- Hydrazides of clozapine: A new class of D1 dopamine receptor subtype selective antagonists
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Acylated and aroylated hydrazinoclozapines are highly potent dopamine D1 antagonists that show remarkable selectivity over other dopamine receptors. The most potent compound in this series is the 2,6-dimethoxybenzhydrazide 33 with a D1 Ki of 1.6 nM and 212-fold selectivity over D2 receptor.
- Sasikumar,Burnett,Zhang,Smith-Torhan,Fawzi,Lachowicz
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Read Online
- BROAD SPECTRUM GPCR BINDING AGENTS
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Provided herein are broad-spectrum G-Protein coupled receptor (GPCR) binding agents, detectable/isolatable compounds comprising such binding agents (e.g., broad-spectrum GPCR binding agents linked to a functional element and/or solid surface), and methods of use thereof for the detection/isolation of GPCRs.
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Page/Page column 17; 41
(2020/07/04)
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- Clozapine intermediate as well as synthesis method and application thereof (by machine translation)
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The invention discloses a clozapine intermediate and a synthesis method and application thereof, and belongs to the technical field of drug synthesis. The synthesis method comprises 1) synthesis of 2 - [(2 - amino -4 - chlorophenyl) amino] benzoic acid, 2) 8 - chlorine -5, 10 - dihydro - 111111H-dibenzo [b, e] [1, 4]-diazepine -11 - ketone. The synthesis method of the clozapine intermediate is simple in preparation process, recyclable in solvent, easy to operate and control, good in color, good in quality, high in purity and high in yield, can be directly used for production and use, and has good practicability. (by machine translation)
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Paragraph 0022-0024; 0029-0035
(2020/10/14)
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- Synthesis and pharmacological evaluation of 11-(1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-dibenzo[b,e][1,4]diazepines with clozapine-like receptor occupancy at dopamine D1/D2 receptor
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Clozapine-like compound without agranulocytosis risk is need to cure the treatment resistant schizophrenia (TRS). We discovered (S)-3 as Clozapine-like dopamine D2/D1 receptor selectivity and improved reactive metabolites formation profile by the modification of piperazine moiety in Clozapine. The optimization of (S)-3 gave compound 5 to be best compound (approximately 10-fold stronger affinity for D2/D1 receptor and similar D2/D1 selectivity ratio with Clozapine). Clozapine-like D2/D1 receptor occupancy profile was proved by in vivo evaluation. In addition, the reactive metabolites derived agranulocytosis risk of compound 5 was considered to be lower than Clozapine. The pharmacology detail of compound 5 is being investigated to develop it for TRS treatment.
- Watanabe, Hitoshi,Ishida, Kyoji,Yamamoto, Masanori,Horiguchi, Masakuni,Isobe, Yoshiaki
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supporting information
(2020/10/02)
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- Reductive Condensation of a Nitro Group with Carboxylic Acids Promoted by Phosphorus(III) Compounds: A Short Route to 5 H -Dibenzo[ b, e ][1,4]diazepin-11(10 H)-ones
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Tributyl- or triphenylphosphine promotes a one-pot, three-step method for the synthesis of differently substituted dibenzodiazepinones from N -aryl-2-nitroanilines. Pyridine analogues and the corresponding thiazepinones can also be formed using this method. The process involves deoxygenation of the nitro group, then formation of an iminophosphorane intermediate and its intramolecular condensation with a carboxyl group placed in the N -aryl group. The role of the carboxyl group in the formation of the iminophosphorane and the mode of cyclization are discussed.
- Tryniszewski, Micha?,Bujok, Robert,Gańczarczyk, Roman,Wróbel, Zbigniew
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p. 3086 - 3094
(2020/08/10)
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- NOVEL and IMPROVED SYNTHESIS OF ANTIPSYCHOTIC DRUG
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The present invention relates to novel as well as improved process for the preparation of Clozapine of Formula I which involves anti-narcotic and highly cost effective raw materials.
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Page/Page column 18
(2020/01/08)
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- Method for preparing clozapine intermediate
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The invention discloses a method for preparing a clozapine intermediate. The method comprises the following steps: (a) dissolving NCNA (N-(4-Chlorine-2-Nitrobenzophenone) o-aminobenzoic acid) sylviteinto water so as to obtain an NCNA sylvite solution; (b) sequentially putting ferric trichloride and activated carbon into the NCNA sylvite solution, uniformly mixing so as to obtain a mixed solution,and adjusting the pH value of the mixed solution to 9-12 by using an alkali solution; (c) heating the mixed solution, dropping a hydrazine hydrate solution into the mixed solution till the mixed solution is completely decolored, heating and filtering for another time, and collecting filtrate; (d) tittering the filtrate till the pH value is 3-5 by using dilute sulfuric acid, and collecting a separated solid; (e) backflowing the solid with the dilute sulfuric acid, thereby obtaining 8-chlorine-5,10-dihydro-11H-dibenzo [b,e] [1,4]-diazepine-11-ketone. By adopting the method disclosed by the invention, introduction of an organic solvent is avoided, production at normal pressure can be achieved, the production security is high, the production cost is low, and in addition, the method is high inyield and small in impurity.
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Sheet 0026; 0027; 0028; 0029; 0030-0070
(2019/05/08)
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- Palladium-catalysed regioselective: N -arylation of anthranilamides: A tandem route for dibenzodiazepinone synthesis
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A palladium-catalyzed domino approach to the synthesis of 10,11-dihydro-5H-dibenzo[b,e][1,4]diazepinones from 2-aminobenzamides and 1,2-dihaloarenes has been developed. Our strategy integrating double N-arylations (inter- and intra-molecular) of 2-aminobenzamides with 1,2-dihaloarenes under palladium-catalyzed conditions is clearly distinct from the current literature available for the synthesis of dibenzodiazepinones. Unlike a previous report described for regioselective N-arylation of 2-aminobenzamide at the amine group, our mechanistic studies support the regioselective N-arylation of 2-aminobenzamide occurring first primarily at the amide group. The translational application of our protocol may be demonstrated in the synthesis of a marketed drug, clozapine.
- Laha, Joydev K.,Manral, Neelam,Hunjan, Mandeep Kaur
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p. 7339 - 7343
(2019/05/24)
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- Synthetic method of key intermediate for preparing clozapine
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The invention discloses a synthetic method of a key intermediate for preparing clozapine, and belongs to the field of drug synthesis. The method comprises the step that 2-((2-amino-4-chlorphenyl)amino)benzoic acid is taken as a raw material to be cyclized under backflow of a sulfuric acid water solution, and 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]-dinitro-11-ketone. The formula is shown in thedescription. The synthetic method utilizes the sulfuric acid water solution to conduct cyclization, and overcomes the multiple defects in the prior art, the reaction is simple, convenient and rapid,the impurities introduced by the raw material can be effectively removed, the product with the higher purity is obtained, and the waste liquid is easy to treat. Meanwhile, increasing cost and environmental pollution caused by using of other solvents are avoided, and the synthetic method has the good industrialized prospect.
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Paragraph 0026; 0027; 0029; 0033; 0034
(2018/12/13)
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- Methods for Treating Cognitive Disorders Using Inhibitors of Histone Deacetylase
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This disclosure relates to compounds for the inhibition of histone deacetylase and treatment of a cognitive disorder or deficit. More particularly, the disclosure provides for compounds of formula (I) wherein Q, J, L and Z are as defined in the specification.
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Paragraph 0407
(2017/01/23)
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- Method for preparing key intermediate of clozapine
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The invention discloses a method for preparing a key intermediate of clozapine. According to the method, 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]-diazepine-11-one is obtained by performing a rearrangement reaction on 1,3-dihydro-5-chloro-1-phenyl-2H-benzimidazole-2-one serving as a starting material under the action of an acid catalyst. The method has the positive progresses and effects that a novel method for synthesizing the 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]-diazepine-11-one is provided; the method is simple in step; the acid catalyst is a solvent, and is also a catalyst; the raw material, namely, the 1,3-dihydro-5-chloro-1-phenyl-2H-benzimidazole-2-one can react completely to increase the output; in the reaction, the used dichloromethane and a toluene solvent can be recycled for use; the after-treatment is easy to operate; the yield can reach 88 percent or higher; the synthesis method provides a new idea and a new method for large-scale production of the key intermediate of the clozapine.
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Paragraph 0020; 0021; 0022; 0023; 0024; 0025; 0026-0051
(2017/08/25)
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- Key clozapine intermediate synthesis method
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The invention discloses a key clozapine intermediate synthesis method and belongs to the field of drug synthesis. The key clozapine intermediate synthesis method comprises the steps that N-(2-halogenated-5-chlorphenyl) amino formic acid and aniline are used as starting raw materials, the aniline serves as a solvent, and 8-chlorine-5,10-dihydro-11H-dibenzo [b,e][1,4]-dinitrogen(shown in the description)-11-ketone is obtained through reaction under the effects of a catalyst and alkali. The key clozapine intermediate synthesis method has the positive and progressive advantages that the novel method for synthesis of the 8-chlorine-5,10-dihydro-11H-dibenzo [b,e][1,4]-dinitrogen(shown in the description)-11-ketone overcome lots of shortcomings in the prior art, adopts simple steps and only needs one-step reaction, the yield is up to 90% or above; the aniline is a reaction solvent and is also a raw material, can not only make reaction of the raw material (2-halogenated-3-pyridyl) carbamic acid complete, but also increase the yield of reaction, cost increase and environmental pollution brought by usage of other solvents are further avoided, the excessive aniline can be continuously used after being poste-treated and evaporated out, the cost is greatly saved, the environment is protected, and the key clozapine intermediate synthesis method has a good industrialized prospect.
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Paragraph 0030; 0031; 0032
(2017/04/18)
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- The first structure-activity relationship studies for designer receptors exclusively activated by designer drugs
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Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand-receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by clozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure-activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10000-fold selectivity for hM3Dq over hM3.
- Chen, Xin,Choo, Hyunah,Huang, Xi-Ping,Yang, Xiaobao,Stone, Orrin,Roth, Bryan L.,Jin, Jian
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p. 476 - 484
(2015/03/30)
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- Design, synthesis and anticancer activity evaluation of diazepinomicin derivatives
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A series of diazepinomicin derivatives were synthesized and evaluated in vitro for their growth inhibitory activity against the human carcinoma cell lines. The results indicated the anticancer selectivity of this kind of compounds. Based on the results, preliminary structure-activity relationships were discussed.
- Yu, Yongguo,Wu, Jianbo,Lei, Fan,Chen, Lei,Wan, Weili,Hai, Li,Guan, Mei,Wu, Yong
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p. 369 - 373
(2013/07/26)
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- A one-pot transition-metal-free tandem process to 1,4-benzodiazepine scaffolds
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An efficient and practical method for the synthesis of 1,4-benzodiazepines is reported. This methodology offers a transition-metal-free tandem process in one pot. This process is applicable to the construction of a wide variety of 1,4-benzodiazepines and other tricyclic systems with high potential biological and pharmacological activities. Georg Thieme Verlag Stuttgart · New York.
- Li, Yanqiu,Zhan, Chunjing,Yang, Bingchuan,Cao, Xiaoqun,Ma, Chen
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p. 111 - 117
(2013/03/13)
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- COMPOUNDS WITH 7-MEMBER CYCLE AND THE PHARMACEUTICAL USE THEREOF FOR PREVENTING AND TREATING DIABETES AND METABOLISM SYNDROME
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The invention discloses a new use of a class of heptacyclic compounds in the preparation of formulations for the prevention and treatment of diabetes and metabolic syndromes; the present invention also discloses a new class of heptacyclic compounds; the present invention also discloses a process for preparing the heptacyclic compounds and a composition containing the same. The heptacyclic compounds of the present invention can be used to effectively preventing or treating diseases such as diabetes and metabolic syndromes.
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Page/Page column 35
(2010/07/06)
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- INHIBITORS OF HISTONE DEACETYLASE
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Compounds which are histone deacetylase inhibitors and their use in treating various disorders, including Alzheimer's Disease.
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Page/Page column 64
(2010/01/29)
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- INHIBITORS OF HISTONE DEACETYLASE
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This invention relates to compounds for the inhibition of histone deacetylase. More particularly, the inven- tion provides for compounds of formula (I) wherein (B), Q, J, L and Z are as defined in the specification
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Page/Page column 105-106
(2008/12/07)
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- NON-STEROIDAL PROGESTERONE RECEPTOR MODULATORS
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The present invention provides compounds according to general Formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a prodrug thereof. More particularly, the present invention provides high affinity non-steroidal compounds which are agonists, partial agonists or antagonists of the progesterone receptor.
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Page/Page column 18; 65
(2010/02/07)
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- Synthesis and preliminary pharmacological evaluation of 4′-arylmethyl analogues of clozapine. I - The effect of aromatic substituents
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As part of a research program to develop compounds with mixed dopamine D4 and serotonin 5-HT2A antagonist activity with potential for the treatment of schizophrenia, we report a family of compounds based on structural modification of the atypical antipsychotic, clozapine (2). The chemical synthesis, structural characterization and pharmacological evaluation of a series 4′-arylmethyl analogues of clozapine are described. Preliminary receptor binding data are presented, examining primarily the electronic and positional effects of substituents on the introduced arylmethyl group, and secondarily the nature of the aryl ring.
- Capuano, Ben,Crosby, Ian T.,Lloyd, Edward J.,Taylor, David A.
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p. 565 - 576
(2007/10/03)
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- Dibenzodiazepines
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This invention provides dibenzodiazepines represented by the formula STR1 wherein R is STR2 The compounds of this invention are useful as antischizophrenics.
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