- Discovery of novel 2,3-dihydro-1H-inden-1-amine derivatives as selective monoamine oxidase B inhibitors
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Inhibition of MAO-B has been an effective strategy for the treatment of Parkinson's disease. To find more potent and selective MAO-B inhibitors with novel chemical scaffold, we designed and synthesized a series of new 2,3-dihydro-1H-inden-1-amine derivatives on basis of our previous study. Furthermore, the corresponding structure-activity relationship (SAR) of these compounds is detailedly discussed. Compounds L4 (IC50 = 0.11 μM), L8 (IC50 = 0.18 μM), L16 (IC50 = 0.27 μM) and L17 (IC50 = 0.48 μM) showed similar MAO-B inhibitory activity as Selegiline. Moreover, L4, L16 and L17 also exhibited comparable selectivity with Selegiline, indicating that L4, L16 and L17 could be promising selective MAO-B inhibitors for further study.
- Li, Shiyu,Lv, Xiao,Cheng, Kai,Tian, Yongbing,Huang, Xufeng,Kong, Haiyan,Duan, Yajun,Han, Jihong,Liao, Chenzhong,Xie, Zhouling
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Read Online
- Synthesis of haloindenes
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The subject invention provides an expedited synthesis of 5, 6, and 7-iodoindenes from the corresponding aminoindan-1-ones in more than 70% yield, employing readily available precursors and reagents. A three-step sequence involves diazotization-iodination of aminoindan-1-one followed by reduction and dehydration. The method has a general character and can be extended for the preparation of various 4-, 5-, 6- or 7-haloindenes using different halogen sources for diazotization-halogenation reaction.
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Page/Page column 4; 16
(2021/03/24)
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- Novel 1-(prop-2-yn-1-ylamino)-2,3-dihydro-1H-indene-4-thiol derivatives as potent selective human monoamine oxidase B inhibitors: Design, SAR development, and biological evaluation
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Successes have been achieved in developing human monoamine oxidase B (hMAO-B) inhibitors as anti-Parkinson's disease (PD) drugs. However, low efficiency and unwanted side effects of the marketed hMAO-B inhibitors hamper their medical applications, therefore, novel potent selective hMAO-B inhibitors are still of great interest. Herein we report 1-(prop-2-yn-1-ylamino)-2,3-dihydro-1H-indene-4-thiol derivatives as hMAO-B inhibitors, which were designed by employing a fragment-based drug design strategy to link rasagiline to hydrophobic fragments. Among the synthesized 31 compounds, K8 and K24 demonstrated very encouraging hMAO-B inhibitory activities and selectivity over hMAO-A, better than rasagiline and safinamide. In vitro studies indicated that K8 and K24 are nontoxic to nervous tissue cells and they have considerable effects against ROS formation and potential neuroprotective activity. Further mice behavioral tests demonstrated these two compounds have good therapeutic effects on MPTP-induced PD model mice. All these experiment results suggest that compounds K8 and K24 can be promising candidates for further research for treatment of PD.
- Kong, Haiyan,Meng, Xianshe,Hou, Rui,Yang, Xiaoxiao,Han, Jihong,Xie, Zhouling,Duan, Yajun,Liao, Chenzhong
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- METHODS FOR MAKING QUINOLINYLDIAMINES
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The present disclosure provides methods for making quinolinyldiamine products from quinolinyl starting materials. In addition, the quinolinyldiamines can be used as ligands or ligand precursors for catalysts, e.g. for use in olefin polymerization.
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Paragraph 0273-0274
(2020/03/23)
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- Iodoindenes: Synthesis and application to cross-coupling
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An expeditious synthesis of 5-, 6-, and 7-iodoindenes from the corresponding aminoindan-1-ones in more than 70% yield employing readily available precursors and ubiquitous reagents is reported. The 4-iodoindene has been prepared analogously in 40% overall yield. A three-step sequence involves diazotization-iodination of aminoindan-1-one followed by the reduction and dehydration. The iodoindenes serve as effective substrates for the regioselective Stille coupling with vinyl stannanes but isomeric mixtures are produced during Sonogashira coupling with alkynes in the presence of triethylamine.
- Howlader, A. Hasan,Diaz, Keili,Mebel, Alexander M.,Kaiser, Ralf I.,Wnuk, Stanislaw F.
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- COVALENT TARGETING OF E3 LIGASES
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Disclosed herein, inter alia, are compositions and methods for targeting E3 ligases. In an aspect is a targeted protein degrader including 1) a targeted protein binder and 2) an E3 Ubiquitin ligase binder, wherein the E3 Ubiquitin ligase is human RNF4 or human RNF114. In an aspect is provided a pharmaceutical composition including a compound as described herein, including embodiments, and a pharmaceutically acceptable excipient.
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Paragraph 0591; 0602; 0700; 0723; 0816; 0842
(2020/05/19)
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- Discovery of N-indanyl benzamides as potent RORγt inverse agonists
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The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is a promising therapeutic target for treatment of Th17 cell-mediated autoimmune diseases. Based on a scaffold hopping/conformational restriction strategy, a series of N-indanyl benzamides as novel RORγt inverse agonists was discovered. Exploration of structure-activity relationship on the piperazine ring, benzoyl moiety and cyclopentyl moiety of N-indanyl benzamides 2a and 2d led to identification of potent RORγt inverse agonists. Compound 5c with (S)-enantiomer was found having an IC50 of 153.7 nM in Fluorescence Resonance Energy Transfer (FRET) assay, and an IC50 of 47.1 nM in mouse Th17 cell differentiation assay, which represents a promising starting point for developing potent small molecule RORγt inverse agonists. Binding modes of the two enantiomers 5c and 5d in RORγt ligand binding domain were also discussed.
- Tian, Jinlong,Sun, Nannan,Yu, Mingcheng,Gu, Xianfeng,Xie, Qiong,Shao, Liming,Liu, Jin,Liu, Li,Wang, Yonghui
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- THERAPEUTIC COMPOUNDS
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The invention provides compounds of formula (I): wherein, A, C, D, X, and Y have any of the values defined in the specification, and salts thereof. The compounds are SIRT2 inhibitors and are useful for treating SIRT2 associated conditions.
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Paragraph 0264; 0265
(2017/01/23)
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- Thiosemicarbazones derived from 1-indanones as new anti-Trypanosoma cruzi agents
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In the present work, we synthesized a series of thiosemicarbazones derived from 1-indanones with good anti-Trypanosoma cruzi activity. Most of them displayed remarkable trypanosomicidal activity. All the compounds showed nonspecific cytotoxicity on human erythrocytes. The ability of the new compounds to inhibit cruzipain, the major cysteine protease of T. cruzi, was also explored. Thiosemicarbazones 12 and 24 inhibited this enzyme at the dose assayed. This interaction was also studied in terms of molecular docking.
- Caputto, María E.,Fabian, Lucas E.,Benítez, Diego,Merlino, Alicia,Ríos, Natalia,Cerecetto, Hugo,Moltrasio, Graciela Y.,Moglioni, Albertina G.,González, Mercedes,Finkielsztein, Liliana M.
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experimental part
p. 6818 - 6826
(2011/12/22)
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- SUBSTITUTED AROMATIC CARBOXAMIDE AND UREA DERIVATIVES AS VANILLOID RECEPTOR LIGANDS
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The invention relates to substituted aromatic carboxamide and urea derivatives, to processes for the preparation thereof, to pharmaceutical compositions containing these compounds and also to the use of these compounds for preparing pharmaceutical compositions (formula (I)).
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Page/Page column 145; 146
(2010/11/18)
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- Study on the synthesis, reduction and reductive amination of nitroindan-1-ones. Preparation of N-β-hydroxyethyl derivatives of 6-aminoindan-1-one and Indan-1,6-diamine
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Synthesis of 6-aminoindan-1-one and 7-amino-5,6-dimethoxyindan-1-one by nitration of corresponding indanones, followed by selective palladium catalyzed reduction under mild conditions has been described. Reactions of the amines with oxirane leading to N.N-bis-(β-hydroxyethyl) derivatives were performed. The study of reductive amination of 6-nitroindan-1-one and 5,6-dimethoxy-7- nitroindan-1-one via azines to the corresponding amines as well as synthesis of N,N-bis-(β-hydroxyethyl) derivatives of the amines was also described.
- Wodnicka,Kwiecien
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experimental part
p. 2133 - 2140
(2009/04/11)
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- SUBSTITUTED FLUOROETHYL UREAS AS ALPHA 2 ADRENERGIC AGENTS
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Therapeutic compounds, and methods, compositions, and medicaments related thereto are disclosed herein.
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Page/Page column 31
(2008/12/04)
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- Aryl sulfonamido indane inhibitors of the Kv1.5 ion channel
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A collection of aryl sulfonamido indanes based on the lead compound 1 was synthesized and evaluated for Kv1.5 inhibitory activity. Kv1.5 inhibitors have the potential to be atrium-selective agents for treatment of atrial fibrillation. (1R,2R)-1 has an IC50 of 0.033 μM against Kv1.5 and is selective against other cardiac ion channels, including hERG.
- Gross, Michael F.,Beaudoin, Serge,McNaughton-Smith, Grant,Amato, George S.,Castle, Neil A.,Huang, Christine,Zou, Anruo,Yu, Weifeng
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p. 2849 - 2853
(2008/02/11)
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- Constrained 7-fluorocarboxychromone-4-aminopiperidine based Melanin-concentrating hormone receptor 1 antagonists: The effects of chirality on substituted indan-1-ylamines
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The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.
- Souers, Andrew J.,Iyengar, Rajesh R.,Judd, Andrew S.,Beno, David W.A.,Gao, Ju,Zhao, Gang,Brune, Michael E.,Napier, James J.,Mulhern, Mathew M.,Lynch, John K.,Freeman, Jennifer C.,Wodka, Dariusz,Chen, Chong J.,Falls, H. Doug,Brodjian, Sevan,Dayton, Brian D.,Diaz, Gilbert J.,Bush, Eugene N.,Shapiro, Robin,Droz, Brian A.,Knourek-Segel, Victoria,Hernandez, Lisa E.,Marsh, Kennan C.,Reilly, Regina M.,Sham, Hing L.,Collins, Christine A.,Kym, Philip R.
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p. 884 - 889
(2007/10/03)
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- CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS
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Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.
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Page/Page column 54-55
(2008/06/13)
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- Synthesis and biological evaluation of 5-substituted 1,4-dihydroindeno[1,2-c]pyrazoles as multitargeted receptor tyrosine kinase inhibitors
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We report the synthesis and biological evaluation of 5-substituted 1,4-dihydroindeno[1,2-c]pyrazoles as multitargeted kinase inhibitors. Initial efforts focused on the development of selective KDR inhibitors, while later strategies involved the improvement of potency toward multiple kinase targets. Thus, several compounds were identified as potent KDR, Flt1, Flt3, and c-Kit inhibitors.
- Akritopoulou-Zanze, Irini,Albert, Daniel H.,Bousquet, Peter F.,Cunha, George A.,Harris, Christopher M.,Moskey, Maria,Dinges, Jurgen,Stewart, Kent D.,Sowin, Thomas J.
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p. 3136 - 3140
(2008/02/05)
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- Vanilloid receptor ligands and their use in treatments
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Compounds having the general structure and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.
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Page/Page column 65
(2010/11/24)
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- TETRAHYDRO-NAPHTHALENE AND UREA DERIVATIVES
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This invention relates to a hydroxy-tetrahydro-naphthalene or an urea derivative formula (I) and salts thereof which are useful as active ingredients of pharmaceutical preparations, wherein A represents formula (II) or (III) wherein # represents the connection position to the molecule and Q1a, Q2a, Q3a and Q4a are defined, and E represents formula (IV) or (V) wherein # represents the connection position to the molecule and Q1b, Q2b, Q3b, Q4b, Q5b, R1b, na, ma, Xa and Ra are defined.
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Page/Page column 48-49
(2008/06/13)
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- TETRAHYDRO-NAPHTHALENE AND UREA DERIVATIVES
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This invention relates to tetrahydro-naphthalene and urea derivatives and salts thereof which are useful as active ingredients of pharmaceutical preparations. The tetrahydro-naphthalene and urea derivatives of the present invention have vanilloid receptor (VR1) antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with VR1 activity, in particular for the treatment of urological diseases or disorders, such as detrusor overactivity (overactive bladder), urinary incontinence, neurogenic detrusor oeractivity (detrusor hyperflexia), idiopathic detrusor overactivity (detrusor instability), benign prostatic hyperplasia, and lower urinary tract symptoms; chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, and inflammatory disorders such as asthma and chronic obstructive pulmonary (or airways) disease (COPD). BHC 03 2 001-Foreign-Countries - 66 - BHC 03 2 001-Foreign-Countries - 65 -
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Page/Page column 75-77
(2015/05/06)
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- TRICYCLIC PYRAZOLE KINASE INHIBITORS
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Compounds of the present invention are useful for inhibiting protein tyrosine kinases. Also disclosed are methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
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Page/Page column 56-57
(2008/06/13)
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- Preparation of alkylation agents for bulged DNA microenvironments
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A designed molecule with capacity to alkylate DNA bulges has been prepared from readily available starting materials. The spirocyclic template utilized was designed on the basis of established architectures, and equipped with a mustard alkylating group. Preliminary studies confirm alkylation of specific bulged sequences, paving the way for second generation substrates with higher affinity.
- Fouad, Farid S.,Xi, Zhen,Goldberg, Irving H.,Jones, Graham B.
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p. 3337 - 3339
(2007/10/03)
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- Sulfonamides having antiangiogenic and anticancer activity
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Compounds having methionine aminopeptidase-2 inhibitory (MetAP2) are described. Also described are pharmaceutical compositions comprising the compounds, methods of treatment using the compounds, methods of inhibiting angiogenesis, and methods of treating cancer.
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- Indanylidenes. 1. Design and synthesis of (E)-2-(4,6-difluoro-1-indanylidene)acetamide, a potent, centrally acting muscle relaxant with antiinflammatory and analgesic activity
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The design of rigid cyclic analogues derived from cinnamamide 1, (E)-N-cyclopropyl-3-(3-fluorophenyl)prop-2-enamide, and β-methylcinnamamide 2, (E)-N-cyclopropyl-3-(3-fluorophenyl)but-2-enamide, has led to the discovery of the potent, centrally acting muscle relaxant (E)-2-(4,6-difluoro-1-indanylidene)acetamide, 17. Compound 17 also possesses potent antiinflammatory and analgesic activity. This paper describes the synthesis and the muscle relaxant, antiinflammatory, and analgesic structure-activity relationships of 17 and 67 of its analogues. Compound 17 has been taken into phase I clinical trials.
- Musso, David L.,Cochran, Felicia R.,Kelley, James L.,McLean, Ed W.,Selph, Jeffrey L.,Rigdon, Greg C.,Orr, G. Faye,Davis, Ronda G.,Cooper, Barrett R.,Styles, Virgil L.,Thompson, James B.,Hall, William R.
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p. 399 - 408
(2007/10/03)
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- 4-Heterocyclic-substituted-2-indanyl alcohols and insecticidal ester derivatives
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Disclosed are novel compounds of the formula STR1 wherein R1 is a heterocyclic radical selected from furanyl, thienyl, pyridyl, pyrimidyl, oxazolyl, pyrrolyl, isoxazolyl, thiazolyl, and isothiazolyl, and R2 is hydrogen, a tetramethylcyclopropanecarbonyl group, a 1-(substituted-phenyl)-2-methylpropyl-1-carbonyl group, a 1-(4-ethoxyphenyl)-2,2-dichlorocyclopropanecarbonyl group, or a substituted-vinylcyclopropanecarbonyl group. The compounds wherein R2 is other than hydrogen are insecticides.
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- 4-Heterocyclic-substituted-2-indanyl alcohols and insecticidal ester derivatives
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Disclosed are novel compounds of the formula STR1 wherein R1 is a heterocyclic radical selected from furanyl, thienyl, pyridyl, pyrimidyl, oxazolyl, pyrrolyl, isoxazolyl, thiazolyl, and isothiazolyl, and R2 is hydrogen, a tetramethylcylopropanecarbonyl group, a 1-(substituted-phenyl)-2-methylpropyl-1-carbonyl group, a 1-(4-ethoxyphenyl)-2-dichlorocyclopropanecarbonyl group, or a substituted-vinyl-cyclopropanecarbonyl group. The compounds wherein R2 is other than hydrogen are insecticides.
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- 4-Heterocyclic-substituted-2-indanyl alcohols and insecticidal ester derivatives
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Disclosed are novel compounds of the formula STR1 wherein R1 is a heterocyclic radical selected from furanyl, thienyl, pyridyl, pyrimidyl, oxazolyl, pyrrolyl, isoxazolyl, thiazolyl, and isothiazolyl, and R2 is hydrogen, a tetramethylcyclopropanecarbonyl group, a 1-(substituted-phenyl)-2-methylpropyl-1-carbonyl group, a 1-(4-ethoxyphenyl)-2,2-dichlorocyclopropanecarbonyl group, or a substituted-vinylcyclopropanecarbonyl group. The compounds wherein R2 is other than hydrogen are insecticides.
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