- Discovery of a new 2-aminobenzhydrol template for highly potent squalene synthase inhibitors
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To obtain small and efficient squalene synthase inhibitors, a flexible 2-aminobenzhydrol open form structure was designed and showed potent inhibitory activity comparable to 4,1-benzoxazepin compounds. Further chemical modification led to the discovery of a novel template with a strong squalene synthase inhibitory activity, and its basic structure-activity relationship was revealed. The X-ray crystallographic data of compound 12 bound to the active site of squalene synthase provided an important insight into the binding mode of this alternative template that formed 11-membered ring conformations with an intramolecular hydrogen bond.
- Ichikawa, Masanori,Yokomizo, Aki,Itoh, Masao,Sugita, Kazuyuki,Usui, Hiroyuki,Shimizu, Hironari,Suzuki, Makoto,Terayama, Koji,Kanda, Akira
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scheme or table
p. 1930 - 1949
(2011/05/03)
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- Synthesis of the antitumoural agent batracylin and related isoindolo[1,2-b]quinazolin-12(10H)-ones
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The synthesis of batracylin and related isoindolo[1,2-b]quinazolin-12-ones from easily accessible o-acylanilines is reported. The preparation of these tetracyclic compounds through a Mitsunobu reaction followed by spontaneous cyclodehydration shows the ability of this methodology to afford good yields of a wide variety of diversely 7, 8, 9, 10-substituted isoindoloquinazolinones in two steps.
- Martínez-Viturro, Carlos M.,Domínguez, Domingo
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p. 1023 - 1026
(2008/02/04)
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- SULPHONAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
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Disclosed are compounds having the general formula (I) as defined herein, the preparation thereof, and the use thereof for the prophylaxis or treatment of any disease involving a dysfunction associated with the orexin 2 receptor such as obesity, appetite or taste disorders including cachexia, anorexia and bulimia, diabetes, metabolic syndromes, vomiting and nausea, depression and anxiety, addictions, mood and behaviour disorders, schizophrenia, sleep disorders, restless legs syndrome, memory learning disorders, sexual and psychosexual dysfunctions, pain, visceral or neuropathic pain, hyperalgesia, allodynia, digestive disorders, irritable bowel syndrome, neuronal degenerescence, ischaemic or haemorrhagic attacks, Cushing's disease, Guillain-Barré syndrome, myotonic dystrophy, urinary incontinence, hyperthyroidism, pituitary function disorders, hypertension or hypotension.
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Page/Page column 65
(2010/11/28)
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- 5-Aryl-imidazo[2,1-c][1,4]benzodiazepine derivatives as tricyclic constrained analogues of diazepam and Ro5-4864. Synthesis and binding properties at peripheral and central benzodiazepine receptors
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Four series of 5-aryl-imidazo[2,1-c][1,4]benzodiazepine derivatives 1a-f, 2a-f, 3a-f, and 4a-f were synthesized and tested for their affinity at both the peripheral and central benzodiazepine receptors. Among the four series, only N-10 and C-11 sites were changed, mainly [N(CH3)-CO], [N-CH], [NH-CO], [NH-CH2], and in each series the halogen site was varied at the positions C-7, C-2′, and C-4′. In particular, 10-methyl-benzodiazepinones 1a and 1b were designed as tricyclic constrained analogues of diazepam and Ro5-4864. All the tested compounds did not show significant binding activity at central benzodiazepine receptors, but relatively good PBzR binding affinities were found for 10-methyl-benzodiazepinone 1c and benzodiazepines 2b, c. Benzodiazepinones 3a-f were prepared by cyclization with 1,1′-carbonyldiimidazole of the corresponding 2-(aryl-imidazol-1-yl- methyl)-arylamines, obtained from the suitable (2-amino-aryl)-aryl-methanols with 1,1′-carbonyldiimidazole in different conditions. N-Alkylation of 3a-f to 1a-f was achieved using dimethylformamide-dimethylacetal. Reduction of 3a-f to 4a-f was accomplished with lithium aluminum hydride or borane and oxidation of 4a-f to 2a-f was performed with manganese (IV) oxide.
- Rizzetto, Elisa,Castellano,Florio,Vadori,Stefancich
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p. 505 - 510
(2007/10/03)
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- ANNELATED QUINOLINE DERIVATIVES AS PESTICIDE
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The invention relates to the use of quinoline derivatives of formula (I), where the dotted bond is either a single- or double-bond and the substituents have the meaning given in the description, as plant treatment agents, in particular, for the prevention
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Page/Page column 89
(2010/02/14)
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- Novel 4,1-benzoxazepine derivatives with potent squalene synthase inhibitory activities
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A series of (3,5-trans)-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine derivatives were synthesized and evaluated for squalene synthase inhibitory and cholesterol biosynthesis inhibitory activities. Through modification of substituents of the lead compounds 1a and 1b, it was found that 4,1-benzoxazepine-3-acetic acid derivatives with isobutyl and neopentyl groups at the 1-position, the chloro atom at the 7-position, and the chloro and methoxy groups at the 2'-position on the 5-phenyl ring, had potent squalene synthase inhibitory activity. Among such compounds, the 5-(2,3-dimethoxyphenyl) derivative 2t exhibited potent inhibition of cholesterol biosynthesis in HepG2 cells. As a result of optical resolution study of 2t, the absolute stereochemistry required for inibitory activity was determined to be 3R,5S. In vivo study showed that the sodium salt of (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceitc acid 20 effectively reduced plasma cholesterol in marmosets. Copyright
- Miki, Takashi,Kori, Masakuni,Mabuchi, Hiroshi,Banno, Hiroshi,Tozawa, Ryu-ichi,Nakamura, Masahira,Itokawa, Shigekazu,Sugiyama, Yasuo,Yukimasa, Hidefumi
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p. 401 - 414
(2007/10/03)
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