- Efficient Synthesis of Benzothiazinone Analogues with Activity against Intracellular Mycobacterium tuberculosis
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8-Nitrobenzothiazinones (BTZs) are a promising class of antimycobacterial agents currently under investigation in clinical trials. Starting from thiourea derivatives, a new synthetic pathway to BTZs was established. It allows the formation of the thiazinone ring system in one synthetic step and is applicable for preparation of a wide variety of BTZ analogues. The synthetic procedure furthermore facilitates the replacement of the sulphur atom in the thiazinone ring system by oxygen or nitrogen to afford the analogous benzoxazinone and quinazolinone systems. 36 BTZ analogues were prepared and tested in luminescence-based assays for in vitro activity against Mycobacterium tuberculosis (Mtb) using the microdilution broth method and a high-throughput macrophage infection assay.
- Richter, Adrian,Narula, Gagandeep,Rudolph, Ines,Seidel, Rüdiger W.,Wagner, Christoph,Av-Gay, Yossef,Imming, Peter
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supporting information
(2021/12/27)
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- The optimization of xanthine derivatives leading to HBK001 hydrochloride as a potent dual ligand targeting DPP-IV and GPR119
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A series of xanthine compounds derived from the previous hit 20i with modification on the terminal side chain was discovered through ring formation strategy. Systematic optimization of the compounds with rigid heterocycles in the hydrophobic side chain led to the new lead compound HBK001 (21h) with the improved DPP-IV inhibition and moderate GPR119 agonism activity in vitro. As a continuing work to further study the PK and PD profiles, 21h and its hydrochloride (22) were synthesized on grams scale and evaluated on the ADME/T and oral glucose tolerance test (OGTT) in ICR mice. Compound 22 showed the improved bioavailability and blood glucose-lowering effect in vivo compared to its free base 21h probably attributed to its improved solubility and permeability. The preliminary toxicity studies on compound 22 exhibited that the result of mini-Ames was negative and the preliminary acute toxicity LD50 in mice was above 1.5 g/kg, while it showed moderate inhibition on hERG channel with IC50 4.9 μM maybe due to its high lipophilicity. These findings will be useful for the future drug design for more potent and safer dual ligand targeting DPP-IV and GPR119 for the treatment of diabetes.
- Li, Gang,Meng, Bingxu,Yuan, Baokun,Huan, Yi,Zhou, Tian,Jiang, Qian,Lei, Lei,Sheng, Li,Wang, Weiping,Gong, Ningbo,Lu, Yang,Ma, Chen,Li, Yan,Shen, Zhufang,Huang, Haihong
-
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- ACID ADDITION SALTS OF PIPERAZINE DERIVATIVES
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The invention relates to acid addition salts of piperazine derivatives, as well as solid forms, such as polymorphic forms, thereof, which are useful as pharmaceutical ingredients and in particular as glycosidase inhibitors.
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Page/Page column 39
(2017/09/09)
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- GLYCOSIDASE INHIBITORS
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Compounds of formula (I) wherein A, R, W, Q, n and m have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
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Page/Page column 106
(2016/03/22)
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- SUBSTITUTED NICOTINIMIDE INHIBITORS OF BTK AND THEIR PREPARATION AND USE IN THE TREATMENT OF CANCER, INFLAMMATION AND AUTOIMMUNE DISEASE
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Compounds of Formula I, as shown below and defined herein: and pharmaceutically acceptable salts, syntheses, intermediates, formulations, and methods of treating diseases including cancer, inflammation, and autoimmune disease mediated at least in part by Bruton's Tyrosine Kinase (BTK).
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Page/Page column 105
(2015/04/15)
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- AZOCYCLIC INHIBITORS OF FATTY ACID AMIDE HYDROLASE
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Disclosed are compounds of Formula 1, including all stereoisomers, N oxides, and salts thereof, wherein A, W, X, G, R1, R2, R3, R4, m and n are as defined in the disclosure. Also disclosed are pharmaceutical compositions containing the compounds of Formula 1 and methods for treating a disease or condition mediated by fatty acid amide hydrolase activity comprising applying a therapeutically effective amount of a compound or a composition of the invention
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Page/Page column 49
(2011/06/26)
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- FUNGICIDAL MIXTURES
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Disclosed is a fungicidal composition comprising (a) at least one compound selected from the compounds of Formula 1 N-oxides, and salts thereof, wherein R1, R2, A, G, W, Z1, X, J, and n are as defined in the disclosure, and (b) at least one additional fungicidal compound. Also disclosed is a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed, a fungicidally effective amount of the aforesaid composition. Also disclosed is a composition comprising component (a) of aforesaid composition and at least one insecticide. Also disclosed are compounds of Formula 1A, 1B and 1C, wherein R1, R2, A, G, W, Z1, X, J, n, Z3, M and J1 are as defined in the disclosure.
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Page/Page column 61
(2010/10/03)
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- N-SULFONYL THIAZOLYLPIPERAZINE DERIVATIVES AND RELATED N-SULFONYL HETEROCYCLIC DERIVATIVES FOR THE TREATMENT OF NEURO DEGENERATIVE DISEASES
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This invention provides thiazolylpiperazine derivatives, and N-sulfonyl heterocyclic derivatives including phenyl- and benzyl-thiazolylpiperidine derivatives, and pharmaceutically acceptable salts thereof, which are useful active ingredients for administration in a method for the treatment of an α-synucleopathy such as Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, multiple system atrophy and Alzheimer's disease. This invention also provides methods for making such derivatives, and pharmaceutical compositions including such derivatives together with pharmaceutically acceptable excipients.
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Page/Page column 77
(2010/08/08)
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- ELECTRONIC COMPONENT HAVING FLEXIBLE PRINTED CIRCUIT BOARD TECHNOLOGY
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The invention relates to an electronic component (1) having a housing comprising at least one base plate (3), a housing cover, and at least two electronic connections (5) between substrates (7) disposed in the interior of the housing and components located outside the housing in the form of printed circuit boards, which can be at least partially fixed on the base plate (3), wherein at least one first partially flexible printed circuit board (5a) and a second printed circuit board (5b) are configured such that they overlap at least in one region (6) in the assembled state. The invention further relates to a method for the production of such an electronic component.
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Page/Page column 81-82
(2008/06/13)
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- UREIDE DERIVATIVE AND USE THEREOF FOR MEDICAL PURPOSES
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This invention relates to a pharmaceutical comprising, as an active ingredient, a ureide derivative represented by formula: or a pharmaceutically acceptable salt thereof. The ureide derivative or a pharmaceutically acceptable salt thereof according to the present invention is useful for relieving pain and treating or preventing neuropathic pain.
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Page/Page column 95
(2009/01/24)
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- Design and synthesis of DPP-IV inhibitors lacking the electrophilic nitrile group
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A series of (4β-substituted)-l-prolylpyrrolidine analogs lacking the electrophilic nitrile function were synthesized and their dipeptidyl peptidase IV (DPP-IV) inhibitory activity and duration of ex vivo activity were evaluated. Structural optimization of a N-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine analog 8, which was found by high-speed analog synthesis, was carried out to improve the potency and duration of action. A representative compound 26 was evaluated to assess its effect on the plasma glucose level after the oGTT (oral glucose tolerance test) in normal rats. Structure-activity relationships (SAR) are also presented.
- Kondo, Takashi,Nekado, Takahiro,Sugimoto, Isamu,Ochi, Kenya,Takai, Shigeyuki,Kinoshita, Atsushi,Hatayama, Akira,Yamamoto, Susumu,Kishikawa, Katsuya,Nakai, Hisao,Toda, Masaaki
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p. 1613 - 1631
(2008/09/20)
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- Design and synthesis of tetracyclic nonpeptidic biaryl nitrile inhibitors of cathepsin K
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The synthesis and biological profile of a novel series of potent and selective inhibitors of cysteine protease cathepsin K (Cat K) are described. Pharmacokinetic evaluation of 12 indicated that some members of this series could be suitable candidates to develop new orally active therapeutic agents for the treatment of osteoporosis.
- Setti, Eduardo L.,Venkatraman, Shankar,Palmer, James T.,Xie, Xiaoming,Cheung, Harry,Yu, Walter,Wesolowski, Gregg,Robichaud, Joel
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p. 4296 - 4299
(2008/02/03)
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- [4-(HETEROARYL) PIPERAZIN-1-YL]-(2,5-SUBSTITUTED -PHENYL)METHANONE DERIVATIVES AS GLYCINE TRANSPORTER 1 (GLYT-1) INHIBITORS FOR THE TREATMENT OF NEUROLOGICAL AND NEUROPSYCHIATRIC DISORDERS
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The present invention relates to compounds of the general formula (I) wherein R1 is-OR1’,-SR1’ or is a heterocycloalkyl group; R1’ is lower alkyl, lower alkyl substituted by halogen or is -(CH2)n
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Page/Page column 65; 71; 78; 80
(2008/06/13)
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- CYSTEINE PROTEASE INHIBITORS
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A compound of the formula (II) wherein one of R1 and R2 is halo and the other is H or halo; R3 is C1-C4 straight or branched chain, optionally fluorinated, alkyl; R4 is H; or R3 together with R4 and the adjoining backbone carbon defines: a spiro-C5-C7 cycloalkyl, optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C1-C4 alkyl or C1-C4 haloalkyl; or optionally bridged with a methylene group; or a C4-C6 saturated heterocycle having a hetero atom selected from O, NRa, S, S(=O)2 ; where Ra is H, C1-C4 alkyl or CH3C(=O); R5 is independently selected from H or methyl; E is -C(=O)-, -S(=O)m-, -NR5S(=O)m-, -NR5C(=O)-, -OC(=O)-, R6 is a stable, optionally substituted, monocyclic or bicyclic, carbocycle or hetorocycle; m is independently 0,1 or 2; are inhibitors of cathepsin K and useful in the treatment or prophylaxis of osteoporosis.
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Page/Page column 71
(2010/02/12)
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- INDOLE DERIVATIVE WITH 5HT1A AFFINITY
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Novel indole derivatives of formula (I), where A , X, R1, R1' and m have the meanings given in claim 1, have a strong affinity for the 5-HT1A and partial affinity for the 5-HT1D receptors. The compounds inhibit serotonin reuptake, display serotonin agonist and antagonist properties and are suitable as antidepressants, anxiolytics and for the treatment of neurodegenerative diseases.
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Page/Page column 25-26
(2008/06/13)
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- N-(2-benzoylphenyl)-L-tyrosine PPARγ agonists. 2. Structure-activity relationship and optimization of the phenyl alkyl ether moiety
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We previously reported the identification of (2S)-((2- benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4- yl)ethoxy]phenyl}propanoic acid (2) (PPARγ pK(i) = 8.94, PPARγ pEC50 = 9.47) as a potent and selective PPARγ agonist. We now report the expanded structure-activity relationship around the phenyl alkyl ether moiety by pursuing both a classical medicinal chemistry approach and a solid-phase chemistry approach for analogue synthesis. The solution-phase strategy focused on evaluating the effects of oxazole and phenyl ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of 2 with several replacements providing potent and selective PPARγ agonists with improved aqueous solubility. Specifically, replacement of the phenyl ring of the phenyloxazole moiety with a 4-pyridyl group to give 2(S)-((2- benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-pyridin-4-yloxazol-4- yl)ethoxy]phenyl}propionic acid (16) (PPARγ pK(i) = 8.85, PPARγ pEC50 = 8.74) or a 4-methylpiperazine to give 2(S)-((2-benzoylphenyl)amino)-3-(4- {2-[5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl]ethoxy}phenyl)propionic acid (24) (PPARγ pK(i) = 8.66, PPARγ pEC50 = 8.89) provided two potent and selective PPARγ agonists with increased solubility in pH 7.4 phosphate buffer and simulated gastric fluid as compared to 2. The second strategy took advantage of the speed and ease of parallel solid-phase analogue synthesis to generate a more diverse set of phenyl alkyl ethers which led to the identification of a number of novel, high-affinity PPARγ ligands (PPARγ pK(i)'s 6.98-8.03). The combined structure-activity data derived from the two strategies provide valuable insight on the requirements for PPARγ binding, functional activity, selectivity, and aqueous solubility.
- Collins, Jon L.,Blanchard, Steven G.,Boswell, G. Evan,Charifson, Paul S.,Cobb, Jeff E.,Henke, Brad R.,Hull-Ryde, Emily A.,Kazmierski, Wieslaw M.,Lake, Debra H.,Leesnitzer, Lisa M.,Lehmann, Jürgen,Lenhard, James M.,Orband-Miller, Lisa A.,Gray-Nunez, Yolanda,Parks, Derek J.,Plunkett, Kelli D.,Tong, Wei-Qin
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p. 5037 - 5054
(2007/10/03)
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