33543-63-4

Upstream product

• 541-41-3 chloroformic acid ethyl ester 
• 2039-67-0 2-(3-methoxyphenyl)-1-ethanamine 
• 19924-43-7 3-methoxyphenylacetonitrile 
• 872496-89-4 (E)-3-(3-methoxyphenyl)acryloyl azide 
• 15851-92-0 (E)-3-methoxycinnamoyl chloride 
• 6099-04-3 trans-3-methoxycinnamic acid 

Downstream Products

• 22246-04-4 7-methoxy-3,4-dihydro-2H-isoquinolin-1-one 
• 921224-62-6 tert-butyl-6-methoxy-7-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate 
• 73903-30-7 8-Methoxy-2-methyl-1,2,3,4-tetrahydroisochinolin 
• 34146-68-4 8-methoxy-1,2,3,4-tetrahydroisoquinoline 
• 74904-29-3 8-methoxy-3,4-dihydroisoquinolin-1(2H)-one 
• 59839-23-5 6-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide 
• 42923-77-3 6-methoxy-1,2,3,4-tetrahydro-isoquinoline 
• 22245-98-3 6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one 
• 308110-09-0 6-[hydroxy(phenyl)methyl]-2-methyl-3,4-dihydro-1(2H)-isoquinolinone 
• 308110-07-8 6-hydroxyl-2-methyl-3,4-dihydroisoquinolin-1(2H)-one 
• 22246-12-4 6-methoxy-1,2,3,4-tetrahydro-1-oxoisoquinoline 
• 33543-62-3 2-(3-methoxyphenyl)-N-methylethan-1-amine 

Relevant academic research and scientific papers

1-[2-(1-Cyclobutylpiperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]propan-1-one: a Histamine H3 Receptor Inverse Agonist with Efficacy in Animal Models of Cognition

A series of chemical optimizations, which was guided by in vitro affinity at histamine H3 receptor (H3R), modulation of lipophilicity, ADME properties and preclinical efficacy resulted in the identification of 1-[2-(1-cyclobutylpiperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]propan-1-one (45 e) as a potent and selective (Ki=4.0 nM) H3R inverse agonist. Dipsogenia induced by (R)-α-methylhistamine was dose dependently antagonized by 45 e, confirming its functional antagonism at H3R. It is devoid of hERG and phospholipidosis issues. Compound 45 e has adequate oral exposures and favorable half-life in both rats and dogs. It has demonstrated high receptor occupancy (ED80=0.22 mg/kg) and robust efficacy in object recognition task and, dose dependently increased acetylcholine levels in brain. The sub-therapeutic doses of 45 e in combination with donepezil significantly increased acetylcholine levels. The potent affinity, selectivity, in vivo efficacy and drug like properties together with safety, warrant for further development of this molecule for potential treatment of cognitive disorders associated with Alzheimer's disease.

Synthesis, in vitro cytotoxicity, and molecular docking study of novel 3,4-dihydroisoquinolin-1(2H)-one based piperlongumine analogues

With the aim of expanding the scope of SAR on piperlongumine (PL), a naturally occurring anticancer molecule, we have designed a novel hybrid molecule bearing 3,4-dihydroisoquinolin-1(2H)-one and trans-cinnamic acids. The structure, based on hybridization strategy, is used for hybridization of naturally occurring scaffolds. We have synthesized 14 hybrid molecules by coupling 3,4-dihydroisoquinolin-1(2H)-one core with cinnamic acids using the mix anhydride approach. The newly synthesized inhibitors were evaluated for cell viability against breast cancer MCF-7 and cervical cancer HeLa cell lines. Furthermore, the active compounds were screened for their potential in breast cancer MDA-MB-231, cervical cancer C33A cell lines, prostate cancer DU-145, PC-3, and normal VERO cells. From the series, compound 10g was seen to inhibit MCF-7 cell growth significantly with GI50 50 = 20 μM) and C33A (GI50 = 3.2 μM). While the inhibitor 10i inhibits MCF-7 breast cancer cell growth GI50 = 3.42 μM along with inhibition of cell growth in MDA-MB-231 (GI50 = 30 μM), HeLa (GI50 = 7.67 μM), C33A (GI50 = 13 μM), DU-145 (GI50 = 6.45 μM), PC-3 (GI50 = 8.68 μM), and VERO (GI50 = 2.93 μM), respectively. Furthermore, molecular docking study demonstrated these compounds could bind tightly to the colchicine domain of tubulin through a network of favorable steric and electrostatic interactions and thus act as a tubulin polymerization inhibitor.

Discovery of 5-phenoxy-2-aminopyridine derivatives as potent and selective irreversible inhibitors of bruton’s tyrosine kinase

As a member of the tyrosine protein kinase Tec (TEC) family, Bruton’s tyrosine kinase (BTK) is considered a promising therapeutic target due to its crucial roles in the B cell receptor (BCR) signaling pathway. Although many types of BTK inhibitors have been reported, there is an unmet need to achieve selective BTK inhibitors to reduce side effects. To obtain BTK selectivity and efficacy, we designed a novel series of type II BTK inhibitors which can occupy the allosteric pocket induced by the DFG-out conformation and introduced an electrophilic warhead for targeting Cys481. In this article, we have described the structure-activity relationships (SARs) leading to a novel series of potent and selective piperazine and tetrahydroisoquinoline linked 5-phenoxy-2-aminopyridine irreversible inhibitors of BTK. Compound 18g showed good potency and selectivity, and its biological activity was evaluated in hematological tumor cell lines. The in vivo efficacy of 18g was also tested in a Raji xenograft mouse model, and it significantly reduced tumor size, with 46.8% inhibition compared with vehicle. Therefore, we have presented the novel, potent, and selective irreversible inhibitor 18g as a type II BTK inhibitor.

Isoquinolinone derivatives as potent CNS multi-receptor D2/5-HT1A/5-HT2A/5-HT6/5-HT7 agents: Synthesis and pharmacological evaluation

In this study, a series of novel Isoquinolinone derivatives were synthesized as potential multi-target antipsychotics. Among these, compound 13 showed high affinity for dopamine D2 and serotonin 5-HT1A, 5-HT2A, 5-HT6, and 5-HT7 receptors, showed low affinity for off-target receptors (5-HT2C, H1, and α1), and negligible effects on ether-a-gogo-related gene (hERG; i.e., reduced QT interval prolongation). An animal behavioral study revealed that compound 13 reversed APO-induced hyperlocomotion, MK-801-induced hyperactivity, and DOI-induced head twitch. Moreover, compound 13 exhibited a high threshold for acute toxicity, a lack of tendency to induce catalepsy, and did not cause prolactin secretion or weight gain when compared to risperidone. Furthermore, in the forced swim test, tail suspension test, and novel object recognition test, treatment with compound 13 resulted in improvements in depression and cognitive impairment. In addition, compound 13 had a favorable pharmacokinetic profile in rats. Thus, the antipsychotic drug-like effects of compound 13 indicate that it may be useful for developing a novel class of drugs for the treatment of schizophrenia.

INDOLINONE COMPOUNDS FOR USE AS MAP4K1 INHIBITORS

The present disclosure is directed to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein ring A, ring C, X1, X2, L1, R1, R2, R3, R4, R5, R6, R7, m and n are as defined herein, which are useful as MAP4K1 inhibitors, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment or prevention of various diseases, conditions and/or disorders mediated by MAP4K1.

Catalyst-free cyclization of anthranils and cyclic amines: One-step synthesis of rutaecarpine

An efficient synthesis of a variety of quinazolinone derivatives via a direct cyclization reaction between commercially available anthranils and cyclic amines is described. The developed transformation proceeds with the merits of high step- and atom-efficiency, a broad substrate scope, and good to excellent yields, without additional catalysts, and offers a practical way for the preparation of rutaecarpine and its derivatives with structural diversity.

Tyrosine Kinase Inhibitor And Uses Thereof

Disclosed is a compound of Formula (I) or a pharmaceutically acceptable salt, ester, or solvate thereof, or their stereoisomers, which can be used as tyrosine kinase inhibitor. Also disclosed is a method for preparing the compound, a pharmaceutical composition and a kit comprising the compound, and uses of the compound. The compound can be used as tyrosine kinase inhibitor, or can be used to reduce or inhibit activity of EGFR or mutant thereof, such as EGFR mutant comprising T790M mutation, in a cell, or to treat and/or prevent a disease associated with overactivity of EGFR, such as cancer.

COMPOSITE PREPARATION, CONTAINING NOVEL 3-(4-(BENZYLOXY)PHENYL)HEX-4-INOIC ACID DERIVATIVE AND ANOTHER ACTIVE INGREDIENT, FOR PREVENTING OR TREATING METABOLIC DISEASES

The present invention relates to a pharmaceutical composition for preventing or treating metabolic diseases, in which a novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative and at least another active ingredient, which is selected from the group consisting of dipeptidyl peptidase-4 (DPPIV) inhibitor-based, sulfonylurea-based, thiazolidinedione (TZD)-based, biguanide-based, and sodium/glucose cotransporter 2 (SGLT2) inhibitor-based drugs, may be administered in combination or in the form of a composite preparation. The use of the composition of the present invention can provide a remarkably excellent blood sugar reducing effect in various animal diabetic disease models, and the composition of the present invention can be favorably used as a pharmaceutical composition for preventing or treating metabolic diseases, such as obesity, diabetes type I, diabetes type II, glucose intolerance symptoms, insulin resistance symptoms, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X.

NOVEL 3-(4(BENZYLOXY)PHENYL)HEX-4-INOIC ACID DERIVATIVE, METHOD OF PREPARING SAME AND PHARMACEUTICAL COMPOSITION FOR PREVENTING AND TREATING METABOLIC DISEASE INCLUDING SAME AS EFFECTIVE INGREDIENT

The present invention relates to a novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative, a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient for the prevention and treatment of metabolic disease. The novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the present invention has excellent activities of activating GPR40 protein and promoting insulin secretion accordingly but has no toxicity when co-administered with other drugs. That is, the novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the present invention can be co-administered with other drugs and can promote the activation of GPR40 protein significantly, so that the composition comprising the same as an active ingredient can be efficiently used as a pharmaceutical composition for the prevention and treatment of metabolic disease such as obesity, type I diabetes, type II diabetes, incompatible glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X, etc.

Exploration of the linkage elements of porcupine antagonists led to potent Wnt signaling pathway inhibitors

The Wnt signaling pathway is a pivotal developmental pathway. It operates through control of cellular functions such as proliferation, differentiation, migration and polarity. Aberrant Wnt signaling has been implicated in the formation and metastasis of tumors. Porcupine is a component of the Wnt signaling pathway. It is a member of the membrane-bound O-acyltransferase family of proteins. Porcupine catalyzes the palmitoylation of Wnt proteins, a process which is essential to their secretion and activity. Here we report a novel series of compounds obtained by a scaffold hybridization strategy from two known porcupine inhibitor classes. The leading compound 62 demonstrated subnanomolar (IC50 0.11 nM) inhibition of Wnt signaling in a paracrine cellular reporter gene assay. Compound 62 also potently inhibited Wnt secretion into culture medium, an indication of direct inhibition of the porcupine protein. Furthermore, compound 62 showed excellent chemical, plasma and liver microsomal stabilities. Collectively, these results strongly support further optimization of this novel scaffold to develop better Wnt pathway inhibitors.