- FUSED PYRAZOLE DERIVATIVES AS JAK INHIBITORS
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Novel fused pyrazole derivatives of Formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
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Page/Page column 44; 45
(2018/04/11)
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- Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome
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On the basis of its essential role in driving inflammation and disease pathology, cell necrosis has gradually been verified as a promising therapeutic target for treating atherosclerosis, systemic inflammatory response syndrome (SIRS), and ischemia injury, among other diseases. Most necrosis inhibitors targeting receptor-interacting protein 1 (RIP1) still require further optimization because of weak potency or poor metabolic stability. We conducted a phenotypic screen and identified a micromolar hit with novel amide structure. Medicinal chemistry efforts yielded a highly potent, selective, and metabolically stable drug candidate, compound 56 (RIPA-56). Biochemical studies and molecular docking revealed that RIP1 is the direct target of this new series of type III kinase inhibitors. In the SIRS mice disease model, 56 efficiently reduced tumor necrosis factor alpha (TNFα)-induced mortality and multiorgan damage. Compared to known RIP1 inhibitors, 56 is potent in both human and murine cells, is much more stable in vivo, and is efficacious in animal model studies.
- Ren, Yan,Su, Yaning,Sun, Liming,He, Sudan,Meng, Lingjun,Liao, Daohong,Liu, Xiao,Ma, Yongfen,Liu, Chunyan,Li, Sisi,Ruan, Hanying,Lei, Xiaoguang,Wang, Xiaodong,Zhang, Zhiyuan
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p. 972 - 986
(2017/02/19)
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- ABHD6 ANTAGONISTS FOR PROMOTING BROWNING OF WHITE ADIPOSE TISSUE AND BROWN ADIPOSE TISSUE FUNCTIONALITY
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The present disclosure relates to compounds of formula I : compositions containing same and methods for treating or preventing a condition associated with brown adipose tissue dysfunction in a subject and/or for converting white adipose tissue into beige/
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Page/Page column 55; 56
(2015/09/28)
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- CRYSTALLINE FORM OF 6-[(4S)-2-METHYL-4-(2-NAPHTHYL)-1,2,3,4-TETRAHYDROISOQUINOLIN-7-YL]PYRIDAZIN-3-AMINE
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The present disclosure generally relates to a crystalline form of 6-[(4S)-2-methyl-4-(naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine. The present disclosure also generally relates to pharmaceutical compositions comprising the crystalline form, as well of methods of using a crystalline form in the treatment of depression and other conditions and methods for obtaining such crystalline form.
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Paragraph 0072; 0145; 0146
(2014/09/30)
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- Antimycobacterial activity of new 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-one derivatives. Molecular modeling investigations
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3H-1,3,4-Oxadiazol-2-one derivatives were synthesized and tested for their in vitro antimycobacterial activity. Oxadiazolone derivatives showed an interesting antimycobacterial activity against the reference strain of Mycobacterium tuberculosis H37Rv. Molecular modeling investigations were performed and showed that the active compounds possess all necessary features to target the protein active site of the mycobacterial cytochrome P450-dependent sterol 14α-demethylase in the sterol biosynthesis pathway as the calculated free energy of binding were in agreement with the corresponding MIC values.
- Zampieri, Daniele,Mamolo, Maria Grazia,Laurini, Erik,Fermeglia, Maurizio,Posocco, Paola,Pricl, Sabrina,Banfi, Elena,Scialino, Giuditta,Vio, Luciano
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experimental part
p. 4693 - 4707
(2009/10/24)
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- DUAL PHARMACOPHORES - PDE4-MUSCARINIC ANTAGONISTICS
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The present invention is directed to novel compounds of Formula's (I) - (VI), and pharmaceutically acceptable salts thereof, pharmaceutical compositions and their use in therapy, for example as inhibitors of phosphodiesterase type IV (PDE4) and as antagonists of muscarinic acetylcholine receptors (mAChRs), in the treatment of and/or prophylaxis of respiratory diseases, including inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rhinitis (e.g. allergic rhinitis), atopic dermatitis or psoriasis.
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- CRYSTALLINE FORM OF 6-[(4S)-2-METHYL-4-(2-NAPHTHYL)-1,2,3,4-TETRAHYDROISOQUINOLIN-7-YL]PYRIDAZIN-3-AMINE
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The present disclosure generally relates to a crystalline form of 6-[(4S)-2-methyl-4-(naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine. The present disclosure also generally relates to pharmaceutical compositions comprising the crystalline form, as well of methods of using a crystalline form in the treatment of depression and other conditions and methods for obtaining such crystalline form.
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Page/Page column 21; 48
(2009/12/28)
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- Dual Pharmacophores - PDE4-Muscarinic Antagonistics
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The present invention relates to novel compounds of Formula (I) and their use in the treatment of respiratory diseases, including anti-inflammatory and allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rhinitis (e.g. allergic rhinitis), atopic dermatitis or psoriasis.
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Page/Page column 72; 73
(2009/08/18)
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- Dual Pharmacophores - PDE4-Muscarinic Antagonistics
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The present invention is directed to novel compounds of Formula (I) and pharmaceutically acceptable salts thereof, pharmaceutical compositions and their use as dual chromaphores having inhibitory activity against PDE4 and muscarinic acetylcholine receptors (mAChRs), and thus being useful for treating respiratory diseases.
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Page/Page column 69
(2009/08/18)
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- Dual Pharmacophores - PDE4-Muscarinic Antagonistics
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The present invention is directed to novel compounds of Formula (I), pharmaceutical compositions and their use in therapy, for example as inhibitors of phosphodiesterase type IV (PDE4) and as antagonists of muscarinic acetylcholine receptors (mAChRs), in the treatment of/and or prophylaxis of respiratory diseases, including antiinflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rhinitis (e.g. allergic rhinitis), atopic dermatitis or psoriasis.
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Page/Page column 103
(2009/08/16)
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- ARYLOXY-AND HETEROARYLOXY-SUBSTITUTED TETRAHYDROBENZAZEPINES AND USE THEREOF TO BLOCK REUPTAKE OF NOREPINEPHRINE, DOPAMINE, AND SEROTONIN
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The aryloxy- and heteroaryloxy-substituted tetrahydrobenzazepine derivative compounds of the present invention are represented by formulae (I) (A-E) having the following structure where the carbon atom designated * is in the R or S configuration and the s
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Page/Page column 67-68; 77; 80; 83-84; 90
(2009/01/20)
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- Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
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The compounds of the present invention are represented by the following aryl- and heteroaryl-substituted tetrahydrobenzazepine and dihydrobenzazapine derivatives having formulae I(A-E) and formula (II): where the carbon atom designated * is in the R or S configuration, and the substituents X and R1-R9 are as defined herein.
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Page/Page column 94; 103
(2008/06/13)
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- Amine derivatives
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The present invention relates to amine derivatives represented by formula (1) or salts thereof. R3represents C1-C3 alkyl, hydroxylated C1-C5 alkyl, C1-C5 acyl; C2-C5 alkenyl, or a halogen atom; and k, l, and m are each an integer of 1 to 4.) Exhibiting excellent antifungal effect, these compounds are highly useful as antifungal agents, antifungal compositions, drugs, etc.
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- Facile preparation of N-methyl secondary amines by titanium(IV) isopropoxide-mediated reductive animation of carbonyl compounds
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A simple, mild and efficient procedure for obtaining N-methyl secondary amines from aldehydes and ketones is reported. Treatment of carbonyl compounds with methylamine hydrochloride, triethylamine and titanium(IV) isopropoxide, followed by in situ sodium borohydride reduction and straightforward aqueous work-up, affords clean products in good to excellent yields.
- Neidigh, Kurt A.,Avery, Mitchell A.,Williamson, John S.,Bhattacharyya, Sukanta
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p. 2527 - 2531
(2007/10/03)
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- N-Nitrosobenzylmethylamine is activated to a DNA benzylating agent in rats
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The ability of rat tissues to activate the esophageal carcinogen, N- nitrosobenzylmethylamine (NBzMA), to a DNA benzylating intermediate was investigated. [3-3H]NBzMA was prepared and given to male F344 rats. Tissues were harvested 4 h after treatment, and DNA was isolated. HPLC analysis with radiochemical detection of chemical and enzymatic hydrolysates of DNA from liver and lung revealed the formation of benzyl adducts. Benzyl alcohol, N2- benzylguanine, 3-benzyladenine, N6-benzyladenine, and 7-benzylguanine were the major radioactive components in the hydrolysates. An unknown adduct was also observed. The adduct distribution was similar to that observed in [3- 3H]benzylnitroseurea ([3-3H]BzNU)treated calf thymus DNA. However, enzymatic hydrolysates of [3-3H]BzNU-treated DNA also contained significant levels of O6-benzyl-2'-deoxyguanosine (O6-BzdG). This radioactive adduct disappeared upon incubation of the DNA with a crude preparation of the repair protein, O6-alkylguanine-DNA alkyltransferase isolated from rat liver. These data provide evidence that O6-BzdG is probably rapidly repaired in vivo. No benzylation of esophageal mucosal DNA was detected. The level of DNA benzylation observed in tissues from [3-3H]NBzMA-treated rats was several orders of magnitude lower than the level of DNA methylation in these same tissues. Therefore, these data indicate that DNA benzylation plays a minor role, if any, in the carcinogenic activity of NBzMA.
- Peterson, Lisa A.
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- Oxidations with Cerium(IV) Sulfate: Intramolecular Cyclization of N-Benzyl-&β-aminoketones Yielding 4-Benzoyl-1,2,3,4-tetrahydroisoquinolines
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Preparation and regiospecific cerium(IV) sulfate of the substituted N-benzyl-β-aminoketones 3 are described. 4-Benzoyl-1,2,3,4-tetrahydroisoquinolines 4 so obtained are reduced by sodium borohydride.
- Holzgrabe, Ulrike
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p. 647 - 654
(2007/10/02)
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- Quantitative structure-activity relationship of the mutagenicity of substituted N-nitroso-N-benzylmethylamines: Possible implications of carcinogenicity
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The relative mutagenicities of substituted N-nitroso-N-benzylmethylamines have been reexamined from a quantitative structure-activity relationship point of view. Most of the compounds were mutagenic toward Salmonella typhimurium TA 1535 with Aroclor-induced male hamster liver S9 activation. The dose-response data were subjected to a multiple linear regression equation calculated in a stepwise manner, which found that the differences in mutagenicities could be explained primarily by differences in the three-bond path molecular connectivity index, with smaller contributions from σ and π. Moreover, a polynomial regression analysis showed that the maximum mutagenicity could be explained by an optimal amount of electron withdrawal by the substituent which could cause a weakening, or activation, of the methylene C-H bond. The possible relevance of these observations to carcinogenesis is discussed.
- Singer,Andrews,Guo
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- Reactions of N-Halobenzylalkylamines with Sodium Methoxide in Methanol
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Reactions of N-halobenzylmethylamines 1 and 2 (X = Cl and Br) with MeONa-MeOH have been investigated.Eliminations from 1 were quantitative, producing only benzylidenemethylamines.Reaction of 2 with MeONa-MeOH produced benzylidenemethylamines and benzylmethylamines.The yield of benzylidenemethylamine increased with electron-withdrawing aryl substituents and increased base concentration and became quantitative when pentane was used as a solvent.The results are interpreted as competing bimolecular elimination and nucleophilic substitution by methoxide on bromine.Product studies for reaction of N-halobenzyl-tert-butylamines with MeONa-MeOH and EtSNa-MeOH establish that the substitution reaction is a general reaction pathway available for the N-haloamines.Transition states for eliminations from 1 and 2 are characterized by Hammett ρ and primary deuterium isotope effect values.
- Cho, Bong Rae,Yoon, Jong Chan,Bartsch, Richard A.
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p. 4943 - 4946
(2007/10/02)
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- Benzylamines: Synthesis and evaluation of antimycobacterial properties
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The synthesis of benzylamines with various N-alkyl chains and substituents in the aromatic system as well as their evaluation on Mycobacterium tuberculosis H 37 Ra are described. The most active compounds in this test, N-methyl-3-chlorobenzylamine (MIC 10.2 μg/mL), N-methyl-3,5-dichlorobenzylamine (93, MIC 10.2 μg/mL), and N-butyl-3,5-difluorobenzylamine (MIC 6.4 μg/mL), also exhibited a marked inhibitory effect on Mycobacterium marinum and Mycobacterium lufu used for the determination of antileprotic properties. The combination of 93 with aminosalicylic acid, streptomycin, or dapsone exert marked supra-additive effects on M. tuberculosis H 37 Ra.
- Meindl,Von Angerer,Schonenberger,Ruckdeschel
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p. 1111 - 1118
(2007/10/02)
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- Folate Antagonists. 18. Synthesis and Antimalarial Effects of N6-(Arylmethyl)-N6-methyl-2,4,6-pteridinetriamines and Related N6,N6-Disubstituted 2,4,6-Pteridinetriamines
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N6-(Arylmethyl)-N6-methyl-2,4,6-pteridinetriamines (1-5) and related N6-substituted 2,4,6-pteridinetriamines (16-20) were obtained by the condensation of 6-chloro-2,4-pteridinediamine with methylarylmethanamine and other selected secondary amines.The requisite N-methylarylmethanamines (21-32) were prepared by the hydrogenation over Pt/C of the corresponding arylcarboxaldehyde in the presence of methanamine.Several of the N6-(arylmethyl)-N6-methyl-2,4,6-pteridinetriamines exhibited exceptional suppressive antimalarial activity against a drug-sensitive line of Plasmodium berghei in mice.N6-Methyl-N6-(1-naphthalenylmethyl)-2,4,6-pteridinetriamine (9), the most active of those compounds, was also shown to be curative at 3.16 mg/kg in a single oral dose against P. cynomolgi in the rhesus monkey.This compound was also shown to be effective against a chloroquine-resistant line of P. berghei in the mouse but showed cross-resistance to a pyrimethamine-resistant strain.Most of the 2,4,6-pteridinetriamines showed strong antibacterial action against Streptococcus faecalis and Staphylococcus aureus.
- Elslager, Edward F.,Johnson, Judith L.,Werbel, Leslie M.
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p. 140 - 145
(2007/10/02)
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