- Analgesic and anticancer activity of benzoxazole clubbed 2-pyrrolidinones as novel inhibitors of monoacylglycerol lipase
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Ten benzoxazole clubbed 2-pyrrolidinones (11–20) as human monoacylglycerol lipase inhibitors were designed on the criteria fulfilling the structural requirements and on the basis of previously reported inhibitors. The designed, synthesized, and characterized compounds (11–20) were screened against monoacylglycerol lipase (MAGL) in order to find potential inhibitors. Compounds 19 (4-NO2 derivative) and 20 (4-SO2 NH2 derivative), with an IC50 value of 8.4 and 7.6 nM, were found most active, respectively. Both of them showed micromolar potency (IC50 value above 50 μM) against a close analogue, fatty acid amide hydrolase (FAAH), therefore considered as selective inhibitors of MAGL. Molecular docking studies of compounds 19 and 20 revealed that carbonyl of 2-pyrrolidinone moiety sited at the oxyanion hole of catalytic site of the enzyme stabilized with three hydrogen bonds (~2 ?) with Ala51, Met123, and Ser122, the amino acid residues responsible for the catalytic function of the enzyme. Remarkably, the physiochemical and pharmacokinetic properties of compounds 19 and 20, computed by QikProp, were found to be in the qualifying range as per the proposed guideline for good orally bioactive CNS drugs. In formalin-induced nociception test, compound 20 reduced the pain response in acute and late stages in a dose-dependent manner. They significantly demonstrated the reduction in pain response, having better potency than the positive control gabapentin (GBP), at 30 mg/kg dose. Compounds 19 and 20 were submitted to NCI, USA, for anticancer activity screening. Compounds 19 (NSC: 778839) and 20 (NSC: 778842) were found to have good anticancer activity on SNB-75 cell line of CNS cancer, exhibiting 35.49 and 31.88% growth inhibition (% GI), respectively.
- Afzal, Obaid,Altamimi, Abdulmalik Saleh Alfawaz,Hassan, Md Quamrul,Riadi, Yassine,Shahroz, Mir Mohammad,Sharma, Hemant Kumar
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- ANALGESIC DRUG USING PAC1 RECEPTOR ANTAGONISTIC DRUG
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This invention relates to an analgesic drug comprising a compound represented by the following formula (I) or (II), wherein R1 is a C1-6-alkoxy group or a C1-6-haloalkoxy group; R2 is a hydrogen atom; and R is an indazolyl group substituted with a halogen atom; a substituted or unsubstituted phenyl group; a pyrazolyl group; or a substituted or unsubstituted aralkyl group; or a salt thereof, or a solvate thereof.
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Paragraph 0110; 0133
(2021/06/26)
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- Synthesis of a novel and potent small-molecule antagonist of PAC1 receptor for the treatment of neuropathic pain
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We recently identified novel small-molecule antagonists of the PACAP type I (PAC1) receptor using docking-based in silico screening followed by in vitro/vivo pharmacological assays. In the present study, we synthesized 18 novel derivatives based on the structure of PA-9, a recently developed antagonist of the PAC1 receptor, with a view to obtain a panel of compounds with more potent antagonistic and analgesic activities. Among them, compound 3d showed improved antagonistic activities. Intrathecal injection of 3d inhibited both pituitary adenylate cyclase-activating polypeptide (PACAP) and spinal nerve ligation-induced mechanical allodynia. The effects were more potent than PA-9. Compound 3d also showed anti-allodynic effects following oral administration. Hence, our results suggest that 3d may become an orally available analgesic in the treatment of the neuropathic pain.
- Takasaki, Ichiro,Ogashi, Haruna,Okada, Takuya,Shimodaira, Ayaka,Hayakawa, Daichi,Watanabe, Ai,Miyata, Atsuro,Kurihara, Takashi,Gouda, Hiroaki,Toyooka, Naoki
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- ANTIVIRAL COMPOUNDS
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The present invention relates to novel compounds of general formula (I) wherein R1 to R4 and n have the meanings given in the description and claims, process for preparing these compounds and their use as for treating, preventing or ameliorating viral infections and their use for treating, preventing or ameliorating diseases which are associated with PLA2G16.
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Paragraph 0727; 0728; 0729
(2019/04/27)
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- Site-Specific Synthesis of β-Fluorinated γ-Butyrolactams via Decarboxylative Fluorination of β-Carboxyl-γ-Butyrolactams
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Monofluorinated cyclic nitrogen-containing compounds are synthetically useful scaffolds in organic synthesis and medicinal applications. In this report, AgNO3 mediated decarboxylative fluorination of β-carboxyl-γ-butyrolactams using Selectfluor as a fluorine source was described to achieve a site-specific synthesis of β-fluorinated γ-butyrolactams.
- Phae-nok, Supasorn,Pohmakotr, Manat,Kuhakarn, Chutima,Reutrakul, Vichai,Soorukram, Darunee
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p. 4710 - 4720
(2019/08/01)
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- PYRROLIDONE DERIVATIVES, OLIGOMERS AND POLYMERS
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Simple organic structures, organic/inorganic polymers, and other substrates have been made, all of which have at least one pyrrolidone moiety present, and found to exhibit low toxicity, low complement activation features and may be used to reduce protein
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Page/Page column 42
(2016/06/01)
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- 1-benzyl-2- [...] -4-amide compound and its preparation method and application
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The invention discloses 1-benzyl-2-pyrroline ketone-4-amide compounds represented by the general formula. According to independent R1, R2, R3, R4, R5, R6, R7, R8, R9 or R10, 1-3 C1-4 alkyl groups substituted by substituent groups are selected from a non-substituent C1-4 alkyl group, a non-substituent C1-3 alkoxy group, halogen, an amine sulfonyl group, a nitryl group and hydrogen or from halogen, a nitryl group, a C1-3 alkyl group and a C1-2 alkoxy group, or 1-3 C1-3 alkoxy groups substituted by substituent groups are selected from halogen, a nitryl group, a C1-3 alkyl group and a C1-2 alkyl group. The halogen is fluorine, chlorine or bromine. The invention further discloses a preparing method and application of the compounds. The compounds can restrain tyrosine kinase signal transduction and unhealthy cell hyperplasia and angiogenesis, and obvious curative effect is achieved on diseases such as tumors especially.
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Paragraph 0055; 0056; 0057
(2016/10/31)
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- Inhibition of noroviruses by piperazine derivatives
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There is currently an unmet need for the development of small-molecule therapeutics for norovirus infection. The piperazine scaffold, a privileged structure embodied in many pharmacological agents, was used to synthesize an array of structurally-diverse derivatives which were screened for anti-norovius activity in a cell-based replicon system. The studies described herein demonstrate for the first time that functionalized piperazine derivatives possess anti-norovirus activity. Furthermore, these studies have led to the identification of two promising compounds (6a and 9l) that can be used as a launching pad for the optimization of potency, cytotoxicity, and drug-like characteristics.
- Dou, Dengfeng,He, Guijia,Mandadapu, Sivakoteswara Rao,Aravapalli, Sridhar,Kim, Yunjeong,Chang, Kyeong-Ok,Groutas, William C.
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supporting information; scheme or table
p. 377 - 379
(2012/02/16)
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- Intramolecular 1,6-addition to 2-pyridones. Mechanism and synthetic scope
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Figure presented The scope and limitations of the intramolecular 1,6-addition of an enolate to a 2-pyridone moiety, a reaction that has found application in the synthesis of the lupin alkaloids, have been probed. This nucleophilic addition process has been shown to be reversible and favored in the case of (less stabilized) amide and lactam enolates, which readily form five- and six-membered bi-/tricyclic products. Alternative enolates (ketone, ester, thiolactam) and a variety of different acceptors (isoquinolinone, pyrimidinone, pyrazinone, pyridopyrazinone) have been evaluated, and a range of competing side reactions have been identified and characterized using various techniques, including in situ IR.
- Gallagher, Timothy,Derrick, Ian,Durkin, Patrick M.,Haseler, Claire A.,Hirschhaeuser, Christoph,Magrone, Pietro
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supporting information; experimental part
p. 3766 - 3774
(2010/08/20)
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- Synthesis of new β-trifluoromethyl containing GABA and β-fluoromethyl containing N-benzylpyrrolidinones
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A whole series of 3-(mono-, di-, trifluoro)methyl-substituted N-benzylpyrrolidinones 5a-c was synthesized by deoxyfluorination of corresponding 3-functionalized N-benzylpyrrolidinones. New β-trifluoromethyl containing GABA 4a was obtained in two alternative ways: by successive hydrolysis and hydrogenolysis of 3-trifluoromethyl N-benzylpyrrolidinone 5a and from trifluoroacetone as starting compound.
- Gerus, Igor I.,Mironets, Roman V.,Shaitanova, Elena N.,Kukhar, Valery P.
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body text
p. 224 - 228
(2010/04/30)
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- PYRROLIDINE DERIVATIVE OR SALT THEREOF
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[PROBLEMS] To provide a compound which can be used for the treatment of a disease associated with a calcium-sensing receptor (CaSR), particularly hyperparathyroidism. [MEANS FOR SOLVING PROBLEMS] It is found that a novel pyrrolidine derivative having an aminomethyl group substituted by an arylaklyl group or the like or a salt thereof has an excellent CaSR agonistic modulation effect and also has an excellent selectivity in the inhibition of CYP2D6 which may cause a drug-drug interaction. Thus, the novel pyrrolidine derivative is useful as a therapeutic agent for a disease associated with CaSR (e.g., hyperparathyroidism, renal osteodystrophy and hypercalcemia).
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Page/Page column 64-65
(2008/06/13)
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- Synthesis of functionalized nitrogen heterocycles by radical decarboxylation of β- and γ-amino acids
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Iodinated or oxygenated nitrogen heterocycles are obtained by radical decarboxylation of β- and γ-amino acids. This mild, versatile reaction is applied to the synthesis of bioactive products, such as 4-arylpiperidines, hydroxylated piperidines, and new antifungal agents.
- Boto, Alicia,Hernandez, Rosendo,De Leon, Yolanda,Murguia, Jose R.,Rodriguez-Afonso, Abigail
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p. 673 - 682
(2007/10/03)
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- CYCLIC AMINE BASE-1 INHIBITORS HAVING A HETEROCYCLIC SUBSTITUENT
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Disclosed are novel compounds of the formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is formula (I) X is -0-, -C(R14)2- or -N(R)-; Z is -C(R14)2- or -N(R)-; t is 0, 1, 2 or 3; each R and R2 is independently H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl or alkynyl; each R14 is H, alkyl, alkenyl, alkynyl, halo, -CN, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, -OR35, -N(R24)(R25)or -SR35; R41 is alkyl, cycloalkyl, -S02(alkyl), -C(O)-alkyl, -C(O)-cycloalkyl or -alkyl-NH-C(O)CH3; and the remaining variables are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula I and methods of treating cognitive or neurodegenerative diseases with compounds of formula (I). Also disclosed are pharmaceutical compositions and methods of treatment comprising compounds of formula I in combination with other agents useful in treating cognitive or neurodegenerative diseases.
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Page/Page column 29
(2008/06/13)
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- Synthesis of pyrrolo[2,3-d][1,2,3]thiadiazole-6-carboxylates via the Hurd-Mori reaction. Investigating the effect of the N-protecting group on the cyclization
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A route to methyl pyrrolo[2,3-d][1,2,3]thiadiazole-6-carboxylates as potential plant activators and inducers of systemic acquired resistance (SAR) is reported. A synthetic strategy based on cyclization of the thiadiazole ring system utilizing thionyl chloride via the Hurd-Mori protocol as key step was developed. Success of the ring closure reaction turned out to be highly dependent on the nature of the N-protecting group of the pyrrolidine precursor. While electron donors such as alkyl gave only poor conversion to the required 1,2,3-thiadiazoles, an electron withdrawing substituent such as methyl carbamate gave superior yields.
- Stanetty, Peter,Turner, Martin,Mihovilovic, Marko D.
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p. 367 - 375
(2007/10/03)
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- CCR5 antagonists as anti-HIV-1 agents. 1. Synthesis and biological evaluation of 5-oxopyrrolidine-3-carboxamide derivatives
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A novel lead compound, N-{3-[4-(4-fluorobenzoyl)piperidin-1-yl]propyl}-1- methyl-5-oxo-N-phenylpyrrolidine-3-carboxamide (1), was identified as a CCR5 antagonist by high-throughput screening using [125I]RANTES and CCR5-expressing CHO cells. The IC50 value of 1 was 1.9 μM. In an effort to improve the binding affinity of 1, a series of 5-oxopyrrolidine-3- carboxamides was synthesized. Introduction of 3,4-dichloro substituents to the central phenyl ring (10i, IC50=0.057 μM; 11b, IC 50=0.050 μM) or replacing the 1-methyl group of the 5-oxopyrrolidine moiety with a 1-benzyl group (12e, IC50=0.038 μM) was found to be effective for improving CCR5 affinity. Compound 10i, 11b, and 12e also inhibited CCR5-using HIV-1 envelope-mediated membrane fusion with IC50 values of 0.44, 0.19, and 0.49 μM, respectively.
- Imamura, Shinichi,Ishihara, Yuji,Hattori, Taeko,Kurasawa, Osamu,Matsushita, Yoshihiro,Sugihara, Yoshihiro,Kanzaki, Naoyuki,Iizawa, Yuji,Baba, Masanori,Hashiguchi, Shohei
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- Benzoquinolizidine and benzoindolizidine derivatives and therapeutic uses thereof
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Benzo[b]quinolizidine and benzo[f]indolizidine derivatives are provided which are useful for the treatment of Alzheimer's disease, senile dementia or other conditions characterized by memory loss. Pharmaceutical compositions containing these compounds, and methods for their use, are also provided.
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- CYCLIC AMIDE COMPOUNDS, PROCESS FOR THE PREPARATION OF THE SAME AND USES THEREOF
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A compound of the formula: wherein R1 is a hydrocarbon group, R2 is a hydrocarbon group having 2 or more carbon atoms, where R1 and R2 may in combination form, together with an adjacent nitrogen atom, a ring optionally having a substituent or substituents, R3 is a hydrocarbon group optionally having a substituent or substituents or a heterocyclic group optionally having a substituent or substituents, R4 is a hydrogen atom, a hydrocarbon group, a heterocyclic group and the like, E is a divalent chain hydrocarbon group and the like, G is CO or SO2, J is a nitrogen atom, a methine group and the like, and Q and R are each a divalent chain C1-3 hydrocarbon group and the like, and a salt thereof show a superior CCR5 antagonistic activity and are useful as agents for the prophylaxis or treatment of HIV infection of human peripheral blood mononuclear cells, particularly AIDS.
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Referential example 44
(2010/01/31)
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- 4-Heterocyclylpiperidines as selective high-affinity ligands at the human dopamine D4 receptor
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5-(4-Chlorophenyl)-3-(1-(4-chlorobenzyl)piperidin-4-yl)pyrazole (3) was identified from screening of the Merck sample collection as a human dopamine D4 (hD4) receptor ligand with moderate affinity (61 nM) and 4-fold selectivity over human D2 (hD2) recepto
- Rowley, Michael,Collins, Ian,Broughton, Howard B.,Davey, William B.,Baker, Raymond,Emms, Frances,Marwood, Rosemarie,Patel, Shil,Patel, Smita,Ragan, C. Ian,Freedman, Stephen B.,Ball, Richard,Leeson, Paul D.
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p. 2374 - 2385
(2007/10/03)
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