Synthetic strategies of pyridazino[4,5-b]indoles

Pyridazino[4,5-b ]indole is an important class of heterocyclic compounds with numerous applications in the field of medicinal chemistry. This review summarizes the synthetic methods of pyridazino[4,5-b ]indoles published during the period from 1962 to 2022. In this review, we have discussed different methods for the synthesis of pyridazino[4,5-b ]indole from various starting materials and the difficulties that scientists faced during the preparation process. We focus on the recent developments in synthetic methods of the pyridazino [4,5-b ]indoles

• Pyridazino [4,5-b]indole ring system has been known for several decades and various biological activity has been reported for a large number of its derivatives.

Introduction
2][3][4] Because of their bioisosterism with γ-and β-carboline, these two heterocyclic compounds have a wide range of uses in medicinal chemistry.
Pyridazino [4,5-b]indole derivatives have therapeutic effects as they act as thromboxane A2 synthetase inhibitors, 5 phosphatidylinositol 3-kinase (PI3K) inhibitors, 6 and they have antimicrobial and antiproliferative effects in different cell types. 7][10][11][12] Moreover, pyridazino [4,5-b]indole derivatives provide powerful therapeutic effects for different diseases related to acute and chronic inflammation, 13 neuroinflammation, and neoplastic progression.Pyridazino [4,5-b]indole-derived drug molecules have been used in the treatment of a number of diseases such as neurological disorders, 15 congestive heart failure (CHF), 16 human immune deficiency virus (HIV-1), 17 arterial hypertension 18 for many years and can be regarded as interesting compounds from a pharmaceutical point of view.Nevertheless, as with other classes of pharmaceutically used compounds, there is continuing interest in the systematic variation of the chemical structure of such agents in order to investigate the possibility of further optimization of their pharmacological and pharmacokinetic profiles as well as discovering new uses.For instance, 1-hydrazino-4-(3,5-dimethyl-1-pyrazolyl)pyridazino [4,5-b]indole (A80a) can be used for treatment of hypertension as a new structural analog of the well-known antihypertensive agents, dihydralazine (Nepresol  ), 19 and hydralazine (Apresoline  ). 20gure 2. Some well-known antihypertensive agents.
Also, Cheung et al. 34 mentioned that, the deprotonation of the commercially available indole 52, with sodium hydride in DMF, followed by treatment with methyl iodide, gave the desired N-methylated intermediate 53.Acylation of 53 at C3 was achieved using TiCl4 and methyl 3-chloro-3-oxopropanoate in dichloroethane at 40 o C for 15 h, which gave keto diester 54.The necessary N,N-dimethylamide moiety at C1 55 was achieved through displacement of the methoxy group of 54 with dimethylamine in toluene and THF in a sealed tube at 110 o C for 15 h.Final condensation with phenylhydrazine (R= phenyl) gave the lead compound 56.To date, this stands as the shortest reported synthesis of this particular TSPO ligand.Diversification at the N3 position of 8 was achieved through condensation of key intermediate 55 with a series of monosubstituted aryl hydrazines (31-50%).The hydrazines chosen focused upon variation of the endogenous N 3 -phenyl ring, with particular attention towards preliminary SAR and functional groups amenable to PET ligand development, namely the presence of a fluorine atom and groups that would facilitate radiolabeling with 18 F through an ipso-type substitution.The groups explored included: a substituted phenyl ring (2-, 3-, 4-positions) (56b-e); a 2-pyridyl ring 56f; a substituted 2-pyridyl ring (56g-h) (Scheme 7).Scheme 7. Condensation of key intermediate 55 with a series of monosubstituted aryl hydrazines.
In a similar fashion, treatment of the hydrazides 58 with aldhydes or ketones in isopropyl alcohol in the presence of HCl effected cyclization into the pyridazinone derivatives 60 in good yield 39 (Scheme 9).

From intramolecular cyclization of (N-methylindole)carbohydrazones.
Intramolecular cyclization of compound 63 in EtOH-HCl and subsequent removal of the ethoxycarbonyl group with NH2NH2 .H2O gave the In 2012, It was reported that, 43 the synthetic pathway to obtain the 5-benzylated compounds is shown in Scheme 13.Key intermediates ethyl indole-2-carboxylates 76, 79, 80 can be prepared by intramolecular cyclization of the corresponding ethyl pyruvate 4-bromophenylhydrazone 78 in polyphosphoric acid (PPA) as a catalyst, according to Fischer's indole synthesis or by esterification of commercially 5-fluoro 77 and 5methoxyindol-2-carboxylic acids 78.Friedel Crafts acylation using aluminium trichloride and acetyl chloride gave indoles 81 and 82 with good yields.Moderate yield obtained for compounds 83 was due to the effect of the electron-donating methoxy group which activates the benzene ring and orients electrophilic attacks in ortho position.Condensation of hydrazine provided 4-oxo-3,4-dihydro-5H-pyridazino [4,5-b]indoles 84-86.Finally, and as expected, treatment of these compounds with sodium hydride and 3-or 4-substituted benzyl bromides afforded the target molecules 87-104.2.5.From 2-acetylindole-3-carboxylic acid.Haider et al. 44 had done a modification on the procedure of preparation of pyridazino [4,5-b]indole 107 which was reported previously by Zhungietu et al. 45 by condensation of 2-acetylindole-3-carboxylic acid 105 with hydrazine hydrate at elevated temperature.This reaction, however, suffers from poorly reproducible yields which reflect the high decarboxylation tendency of the starting material, causing a significant side reaction (formation of 2-acetylindole or its hydrazone, respectively).It could substantially improve this step by first transforming the keto acid 105 into a suitable activated derivative under mild conditions and subsequent treatment of this intermediate with hydrazine hydrate.For this purpose, the imidazolide 107 was found to be a good choice, as it can be easily prepared in an inert solvent at room temperature by treatment of 105 with 1,1'-carbonyldiimidazole (CDI), and without isolation this compound smoothly undergoes hydrazinolysis to afford the pyridazinone 107.Also monosubstituted hydrazines can be employed in the cyclization reaction with 107 to afford the 2-substituted products 108a and 109, although yields are somewhat lower and, in the case of methylhydrazine, formation of small amounts of an isomeric side product 108b was observed (Scheme 14).In 2008, Haider et al. reported that 25 the introduction of the desired alkyl residues at the indole nitrogen is preferentially accomplished before the pyridazinone unit is formed.Thus, the reaction of 2-acetylindole-3carboxylic acid 46 105 with a larger excess of alkylating agent (generally an alkyl iodide, with the exception of benzyl bromide) can be safely employed, effecting N-alkylation and esterification of the carboxylic group at the same time.The resulting ester 112 functionality, in turn, offers the additional advantage of facilitating the subsequent ring-closure reaction with hydrazine, because free carboxylic acids of this type have been known to undergo concurrent decarboxylation very easily. 47Although also this procedure gives only low to moderate yields, the sequence can be carried out very conveniently in a one-pot manner and opens a simple and short In continuation of some previous work, the tautomeric ratio for 1,2,3,4-tetrahydro-1,4-dioxo-5Hpyridazino [4,5-b]indole 123 was investigated. 49Unlike the tautomeric pyridazine-3,6-dione system which has three possible tautomeric forms, 33 the 1,4-dioxygenated pyridazinoindole can exist not only in the dioxo form 123a and the dihydroxy form 123d, but there is also the possibility of two non-equivalent mono-hydroxy mono-oxo forms 123b and 123c.The 5-H and 5-methyl pyridazino [4,5-b]indoles 123 and 124 were prepared by reaction of dimethyl indole-2,3-dicarboxylate 121 49,34 or dimethyl 1-methylindole-2,3-dicarboxylate 122 34,49,50 with hydrazine hydrate in refluxing ethanol or propanol in good yields 49 (Scheme 20).
In 2016, Farghaly et al reported that, 7 an attempts were done to prepare the 4,5-dimethyl-2,5-dihydro-1H-pyridazino [4,5-b]indol-1-one 148 by the reaction of methyl indole-3-carboxylate 144 with methyl iodide in dry DMF in the presence of sodium hydride affords the N-methylated ester 145 in 81% yield.hydrazinolysis of the later compound 145 gave the corresponding hydrazide 146 which was reacted with acetic anhydride at room temperature for 2-3 hours giving the mono acetyl derivative 147 in a good yield (72%).Treatment of 147 with POCl3 under various conditions (at room temperature or at 100 °C for 1-4 hours) did not give the corresponding pyridazinone 148 but afforded the oxadiazole derivative 149 in 77% yield (Scheme 28).
In 2001, Kurumi et al. reported that, 62 treatment of naphthylamine derivatives 167a-d with sodium nitrite in a mixture of AcOH/H2SO4 and sodium azide gave the corresponding 1-azidonaphthalene 168a-d.Consequently compounds 168b-d were used in the next step without further purification.The reactions of compounds 168a-d with dimethyl acetylenedicarboxylate (DMAD) at room temperature for 10 days in the dark afforded the corresponding triazoles 169a-d.These triazoles 169a-d were transformed into the corresponding dimethyl 1H-benz[g]indole-2,3-carboxylates 170a-d via photocyclization using a 500-watt mercury high pressure lamp by the method of Nagawa et al. 63,64 Compounds 170a-d were converted to the corresponding benzopyridazinoindoles 171a-d by reaction with hydrazine hydrate.These reactions proceeded by using a large excess of hydrazine hydrate and heating at reflux (Scheme 33).

Scheme 33. Synthesis of benzopyridazinoindoles 171a-d
In the year 2000, it was found 59 that pyridazino [4,5-b]indoles can be prepared by reaction of aniline with sodium nitrite in a mixture of AcOH/H2SO4 and sodium azide according to Forster et al. 63 This method gave the azido compound 173 which reacted with dimethyl acetylenedicarboxylate (DMAD) to afford the 4,5dicarboxylate derivative 174.This compound was transformed into indole-2,3-dicarboxylate 175 by photocyclization reaction followed by loss of nitrogen. 64Treatment of later compound 175 with hydrazine hydrate afforded the corresponding pyridazinoindole derivative 176 (Scheme 34).

Scheme 9 .
Scheme 9. Treatment of the hydrazides 58 with aldehydes and ketones.