- Synthesis and SAR of Imidazo[1,5-a[pyridine derivatives as 5-HT4 receptor partial agonists for the treatment of cognitive disorders associated with Alzheimer's disease
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Alzheimer's disease (AD) is a neurodegenerative disease which has a higher prevalence and incidence in older people. The need for improved AD therapies is unmet. The 5-hydroxytryptamine4 receptor (5-HT4R) partial agonists may be of benefit for both the symptomatic and disease-modifying treatment of cognitive disorders associated with AD. Herein, we report the design, synthesis and SAR of imidazo[1,5-a] pyridine derivatives as 5-HT4R partial agonists. The focused SAR, optimization of ADME properties resulted the discovery of compound 5a as potent, selective, brain penetrant 5-HT4 partial agonist as a lead compound with good ADME properties and efficacy in both symptomatic and disease modifying animal models of cognition.
- Nirogi, Ramakrishna,Mohammed, Abdul Rasheed,Shinde, Anil K.,Bogaraju, Narsimha,Gagginapalli, Shankar Reddy,Ravella, Srinivasa Rao,Kota, Laxman,Bhyrapuneni, Gopinadh,Muddana, Nageswara Rao,Benade, Vijay,Palacharla, Raghava Chowdary,Jayarajan, Pradeep,Subramanian, Ramkumar,Goyal, Vinod Kumar
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Read Online
- Structure-Guided Development of a Potent and Selective Non-covalent Active-Site Inhibitor of USP7
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Deubiquitinating enzymes (DUBs) have garnered significant attention as drug targets in the last 5–10 years. The excitement stems in large part from the powerful ability of DUB inhibitors to promote degradation of oncogenic proteins, especially proteins that are challenging to directly target but which are stabilized by DUB family members. Highly optimized and well-characterized DUB inhibitors have thus become highly sought after tools. Most reported DUB inhibitors, however, are polypharmacological agents possessing weak (micromolar) potency toward their primary target, limiting their utility in target validation and mechanism studies. Due to a lack of high-resolution DUB?small-molecule ligand complex structures, no structure-guided optimization efforts have been reported for a mammalian DUB. Here, we report a small-molecule?ubiquitin-specific protease (USP) family DUB co-structure and rapid design of potent and selective inhibitors of USP7 guided by the structure. Interestingly, the compounds are non-covalent active-site inhibitors. Lamberto et al. report the structure-guided development of inhibitors of the deubiquitinating enzyme (DUB) USP7. The studies provide optimized and well-characterized probes for studying USP7 in normal and disease biology and, furthermore, lend validation to the notion that potent and selective active-site inhibitors of DUBs can be achieved.
- Lamberto, Ilaria,Liu, Xiaoxi,Seo, Hyuk-Soo,Schauer, Nathan J.,Iacob, Roxana E.,Hu, Wanyi,Das, Deepika,Mikhailova, Tatiana,Weisberg, Ellen L.,Engen, John R.,Anderson, Kenneth C.,Chauhan, Dharminder,Dhe-Paganon, Sirano,Buhrlage, Sara J.
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Read Online
- The synthesis of a 2-azabicyclo[3.1.0]hexane by rearrangement of a spirocyclic epoxide
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An unusual rearrangement of a 1-oxa-6-azaspiro[2.5]octane derivative giving access to novel 5-substituted 2-azabicyclo[3.1.0]hexanes is described. The synthetic application of the reaction is demonstrated by the synthesis of N-Boc-2,3-methano-β-proline. The amino acid was prepared through a three-step synthesis from easily available reagents in an overall yield of 15%.
- Adamovskyi, Mykhailo I.,Artamonov, Oleksiy S.,Tymtsunik, Andriy V.,Grygorenko, Oleksandr O.
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Read Online
- Synthesis of 5-Acyl-4-methylene-1,2,3,4-Tetrahydropyridines
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Several approaches to monocyclic N-protected 4-methylene-1,2,3,4-Tetrahydropyridines are reported. N-Boc-4-methylenepiperidin-3-one was found to be unstable and its enol triflate was not easily accessible. However, N-protected 2,3-dihydropyridin-4-ones ar
- Longshaw, Alistair I,Thomas, Eric J
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- Design, synthesis, biological evaluation and structure-activity relationship study of quinazolin-4(3H)-one derivatives as novel USP7 inhibitors
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Recent research has indicated that the abnormal expression of the deubiquitinase USP7 induces tumorigenesis via multiple cell pathways, and in particular, the p53-MDM2-USP7 pathway is well understood. USP7 is emerging as a promising target for cancer therapy. However, there are limited reports on USP7 inhibitors. Here we report design, synthesis and biological evaluation of novel quinazolin-4(3H)-one derivatives as potent USP7 inhibitors. Our results indicated that the compounds C9 and C19 exhibited the greatest potency against the USP7 catalytic domain, with IC50 values of 4.86 μM and 1.537 μM, respectively. Ub-AMC assays further confirmed IC50 values of 5.048 μM for C9 and 0.595 μM for C19. MTT assays indicated that gastric cancer MGC-803 cells were more sensitive to these compounds than BGC-823 cells. Flow cytometry analysis revealed that C9 restricted cancer cell growth at the G0/G1 and S phases and inhibited the proliferation and clone formation of MGC-803 cells. Further biochemical experiments indicated that C9 decreased the MDM2 protein level and increased the levels of the tumour suppressors p53 and p21 in a dose-dependent manner. Docking studies predicted that solvent exposure of the side chains of C9 and C19 would uniquely form hydrogen bonds with Met407 of USP7. Additionally, C9 exhibited a remarkable anticancer effect in a zebrafish gastric cancer MGC-803 cell model. Our results demonstrated that quinazolin-4(3H)-one derivatives were suitable as leads for the development of novel USP7 inhibitors and especially for anti-gastric cancer drugs.
- Li, Peng,Liu, Ying,Yang, Hua,Liu, Hong-Min
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- Synthesis of Non-symmetrical Dispiro-1,2,4,5-Tetraoxanes and Dispiro-1,2,4-Trioxanes Catalyzed by Silica Sulfuric Acid
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A novel protocol for the preparation of non-symmetrical 1,2,4,5-tetraoxanes and 1,2,4-trioxanes, promoted by the heterogeneous silica sulfuric acid (SSA) catalyst, is reported. Different ketones react under mild conditions with gem-dihydroperoxides or peroxysilyl alcohols/β-hydroperoxy alcohols to generate the corresponding endoperoxides in good yields. Our mechanistic proposal, assisted by molecular orbital calculations, at the ωB97XD/def2-TZVPP/PCM(DCM)//B3LYP/6-31G(d) level of theory, enhances the role of SSA in the cyclocondensation step. This novel procedure differs from previously reported methods by using readily available and inexpensive reagents, with recyclable properties, thereby establishing a valid alternative approach for the synthesis of new biologically active endoperoxides.
- Amado, Patrícia S. M.,Coelho, Jaime A. S.,Cristiano, Maria L. S.,Frija, Luís M. T.,O'neill, Paul M.
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p. 10608 - 10620
(2021/07/31)
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- IMINO SULFANONE INHIBITORS OF ENPP1
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The present disclosure relates generally to inhibitors of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), compositions thereof, and methods of using said compounds and compositions thereof. More specifically, the present disclosure relates to sulfoximine- based inhibitors of ENPP1 of Formula (I) and methods of their use for treating disease mediated by ENPP1.
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Paragraph 0226
(2021/11/13)
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- Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate
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The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.
- Zhou, Yu,Fu, Yan,Yin, Wanchao,Li, Jian,Wang, Wei,Bai, Fang,Xu, Shengtao,Gong, Qi,Peng, Tao,Hong, Yu,Zhang, Dong,Zhang, Dan,Liu, Qiufeng,Xu, Yechun,Xu, H. Eric,Zhang, Haiyan,Jiang, Hualiang,Liu, Hong
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p. 1844 - 1855
(2021/03/01)
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- Discovery of EST73502, a Dual μ-Opioid Receptor Agonist and σ1Receptor Antagonist Clinical Candidate for the Treatment of Pain
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The synthesis and pharmacological activity of a new series of 4-alkyl-1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the σ1 receptor (σ1R) and the μ-opioid receptor (MOR) are reported. A lead optimization program over the initial 4-aryl analogues provided 4-alkyl derivatives with the desired functionality and good selectivity and ADME profiles. Compound 14u (EST73502) showed MOR agonism and σ1R antagonism and a potent analgesic activity, comparable to the MOR agonist oxycodone in animal models of acute and chronic pain after single and repeated administration. Contrary to oxycodone, 14u produces analgesic activity with reduced opioid-induced relevant adverse events, like intestinal transit inhibition and naloxone-precipitated behavioral signs of opiate withdrawal. These results provide evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics and were the basis for the selection of 14u as a clinical candidate for the treatment of pain.
- García, Mónica,Virgili, Marina,Alonso, Mònica,Alegret, Carles,Farran, Joan,Fernández, Bego?a,Bordas, Magda,Pascual, Rosalia,Burgue?o, Javier,Vidal-Torres, Alba,Fernández De Henestrosa, Antonio R.,Ayet, Eva,Merlos, Manuel,Vela, Jose Miguel,Plata-Salamán, Carlos R.,Almansa, Carmen
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p. 15508 - 15526
(2020/11/17)
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- N-benzylpiperidinol derivatives as novel USP7 inhibitors: Structure–activity relationships and X-ray crystallographic studies
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USP7 as a deubiquitinase plays important roles in regulating the stability of some oncoproteins including MDM2 and DNMT1, and thus represents a potential anticancer target. Through comparative analysis of USP7 co-crystal structures in complex with the rep
- Chen, Caiping,Chen, Hui,Cheng, Keguang,Li, Minglei,Liu, Jun,Liu, Shengjie,Sun, Hongbin,Wang, Yue,Wen, Xiaoan,Xu, Qing-Long,Yuan, Haoliang,Zhou, Jin,Zhou, Shuxi,Zhou, Xinyu
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supporting information
(2020/06/03)
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- 4-Aryl-1-oxa-4,9-diazaspiro[5.5]undecane Derivatives as Dual μ-Opioid Receptor Agonists and σ1 Receptor Antagonists for the Treatment of Pain
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The synthesis and pharmacological activity of a new series of 1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the sigma-1 receptor (σ1R) and the μ-opioid receptor (MOR) are reported. The different positions of the central scaffold, designed using a merging strategy of both target pharmacophores, were explored using a versatile synthetic approach. Phenethyl derivatives in position 9, substituted pyridyl moieties in position 4 and small alkyl groups in position 2 provided the best profiles. One of the best compounds, 15au, showed a balanced dual profile (i.e., MOR agonism and sigma antagonism) and a potent analgesic activity, comparable to the MOR agonist oxycodone in the paw pressure test in mice. Contrary to oxycodone, as expected from the addition of σ1R antagonism, 15au showed local, peripheral activity in this test, which was reversed by the σ1R agonist PRE-084. At equianalgesic doses, 15au showed less constipation than oxycodone, providing evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics.
- García, Mónica,Virgili, Marina,Alonso, Mònica,Alegret, Carles,Fernández, Bego?a,Port, Adriana,Pascual, Rosalía,Monroy, Xavier,Vidal-Torres, Alba,Serafini, María-Teresa,Vela, José Miguel,Almansa, Carmen
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p. 2434 - 2454
(2019/12/25)
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- HYDROXYLATED DERIVATIVES OF 1-OXA-4,9-DIAZASPIRO UNDECANE COMPOUNDS HAVING MULTIMODAL ACTIVITY AGAINST PAIN
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The present invention relates to compounds having dual pharmacological activity towards both the sigma (σ) receptor, and the μ-opioid receptor and more particularly to hydroxylated derivatives of 1-oxa-4,9-diazaspiro undecane compounds having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.
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Page/Page column 97
(2020/08/22)
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- Quinazolinone USP7 inhibitor as well as preparation method and application thereof
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The invention discloses a quinazolinone USP7 inhibitor, which has a structure shown in a general formula I, has a good inhibition effect on ubiquitin-specific protease 7, can be used for preparing a medicine for inhibiting the ubiquitin-specific protease 7, and shows good inhibition activity on a gastric cancer cell line, especially an MGC803 cell line. A lead compound structure is provided for anti-cancer drugs, and the compound has a good application prospect. The invention further provides a preparation method of the quinazolinone USP7 inhibitor. The preparation method is simple, mild in reaction condition, few in by-product, high in reaction yield and convenient for batch production and commercial application.
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Paragraph 0018; 0044-0046
(2020/12/29)
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- COMPOUNDS AND USES THEREOF
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The present invention features compounds useful in the treatment of neurological disorders and primary brain cancer. The compounds of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing neurological disorders and primary brain cancer.
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Page/Page column 166
(2020/08/13)
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- Discovery and Optimization of Non-bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis
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Farnesoid X receptor (FXR) plays a key role in bile acid homeostasis, inflammation, fibrosis, and metabolism of lipid and glucose and becomes a promising therapeutic target for nonalcoholic steatohepatitis (NASH) or other FXR-dependent diseases. The phase III trial results of obeticholic acid demonstrate that the FXR agonists emerge as a promising intervention in patients with NASH and fibrosis, but this bile acid-derived FXR agonist brings severe pruritus and an elevated risk of cardiovascular disease for patients. Herein, we reported our efforts in the discovery of a series of non-bile acid FXR agonists, and 36 compounds were designed and synthesized based on the structure-based drug design and structural optimization strategies. Particularly, compound 42 is a highly potent and selective FXR agonist, along with good pharmacokinetic profiles, high liver distribution, and preferable in vivo efficacy, indicating that it is a potential candidate for the treatment of NASH or other FXR-dependent diseases.
- Li, Junyou,Liu, Mengqi,Li, Yazhou,Sun, Dan-Dan,Shu, Zhihao,Tan, Qian,Guo, Shimeng,Xie, Rongrong,Gao, Lixin,Ru, Hongbo,Zang, Yi,Liu, Hong,Li, Jia,Zhou, Yu
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p. 12748 - 12772
(2020/12/17)
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- DEUTERATED DERIVATIVES OF 9-(2,5-DIFLUOROPHENETHYL)-4-ETHYL-2-METHYL-1-OXA-4,9-DIAZASPIRO[5.5]UNDECAN-3-ONE
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The present invention relates to deuterated derivatives of 9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one having pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions co
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Page/Page column 27
(2019/09/06)
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- NOVEL USP7 INHIBITORS FOR TREATING MULTIPLE MYELOMA
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The present disclosure relates to inhibitors of USP7 useful in the treatment of and other USP7 mediated diseases, having the Formula: wherein R1, R2, R3, R4, R5, R 6, and n are described herein.
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Page/Page column 44; 45
(2019/04/26)
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- Solid dispersions containing an apoptosis-inducing agent
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A pro-apoptotic solid dispersion comprises, in essentially non-crystalline form, a Bcl-2 family protein inhibitory compound of Formula I as defined herein, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier and (b) a pharmaceutically acceptable surfactant. A process for preparing such a solid dispersion comprises dissolving the compound, the polymeric carrier and the surfactant in a suitable solvent, and removing the solvent to provide a solid matrix comprising the polymeric carrier and the surfactant and having the compound dispersed in essentially non-crystalline form therein. The solid dispersion is suitable for oral administration to a subject in need thereof for treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, for example cancer.
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Page/Page column 187
(2019/03/15)
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- Fluorine-containing isoxazole compound as well as preparation method, pharmaceutical composition and application thereof (by machine translation)
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The invention relates to a fluorine-containing isoxazole compound and a preparation method, a pharmaceutical composition and application thereof. In particular, the present invention discloses a I compound represented by formula (I) or an enantiomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a mixture thereof. And discloses that the compound is a small FXR molecule agonist targeting a molecule, and can be used for treating FXR the disease mediated by the disease. (by machine translation)
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Paragraph 0159; 0176-0178
(2019/11/25)
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- A compound for the treatment of tumor (by machine translation)
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Formula (I) indicated by the compound or its pharmaceutically acceptable salt, or solvate thereof: Wherein R1 Is selected from R2 , R3 Are independently selected from H, halogen, alkyl, Or R2 And R3 Connected with a carbon atom containing 1 - 2 heteroatoms 1 substituted or multi-substituted six-membered aromatic heterocycle; R4 , R5 , R6 Are respectively represents a benzene ring on the 0 - 3 substituted, R4 , R5 , R6 Are independently selected from H, halogen atom, C1 - 6 Alkyl, C1 - 6 Alkoxy, hydroxy, amino, carboxyl, nitro, CH3 O (CH2 )n CH2 O -, Wherein n is 1 - 6 of the integer. The present invention provides the compounds in the preparation of a medicament for the treatment of tumor in use. Compound of the present invention the potency is clear. (by machine translation)
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Paragraph 0115; 0118; 0120
(2018/11/22)
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- NON-FUSED TRICYCLIC 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 00510
(2018/11/26)
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- PHARMACEUTICAL COMPOUNDS
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The present invention relates to compounds of Formula (I) that are useful as inhibitors of the activity of the ubiquitin specific protease USP19. The present invention also relates to pharmaceutical compositions comprising these compounds and to methods of using these compounds in therapy.
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Page/Page column 92
(2018/02/28)
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- PIPERIDINE DERIVATIVES AS INHIBITORS OF UBIQUITIN SPECIFIC PROTEASE 7
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The present invention concerns the identification of inhibitors of ubiquitin specific protease 7 (USP7), and methods of use thereof.
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Page/Page column 57; 58
(2018/05/16)
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- Application of novel compound in preparing medicine for treating tumor
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The invention discloses application of a compound as shown in the formula (I), a pharmaceutically acceptable salt or a solvent compound of the compound in preparing a medicine for treating tumor. In the formula, R1 is selected from formulae as shown in the description; R2 and R3 are respectively independently selected from H, halogen, alkyl and a formula as shown in the description; or R2 and R3 form a one-substituted or polysubstituted hexahydric aromatic heterocyclic ring with 1-2 heteroatoms together with carbon atoms connected with R2 and R3; R4, R5 and R6 respectively represent 0-3 substitution on a benzene ring; R4, R5 and R6 are respectively and independently selected from H, halogen atoms, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, amino, carboxyl, nitryl, CH3O(CH2)nCH2O- and a formula as shown in the description; and in the formula, n is an integer of 1-6. The compound disclosed by the invention is definite in medicinal effect when being used for treating tumor.
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Paragraph 0123; 0126-0128
(2018/12/02)
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- NEW (HETERO)ARYL-SUBSTITUTED-PIPERIDINYL DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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Compounds of formula (I):wherein R1, R2, J, K, L, n and W are as defined in the description. Medicaments.
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Page/Page column 56; 57
(2018/05/26)
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- OXADIAZASPIRO COMPOUNDS FOR THE TREATMENT OF DRUG ABUSE AND ADDICTION
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The present invention relates to compounds having pharmacological activity towards the sigma (σ) receptor, and more particularly to oxadiazaspiro compounds having this pharmacological activity, to processes of preparation of such compounds, to pharmaceuti
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Page/Page column 185; 186
(2017/06/12)
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- HIV PROTEASE INHIBITORS
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The present invention is directed to 2,6-morpholine derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein Z1, Z2, V1, V2, V3, R6, R6A, and X are defined herein. The invention also relates to methods of using the 2,6-morpholine derivatives of the invention for the inhibition of HV protease, the inhibition of HV replication, the prophylaxis of infection by HIV, the treatment of infection by HIV, and the prophylaxis, treatment, and delay in the onset or progression of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.
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Paragraph 0475; 0476
(2017/08/26)
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- OXYSTEROLS AND METHODS OF USE THEREOF
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Compounds are provided according to Formula (I), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein A, R1, and R5 are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.
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Paragraph 00136
(2017/10/31)
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- AMIDE COMPOUNDS AS 5-HT4 RECEPTOR AGONISTS
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The present invention relates to compounds of formula (I), including their stereoisomers and pharmaceutically acceptable salts. This invention also relates to methods of making such compounds and pharmaceutical compositions comprising such compounds. The compounds of this invention are useful in the treatment of various disorders that are related to 5-hydroxytryptamine 4 (5-HT4) receptor.
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Page/Page column 34-35
(2016/09/22)
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- SUBSTITUTED BENZAMIDES AND METHODS OF USE THEREOF
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The invention provides compounds having activity as sodium channel (e.g., NaV1.7) inhibitors that are useful for treating sodium channel-mediated diseases or conditions, such as pain, as well as other diseases and conditions associated with the mediation of sodium channels, and compositions containing such compounds and methods for using such compounds and compositions.
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Paragraph 0253;0254; 0255
(2016/12/12)
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- ALKYL AND ARYL DERIVATIVES OF 1-OXA-4,9-DIAZASPIRO UNDECANE COMPOUNDS HAVING MULTIMODAL ACTIVITY AGAINST PAIN
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The present invention relates to compounds of general formula (I) having dual pharmacological activity towards both the sigma (σ) receptor, and the μ-opiod receptor and more particularly to diazaspiro undecane compounds having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.
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Page/Page column 169
(2015/12/30)
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- AMIDE DERIVATIVES OF 1-OXA-4,9-DIAZASPIRO UNDECANE COMPOUNDS HAVING MULTIMODAL ACTIVITY AGAINST PAIN
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The present invention relates to compounds having dual pharmacological activity towards both the sigma (σ) receptor, and the μ-opioid receptor and more particularly to diazaspiro undecane compounds having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain. (formula 1) wherein Y is (formula 2) or (formula 3) ? n is 1 or 2; ? q is 1, 2, 3, 4, 5 or 6; ? X is a bond, -C(O)O-, -C(0)NR 8-, -C(O)-, -0- or -C(R 4R 4.)-; ? R 1is C(0)R 5or S(O) 2R 5.
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Page/Page column 136; 137
(2015/12/30)
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- ALKYL DERIVATIVES OF 1-OXA-4,9-DIAZASPIRO UNDECANE COMPOUNDS HAVING MULTIMODAL ACTIVITY AGAINST PAIN
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The present invention relates to compounds having dual pharmacological activity towards both the sigma (σ) receptor, and the μ-opiod receptor and more particularly to diazaspiro undecane compounds having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.
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Page/Page column 77-78
(2016/02/10)
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- INDAZOLE COMPOUNDS AS 5-HT4 RECEPTOR AGONISTS
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The present invention relates to novel indazole compounds of the Formula (I), wherein, R1 is alkyl or cycloalkyl; (Formula II) including their stereoisomers and their pharmaceutically acceptable salts. This invention also relates to methods of making such compounds and pharmaceutical compositions comprising such compounds. The compounds of this invention are useful in the treatment of various disorders that are related to 5-Hydroxytryptamine 4 (5-HT4) receptor agonists
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Page/Page column 26; 27
(2015/07/07)
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- FLUORINE SUBSTITUTED CYCLIC AMINE COMPOUNDS AND PREPARATION METHODS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
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The present invention relates to the field of pharmaceutical chemistry and pharmacotherapeutics, and in particular to compounds of general formula I, racemates, R-isomers, S-isomers, and pharmaceutically acceptable salts thereof and their mixtures, and the preparation methods thereof and a pharmaceutical composition containing the compounds and uses thereof as an acetylcholine esterase inhibitor.
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Paragraph 0052; 0053
(2015/09/23)
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- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
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Compounds of general formula (I) and compositions comprising compounds of general formula (I) that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.
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Page/Page column 249
(2014/09/29)
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- IMIDAZOLE DERIVATIVES AND METHODS OF USE THEREOF FOR IMPROVING THE PHARMACOKINETICS OF A DRUG
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The present invention relates to Imidazole Derivatives of Formula (I), and pharmaceutically acceptable salts thereof, wherein A, B, Y, R1 and R2 are as defined herein. The present invention also relates to compositions comprising at least one Imidazole Derivative, and and methods of using the Imidazole Derivatives for inhibiting CYP450 3A. Inhibition of CYP450 3A can be used to improve the pharmacokinetics of a drug that is metabolized by CYP450 3A4.
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Page/Page column 90; 91
(2015/01/06)
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- 5-AMINO-QUINOLINE-8-CARBOXAMIDE DERIVATIVES AS 5-HT4 RECEPTOR AGONISTS
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The present invention relates to novel quinoline compounds of formula (I), and their pharmaceutically acceptable salts and process for their preparation. The compounds of formula (I) are useful in the treatment of various disorders that are related to 5-HT4 receptor agonists.
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Page/Page column 31; 32
(2014/10/03)
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- FATTY ACID SYNTHASE INHIBITORS
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This invention relates to novel spirocyclic piperidines according to Formula (I) which are inhibitors of fatty acid synthase (FAS), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the treatment of cancers.
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Page/Page column 56
(2014/01/18)
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- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
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Compounds of general formula (I) and compositions comprising compounds of general formula I that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.
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Page/Page column 163
(2014/09/29)
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- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
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Compounds of general formula I: and compositions comprising compounds of general formula I that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.
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Paragraph 0656; 0657; 0658
(2014/09/30)
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- IMIDAZOLE DERIVATIVES AND METHODS OF USE THEREOF FOR IMPROVING PHARMACOKINETICS OF DRUG
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Imidazole derivatives of formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising at least one imidazole derivative are disclosed. The imidazole derivatives are effective to inhibit CYP450 3A and can be used to improve the pharmacokinetics of a drug that is metabolized by CYP450 3A4.
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Page/Page column 83-84
(2015/01/06)
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- Pyrazolopyrrolidine compounds
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The invention relates to compounds of formula (I) as described herein, pharmaceutical preparations comprising such compounds, uses and methods of use for such compounds in the treatment of a disorder or a disease mediated by the activity of MDM2 and/or MDM4, and combinations comprising such compounds.
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Page/Page column 142
(2013/06/27)
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- FATTY ACID SYNTHASE INHIBITORS
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This invention relates to spirocyclic piperidines according to Formula (I) and the use of spirocyclic piperidines for the modulation, notably the inhibition of the activity or function of fatty acid synthase (FAS). Suitably, the present invention relates to the use of spirocyclic piperidines in the treatment of cancer.
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Page/Page column 48-49
(2013/03/26)
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- FATTY ACID SYNTHASE INHIBITORS
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Disclosed are compounds having Formula (I), or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R5, R6, R7, R8, R8a, R9 Y, and m are defined herein and methods of using the same.
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Page/Page column 39; 40
(2013/04/24)
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- FATTY ACID SYNTHASE INHIBITORS
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Disclosed are compounds having Formula (I), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Y, m, and n are defined herein and methods of using the same.
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Page/Page column 41; 42
(2014/01/07)
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- Selective and reversible inhibitors of ubiquitin specific protease 7
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The present invention relates to compounds of formula (I) their process of preparation and uses thereof. These compounds are useful as selective and reversible inhibitors of ubiquitin specific proteases, particularly USP7, for treating e.g. cancer, neurodegenerative diseases, inflammatory disorders and viral infections.
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Paragraph 0128
(2013/03/26)
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- SELECTIVE AND REVERSIBLE INHIBITORS OF UBIQUITIN SPECIFIC PROTEASE 7
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The present invention relates to quinazolin-4-one compounds of formula (I'), their process of preparation and uses thereof. These compounds are useful as selective and reversible inhibitors of ubiquitin specific proteases, particularly USP7, for treating
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Page/Page column 30; 31
(2013/03/28)
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- IMIDAZO[1,2-a]PYRIDINE DERIVATIVE
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[Problem] To provide a compound useful as medicine having PDE4B inhibitory activity, in particular, as an active ingredient of a composition for treating or preventing schizophrenia, Alzheimer's disease, dementia, depression and the like. [Measures for Solution] The present inventors examined compounds having PDE4B inhibitory activity and found that a tricyclic or tetracyclic imidazo[1,2-a]pyridine derivative or salts thereof had a superior PDE4B inhibitory activity, thereby completing the present invention. The imidazo[1,2-a]pyridine derivative can be used as an agent for treating or preventing schizophrenia, Alzheimer's disease, dementia, depression and the like.
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Paragraph 0075
(2013/03/26)
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- OXASPIRO [2.5] OCTANE DERIVATIVES AND ANALOGS
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The invention provides oxaspiro[2.5]octane derivatives and analogs, methods for preparation thereof, intermediates thereto, pharmaceutical compositions, and uses thereof in the treatment of various disorders and conditions, such as overweight and obesity.
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Page/Page column 98-99
(2012/09/22)
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