- 6,7-DIHYDRO-5H-PYRIDO[2,3-C]PYRIDAZINE DERIVATIVES AND RELATED COMPOUNDS AS BCL-XL PROTEIN INHIBITORS AND PRO-APOPTOTIC AGENTS FOR TREATING CANCER
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The present invention discloses 6,7-dihydro-5H-pyrido[2,3- c]pyridazine, 1,2,3,4-tetrahydroquinoline, 1H-indole, 3,4- dihydro-2H-1,4-benzoxazine, 1H-pyrrolo[2,3-b]pyridin-1-yl, 7H- pyrrolo[2,3-c]pyridazine, 5H,6H,7H,8H,9H-pyridazino[3,4-b]azepine derivatives and related compounds of formula (I) as Bcl-xL protein inhibitors for use as pro-apoptotic agents for treating cancer, autoimmune diseases or immune system diseases. Formula (I). The description discloses the preparation of exemplary compounds (e.g. pages 113 to 354 examples 1 to 221) as well as pharmacological studies with relevant data (e.g. pages 355 to 367; examples A to E; tables 1 to 5). Exemplary compounds are e.g. 2-{6-[(1,3-benzothiazol-2-yl) amino]-1,2,3,4-tetrahydroquinolin-1-yl}-1,3-thiazole-4-carboxylic acid (example 1) or e.g. 3-{1-[(adamantan-1-yl)methyl]-5- methyl-1H-pyrazol-4-yl}-6-{3-[(1,3-benzothiazol-2-yl)amino]-4- methyl-5H,6H,7H,8H-pyrido[2,3-c]pyridazin-8-yl]pyridine-2-carboxylic acid (example 24).
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Page/Page column 81
(2021/02/05)
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- BICYCLIC COMPOUNDS
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Provided herein are compounds and pharmaceutical compositions comprising said compounds that are useful for treating cancers. Specific cancers include those that are mediated by YAP/TAZ or those that are modulated by the interaction between YAP/TAZ and TEAD.
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Paragraph 00700
(2020/06/01)
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- Benzazepine Dicarboxamide Compounds
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This invention relates to novel benzazepine dicarboxamide compounds of the formula wherein R1 to R4 are as defined in the description and in the claims, as well as pharmaceutically acceptable salts thereof. These compounds are TLR agonists and may therefore be useful as medicaments for the treatment of diseases such as cancer, autoimmune diseases, inflammation, sepsis, allergy, asthma, graft rejection, graft-versus-host disease, immunodeficiencies, and infectious diseases.
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- AMIDE COMPOUNDS AS TRYPTOPHAN HYDROXYLASE INHIBITORS
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The present invention is directed to amide compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPH1), that are useful in the treatment or prevention of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, fibrotic, and low bone mass diseases, as well as cancer.
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Page/Page column 62
(2016/07/27)
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- Synthesis and evaluation of N-alkyl-S-[3-(piperidin-1-yl)propyl] isothioureas: High affinity and human/rat species-selective histamine H 3 receptor antagonists
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S-Alkyl-N-alkylisothiourea compounds containing various cyclic amines were synthesized in the search for novel nonimidazole histamine H3 receptor (H3R) antagonists. Among them, four N-alkyl S-[3-(piperidin-1-yl)propyl]isothioureas 18, 19, 22, and 23 were found to exhibit potent and selective H3R antagonistic activities against in vitro human H3R, but were inactive against in vitro human H 4R. Furthermore, three alkyl homologs 18-20 showed inactivity for histamine release in in vivo rat brain microdialysis, suggesting differences in antagonist affinities between species. In addition, in silico docking studies of N-[4-(4-chlorophenyl)butyl]-S-[3-piperidin-1-yl)propyl]isothiourea 19 and a shorter homolog 17 with human/rat H3Rs revealed that structural differences between the antagonist-docking cavities of rat and human H 3Rs were likely caused by the Ala122/Val122 mutation.
- Harusawa, Shinya,Sawada, Koichi,Magata, Takuji,Yoneyama, Hiroki,Araki, Lisa,Usami, Yoshihide,Hatano, Kouta,Yamamoto, Kouichi,Yamamoto, Daisuke,Yamatodani, Atsushi
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p. 6415 - 6420
(2013/11/19)
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- A σ1 receptor pharmacophore derived from a series of N-substituted 4-azahexacyclo[5.4.1.02,6.03,10.0 5,9.08,11]dodecan-3-ols (AHDs)
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A library of N-substituted 4-azahexacyclo[5.4.1.02,6.0 3,10.05,9.08,11]dodecan-3-ols (AHDs) was synthesized and subjected to competition binding assays at σ1 and σ2 receptors, as well as off-target screening of representative members at 44 other common central nervous system (CNS) receptors, transporters, and ion channels. Excluding 3 low affinity analogs, 31 ligands demonstrated nanomolar Ki values for either σ receptor subtype. Several selective σ1 and σ2 ligands were discovered, with selectivities of up to 29.6 times for σ1 and 52.4 times for σ2, as well as several high affinity, subtype non-selective ligands. The diversity of structures and σ1 affinities of the ligands allowed the generation of a σ1 receptor pharmacophore that will enable the rational design of increasingly selective and potent σ1 ligands for probing σ1 receptor function.
- Banister, Samuel D.,Manoli, Miral,Doddareddy, Munikumar Reddy,Hibbs, David E.,Kassiou, Michael
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supporting information
p. 6053 - 6058
(2012/10/30)
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- OXO-HETEROCYCLICALLY SUBSTITUTED ALKYL CARBOXYLIC ACIDS AND USE THEREOF
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The present application relates to novel alkylcarboxylic acids having an oxo-substituted azaheterocyclic partial structure, to processes for their preparation, to their use for the treatment and/or prevention of diseases, and to their use for producing medicaments for the treatment and/or prevention of diseases, especially for the treatment and/or prevention of cardiovascular disorders.
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Page/Page column 18
(2012/02/06)
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- Convenient route to primary (Z)-allyl amines and homologs
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A convenient two-step procedure for the synthesis of primary (Z)-allyl amines, (Z)-homoallyl amines [(Z)-but-3-enylamines], and (Z)-pent-4-enylamines using the Wittig reaction was achieved. The use of nonstabilized ylides from triphenylphosphonium salt, potassium salt, and apolar solvent produced (Z/E)-geometric isomer ratios generally greater than 1.6. The amine moiety was masked using a phtalimide group that was removed successfully in the last step of the process in two different conditions, NH2NH2/EtOH/rt or CH3NH2/EtOH/rt. However, in some cases, reduction of the C = C double bond in the deprotection with hydrazine was concomitantly observed. Copyright Taylor & Francis Group, LLC.
- Gerpe, Alejandra,Bollini, Mariela,Gonzalez, Mercedes,Cerecetto, Hugo
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experimental part
p. 29 - 47
(2009/04/06)
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- 6-SUBSTITUTED PHENOXYCHROMAN CARBOXYLIC ACID DERIVATIVES
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Compounds of Formula (I): in which A1, A2, W, L, G, R7a, R7b, R8, R9 and R10 have the meanings given in the specification, are DP2 receptor modulators useful in the treatment of immunologic diseases.
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Page/Page column 84
(2010/01/30)
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- Novel H3 receptor antagonists. Sulfonamide homologs of histamine.
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Sulfonamides derived from 4(5)-(omega-aminoalkyl)-1H-imidazoles containing chain lengths of three- to five-carbons were synthesized. Good to moderate H3 receptor binding affinities were observed for several butyl and pentyl homologs, whereas binding affinities were considerably weaker in the propyl series. Separation of the imidazole ring and the sulfonamide unit by a four- or five-carbon tether afforded potent H3 receptor antagonists.
- Wolin,Connolly,Afonso,Hey,She,Rivelli,Willams,West Jr.
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p. 2157 - 2162
(2007/10/03)
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- Alpha-halomethyl derivatives of amines
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Novel halomethyl derivatives of amines of the following general structure: STR1 WHEREIN Y is FCH2 --, F2 CH-- or F3 C--; Z is β-methylthioethyl, β-benzylthioethyl, S-(5'-desoxyadenosin-5'-yl)-S-methylthioethyl, γ-guanidinopropyl, or STR2 WHEREIN N IS 2 OR 3 AND R1 is hydrogen or lower alkyl of from 1 to 4 carbon atoms with the proviso that when R1 is other than hydrogen, n is 2; and each of Ra and Rb is hydrogen, alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, alkoxycarbonyl wherein the alkoxy moiety has from 1 to 4 carbon atoms and is straight or branched, or STR3 wherein R2 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl; with the provisos that when Z is β-benzylthioethyl or S-(5'-desoxyadenosin-5'-yl)-S-methylthioethyl, Rb is hydrogen, when Z is β-methylthioethyl, Y is other than F3 C--, and when Z is STR4 EACH OF Ra and Rb can be the same or different; and pharmaceutically acceptable salts and individual optical isomers thereof.
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- Synthesis and antitumor properties of some isoindolylalkylphosphonium salts
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Antitumor evaluation of 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyltriphenylphosphonium bromide (1) revealed significant activity in P-388 lymphocytic leukemia (T/C = 160%). As a follow-up to this chemical lead, a series of closely related phosphonium salts was prepared in which the 1,3-dihydro-1,3-dioxo-2H-isoindole ring system was maintained or in which it was replaced by other moieties such as maleimido, bromo, methoxy, and isoindoline. Syntheses generally involved treatment of the appropriate N-(bromoalkyl)phthalimide with the required phosphine or condensation of the K salt of the substituted imide with β-(bromoethyl) triphenylphosphonium bromide. From the biological data obtained for these compounds, several requirements can be defined for substantial antileukemic activity. Of utmost importance is the presence of a triarylphosphonium halide moiety, coupled to an alkyl chain of two or three carbon atoms. The preferred terminus of the alkyl chain is the 1,3-dihydro-1,3-dioxo-2H-isoindole ring system, although the observed activity of β-(bromoethyl)triphenylphosphonium bromide (T/C = 127%) would suggest that a superior carrier molecule could be developed.
- Dubois,Lin,Beisler
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p. 303 - 306
(2007/10/04)
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