Conformationally restricted tricyclic antidepressants. 1. Octahydrodibenzazepinonaphthyridines as rigid imipramine analogs

Martin, Arnold R.; Paradkar, Vidyadhar M.; Peng, Geoffrey W.; Speth, Robert C.; Yamamura, Henry I.; Horn, Alan S.

doi:10.1021/jm00182a011

Cited by 17 publications

(3 citation statements)

References 11 publications

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“…Alternatively, crotonic acid was converted to trimethylsilyl 4-bromocrotonate and then treated with oxalyl chloride to yield 4-bromocrotonyl chloride. Compounds 2 , 17 , and 18 were synthesized by treatment of 6 with the corresponding commercially available acyl chlorides, whereas compounds 19 and 20 were prepared by reacting 6 with 4-methoxycrotonyl chloride and N -methyl-1,2,5,6-tetrahydronicotinyl chloride hydrochloride, respectively. 2-(4-Morpholinylmethyl)acrylamide 23 was prepared by coupling 6 with the mixed anhydride 22 , which was made from 2-(4-morpholinylmethyl)acrylic acid 21, as shown in Scheme .…”

Section: Chemistrymentioning

confidence: 99%

6-Substituted-4-(3-bromophenylamino)quinazolines as Putative Irreversible Inhibitors of the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor (HER-2) Tyrosine Kinases with Enhanced Antitumor Activity

Tsou¹,

Mamuya²,

Johnson³

et al. 2001

J. Med. Chem.

258

212

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A series of new 6-substituted-4-(3-bromophenylamino)quinazoline derivatives that may function as irreversible inhibitors of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases have been prepared. These inhibitors have, at the C-6 position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(3-bromophenylamino)quinazoline with unsaturated acid chlorides or mixed anhydrides. We show that attaching a basic functional group onto the Michael acceptor results in greater reactivity, due to intramolecular catalysis of the Michael addition and/or an inductive effect of the protonated basic group. This, along with improved water solubility, results in compounds with enhanced biological properties. We present molecular modeling and experimental evidence that these inhibitors interact covalently with the target enzymes. One compound, 16a, was shown to have excellent oral activity in a human epidermoid carcinoma (A431) xenograft model in nude mice.

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Section: Chemistrymentioning

confidence: 99%

6-Substituted-4-(3-bromophenylamino)quinazolines as Putative Irreversible Inhibitors of the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor (HER-2) Tyrosine Kinases with Enhanced Antitumor Activity

Tsou¹,

Mamuya²,

Johnson³

et al. 2001

J. Med. Chem.

258

212

View full text Add to dashboard Cite

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“…An optimal bridge seems to be obtained in either the phenothiazine 21 or the 10,11-dihydro-5H-dibenz[ b , f ]azepine 23 . In these two ring systems the fold angles between the two planes of the benzo rings , may be optimal in order to fulfill the out-of-plane geometry of the two aryl groups as previously described for other potent GABA uptake inhibitors. ,, It is evident from the data in Table that the most successful exchanges are those performed on the diphenylamino derivative 10 . All the transformations performed from the other parent compounds 4, 7 − 9 , and 11 , which all contain a carbon atom between the aryl groups and which connect the tricycle to the chain, lead to a major decrease in GABA uptake inhibition.…”

Section: Biological Results and Discussionmentioning

confidence: 99%

“…An optimal bridge seems to be obtained in either the phenothiazine 21 or the 10,11dihydro-5H-dibenz[b,f]azepine 23. In these two ring systems the fold angles between the two planes of the benzo rings 79,80 may be optimal in order to fulfill the out-of-plane geometry of the two aryl groups as previ- ously described for other potent GABA uptake inhibitors. 1,42,48 It is evident from the data in Table 1 that the most successful exchanges are those performed on the diphenylamino derivative 10.…”

Section: Biological Results and Discussionmentioning

confidence: 99%

Synthesis of Novel γ-Aminobutyric Acid (GABA) Uptake Inhibitors. 5. Preparation and Structure−Activity Studies of Tricyclic Analogues of Known GABA Uptake Inhibitors

et al. 2001

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On the basis of the SAR of a series of known gamma-aminobutyric acid (GABA) uptake inhibitors, including 4 (SKF 89976), new tricyclic analogues have been prepared. These novel compounds are derivatives of nipecotic acid, guvacine, and homo-beta-proline, substituted at the nitrogen of these amino acids by various lipophilic moieties such as (10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)alkoxyalkyl or (10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)alkoxyalkyl. The in vitro values for inhibition of [(3)H]-GABA uptake in rat synaptosomes was determined for each compound in this new series, and it was found that several of the novel compounds showed a high potency comparable with that of the reference compounds 4, 5 (tiagabine), and 6 (CI-966). Several of the novel compounds were also evaluated for their ability in vivo to inhibit clonic seizures induced by a 15 mg/kg (ip) dose of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). One compound, (R)-1-(2-(2-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid (23), was selected for further biological investigations and showed a protective index comparable to or slightly better than that of the recently launched anticonvulsant product 5 ((R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid).

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Reaction of Vinyl Aziridines with Arynes: Synthesis of Benzazepines and Branched Allyl Fluorides

Kaldas

Kran

Mück‐Lichtenfeld

et al. 2020

Chemistry A European J

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We report the cycloaddition betweenv inyl aziridines and arynes. Depending on the reactionc onditions and the choice of the aryne precursor,t he aziridinium intermediate can be trapped through two distinct mechanistic pathways. The first one proceeds through af ormal [5+ +2] cycloaddition to furnish valuable multi-substituted benzazepines. In the second pathway,t he aziridinium is interceptedb yafluoride ion to afford allylic fluoridesi n good yields. Both reactions proceed stereospecifically and furnish enantiopure benzazepines and allylic fluorides.The ongoing resurgencei na ryne chemistry can be attributed to the development of modern methodologies that enable the efficient generation of arynesins itu under mild reaction conditions. [1] This advancementh as allowed the scope of aryne chemistry to expand significantly into the areaso ft ransitionmetal catalysis and multicomponent reactions, among others. [2] Amination reactions are an area in which aryne chemistry has been particularly successful. As ar esult,a minations of arynes have found great utility in the total synthesis of alkaloids. [3] As ap art of our ongoing programs in aryne chemistry [4] and the synthesis of aza-heterocycles from aziridines, [5] we werei nterested in exploringt he reactivity of vinyl aziridines toward arynes. We envisioned that the [5+ +2] cycloaddition between an aryne and av inyl aziridine couldp roceed through af ormal cycloaddition [6] reactiont of urnish valuableb enzazepines (Figure 1a). [7] The 7-membered aza-heterocyclei sa ni mportant scaffold in medicinal chemistrya nd is found in aw ider ange of bioactive compounds, [8] naturalp roducts, [9] dipeptide mimics, [10] and dyes [11] (Figure 1b). Due to the importance of this class of heterocycle, several methods have been developed for the synthesis of this and similarscaffolds. [12] We initiated our study by screening differentc onditions for benzyne generation in the presence of 1-benzyl-2-vinyl aziridine (2a)a samodel vinyl aziridine (Scheme 1). Utilizing the conditions developed by Kobayashi, [13] we only observed trace amountso ft he desired benzazepine 3a.H owever,w eo bserved the formationo fa llylic fluoride 6a,w hich is most likely formed from an attack of the fluoridea nion onto the internal allylic positiono ft he electrophilic aziridinium cation.T his led us to screen methods for fluoride-free aryne generation. Utilizing the aryne precursor 1b and iPrMgCl·LiCl, [14] only 2a was recovered.I th as been reported that magnesiated 1b is highly reactive and decomposest ot he aryne at À78 8C, presumably before nucleophilic attack of 2a.W ew ere pleasedt os ee that by utilizing the same conditions, but switching to the more stable aryne precursor 1c, [15] we werea ble to observe the formation of benzazepine 3a in an encouraging 45 %y ield. [16] After this initial hit, further optimization of the annulation reaction was performed (Table 1). Switching the solventf rom Et 2 OtoT HF hadadeleterious effect (34 %, entry 1). Exchanging Figure 1. (a) Reactionofv inyl ...

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Conformationally restricted tricyclic antidepressants. 1. Octahydrodibenzazepinonaphthyridines as rigid imipramine analogs

Cited by 17 publications

References 11 publications

6-Substituted-4-(3-bromophenylamino)quinazolines as Putative Irreversible Inhibitors of the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor (HER-2) Tyrosine Kinases with Enhanced Antitumor Activity

6-Substituted-4-(3-bromophenylamino)quinazolines as Putative Irreversible Inhibitors of the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor (HER-2) Tyrosine Kinases with Enhanced Antitumor Activity

Synthesis of Novel γ-Aminobutyric Acid (GABA) Uptake Inhibitors. 5. Preparation and Structure−Activity Studies of Tricyclic Analogues of Known GABA Uptake Inhibitors

Reaction of Vinyl Aziridines with Arynes: Synthesis of Benzazepines and Branched Allyl Fluorides

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