5814-41-5

A series of thirteen 5H-dibenzo [b,e][1,4]diazepin-11(10H)-one structural derivatives has been synthesized and evaluated for anti-proliferative activity against five human cancer cell lines. Compound 9a exhibited potent tumour growth inhibition in all cel

Despite the structural similarity with imines, α-iminocarboxylic acids have seldom been used in heterocycles synthesis. The reactions of ortho-substituted anilines and arylglyoxylic acids in DMSO at 40 °C gave various benzo-fused five- to six-membered N-heterocycles in good to excellent yields. The reaction proceeds via intramolecular Michael addition of α-iminocarboxylic acids, generated in situ, with an ortho-substituted nucleophile, yielding an isolable unprecedented tetrahedral carboxylic acids, which upon decarboxylation without any aid of additional reagents forms the N-heterocycles. DMSO is crucial in this reaction, perhaps because of improved solubility and the ease of decarboxylation of these tetrahedral carboxylic acids. However, a copper-catalyzed reaction of ortho-substituted anilines and 2-bromoarylglyoxylic acids gave a dibenzo-fused seven-membered N-heterocycle under a basic reaction condition. Unlike intramolecular cyclization with α-iminocarboxylic acids in the first case, α-iminocarboxylic acid undergoes a competitive decarboxylation under the copper-catalyzed conditions, which upon subsequent heteroarylation form the heterocycles. Taken together, the study described herein represents two different modes of decarboxylation observed with α-iminocarboxylic acids, leading to the synthesis of divergent heterocycles and pharmaceuticals, which remained unexplored previously.

The present invention discloses a receptor inhibitor of formula (I), a composition comprising the same and the usage thereof.

Abstract: A series of dibenzodiazepine 2-position derivatives, bearing N-methylpiperazine at the C-11 position, were prepared by using a concise approach. Their inhibitory activities of tumor cell proliferation in vitro were tested in five cell lines, including breast cancer cell BCAP37, gastric cancer cell SGC7901, liver cancer cell HepG2, cervical cancer cell HeLa and acute promyelocytic leukemia cell HL-60. Several compounds showed efficient tumor activity with IC50 values down to 0.30?μM. These compounds are expected to be a new class of potential anticancer lead compounds. Graphic abstract: [Figure not available: see fulltext.]

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.

The 18 kDa translocator protein (TSPO) is a target for the development of imaging agents to detect neuroinflammation. The clinical utility of second-generation TSPO ligands has been hindered by the presence of a polymorphism, rs6971, which causes a non-co

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.

The invention discloses a dibenzodiazepine*ketone derivative with anti-tumor activity and a preparation method and application of the dibenzodiazepine*ketone derivative and belongs to the technical field of medicine compounds with anti-tumor activity. Acc

The invention discloses a dibenzozepine compound and a preparation method and application thereof. The structure of the dibenzozepine compound is as shown in the general formula 1 or general formula 2, wherein R1 is selected from methyl, hydrogen, chlorin

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.

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.

A series of new dibenzodiazepinone-type muscarinic receptor ligands, including two homo-dimeric compounds, was prepared. Sixteen representative compounds were characterized in equilibrium binding studies with [3H]N-methylscopolamine ([3H]NMS) at the muscarinic receptor subtype M2, and seven selected compounds were additionally investigated at M1, M3, M4 and M5 with respect to receptor subtype selectivity. The side chain of the known M2 preferring muscarinic receptor antagonist DIBA was widely varied with respect to chain length and type of the basic group (amine, imidazole, guanidine and piperazine). Most of the structural changes were well tolerated with respect to muscarinic receptor binding, determined by displacement of [3H]NMS. Compounds investigated at all subtypes shared a similar selectivity profile, which can be summarized as M2 > M1 ≈ M4 > M3 ≈ M5 (46, 50, 57, 62-64) and M2 > M1 ≈ M4 > M3 > M5 (1, 58). The homo-dimeric dibenzodiazepinone derivatives UNSW-MK250 (63) and UNSW-MK262 (64) exhibited the highest M2 receptor affinities (pIC50 = 9.0 and 9.2, respectively). At the M2 receptor a steep curve slope of -2 was found for the dimeric ligand 63, which cannot be described according to the law of mass action, suggesting a more complex mechanism of binding. In addition to equilibrium binding studies, for selected ligands, we determined pEC50,diss, an estimate of affinity to the allosteric site of M2 receptors occupied with [3H]NMS. Compounds 58 and 62-64 were capable of retarding [3H]NMS dissociation by a factor >10 (Emax,diss >92%), with highest potency (pEC50,diss = 5.56) residing in the dimeric compound 64. As the monomeric counterpart of 64 was 100 times less potent (62: pEC50,diss = 3.59), these data suggest that chemical dimerization of dibenzodiazepinone-type M receptor ligands can enhance allosteric binding.

A novel tandem oxidative conversion of 10,11-dihydro-5H-dibenzo[b,e][1,4]diazepines to phenazines has been achieved under transition-metal-free, mild conditions using K2S2O8 or DDQ as the oxidizing agent. The transformation proceeds through oxidative removal of a benzylic methylene group by C-C and C-N bond cleavage followed by a new aryl C-N bond formation under radical conditions.

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.

A general and highly efficient protocol for the synthesis of dibenzodiazepines and their structural analogues is reported. In the presence of catalytic quantities of palladium, readily accessible precursors are cross-coupled with ammonia and then spontaneously undergo an intramolecular condensation to form the corresponding dibenzodiazepines in one step. This new strategy is applicable to the construction of a wide variety of dibenzooxazepines and other structurally related heterocycles.

An effective protocol for the synthesis of potentially bioactive benzo[e]chromeno[6,5-b][1,4]diazepine-3,8(7H,13H)-dione and dibenzo[b,e][1,4] diazepin-11(10H)-one derivatives in good to excellent yields has been achieved by CuI/l-Proline catalyzed coupling reaction as the key step. The methodology offers clean reaction conditions and easy isolation of the products in 61-92% yields.

A synthesis of 11-(piperazin-1yl)-5H-dibenzo[b,e][1,4]diazepine on kilo scale without any chromatographic purification step is reported. Key steps involved are Ullmann condensation, catalytic hydrogenation, and catalyzed cyclization. Copyright E-Journal o

The present invention provides one step processes for the preparation of substituted dibenzo[b,e][1,4]-diazepine-11-ones by the reaction of substituted isatoic anhydrides with substituted 1,2-phenylenediamines in the presence of aqueous acetic acid.

Compounds which are histone deacetylase inhibitors and their use in treating various disorders, including Alzheimer's Disease.

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

New N-hydroxyamides of n-alkyl carboxylic acids omega substituted with suitable tricyclic systems characterised by a central 7-membered ring, having activity as inhibitors of histone deacetylase (HDAC).

Disclosed is a process for preparing a compound of formula A - N=C(D)(B), from a compound of formula A-N=C(E)(B) and a compound of formula D-M using an iron catalyst, where the process has is represented by Equation (I).

Disclosed herein is the use of N-desmethylclozapine (NDMC) and related compounds to treat a variety of neuropsychiatric diseases including psychosis. It is shown that NDMC and related compounds are agonists or partial agonists at D2 and D3 dopamine receptors and thus may be effective as a dopamine stabilizing agent, allowing it to be used to treat or provide reduced incidence of Extrapyramidal symptoms (EPS) and/or tardive dyskinesias (TD). Also disclosed is administering NDMC and related compounds in combination with other anti-psychotic agents.

Efficient syntheses of dibenz[b,f][1,4]oxazepin-11(10H)-one, 5,10-dihydro-11H-dibenzo[b,e][1,4]-diazepin-11-one and 5,11-dihydro-6H-dibenz[b, e]azepin-6-one are described using a tandem reduction-lactamization sequence. Precursors for these ring systems are available in 1-3 steps using nucleophilic aromatic substitution and Ullmann coupling methodology. Direct reduction-lactamization of these compounds using iron powder in acetic acid at 115° affords the target heterocycles in ≥90% yield.

New N-hydroxyamides of n-alkyl carboxylic acids omega substituted with suitable tricyclic systems characterised by a central 7-membered ring, having activity as inhibitors of histone deacetylase (HDAC).

Disclosed herein are analogs of clozapine and pharmaceutically acceptable salts, esters, amides, or prodrugs thereof; methods of synthesizing the analogs; and methods of using the analogs for treating neuorpsychiatric disorders. In some embodiments, the analogs are amino substituted diaryl[a,d]cycloheptenes.

A compound having a general formula (II) wherein R1is saturated or unsaturated alkyl, amino-alcohol, diamino, cycloalkyl, and C(═O)(CH2)nNR′R″, (CH2)nCHOHCH2NR′R″, wherein n is an integer, RQ, RT, R′, and R″ are each independently a hydrogen, halogen, hydroxyl, saturated, unsaturated, aliphatic, or branched alkyl, substituted or unsubstituted (CH2)m-(hetero)aryl, and sulfonylamide; q and r are each an integer independently selected from 1-4; and pharmaceutically acceptable salts thereof, and the new therapeutic uses thereof and similar compounds as defibrillating, and/or anti-fibrillatory, and/or anti-arrhythmic and/or anti-ischemic drugs.

Novel tricyclic benzazepine derivatives were synthesized as arginine vasopressin (AVP) antagonists. Several tricyclic compounds showed potent antagonistic activity in rat AVP receptors V1a and V2. Derivatives containing pyrrolo-tricy

Novel dibenzoazepine and 11-oxo-dibenzodiazepine derivatives are shown to be effective ventricular defibrillating drug candidates. They exhibit significant in vivo defibrillatory activity with no observed changes in ECG either before or after the VF event. These compounds also exhibit antifibrillatory activity by elevating the fibrillation threshold potential, all suggesting that such drugs could be used to treat VF either by themselves or together with electrical defibrillators.

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Some fluoro- and iodo-derivative of 5-[[4-[(4-diisobutylamino)butyl]-1- phenyl]acetyl]-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11-one and 11-[[4- [(dialkylamino)butyl]-1-phenyl]acetyl]-5,11-dihydro-6H-pyrido[2,3- b][1,4]benzodiazepin-6-ones 6 (Scheme 1) and their analogues were synthesized. The synthesis of dibenzodiazepinones 1 (Scheme 1) is based on the reaction between 1,4-phenylenediamine and substituted benzoic acids. The intermediate pyridobenzodiazepinones 3 (Scheme 1) were prepared by condensation of 2-chloro-3-aminopyridine with methyl anthranilate and its chlorine derivative. The condensation of 4-[(halo)alkyl]phenylacetyl chloride with dibenzodiazepinones and pyridobenzodiazepinones followed by the reaction of mono- or dialkyl- or dialkenylamine provides 6 (Scheme 1).

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The preparation of sixteen novel substituted [(10-N-methyl) and (12-N-methyl)]-11-(o-, and p-substituted-anilino)-5H-dibenzo[b,e][1,4]diazepines which have potentially useful pharmacological properties is described. The structure and the isomeric differen

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The pyrrolobenzodiazepine and dibenzodiazepine skeletons were rapidly generated from salicylic acids.The key step in these syntheses was the substitution of an aryl triflate.

A series of 5-[[[(dialkylamino)alkyl]-1-piperidinyl]acetyl]-10,11-dihydro- 5H-dibenzo[b,e][1,4]-diazepin-11-ones were prepared as potential M2- selective ligands. The compounds were evaluated for their affinity and selectivity for the muscarinic cholinergic receptor. The best M2-selective antimuscarinic agent studied is 5-[[4-[4-(diethylamino)butyl]-1- piperidinyl]acetyl]-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11-one, which is approximately 10 times more potent at M2 receptors than previously known compounds such as 11-[[4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl]-5,11- dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (AQ-RA 741).

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11-Oxo (IIa-c) and 11,11-diphenyl (IVa-c) derivatives of dibenzothiazepine, dibenzooxazepine and dibenzodiazepine have been prepared by treating the lithiated intermediates with carbon dioxide and benzophenone respectively.