Synthesis and Biological Activity of 3-Substituted 1H-Spiro[Benzo[ h ]-Quinazoline-5,1 ' -Cycloheptane]-2,4(3 H ,6 H )-D
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Pharmaceutical Chemistry Journal, Vol. 54, No. 5, August, 2020 (Russian Original Vol. 54, No. 5, May, 2020)
SYNTHESIS AND BIOLOGICAL ACTIVITY OF 3-SUBSTITUTED 1H-SPIRO[BENZO[h ]QUINAZOLINE-5,1¢-CYCLOHEPTANE]-2,4(3H,6H)-DIONES A. I. Markosyan,1,* A. S. Ayvazyan,1 S. H. Gabrielyan,1 S. S. Mamyan,1 F. H. Arsenyan,1 R. E. Muradyan,1 and J. A. Avakimyan1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 5, pp. 21 – 25, May, 2020.
Original article submitted March 16, 2020. A method for the synthesis of ethyl 4¢-(phenoxycarbonylamino)-1¢H-spiro[cycloheptane-1,2¢-naphthalene]-3¢-carboxylate from ethyl 4¢-amino-1¢H-spiro[cycloheptane-1,2¢-naphthalene]-3¢-carboxylate (aminoester) was developed. Reaction of the former with primary amines produced 3-substituted 1H-spiro[benzo[h ]quinazoline-5,1¢-cycloheptane]-2,4(3H,6H)-diones. Condensation of the aminoester with m-chlorophenylisocyanate synthesized ethyl 4¢-{[(3-chlorophenyl)carbamoyl]imino}-3¢,4¢-dihydro-1¢H-spiro(cycloheptane1,2¢-naphthalene)-3¢-carboxylate, which cyclized into 3-(3-chlorophenyl)-1H-spiro[benzo[h ]quinazoline5,1¢-cycloheptane]-2,4(3H,6H)-dione. The synthesized compounds were shown to possess antitumor and anti-monoamine oxidase activities. Keywords: aminoester, carbamate, benzo[h ]quinazoline, antitumor, antibacterial, anti-monoamine oxidase activity.
Benzo[h ]quinazolines have been reported to exhibit valuable biological properties [1 – 7]. Our previous research on the synthesis and biological properties of spirocyclic benzo[h ]quinazolines showed that they possessed antitumor, antibacterial, anti-monoamine oxidase, and anticonvulsant properties [8 – 13]. The present article reports the synthesis and biological properties of benzo[h ]quinazoline-2,4-diones spiro-condensed at the 5-position with cycloheptane. For this, ethyl 4¢-amino-1¢H-spiro[cycloheptane-1,2¢-naphthalene]-3¢-carboxylate (I) was condensed with phenyl chloroformate to give ethyl 4¢-[(phenoxycarbonyl)amino]-1¢H-spiro[cycloheptane-1,2¢-naphthalene]-3¢-carboxylate (II) (carbamate). The latter in EtOH reacted with aliphatic, aromatic, and heteroaromatic primary amines with subsequent cyclization of the intermediate ureas in the presence of base. Acidification of the reaction mixtures with HCl produced 3-substi-
tuted 1H-spiro[benzo[h ]quinazoline-5,1¢-cycloheptane]2,4(3H,6H)-diones (III-XIII), IR spectra of which showed absorption bands at 1610 – 1615 cm–1 (aromatic C=C), 1636 – 1648 (NHC=O), 1700 – 1707 (C=O), and 3230 – 3280 (NH). The second synthetic method developed by us for dioxobenzo[h ]quinazolines was based on the reaction of the aminoester with 3-chlorophenylisocyanate to give the corresponding urea XIV. NMR spectra of urea XIV were consistent with an imine structure, i.e., ethyl 4¢-{[(3-chlorophenyl)-carbamoyl]imino}-3¢,4¢-dihydro-1¢H-spiro[cycloheptane1,2¢-naphthalene]-3¢-carboxylate (XV). In particular, a singlet in the PMR spectrum at 3.84 ppm with 1H integrated intensity corresponded to a methine proton next to an ethoxycarbonyl group. Compound XV cyclized in b
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