Day: October 19, 2022

On February 5, 1998, Murugesan, Natesan; Barrish, Joel C.; Stein, Philip D. published a patent.Computed Properties of 160377-42-4 The title of the patent was Preparation of heterocyclyl-substituted biphenylsulfonamide as endothelin antagonists. And the patent contained the following:

Compounds of formula (I; R1 and R2 are directly bonded to a ring carbon and are each independently hydrogen, alkyl or alkoxy, hydroxyl, halo, or amino; one of X and Y is N and the other is O: R3 and R4 are each directly bonded to a ring carbon and are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted or R3 and R4 together may also be alkylene or alkenylene, either of which may be substituted, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; R11 – R14 are each independently are hydrogen alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl, aralkoxy, or heterocyclyl, any of which may be substituted, halo, OH, cyano, NO2, CHO, CO2H, etc.; J, K, L, T, and U are each independently N or C, provided that at least one is N, and at most two are N; and when only one of J, K, L, T, and U is N, the N may be substituted with O- so that N-oxide is formed), which inhibit the activity of endothelin (no data), are prepared Also claimed is a method for treating endothelin-related disorders in a mammal, such as (1) hypertension, (2) pulmonary hypertension, (3) renal, glomerular, or mesangial cell disorders, (4) endotoxemia, (5) ischemia, (6) atherosclerosis, (7) restenosis, (8) subarachnoid hemorrhage, (9) prostatic hypertrophy, and (10) congestive heart failure, and a method for inhibiting cell growth. Said compound I is used in combination with at least one angiotensin II receptor antagonist, renin inhibitor, angiotensin converting enzyme (ACE) inhibitor, or a dual neutral endopeptidase-ACE inhibitor for treating the endothelin-related disorder. A pharmaceutical composition for the treating the endothelin-related disorders comprises said compound optionally in combination with at least one angiotensin II receptor antagonist, renin inhibitor, angiotensin converting enzyme (ACE) inhibitor, or a dual neutral endopeptidase-ACE inhibitor. Thus, 2-(4-bromophenyl)pyrimidine is coupled with 2-borono-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide in the presence of (Ph3P)4Pd in a mixture of toluene, 2 M aqueous Na2CO3, and 95% ethanol under reflux for 1.5 h to give the title compound, N-isoxazolylpyrimidinylbiphenylsulfonamide (II). The experimental process involved the reaction of 5-(4-Bromophenyl)pyrimidine(cas: 160377-42-4).Computed Properties of 160377-42-4

The Article related to angiotensin ii receptor antagonists, antiatherosclerotics, antihypertensives, benign prostatic hyperplasia, cell (renal, glomerular, or mesangial cell disorders), endotoxemia, growth inhibitors, animal role: spn (synthetic preparation), thu (therapeutic use), prep (preparation), biol (biological study), uses (uses), heart failure, ischemia, mesangium (disorders), subarachnoid hemorrhage and other aspects.Computed Properties of 160377-42-4

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Brawn, Ryan A.; Cook, Andrew; Omoto, Kiyoyuki; Ke, Jiyuan; Karr, Craig; Colombo, Federico; Virrankoski, Milena; Prajapati, Sudeep; Reynolds, Dominic; Bolduc, David M.; Nguyen, Tuong-Vi; Gee, Patricia; Borrelli, Deanna; Caleb, Benjamin; Yao, Shihua; Irwin, Sean; Larsen, Nicholas A.; Selvaraj, Anand; Zhao, Xuesong; Ioannidis, Stephanos published their research in ACS Medicinal Chemistry Letters in 2021. The article was titled 《Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3》.Product Details of 3764-01-0 The article contains the following contents:

Fibroblast growth factor receptors (FGFR) 2 and 3 have been established as drivers of numerous types of cancer with multiple drugs approved or entering late stage clin. trials. A limitation of current inhibitors is vulnerability to gatekeeper resistance mutations. Using a combination of targeted high-throughput screening and structure-based drug design, we have developed a series of aminopyrazole based FGFR inhibitors that covalently target a cysteine residue on the P-loop of the kinase. The inhibitors show excellent activity against the wild-type and gatekeeper mutant versions of the enzymes. Further optimization using SAR anal. and structure-based drug design led to analogs with improved potency and drug metabolism and pharmacokinetics properties. The results came from multiple reactions, including the reaction of 2,4,6-Trichloropyrimidine(cas: 3764-01-0Product Details of 3764-01-0)

2,4,6-Trichloropyrimidine(cas: 3764-01-0) is a member of organic chlorides. Almost all organochlorine compounds are synthesized. It is widely used as intermediates, solvents and pesticides of chemical synthetic products.Product Details of 3764-01-0

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Meng, Fan-Jie; Shao, Bing-Ru; Velopolcek, Maria K.; Guo, Xuan; Feng, Guang-Shou; Shi, Lei published their research in Organic & Biomolecular Chemistry in 2021. The article was titled 《Redox deracemization of phosphonate-substituted dihydropyrimidines》.Name: 2,4-Dichloropyrimidine The article contains the following contents:

An efficient redox deracemization of the phosphonic ester substituted 3,4-dihydropyrimidin-2-one (DHPM) derivatives I (R = Ph, Me, naphth-2-yl, etc.; R1 = H, Me, Ph) is described. The one-pot deracemization strategy consisted of the oxidization to destroy the stereocenter center and the following asym. transfer hydrogenation to regenerate the chiral carbon center with the vicinal phosphonic ester group, providing a series of optically active phosphonate substituted DHPMs with up to 96% ee. The results came from multiple reactions, including the reaction of 2,4-Dichloropyrimidine(cas: 3934-20-1Name: 2,4-Dichloropyrimidine)

2,4-Dichloropyrimidine(cas: 3934-20-1) is a member of organic chlorides. Almost all organochlorine compounds are synthesized. It is widely used as intermediates, solvents and pesticides of chemical synthetic products.Name: 2,4-Dichloropyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Davis, Ryan R.; Li, Baoli; Yun, Sang Y.; Chan, Alice; Nareddy, Pradeep; Gunawan, Steven; Ayaz, Muhammad; Lawrence, Harshani R.; Reuther, Gary W.; Lawrence, Nicholas J.; Schonbrunn, Ernst published an article in 2021. The article was titled 《Structural Insights into JAK2 Inhibition by Ruxolitinib, Fedratinib, and Derivatives Thereof》, and you may find the article in Journal of Medicinal Chemistry.Synthetic Route of C6H3Cl2N3 The information in the text is summarized as follows:

The discovery that aberrant activity of Janus kinase 2 (JAK2) is a driver of myeloproliferative neoplasms (MPNs) has led to significant efforts to develop small mol. inhibitors for this patient population. Ruxolitinib and fedratinib have been approved for use in MPN patients, while baricitinib, an achiral analog of ruxolitinib, has been approved for rheumatoid arthritis. However, structural information on the interaction of these therapeutics with JAK2 remains unknown. Here, we describe a new methodol. for the large-scale production of JAK2 from mammalian cells, which enabled us to determine the first crystal structures of JAK2 bound to these drugs and derivatives thereof. Along with biochem. and cellular data, the results provide a comprehensive view of the shape complementarity required for chiral and achiral inhibitors to achieve highest activity, which may facilitate the development of more effective JAK2 inhibitors as therapeutics. The results came from multiple reactions, including the reaction of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4Synthetic Route of C6H3Cl2N3)

2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4) belongs to pyrimidine. Pyrimidine nucleotide derivatives have a wide range of biological applications. For example, pyrimidine derivatives are useful in DNA repair studies involving cancer and epigenetics. Synthetic Route of C6H3Cl2N3

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Electric Literature of C6H3Cl2N3In 2021 ,《Discovery of 6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor》 appeared in Journal of Medicinal Chemistry. The author of the article were Czako, Barbara; Sun, Yuting; McAfoos, Timothy; Cross, Jason B.; Leonard, Paul G.; Burke, Jason P.; Carroll, Christopher L.; Feng, Ningping; Harris, Angela L.; Jiang, Yongying; Kang, Zhijun; Kovacs, Jeffrey J.; Mandal, Pijus; Meyers, Brooke A.; Mseeh, Faika; Parker, Connor A.; Yu, Simon S.; Williams, Christopher C.; Wu, Qi; Di Francesco, Maria Emilia; Draetta, Giulio; Heffernan, Timothy; Marszalek, Joseph. R.; Kohl, Nancy E.; Jones, Philip. The article conveys some information:

Src homol. 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-mol. therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-á-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100μM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRASmut xenograft models in vivo. The results came from multiple reactions, including the reaction of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4Electric Literature of C6H3Cl2N3)

2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4) belongs to pyrimidine. Pyrimidine nucleotide derivatives have a wide range of biological applications. For example, pyrimidine derivatives are useful in DNA repair studies involving cancer and epigenetics. Electric Literature of C6H3Cl2N3

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

COA of Formula: C4H2Cl2N2In 2019 ,《Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of non-small cell lung cancer》 appeared in Bioorganic & Medicinal Chemistry. The author of the article were Wang, Xueyuan; Bai, Enhe; Zhou, Hui; Sha, Sijia; Miao, Hang; Qin, Yanru; Liu, Zhaogang; Wang, Jia; Zhang, Haoyang; Lei, Meng; Liu, Jia; Hai, Ou; Zhu, Yongqiang. The article conveys some information:

Valosine containing protein (VCP/p97) is a member of the AAA ATPase family involved in several essential cellular functions and plays an important role in the ubiquitin-mediated degradation of misfolded proteins. P97 has a significant role in maintaining the cellular protein homeostasis for tumor cell growth and survival and has been found overexpressed in many tumor types. No new mol. entities based on p97 target were approved in clinic. Herein, a series of novel pyrimidine structures as p97 inhibitors were designed and synthesized. After enzymic evaluations, structure-activity relationships (SAR) were discussed in detailed. Among the screened compounds, derivative 35 showed excellent enzymic inhibitory activity (IC50, 36 nM). The cellular inhibition results showed that compound 35 had good antiproliferative activity against the non-small cell lung cancer A549 cells (IC50, 1.61 μM). Liver microsome stability showed that the half-life of compound 35 in human liver microsome was 42.3 min, which was more stable than the control CB-5083 (25.8 min). The in vivo pharmacokinetic results showed that the elimination phase half-lives of compound 35 were 4.57 h for ig and 3.64 h for iv, resp. and the oral bioavailability was only 4.5%. These results indicated that compound 35 could be effective for i.v. treatment of non-small cell lung cancer. In the experiment, the researchers used many compounds, for example, 2,4-Dichloropyrimidine(cas: 3934-20-1COA of Formula: C4H2Cl2N2)

2,4-Dichloropyrimidine(cas: 3934-20-1) is a member of organic chlorides. Organic chlorides are compounds containing a carbon-chlorine bond, which are widely used in the oil field as a wax dissolver. They are generally not present in crude oils and are typically the result of additives, cleaning solutions or chemicals used for oil recovery.COA of Formula: C4H2Cl2N2

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Application In Synthesis of 2,4-DichloropyrimidineIn 2021 ,《Discovery of N-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a Novel, Potent, and Oral Cyclin-Dependent Kinase Inhibitor against Haematological Malignancies》 was published in Journal of Medicinal Chemistry. The article was written by Huang, Jianhang; Wang, Xinren; Dong, Ruinan; Liu, Xiaoyue; Li, Hongmei; Zhang, Tianyi; Xu, Junyu; Liu, Chenhe; Zhang, Yanmin; Hou, Shaohua; Tang, Weifang; Lu, Tao; Chen, Yadong. The article contains the following contents:

Hematol. malignancies (HM) start in blood forming tissue or in the cells of the immune system. Cyclin-dependent kinases (CDKs) regulate cell cycle progression, and some of them control cellular transcription. CDK inhibition can trigger apoptosis and could be particularly useful in hematol. malignancies. Herein, we describe our efforts toward the discovery of a novel series of quinazoline derivatives as CDK inhibitors. Intensive structural modifications lead to the identification of compound 37d as the most active inhibitors of CDKs 1, 2, 4, 8 and 9 with balancing potency and selectivity against CDKs. Further biol. studies revealed that compound 37d can arrest the cell cycle and induce apoptosis via activating PARP and caspase 3. More importantly, compound 37d showed good antitumor efficacy in multiple HM mice xenograft models with no obvious toxicity. These results indicated that CDK 1, 2, 4, 8, and 9 inhibitors could be potentially used to treat certain hematol. malignancies. In the experiment, the researchers used 2,4-Dichloropyrimidine(cas: 3934-20-1Application In Synthesis of 2,4-Dichloropyrimidine)

2,4-Dichloropyrimidine(cas: 3934-20-1) is a member of organic chlorides. Organic chlorides are compounds containing a carbon-chlorine bond, which are widely used in the oil field as a wax dissolver. They are generally not present in crude oils and are typically the result of additives, cleaning solutions or chemicals used for oil recovery.Application In Synthesis of 2,4-Dichloropyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

《A pyrrolo-pyrimidine derivative targets human primary AML stem cells in vivo》 was written by Saito, Yoriko; Yuki, Hitomi; Kuratani, Mitsuo; Hashizume, Yoshinobu; Takagi, Shinsuke; Honma, Teruki; Tanaka, Akiko; Shirouzu, Mikako; Mikuni, Junko; Handa, Noriko; Ogahara, Ikuko; Sone, Akiko; Najima, Yuho; Tomabechi, Yuri; Wakiyama, Motoaki; Uchida, Naoyuki; Tomizawa-Murasawa, Mariko; Kaneko, Akiko; Tanaka, Satoshi; Suzuki, Nahoko; Kajita, Hiroshi; Aoki, Yuki; Ohara, Osamu; Shultz, Leonard D.; Fukami, Takehiro; Goto, Toshio; Taniguchi, Shuichi; Yokoyama, Shigeyuki; Ishikawa, Fumihiko. Computed Properties of C23H22N4O And the article was included in Science Translational Medicine on April 17 ,2013. The article conveys some information:

Leukemia stem cells (LSCs) that survive conventional chemotherapy are thought to contribute to disease relapse, leading to poor long-term outcomes for patients with acute myeloid leukemia (AML). We previously identified a Src-family kinase (SFK) member, hematopoietic cell kinase (HCK), as a mol. target that is highly differentially expressed in human primary LSCs compared with human normal hematopoietic stem cells (HSCs). We performed a large-scale chem. library screen that integrated a high-throughput enzyme inhibition assay, in silico binding prediction, and crystal structure determination and found a candidate HCK inhibitor, RK-20449, a pyrrolo-pyrimidine derivative with an enzymic IC50 (half maximal inhibitory concentration) in the subnanomolar range. A crystal structure revealed that RK-20449 bound the activation pocket of HCK. In vivo administration of RK-20449 to nonobese diabetic (NOD)/severe combined immunodeficient (SCID)/IL2rgnull mice engrafted with highly aggressive therapy-resistant AML significantly reduced human LSC and non-stem AML burden. By eliminating chemotherapy-resistant LSCs, RK-20449 may help to prevent relapse and lead to improved patient outcomes in AML.7-Cyclopentyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(cas: 213743-31-8Computed Properties of C23H22N4O) was used in this study.

7-Cyclopentyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(cas: 213743-31-8) belongs to pyrimidine. Pyrimidine derivatives also play an important role in drug development, either in concert with other compounds or on their own. Computed Properties of C23H22N4OThey have been used in a wide variety of pharmaceuticals including general anesthetics, anti-epilepsy medication, anti-malaria medication, drugs for treating high blood pressure, and HIV medication.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

《Tyrosine kinase inhibitor prodrug-loaded liposomes for controlled release at tumor microenvironment》 was written by Salmaso, Stefano; Mastrotto, Francesca; Roverso, Marco; Gandin, Valentina; De Martin, Sara; Gabbia, Daniela; De Franco, Michele; Vaccarin, Christian; Verona, Marco; Chilin, Adriana; Caliceti, Paolo; Bogialli, Sara; Marzaro, Giovanni. HPLC of Formula: 1193-21-1This research focused ontyrosine kinase inhibitor prodrug liposomes controlled release tumor microenvironment; Drug release; Kinase inhibitors; Liposomes; Microsomes; pH-dependent hydrolysis. The article conveys some information:

Tyrosine kinase inhibitors (TKIs) represent one of the most advanced class of therapeutics for cancer treatment. Most of them are also cytochrome P 450 (CYP) inhibitors and/or substrates thereof. Accordingly, their efficacy and/or toxicity can be affected by CYP-mediated metabolism and by metabolism-derived drug-drug interactions. In order to enhance the therapeutic performance of these drugs, we developed a prodrug (Pro962) of our TKI TK962 specifically designed for liposome loading and pH-controlled release in the tumor. A cholesterol moiety was linked to TK962 through pH-sensitive hydrazone bond for anchoring to the liposome phospholipid bilayer to prevent leakage of the prodrug from the nanocarrier. Bioactivity studies performed on isolated target kinases showed that the prodrug maintains only partial activity against them and the release of TK962 is required. Biopharmaceutical studies carried out with prodrug loaded liposomes showed that the prodrug was firmly associated with the vesicles and the drug release was prevented under blood-mimicking conditions. Conversely, conventional liposome loaded with TK962 readily released the drug. Flow cytometric studies showed that liposomes efficiently provided for intracellular prodrug delivery. The use of the hydrazone linker yielded a pH-controlled drug release, which resulted in about 50% drug release at pH 4 and 5 in 2 h. Prodrug, prodrug loaded liposomes and active lead compound have been tested against cancer cell lines in either 2D or 3D models. The liposome formulation showed higher cytotoxicity than the unformulated lead TK962 in both 2D and 3D models. The stability of prodrug, prodrug loaded liposomes and active lead compound in human serum and against human, mouse, and rat microsomes was also assessed, demonstrating that liposome formulations impair the metabolic reactions and protect the loaded compounds from catabolism. The results suggest that the liposomal formulation of pH releasable TKI prodrugs is a promising strategy to improve the metabolic stability, intracellular cancer cell delivery and release, and in turn the efficacy of this class of anticancer drugs. In the experiment, the researchers used 4,6-Dichloropyrimidine(cas: 1193-21-1HPLC of Formula: 1193-21-1)

4,6-Dichloropyrimidine(cas: 1193-21-1) is a member of organic chlorides. Organic chlorides are compounds containing a carbon-chlorine bond, which are widely used in the oil field as a wax dissolver. They are generally not present in crude oils and are typically the result of additives, cleaning solutions or chemicals used for oil recovery.HPLC of Formula: 1193-21-1

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Electric Literature of C23H22N4OOn September 1, 2015 ,《Discovery of thieno[3,2-c]pyridin-4-amines as novel Bruton’s tyrosine kinase (BTK) inhibitors》 was published in Bioorganic & Medicinal Chemistry. The article was written by Zhao, Xinge; Xin, Minhang; Wang, Yazhou; Huang, Wei; Jin, Qiu; Tang, Feng; Wu, Gang; Zhao, Yong; Xiang, Hua. The article contains the following contents:

A novel series of BTK inhibitors bearing thieno[3,2-c]pyridin-4-amine framework as the core scaffold were designed, synthesized and well characterized. In this paper, twenty one compounds displayed variant inhibitory activities against BTK in vitro, and compound 14g showed the most potent inhibitory activity against BTK enzyme, with the IC50 value of 12.8 nM. Moreover, compounds 14g displayed relatively good kinase selectivity and was subsequently evaluated in vivo for profiling its PK properties. This work identified the thieno[3,2-c]pyridin-4-amine derivatives as novel BTK inhibitors and verified the value of thieno[3,2-c]pyridin-4-amine scaffold in drug design. After reading the article, we found that the author used 7-Cyclopentyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(cas: 213743-31-8Electric Literature of C23H22N4O)

7-Cyclopentyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(cas: 213743-31-8) belongs to pyrimidine. The pyrimidine ring system has wide occurrence in nature as substituted and ring fused compounds and derivatives, including the nucleotides cytosine, thymine and uracil, thiamine (vitamin B1) and alloxan. Electric Literature of C23H22N4O

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia