,Ruiz, Claudia,Khan, Susan,Cameron, Michael D.,Grant, Wayne,Pocas, Jennifer,Eid, Nibal,Park, Hajeung,Schr?ter, Thomas,Lograsso, Philip V.,Feng, Yangbo
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p. 3568 - 3581
(2013/06/27)
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- 4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors
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Novel 4-phenyl tetrahydroisoquinolines that inhibit both dopamine and norepinephrine transporters were designed and prepared. In this Letter, we describe the synthesis, in vitro activity and associated structure-activity relationships of this series. We also report the ex vivo NET occupancy of a representative compound, 41.
- Pechulis, Anthony D.,Beck, James P.,Curry, Matt A.,Wolf, Mark A.,Harms, Arthur E.,Xi, Ning,Opalka, Chet,Sweet, Mark P.,Yang, Zhicai,Vellekoop, A. Samuel,Klos, Andrew M.,Crocker, Peter J.,Hassler, Carla,Laws, Mia,Kitchen, Douglas B.,Smith, Mark A.,Olson, Richard E.,Liu, Shuang,Molino, Bruce F.
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p. 7219 - 7222
(2013/01/15)
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- Highly enantioselective synthesis of tetrahydroquinolines via cobalt(II)-catalyzed tandem 1,5-hydride transfer/cyclization
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A chiral catalyst prepared from N,N′-dioxide and Co(BF 4)2·6H2O was applied in the asymmetric hydride transfer initiated cyclization reaction, giving optically active tetrahydroquinolines in good yields with high enantioselectivities under mild reaction conditions. Meanwhile, in light of the absolute configuration of the product, a possible working model was proposed to explain the origin of the activation and asymmetric induction.
- Cao, Weidi,Liu, Xiaohua,Wang, Wentao,Lin, Lili,Feng, Xiaoming
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p. 600 - 603
(2011/04/15)
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- ARYL, HETEROARYL, AND HETEROCYCLE SUBSTITUTED TETRAHYDROISOQUINOLINES AND USE THEREOF
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Novel aryl, heteroaryl, and non-aromatic heterocyle substituted tetrahydroisoquinolines are described in the present invention. These compounds are used in the treatment of various neurological and physiological disorders. Methods of making these compounds are also described in the present invention.
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Page/Page column 74; 101-102
(2010/12/17)
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- 7-([1,2,4,]TRIAZOLO[1,5,-A]PYRIDIN-6-YL)-4-(3,4-DICHLOROPHENYL)-1,2,3,4- TETRAHYDROISOQUINOLINE AND USE THEREOF
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Novel [l,2,4]triazolo[l,5-α]pyridinyl-6-yl-substituted tetrahydroisoquinolines are described in the present invention. These compounds and crystalline forms SAl and N-2 are used in the treatment of various neurological and physiological disorders. Methods of making these compounds and crystalline forms SA-I and N-2 are also described in the present invention.
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Page/Page column 31
(2010/12/17)
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- CRYSTALLINE FORMS OF (S)-7-([1,2,4]TRIAZOLO[1,5-a]PYRIDIN-6-YL)-4-(3,4-DICHLOROHPHENYL)-1,2,3,4-TETRAHYDROISOQUINOLINE AND USE THEREOF
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Novel [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinolines are described in the present invention. These compounds and crystalline forms SA1 and N-2 are used in the treatment of various neurological and physiological disorders. Methods of making these compounds and crystalline forms SA-1 and N-2 are also described in the present invention.
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Page/Page column 32
(2010/12/17)
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- A novel construction of 2-benzazepine scaffold based on TiCl 4-mediated tandem Mannich reaction - Aromatic electrophilic substitution
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A novel construction of 2-benzazepine derivatives based on TiCl 4-mediated tandem Mannich reaction of electron-rich benzyl iminium ions with alkenyl ethers and Friedel - Crafts-type alkylation is described. The protocol is amenable to provide the tricyclic furo[3,2-d][2]benzazepine and pyrano[3,2-d][2]benzazepine derivatives, respectively, with 2,3-dihydrofuran or 3,4-dihydro-2H-pyran as the substrates.
- Li, Liangxi,Li, Zhiming,Wang, Quanrui
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experimental part
p. 2754 - 2761
(2010/04/02)
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- CRYSTALLINE FORM OF 6-[(4S)-2-METHYL-4-(2-NAPHTHYL)-1,2,3,4-TETRAHYDROISOQUINOLIN-7-YL]PYRIDAZIN-3-AMINE
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The present disclosure generally relates to a crystalline form of 6-[(4S)-2-methyl-4-(naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine. The present disclosure also generally relates to pharmaceutical compositions comprising the crystalline form, as well of methods of using a crystalline form in the treatment of depression and other conditions and methods for obtaining such crystalline form.
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Page/Page column 19; 23
(2009/12/28)
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- Cholinesterase inhibitors: SAR and enzyme inhibitory activity of 3-[ω-(benzylmethylamino)alkoxy]xanthen-9-ones
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In this work, we further investigated a previously introduced class of cholinesterase inhibitors. The removal of the carbamic function from the lead compound xanthostigmine led to a reversible cholinesterase inhibitors 3. Some new 3-[ω-(benzylmethylamino)alkoxy]xanthen-9-one analogs were designed, synthesized, and evaluated for their inhibitory activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The length of the alkoxy chain of compound 3 was increased and different substituents were introduced. From the IC50 values, it clearly appears that the carbamic residue is crucial to obtain highly potent AChE inhibitors. On the other hand, peculiarity of these compounds is the high selectivity toward BuChE with respect to AChE, being compound 12 the most selective one (6000-fold). The development of selective BuChE inhibitors may be of great interest to clarify the physiological role of this enzyme and to provide novel therapeutics for various diseases.
- Piazzi, Lorna,Belluti, Federica,Bisi, Alessandra,Gobbi, Silvia,Rizzo, Stefano,Bartolini, Manuela,Andrisano, Vincenza,Recanatini, Maurizio,Rampa, Angela
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p. 575 - 585
(2008/03/12)
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- Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
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The compounds of the present invention are represented by the following aryl- and heteroaryl-substituted tetrahydrobenzazepine and dihydrobenzazapine derivatives having formulae I(A-E) and formula (II): where the carbon atom designated * is in the R or S configuration, and the substituents X and R1-R9 are as defined herein.
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Page/Page column 57; 59; 60; 62; 63; 64-65; 66; 70; 71; 73; 74; 88
(2008/06/13)
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- TACHYKININ RECEPTOR ANTAGONISTS
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The present invention relates to selective NK-1 receptor antagonists of Formula (I) or a pharmaceutically acceptable salt thereof, for the treatment of disorders associated with an excess of tachykinins.
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- Facile preparation of N-methyl secondary amines by titanium(IV) isopropoxide-mediated reductive animation of carbonyl compounds
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A simple, mild and efficient procedure for obtaining N-methyl secondary amines from aldehydes and ketones is reported. Treatment of carbonyl compounds with methylamine hydrochloride, triethylamine and titanium(IV) isopropoxide, followed by in situ sodium borohydride reduction and straightforward aqueous work-up, affords clean products in good to excellent yields.
- Neidigh, Kurt A.,Avery, Mitchell A.,Williamson, John S.,Bhattacharyya, Sukanta
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p. 2527 - 2531
(2007/10/03)
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- Cholinergic Agents. Synthesis and Acetylcholinesterase Inhibitory Activity of Some ω-[N-Methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyxanthen-9-ones
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A series of ω-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyxanthen-9-ones was prepared. The alkoxy chain occupies, alternatively, the positions 2, 3 and 4 of the xanthone moiety and has a variable length. The compounds were evaluated for acetylcholinesterase inhibitory activity. Some in this series were revealed to be more potent than physostigmine. Optimum activity was found with the 3 position and with a four or three carbon chain length separating the benzylamino group from the xanthenonyloxy moiety.
- Valentini, Piero,Rampa, Angela,Bisi, Alessandra,Fabbri, Giuseppina,Andrisano, Vincenza,Cavrini, Vanni
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p. 255 - 264
(2007/10/03)
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- Synthesis of 1,2-Dihydroisoquinoline-3-carbaldehydes
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ortho-Formylation of N-(2,2-diethoxyethyl)benzylamines followed by acid-catalyzed cyclisation leads to 1,2-dihydroisoquinoline-3-carbaldehydes.
- Simig, Gyula
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p. 1613 - 1616
(2007/10/02)
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- 3(2H)pyridazinone, process for its preparation and anti-allergic agent containing it
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A 3(2H)pyridazinone of the formula: STR1 wherein R1 is C2 -C5 alkyl; R2 is hydrogen, C1 -C3 alkyl, chlorine or bromine; R3 is hydrogen or C1 -C4 alkyl; and each of Y1, Y2 and Y3 which may be the same or different, is hydrogen, C1 -C8 alkyl, C2 -C8 alkenyl, halogen, --(CH2)l A [wherein A is substituted amino of the formula --N(R4) (R5) (wherein each of R4 and R5 which may be the same or different, is C1 -C4 alkyl, or R4 and R5 together form C4 -C6 alkylene), morpholino, 4-R6 -piperazin-1-yl (wherein R6 is C1 -C3 alkyl) or --OR7 (wherein R7 is hydrogen or C1 -C3 alkyl), and l is an integer of 0 to 3], --OR8 [wherein R8 is hydrogen, C1 -C8 alkyl, C3 -C5 alkenyl, benzyl or --(CH2)q --R9 [wherein R9 is CO2 R3 (wherein R3 is as defined above), --CONHR3 (wherein R3 is as defined above) or --CH2 OR7 (wherein R7 is as defined above), and q is an integer of 1 to 5]], --CO2 R3 (wherein R3 is as defined above), --CON(R10) (R11) [wherein each of R10 and R11 which may be the same or different, is hydrogen, C1 -C4 alkyl or C3 -C5 alkenyl, or R10 and R11 together form C4 -C6 alkylene, --(CH2)2 O(CH2)2 -- or --(CH2)2 N(R6)(CH2)2 -- (wherein R6 is as defined above)], --CONH(CH2)m A (wherein A is as defined above, and m is an integer of 2 to 4), --CH=CHCOR12 (wherein R12 is hydroxy, C1 -C4 alkoxy or --N(R13) (CH2)n CO2 R3 (wherein R13 is hydrogen, C1 -C6 alkyl or cycloalkyl, R3 is as defined above, and n is an integer of 1 to 4)), --SR14 (wherein R14 is C1 -C4 alkyl), --CN or STR2 wherein R3 is as defined above), or two of Y1, Y2 and Y3 together form STR3 (wherein p is an integer of 1 or 2), and a pharmaceutically acceptable salt thereof.
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- A New Synthesis of 1,2,3,4-Tetrahydro-2-methyl-4-phenylisoquinolines
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1,2,3,4-Tetrahydro-2-methyl-4-phenylisoquinolines 6 are obtained from aromatic aldehydes 1, methyl amine and α-haloacetophenones 2 in the presence of sodium borohydride followed by cyclization with sulfuric acid and zinc in methanol.
- Venkov, Atanas P.,Vodenicharov, Daniel M.
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p. 253 - 255
(2007/10/02)
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- Oxidations with Cerium(IV) Sulfate: Intramolecular Cyclization of N-Benzyl-&β-aminoketones Yielding 4-Benzoyl-1,2,3,4-tetrahydroisoquinolines
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Preparation and regiospecific cerium(IV) sulfate 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.
- Holzgrabe, Ulrike
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p. 647 - 654
(2007/10/02)
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- Quantitative structure-activity relationship of the mutagenicity of substituted N-nitroso-N-benzylmethylamines: Possible implications of carcinogenicity
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The relative mutagenicities of substituted N-nitroso-N-benzylmethylamines have been reexamined from a quantitative structure-activity relationship point of view. Most of the compounds were mutagenic toward Salmonella typhimurium TA 1535 with Aroclor-induced male hamster liver S9 activation. The dose-response data were subjected to a multiple linear regression equation calculated in a stepwise manner, which found that the differences in mutagenicities could be explained primarily by differences in the three-bond path molecular connectivity index, with smaller contributions from σ and π. Moreover, a polynomial regression analysis showed that the maximum mutagenicity could be explained by an optimal amount of electron withdrawal by the substituent which could cause a weakening, or activation, of the methylene C-H bond. The possible relevance of these observations to carcinogenesis is discussed.
- Singer,Andrews,Guo
-
-
- A NEW PATHWAY TO 1,3,4(2H)-ISOQUINOLINETRIONES AND SUBSTITUTED ISOINDOLINONES
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A new synthesis in the isoquinoline series is discussed: the reaction of appropriate benzamides and oxalyl chloride affords isoquinolinetrions along N-aroyloxamoyl chlorides.The solvent effect, the acid catalysis and the isomer distribution are accounted
- Vekemans, Jozef,Hoornaert, Georges
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p. 943 - 950
(2007/10/02)
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