- New 1,2,3,4-tetrahydroisoquinoline derivatives as modulators of proteolytic cleavage of amyloid precursor proteins
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A type of new 1,2,3,4-tetrahydroisoquinoline derivatives was synthesized via concise procedure from commercially available tetrahydroisoquinoline. These derivatives were delicately designed to possess propargyl-related pharmacophores simulated with a monoamine oxidase inhibitor rasagiline. We investigated the effect of these synthetic tetrahydroisoquinoline derivatives on the regulation of proteolytic processing of amyloid precursor protein (APP) by an ERK-dependent signaling pathway. Additionally, these compounds were also evaluated on the prevention of the proteolytic processing of C99 as γ-secretase inhibitors by using a highly efficient cell-based reporter gene assay for γ-secretase. The results suggested that certain compounds might be explored to possess both sAPPα-releasing stimulation and γ-secretase inhibitory potency, which may reflect the synergetic potential of neuroprotective activities for the treatment of Alzheimer's disease as they possessed both ERK activation and inhibition of amyloidogenic Aβ release.
- Hu, Ming-Kuan,Liao, Yung-Feng,Chen, Jung-Fang,Wang, Bo-Jeng,Tung, Ying-Tsen,Lin, Hui-Ching,Lee, Kang-Po
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Read Online
- Electrochemical approach to trifluoroacetamide synthesis from 1,1,1-trichloro-2,2,2-trifluoroethane (CFC-113a) catalyzed by B12complex
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One-pot synthetic approach to produce trifluoroacetamide has been developed using an electrochemical method with the B12 complex as a catalyst under mild conditions, in open air at room temperature. Thirty examples of trifluoroacetamide were synthesized from 1,1,1-trichloro-2,2,2-trifluoroethane (CFC-113a) in moderate to good yields. This user-friendly strategy is compatible with a broad range of trifluoroacetamide syntheses.
- Moniruzzaman, Mohammad,Yano, Yoshio,Ono, Toshikazu,Hisaeda, Yoshio,Shimakoshi, Hisashi
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- N-(Pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine Derivatives as Selective Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms
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In this study, we described a series of N-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine derivatives as selective JAK2 (Janus kinase 2) inhibitors. Systematic exploration of the structure-activity relationship though cyclization modification based on previously reported compound 18e led to the discovery of the superior derivative 13ac. Compound 13ac showed excellent potency on JAK2 kinase, SET-2, and Ba/F3V617F cells (high expression of JAK2V617F mutation) with IC50 values of 3, 11.7, and 41 nM, respectively. Further mechanistic studies demonstrated that compound 13ac could downregulate the phosphorylation of downstream proteins of JAK2 kinase in cells. Compound 13ac also showed good selectivity in kinase scanning and potent in vivo antitumor efficacy with 82.3% tumor growth inhibition in the SET-2 xenograft model. Moreover, 13ac significantly ameliorated the disease symptoms in a Ba/F3-JAK2V617F allograft model, with 77.1% normalization of spleen weight, which was more potent than Ruxolitinib.
- Yang, Tao,Hu, Mengshi,Chen, Yong,Xiang, Mingli,Tang, Minghai,Qi, Wenyan,Shi, Mingsong,He, Jun,Yuan, Xue,Zhang, Chufeng,Liu, Kongjun,Li, Jiewen,Yang, Zhuang,Chen, Lijuan
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p. 14921 - 14936
(2020/12/22)
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- COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
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In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured.The variables shown in Formula AA are as defined in the claims. The compounds of formula AA are NLRP3 activity modulators and, as such, can be used in the treatment of metabolic disorders (e.g. Type 2 diabetes, atherosclerosis, obesity or gout), a disease of the central nervous system (e.g. Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis or Parkinson's disease), lung disease (e.g. asthma, COPD or pulmonary idiopathic fibrosis), liver disease (e.g. NASH syndrome, viral hepatitis or cirrhosis), pancreatic disease (e.g. acute pancreatitis or chronic pancreatitis), kidney disease (e.g. acute kidney injury or chronic kidney injury), intestinal disease (e.g. Crohn's disease or Ulcerative Colitis), skin disease (e.g. psoriasis), musculoskeletal disease (e.g. scleroderma), a vessel disorder (e.g. giant cell arteritis), a disorder of the bones (e.g. osteoarthritis, osteoporosis or osteopetrosis disorders), eye disease (e.g. glaucoma or macular degeneration), a disease caused by viral infection (e.g. HIV or AIDS), an autoimmune disease (e.g. Rheumatoid Arthritis, Systemic Lupus Erythematosus or Autoimmune Thyroiditis), cancer or aging.
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Page/Page column 501; 502
(2019/02/13)
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- Synthesis of trifluoromethyl moieties by late-stage copper (I) mediated nucleophilic fluorination
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The nucleophilic fluorination of bromodifluoromethyl derivatives mediated by the complex (PPh3)3CuF is described. Under the reaction conditions, different trifluoroacetates, trifluoroketones, trifluoroarenes and trifluoroacetamides were obtained in good yields.
- Bermejo Góme, Antonio,González, Miguel A. Cortés,Lübcke, Marvin,Johansson, Magnus J.,Schou, Magnus,Szabó, Kálmán J.
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- Efficient DBU accelerated synthesis of 18F-labelled trifluoroacetamides
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Nucleophilic 18F-fluorination of bromodifluoromethyl derivatives was performed using [18F]Bu4NF in the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). This novel procedure provided a diverse set of [18F]trifluoroacetamides in good to excellent radiochemical conversions. A mechanism where DBU acts as organomediator in this transformation is proposed.
- Gómez, Antonio Bermejo,Cortés González, Miguel A.,Lübcke, Marvin,Johansson, Magnus J.,Halldin, Christer,Szabó, Kálmán J.,Schou, Magnus
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supporting information
p. 13963 - 13966
(2016/12/09)
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- An efficient and convenient synthesis of acyl coa: Monoacylglycerol acyltransferase 2 inhibitor, 2-[2-(4-tert-butylphenyl)ethyl]-N-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide
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An efficient and convenient synthesis of MGAT2 inhibitor, 2-[2-(4-tert-butylphenyl)ethyl]-N-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-1,2,3, 4-tetrahydroisoquinoline-6-sulfonamide (1), is reported. The optimized route consists of an effective chlorosulfonylation and debromination, resulting in an increase in the total yield from 6.8% to 45%, compared with our previous method. This synthetic approach enabled the synthesis of 1 to be scaled-up to a multi-gram scale.
- Busujima, Tsuyoshi,Tanaka, Hiroaki
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p. 470 - 484
(2016/04/10)
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- Identification of 2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide (29) as an orally available MGAT2 inhibitor
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MGAT2 (monoacylglycerol acyltransferase 2) is expected to be an attractive target for the drug treatment of obesity, diabetes, and other disease. We describe our exploration and structure-activity relationship (SAR) study of 2,3-dihydro-1H-isoindole-5-sul
- Busujima, Tsuyoshi,Tanaka, Hiroaki,Shirasaki, Yoshihisa,Munetomo, Eiji,Saito, Masako,Kitano, Kiyokazu,Minagawa, Toshiya,Yoshida, Koji,Osaki, Naoto,Sato, Nagaaki
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p. 5922 - 5931
(2015/11/11)
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- S1P RECEPTORS MODULATORS
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The invention relates to novel compounds that have S1P receptor modulating activity and, preferably, apoptotic activity and/or anti proliferative activity against cancer cells and other cell types. Further, the invention relates to a pharmaceutical comprising at least one compound of the invention for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression, for example, cancer. A further aspect of the invention relates to the use of a pharmaceutical comprising at least one compound of the invention for the manufacture of a medicament for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression such as cancer.
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Page/Page column 57
(2010/04/30)
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- 1,2,3,4-Tetrahydroisoquinoline Derivatives, Preparation Process therefor and Pharmaceutical Composition Containing the Same
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The invention provides a type of novel 1,2,3,4-tetrahydroisoquinoline derivatives with a structure of formula (I): wherein R1 represents propargyl or cyclopropylmethyl; wherein R2 represents N-ethyl-N-methylamino, 1-Pyrrolidyl, 1-Piperidinyl, or 1-Morpholinyl. The invention provides further a process for preparing said derivatives and a pharmaceutical composition containing the same. Said derivatives can be used to modulate the proteolytic process of amyloid precursor proteins (APP), and provides further novel compounds useful for treating Alzheimer's disease (AD).
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Page/Page column 3
(2010/02/17)
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- Keto Lactam Compounds and Use Thereof
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The invention relates to novel keto lactam compounds, hydrogenated derivatives and tautomers thereof. These compounds have valuable therapeutic properties and are particularly suited for treating diseases that respond to the modulation of the dopamine D3 receptor. The keto lactams have general formula (I), wherein: (a) represents a group of formulas (b) or (c), wherein D is bound to the nitrogen atom and W, Rp and Rq have the meanings cited in Claim 1; —B— represents a bond or (d), wherein Rm and Rn have the meanings cited in Claim 1; (e) represents a single bond or a double bond; Rv, Rw, Rx and Ry have the meanings cited in Claim 1; D represents a linear or branched 2 to 10-membered alkylene chain that can have, as chain members, a heteroatom group K, which is selected among O, S, S(O), S(O)2, N—R8, CO—O, C(O)NR8 and/or 1 or 2 non-adjacent carbonyl groups and which can have a cycloalkane diyl group and/or a double or triple bond: (f) represents a saturated or monounsaturated monocyclic nitrogen heterocyclic compound having 5 to 8 cyclic members or a bicyclic saturated nitrogens heterocyclic compound having 7 to 12 cyclic members.
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- ALKYLAMINE-SUBSTITUTED BICYCLIC ARYL COMPOUNDS USEFUL AS MODULATORS OF PPAR
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The present invention relates to novel alkylamine-substituted bicyclic aryl compounds, pharmaceutical compositions comprising the same, useful as modulators of PPAR, and methods for the treatment or prevention of disease.
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Page/Page column 11; 16
(2008/06/13)
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- Direct ortho iodination of β- and γ-aryl alkylamine derivatives
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Two in one! A trifluoroacetamide protecting group not only masks an amine functionality, but also mimics peptidyl directing effects as a controlling unit in an efficient ortho iodination of a variety of biologically relevant small molecules (see example). (Chemical Equation Presented).
- Barluenga, Jose,Alvarez-Gutierrez, Julia M.,Ballesteros, Alfredo,Gonzalez, Jose M.
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p. 1281 - 1283
(2008/03/27)
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- N-SUBSTITUTED PIPERIDINE AND PIPERAZINE DERIVATIVES
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This invention relates to compounds of the formula 1 wherein R1, R2, R7, R8, R9, U, V, Z, A, W, X, M, E, L, T and D are defined as in the specification, pharmaceutical compositions containing them and their use in the treatment of central nervous system and other disorders.
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Page/Page column 107-108
(2010/02/12)
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- KETO LACTAM COMPOUNDS AND USE THEREOF
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The invention relates to novel keto lactam compounds, hydrogenated derivatives and tautomers thereof. These compounds have valuable therapeutic properties and are particularly suited for treating diseases that respond to the modulation of the dopamine D3 receptor. The keto lactams have general formula (I), wherein: (a) represents a group of formulas (b) or (c), wherein D is bound to the nitrogen atom and W, Rp and Rq have the meanings cited in Claim 1;-B-represents a bond or (d), wherein Rm and Rn have the meanings cited in Claim 1; (e) represents a single bond or a double bond; Rv, Rw, Rx and Ry have the meanings cited in Claim 1; D represents a linear or branched 2 to 10-membered alkylene chain that can have, as chain members, a heteroatom group K, which is selected among O, S, S(O), S(O)2, N-R8, CO-O, C(O)NR8 and/or 1 or 2 non-adjacent carbonyl groups and which can have a cycloalkane diyl group and/or a double or triple bond; (f) represents a saturated or monounsaturated monocyclic nitrogen heterocyclic compound having 5 to 8 cyclic members or a bicyclic saturated nitrogen heterocyclic compound having 7 to 12 cyclic members.
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Page/Page column 65
(2010/02/12)
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- TRIAZOLE COMPOUNDS AND THE THERAPEUTIC USE THEREOF
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The invention relates to triazole compounds of general formula (I), wherein A, B, R1, R2, R3 and R4 have the meaning cited in claim 1. The invention also relates to a pharmaceutical agent containing at least one compound of general formula (I) in addition to the use of the compound (I) for producing a pharmaceutical agent for treating illnesses, responding to the effects of dopamine-D3-receptor antagonists or dopamine-D3-receptor agonists, especially for treating disorders in the central nervous system.
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Page/Page column 31
(2008/06/13)
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- Melanin-concentrating hormone antagonist
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A melanin-concentrating hormone antagonist comprising a compound of the formula: wherein R is hydrogen atom or a cyclic group which may be substituted; X is a bond or a spacer having a main chain of 1 to 10 atoms; Y is a spacer having a main chain of 1 to 6 atoms; ring A is benzene ring which may be further substituted; ring B is a 5- to 9-membered nitrogen-containing non-aromatic heterocyclic ring which may be further substituted; R1 and R2 are the same or different and are hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; or R1 and R2, together with the adjacent nitrogen atom, may form a nitrogen-containing heterocyclic ring which may be substituted; or R2, together with the adjacent nitrogen atom and Y, may form a nitrogen-containing heterocyclic ring which may be substituted; or a salt thereof is useful as a preventive or therapeutic agent for obesity, etc.
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- Heterocyclic derivatives and their use as antithrombotic agents
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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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- Preparation of 1,2,3,4-tetrahydroisoquinolines lacking electron donating groups - An intramolecular cyclization complementary to the Pictet-Spengler reaction
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The synthesis of 1,2,3,4-tetrahydroisoquinolines via an intramolecular cyclization of N-trifluoroacylated phenethylamines devoid of electron donating groups, with paraformaldehyde mediated by acetic/sulfuric acid milieu is described.
- Stokker
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p. 5453 - 5456
(2007/10/03)
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- 7- and/or 8-Sulfur substituted 1,2,3,4-tetrahydroisoquinoline compounds
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1,2,3,4-Tetrahydroisoquinoline compounds having 7- and/or 8-sulfur substituents are inhibitors of phenylethanolamine N-methyltransferase.
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- Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 2. 1,2,3,4-Tetrahydroisoquinoline-7-sulfonanilides.
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1,2,3,4-Tetrahydroisoquinoline-7-sulfonanilides (1-14) related to 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (21,SK&F 29661) were prepared and studied for their ability to inhibit phenylethanolamine N-methyltransferase (PNMT) in vitro. The choice of substituents on the 7-phenyl group of the sulfonanilides was based on the Topliss approach to structure-activity relationship studies. Information about the importance of an acidic hydrogen atom on the sulfonamide nitrogen atom was obtained from the preparation and testing of a tertiary N-methylsulfonanilide (15). Other THIQ's (1,2,3,4-tetrahydroisoquinolines) containing sulfur substituents in the 7 position were prepared and tested and consisted of 7-N-benzyl and 7-N-phenethyl derivatives of SK&F 29661 (16-18) and 7-(phenacylthio)-and 7-(phenacylsulfonyl)-THIQ (19 and 20). The two most potent inhibitors were the 7-p-bromo- and -chlorosulfonanilides, 2 and 6. However, neither was an effective inhibitor of norepinephrine to epinephrine conversion when tested in an in vivo mouse assay at unit doses of 25 or 100 mg/kg.
- Blank,Krog,Weiner,Pendleton
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p. 837 - 840
(2007/10/02)
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