- Synthesis and structural characterization of the C-6 fluoroalkylated pyrimidine derivatives
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C-6 substituted fluoroalkenyl 2,4-dimethoxypyrimidine derivative (4) was synthesized by lithiation of 2,4-dimethoxy-6-methylpyrimidine (3) and subsequent reaction of thus obtained organolithium intermediate with ethyl pentafluoropropionate. The novel 2,4-pyrimidinedione containing 3,3,4,4,4-pentafluoro-1-butenyl side chain (5) was prepared by demethoxylation of 4 using sodium iodide and chlorotrimethylsilane. The structures of 4 and 5 were confirmed by 1H, 13C and 19F NMR spectra, as well as IR spectra. The structure of 4 was also unambiguously confirmed by X-ray crystal structure analysis. The molecules of 4 are weakly linked by aromatic π···π stacking interactions into infinite chains parallel to the a axis.
- Kri?tafor, Svjetlana,Gazivoda, Tatjana,Cetina, Mario,Makuc, Damjan,Plavec, Janez,Rai?-Mali?, Silvana
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Read Online
- Novel triazole-sulfonamide bearing pyrimidine moieties with carbonic anhydrase inhibitory action: Design, synthesis, computational and enzyme inhibition studies
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A series of new triazole-sulfonamide bearing pyrimidine derivatives were designed and synthesized via click chemistry. All new compounds (SH-1 to SH-28) were validated by 1HNMR, 13CNMR, HRMS, and SH-3 was further structurally validated by X-Ray single diffraction study. These compounds (SH-1 to SH-28) were tested as inhibitors of human carbonic anhydrase (hCA) isoforms, such as hCA I, II, IX and XII, using a stopped flow CO2 hydrase assay. Most of the compounds exhibited significant inhibitory activity against hCA II and weak inhibitory activity against hCA I. The target compounds also displayed moderate to excellent inhibitory activity against tumor-related hCAs IX and XII. Some compounds, e.g., SH-20 (Ki = 9.4 nM), SH-26 (Ki = 1.8 nM) and SH-28 (Ki = 0.82 nM) exhibited excellent inhibitory activity and selectivity profile against hCAs XII over IX. SH-23 displayed promising inhibitory activity and selectivity profile against both tumor-related hCAs IX (Ki = 2.9 nM) as well as XII (Ki = 0.82 nM) over hCA I and II. To understand the molecular interactions, molecular docking study of compounds SH-20, SH-23, SH-26 and SH-28 with hCA XII and SH-23 also with hCA IX were performed. The computational study evidenced favorable interaction between the inhibitors and active residues of both proteins. Some of these derivatives are promising leads for the development of selective, anticancer agents based on CA inhibitors.
- Hoda, Nasimul,Manzoor, Shoaib,Petreni, Andrea,Raza, Md Kausar,Supuran, Claudiu T.
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- Efficient Phosphorus-Free Chlorination of Hydroxy Aza-Arenes and Their Application in One-Pot Pharmaceutical Synthesis
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The chlorination of hydroxy aza-arenes with bis(trichloromethyl) carbonate (BTC) and SOCl2 has been effectively performed by refluxing with 5 wt % 4-dimethylaminopyridine (DMAP) as a catalyst. Various substrates are chlorinated with high yields. The obtained chlorinated aza-arenes can be used directly with simple workup for succedent one-pot synthesis on a large scale.
- Wang, Jian,Li, Yan-Hui,Pan, Song-Cheng,Li, Ming-Fang,Du, Wenting,Yin, Hong,Li, Jing-Hua
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supporting information
p. 146 - 153
(2020/03/10)
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- AMINE-SUBSTITUTED HETEROCYCLIC COMPOUNDS AS EHMT2 INHIBITORS, SALTS THEREOF, AND METHODS OF SYNTHESIS THEREOF
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The present disclosure relates to amine-substituted heterocyclic compounds. The present disclosure also relates to pharmaceutical compositions containing these compounds and methods of treating a disorder (e.g., cancer) by administering an amine-substituted heterocyclic heterocyclic compound disclosed herein or a pharmaceutical composition thereof to subjects in need thereof. The present disclosure also relates to the use of such compounds for research or other non-therapeutic purposes.
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Paragraph 01612
(2019/05/10)
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- APOPTOSIS INHIBITORS
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The invention provides compounds that are inhibitors or covalent modifiers of succinate dehydrogenase subunit B (SDHB) and/or inhibitors of apoptosis, and pharmaceutically acceptable salts, hydrides and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the compound or composition.
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Paragraph 0472; 0473
(2018/02/27)
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- COMPOUNDS FOR TREATING TUBERCULOSIS
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The present invention relates to pyrimidine compounds and compositions for treating tuberculosis. These compounds may be used to target the F1 domain of F-ATP synthase and may be used with bedaquiline or 6-chloro-2-ethyl-N-[[4-[4- [4-(trifluoromethoxy)phenyl]piperidin-1 -yl]phenyl]methyl]imidazo[1,2-a]pyridine-3-carboxamide (Q203) or a combination thereof.
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Paragraph 0098
(2018/09/18)
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- Exploring the potential of newly synthesized 4-methyl-6-morpholino-pyrimidine derivatives as antiproliferative agents
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In view of exploring the potential of pyrimidine derivatives as anticancer agents, a series of 4-methyl-6-morpholinopyrimidine derivatives was synthesised and characterised by NMR (1H & 13C), SC-XRD and mass spectral analysis. The in vitro anticancer activity of these compounds was investigated using different human cancer cell lines, namely HeLa (cervix), NCI-H460 (lung), MCF-7 (breast), HepG2 (liver) and IMR-32 (brain). Compounds 4c and 5h exhibited potent anticancer activity in a dose-dependent manner as compared to other derivatives, with IC50 values of 5.88 ± 1.22 and 6.11 ± 2.12 μM on HeLa and NCI-H460, cells respectively. The inhibitory effect of 4c and 5h on cancer cell proliferation was shown to be a consequence of reactive oxygen species (ROS) generation and subsequent induction of cellular apoptosis, as evidenced by an increase in hypodiploid (subG1) population, early apoptotic cell population, caspase-3/7 activity, loss of mitochondrial membrane potential and degradation of nuclear DNA. Furthermore, molecular docking studies revealed that 4c and 5h compounds bind to the ATP binding pocket of the mammalian target of rapamycin (mTOR). Based on our results, we conclude that 4-methyl-6-morpholinopyrimidine derivatives prevent cancer cell proliferation by inducing apoptosis and thus have potential to be further explored for anticancer properties.
- Gaonkar, Supreet,Savanur, Mohammed Azharuddin,Sunagar, Manjunath G.,Puthusseri, Bijesh,Deshapande, Narahari,Nadaf, Afra A.,Khazi, Imtiyaz Ahmed M.
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p. 2790 - 2803
(2018/02/19)
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- COMPOUNDS AND METHODS FOR TREATING TUBERCULOSIS
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The present invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from methyl, pyrrolidinyl optionally substituted with one or more of fluorine, methyl and hydroxyl, piperidinyl, morpholinyl, fluorobenzylazetidinyl, methylamino substituted with one or more of phenyl, methyl and chlorophenyl, and benzylhydroxylamino; and R2 is selected from phenyl substituted with chlorine or –CHF2, pyridinyl substituted with methyl or –CHF2, -CHF2, cyclopropyl and benzylpyrrolidinyl, to pharmaceutical composition comprising the compounds, to their use in the treatment and or prevention of tuberculosis caused by mycobacterial species, and to their methods of preparation.
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Page/Page column 16
(2015/12/18)
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- ALPHA,BETA-UNSATURATED MONOMERS CAPABLE OF MULTIMERIZATION IN AN AQUEOUS SOLUTION, AND METHODS OF USING SAME
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Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. In one aspect, such monomers may be capable of binding to another monomer in an aqueous media (e.g. in vivo) to form a multimer, (e.g. a dimer). Contemplated monomers may include a ligand moiety, a linker element, and a connector element that joins the ligand moiety and the linker element. In an aqueous media, such contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding domains on a protein or on different proteins.
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Paragraph 0300
(2015/03/28)
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- Large-scale solvent-free chlorination of hydroxy-pyrimidines,-pyridines,- pyrazines and-amides using equimolar POCl3
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Chlorination with equimolar POCl3 can be efficiently achieved not only for hydroxypyrimidines, but also for many other substrates such as 2-hydroxy-pyridines,-quinoxalines, or even-amides. The procedure is solvent-free and involves heating in a sealed reactor at high temperatures using one equivalent of pyridine as base. It is suitable for large scale (multigram) batch preparations.
- Wang, Han,Wen, Kun,Wang, Le,Xiang, Ye,Xu, Xiaocheng,Shen, Yongjia,Sun, Zhihua
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experimental part
p. 4533 - 4544
(2012/06/30)
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- COFERONS AND METHODS OF MAKING AND USING THEM
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The present invention is directed to a monomer useful in preparing therapeutic compounds. The monomer includes one or more pharmacophores which potentially binds to a target molecule with a dissociation constant of less than 300 μM and a linker element connected to the pharmacophore. The linker element has a molecular weight less than 500 daltons, is connected, directly or indirectly through a connector, to the pharmacophore.
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Page/Page column 197
(2012/12/13)
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- Anilinopyrimidines as novel antituberculosis agents
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A selection of novel anilinopyrimidine analogues have been found to have micromolar activity against Mycobacterium tuberculosis. This could potentially generate new lead compounds in the fight against multi-drug resistant tuberculosis.
- Morgan, Jody,Haritakul, Rachada,Keller, Paul A.
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p. 1755 - 1757
(2007/10/03)
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- Synthesis, molecular modeling and biological activity of methyl and thiomethyl substituted pyrimidines as corticotropin releasing hormone type 1 antagonists
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Four small, targeted libraries of differentially substituted amino pyrimidines were synthesized in moderate to good yields. Excellent regiochemistry was observed for substitution at C2/C4 with selectivity >50 : 1 noted. All analogues were screened for their ability to interact with CRH 1 and CRH2 receptors. In all instances only poor agonistic and/or antagonistic behaviour was noted at CRH2. However, several compounds were potent and selective CRH1 antagonists, most notably 13a K1 = 39 nM. Additionally we have utilized these data and that recently reported by others to refine our original CRH1 pharmacophore (J. Med. Chem., 1999, 42, 2351-2357).
- McCluskey, Adam,Keller, Paul A.,Morgan, Jody,Garner, James
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p. 3353 - 3361
(2007/10/03)
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- Pyri(mi)dyl-oxy-and -thio-benzoic acid derivatives useful as herbicides and plant growth regulants
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New pyri(mi)dyl-oxy- or -thio-benzoic acid derivatives of the formula STR1 are taught which have herbicidal and plant growth regulating activity. In the formula Z can be Ch or N, X is oxygen or sulphur, A is oxygen, sulphur, a radical R5 --N=or a radical R6 O--N=and B is oxygen, sulphur, a radical STR2 with the proviso that at least one of the radicals R1, R2 or R3 represents alkyl or a part of a 3- to 6-membered fused carbocyclic ring.
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- Pyrimidines. 7. A Study of the Chlorination of Pyrimidines with Phosphorus Oxychloride in the Presence of N,N-Dimethylaniline
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The chlorination of 6-trifluoromethyluracils by phosphorus oxychloride in the presence of N,N-dimethylaniline was studied and compared with results obtained with 6-methyluracils. 6-Trifluoromethyluracils and its 5-chloro analog afforded moderate yields of the di- and trichloropyrimidines, accompanied by good yields of the 2-N-methylanilino by-products, after a 3-hour reaction time.After 24 hours, the 2-N-methylanilinopyrimidines were the primary or sole products.A small yield of 2,4-bis(N-methylanilino)-6-trifluoromethylpyrimidine was also obtained.The 6-methyluracils afforded high yields of the di- and trichloropyrimidines, after 3 and 24 hours, along with minor amounts of the 2-N-methylanilino by-products.After 48 hours, the proportion of 2,4-dichloro-6-methylpyrimidine decreased, and the 2-N-methylanilino product increased. 2-Chloro-4-methylanilino-6-methylpyrimidine and bis(2-N-methylanilino)-6-methylpyrimidine were also formed in small amounts.The chlorination products from 5-chloro-6-methyluracil remained constant over 188 hours of reaction time. It appears that the Π electron distribution around the ring, as influenced by the substituents, controls the course of the chlorination and by-product formation.Since the amination by a tertiary amine is a type of Hoffmann reaction, the presence of the chlorine in 5 position of the ring adds steric hindrance and thus enhances the regiospecificity of the formation of by-products.
- Gershon, Herman,Grefig, Anthony T.
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p. 1161 - 1167
(2007/10/02)
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