- Development of SPECT imaging agents for the norepinephrine transporters: [123I]INER
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A series of reboxetine analogs was synthesized and evaluated for in vitro binding as racemic mixtures. The best candidate (INER) was synthesized as the optically pure (S,S) enantiomer, labeled with iodine-123 and its in vivo binding determined by SPECT im
- Tamagnan, Gilles D.,Brenner, Eric,Alagille, David,Staley, Julie K.,Haile, Colin,Koren, Andrei,Early, Michelle,Baldwin, Ronald M.,Tarazi, Frank I.,Baldessarini, Ross J.,Jarkas, Nachwa,Goodman, Mark M.,Seibyl, John P.
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Read Online
- Radiosynthesis and evaluation of 18F-labeled dopamine D4-receptor ligands
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Introduction: The dopamine D4 receptor (D4R) has attracted considerable attention as potential target for the treatment of a broad range of central nervous system disorders. Although many efforts have been made to improve the performance of putative radioligand candidates, there is still a lack of D4R selective tracers suitable for in vivo PET imaging. Thus, the objective of this work was to develop a D4-selective PET ligand for clinical applications. Methods: Four compounds based on previous and new lead structures were prepared and characterized with regard to their D4R subtype selectivity and predicted lipophilicity. From these, 3-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridine I and (S)-4-(3-fluoro-4-methoxybenzyl)-2-(phenoxymethyl)morpholine II were selected for labeling with fluorine-18 and subsequent evaluation by in vitro autoradiography to assess their suitability as D4 radioligand candidates for in vivo imaging. Results: The radiosynthesis of [18F]I and [18F]II was successfully achieved by copper-mediated radiofluorination with radiochemical yields of 7% and 66%, respectively. The radioligand [18F]II showed specific binding in areas where D4 expression is expected, whereas [18F]I did not show any uptake in distinct brain regions and exhibited an unacceptable degree of non-specific binding. Conclusions: The compounds studied exhibited high D4R subtype selectivity and logP values compatible with high brain uptake, but only ligand [18F]II showed low non-specific binding and is therefore a good candidate for further evaluation. Advances in knowledge: The discovery of new lead structures for high-affinity D4 ligands opens up new possibilities for the development of suitable PET-radioligands. Implications for patient: PET-imaging of dopamine D4-receptors could facilitate understanding, diagnosis and treatment of neuropsychiatric and neurodegenerative diseases.
- Willmann, Michael,Ermert, Johannes,Prante, Olaf,Hübner, Harald,Gmeiner, Peter,Neumaier, Bernd
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- Novel Hydrazinone-substituted Pyrimidine Derivatives and Use Thereof
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The present invention relates to a pyrimidine derivative substituted with novel hydrazine or a pharmaceutically acceptable salt thereof, and to a pharmaceutical composition for inhibiting c-Met tyrosine kinase activity and to a pharmaceutical composition for preventing or treating hyperproliferative disorders, which comprise same as an active ingredient. The present invention can be effectively used as a treatment agent for various hyperproliferative disorders related to excessive cell proliferation and growth caused by abnormal kinase activity, such as cancer, psoriasis, rheumatoid arthritis, and diabetic retinopathy by efficiently inhibiting c-Met tyrosine kinase activity.
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Paragraph 0114-0116
(2018/05/29)
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- Discovery of substituted pyrazol-4-yl pyridazinone derivatives as novel c-Met kinase inhibitors
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A series of pyridazin-3-one substituted with morpholino-pyrimidine derivatives was synthesized and evaluated as tyrosine kinase inhibitors against c-Met enzyme, and anti-proliferative activities of Hs746T human gastric cancer cell line. Most of compounds exhibited good biological activity, while compound 10, 12a, 14a displayed excellent c-Met enzyme inhibitory activities and Hs746T cell-based activities.
- Kim, Eun-Young,Kang, Seung-Tae,Jung, Heejung,Park, Chi Hoon,Yun, Chang-Soo,Hwang, Jong Yeon,Byun, Byung Jin,Lee, Chong Ock,Kim, Hyoung Rae,Ha, Jae Du,Ryu, Do Hyun,Cho, Sung Yun
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p. 453 - 464
(2016/04/26)
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- Discovery of substituted 6-pheny-3H-pyridazin-3-one derivatives as novel c-Met kinase inhibitors
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We report a series of phenyl substituted pyridazin-3-ones substituted with morpholino-pyrimidines. The SAR of the phenyl was explored and their c-Met kinase and cell-based inhibitory activity toward c-Met driven cell lines were evaluated. Described herein
- Kang, Seung-Tae,Kim, Eun-Young,Archary, Raghavendra,Jung, Heejung,Park, Chi Hoon,Yun, Chang-Soo,Hwang, Jong Yeon,Choi, Sang Un,Chae, Chonghak,Lee, Chong Ock,Kim, Hyoung Rae,Ha, Jae Du,Ryu, Dohyun,Cho, Sung Yun
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supporting information
p. 5093 - 5097
(2014/12/11)
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- MORPHOLINO COMPOUNDS, USES AND METHODS
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The invention relates to morpholino-derivatives according to Formula (I) or stereoisomers or pharmaceutically acceptable salts or solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7/s
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Paragraph 0172-0175
(2014/06/11)
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- BIARYL AMIDE COMPOUNDS AS KINASE INHIBITORS
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The present invention provides compounds of Formula (I) as described herein, and salts thereof, and therapeutic uses of these compounds for treatment of disorders associated with Raf kinase activity. The invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds and a therapeutic co-agent.
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Paragraph 0195
(2014/09/29)
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- MORPHOLINO COMPOUNDS, USES AND METHODS
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The invention relates to morpholino-derivatives according to Formula (I) or stereoisomers or pharmaceutically acceptable salts or solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7/s
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Page/Page column 48
(2012/12/13)
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- Sulfinamides as highly effective amine protecting groups and their use in the conversion of Amino alcohols into morpholines
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1,2-Amino alcohols have been converted into morpholines by using sulfinamides as temporary protecting/activating groups on the amine. We have developed a procedure for the selective synthesis of monoprotected N-sulfinyl amino alcohols through a double sul
- Fritz, Sven P.,Mumtaz, Amara,Yar, Muhammad,McGarrigle, Eoghan M.,Aggarwal, Varinder K.
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experimental part
p. 3156 - 3164
(2011/06/28)
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- PYRAZIN-2-YL-PYRIDIN-2-YL-AMINE AND PYRAZIN-2-YL-PYRIMIDIN-4-YL-AMINE COMPOUNDS AND THEIR USE
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The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain biarylamine compounds (referred to herein as BAA compounds), and especially certain pyrazin- 2 - yl -pyridin- 2 -yl -amine and pyrazine - 2 - yl -pyrimidin- 4 - yl -amine compounds of formula (I), which, inter alia, inhibit Checkpoint Kinase 1 (CHK1 ) kinase function The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1. that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionisiπq radiation. wherein: -X= is independently -CRA5= or -N=; and the rest of the substituents are as specified in the claims.
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Page/Page column 258-259
(2009/05/29)
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- PIPERAZINES AS ANTI-OBESITY AGENTS
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The present invention relates to new compounds of formula (I), to pharmaceutical compositions comprising these compounds, to processes for their preparation, and to the use of these compounds as leptin receptor modulator mimetics in the preparation of medicaments against conditions associated with weight gain, type 2 diabetes and dyslipidemias.
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Page/Page column 30
(2009/07/17)
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- METHODS OF USE FOR INHIBITORS OF AKT ACTIVITY
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Invented is the use of 1 H-imidazo[4,5-c]pyridin-2-yl compounds in the treatment of specified cancers.
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Page/Page column 44
(2008/12/04)
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- Concise synthesis of (S)-N-BOC-2-hydroxymethylmorpholine and (S)-N-BOC-morpholine-2-carboxylic acid
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(Chemical Equation Presented) An operationally simple synthesis of N-BOC-2-hydroxymethylmorpholine (1) and N-BOC-morpholine-2-carboxylic acid (2) from epichlorohydrin has been developed. No chromatography is required in the processing, which allows high p
- Henegar, Kevin E.
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p. 3662 - 3665
(2008/09/20)
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- MORPHOLINO-SUBSTITUTED BICYCLOHETEROARYL COMPOUNDS AND THEIR USE AS ANTI CANCER AGENTS
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The present invention pertains generally to the field of therapeutic compounds, and mor specifically to certain morpholino-substituted bicydoheteroaryl compounds (referred to herein as MBHA compounds), of the following formula: and especially certain morp
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Page/Page column 105
(2008/12/06)
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- INHIBITORS OF AKT ACTIVITY
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Invented are novel 1 H-imidazo[4,5-c]pyridin-2-yl compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.
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Page/Page column 50
(2008/06/13)
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- NOREPINEPHRINE TRANSPORTER RADIOTRACERS AND METHODS OF SYNTHESES THEREOF
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The present invention provides compounds and radiotracers thereof for locating, diagnosing, identifying, evaluating, detecting or quantitating NET by in vivo imaging. The invention also provides methods for locating, diagnosing, identifying, evaluating, detecting or quantitating NET, using radiotracers of high-affinity or labeled compounds of the invention, which exhibit low toxicity, can cross the blood-brain barrier and, preferably, distinguish among normal and abnormal brains. For example, a radiotracer of the invention can be administered to a patient in an amount suitable for in vivo imaging thereof. Preferably, radiotracers of the invention can also be used to locate, diagnosis, identify, evaluate, detect and quantitate NET in such diseases, disorders, conditions or maladies as, without limitation, depression, anxiety, ADHD and drug dependency.
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Page/Page column 51; 52
(2008/06/13)
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- CYSTEINE PROTEASE INHIBITORS
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Stereoisomers of the formula (III) wherein R is H or C1-C3 optionally halo-substituted alkyl; or pharmaceutically acceptable salts, hydrates or N-oxides thereof have utility in the treatment of disorders mediated by inappropriate exp
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Page/Page column 38
(2008/06/13)
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- Asymmetric synthesis of (+)-(S,S)-reboxetine via a new (S)-2- (hydroxymethyl)morpholine preparation
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(Chemical Equation Presented) (S,S)-Reboxetine was synthesized stereospecifically in 30% overall yield and 99% ee in eight steps. Key steps were selective oxidation of an N-protected hydroxymethylmorpholine and aryl-chromium-mediated aromatic nucleophilic substitution.
- Brenner, Eric,Baldwin, Ronald M.,Tamagnan, Gilles
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p. 937 - 939
(2007/10/03)
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- (R)-(+)-2-[[[3-(morpholinomethyl)-2H-chromen-8-yl]oxy]methyl]morpholine methanesulfonate: A new selective rat 5-hydroxytryptormine(1b) receptor antagonist
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In the search for new 5-hydroxytryptamine (5-HT) receptor antagonists it was found that the compound (R)-(+)-2-[[[3-(morpholinomethyl)-2H-chromen-8- yl]oxy]methyl]morpholine methanesulfonate, (R)-25, is a selective rat 5- hydroxytryptamine(1B) (r5-HT(1B)) receptor antagonist. The binding profile showed a 13-fold preference for r5-HT(1B) (Ki = 47 ± 5 nM; n = 3) vs bovine 5-HT(1B) (Ki = 630 nM; n = 1) receptors. The compound had very low affinity for other monoaminergic receptors examined. The r5-HT(1B) receptor antagonism was demonstrated by the potentiation of the K+-stimulated release of [3H]- 5-HT from superfused rat brain slices in vitro, an effect that was antagonized by addition of 5-HT to the superfusion fluid. (R)-25 at 20 mg/kg sc enhanced the 5-HT turnover in four rat brain regions (hypothalamus, hippocampus, striatum, and frontal cortex) with about 40% measured as the 5- HTP accumulation after decarboxylase inhibition with 3- hydroxybenzylhydrazine. At 3 mg/kg sc (R)-25 produced a significant increase in the number of wet dog shakes in rats, a 5-HT(2A)/5-HT(2C) response that was abolished by depletion of 5-HT after pretreatment with the tryptophan hydroxylase inhibitor p-chlorophenylalanine. The observations show that (R)- 25, by inhibiting terminal r5-HT(1B) autoreceptors, increases the 5-HT turnover and the synaptic concentration of 5-HT.
- Berg, Stefan,Larsson, Lars-Gunnar,Rényi, Lucy,Ross, Svante B.,Thorberg, Seth-Olof,Thorell-Svantesson, Gun
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p. 1934 - 1942
(2007/10/03)
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- FACILE SYNTHESIS OF OPTICALLY ACTIVE SULFONATES OF 4-tert-BUTOXYCARBONYL-2-HYDROXYMETHYLMORPHOLINE
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Optically active sulfonates of 4-tert-butoxycarbonyl-2-hydroxymethylmorpholine were prepared from 1,2:5,6-di-O-D-mannitol by practical procedures.These compounds are versatile intermediates for optically active isomers of a number of neuropharmacologicall
- Yanagisawa, Hiroaki,Kanazaki, Takuro
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p. 105 - 109
(2007/10/02)
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