Antiproliferative Activity Missing in 6-Substituted Polycarbonitrile Derivatives of 3-Azabicyclo[3.1.0]Hexane
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Pharmaceutical Chemistry Journal, Vol. 54, No. 8, November, 2020 (Russian Original Vol. 54, No. 8, August, 2020)
ANTIPROLIFERATIVE ACTIVITY MISSING IN 6-SUBSTITUTED POLYCARBONITRILE DERIVATIVES OF 3-AZABICYCLO[3.1.0]HEXANE I. N. Bardasov,1,* A. Yu. Alekseeva,1 O. V. Ershov,1 and M. A. Mar’yasov1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 8, pp. 7 – 9, August, 2020.
Original article submitted May 18, 2020. The antiproliferative activity of 6-substituted polycarbonitrile derivatives of 3-azabicyclo[3.1.0]hexane was studied. It was established that the activity of the substances was directly related to the presence of a 6-substituent. Thus, 6-substituted derivatives of 3-azabicyclo[3.1.0]hexane did not possess antiproliferative activity and could be of interest only as potential antitussive and hypoglycemic drugs. Keywords: 3-azabicyclo[3.1.0]hexane, carbonitriles, antiproliferative activity.
and g-aminobutyric acids [5 – 7]; and a expansive class of pharmacologically active substances. The international patent literature comprises >500 descriptions of antiasthmatic and antitussive drugs and drugs used for disorders of the genitourinary system that contain this fragment in their structures. Furthermore, compounds with hypoglycemic activity are known. This spectrum of activity is due to a variety of biological targets for this type of compounds, e.g., serotonin 5-HT [8] and m-opioid (CP-886,087) receptors [9 – 11], vari-
Azabicyclo[3.1.0]hexane is known to be a fragment of many biologically active natural compounds such as ergot alkaloids (cycloclavine) [1]; antibiotics (CC-1065, duocarmycin, indolizomycin) [2, 3]; amino acids (cis-3,4-methyleneL-proline) [4]; structural analogs of lysine and L-glutamic 1 *
I. N. Ul’yanov Chuvash State University, Cheboksary, Chuvash Republic, 428015 Russia. e-mail: [email protected]
O
NC
O NH
Ar
10% H2 SO4
NC
O
N Ar
NC O 2a,b
NH2
NC
R'O 1a,b
CH3COOH
N Ar
OR'
NH2
NC
O
NC 3a
O
1, 2, 3: R' = NC(CH 3)2, Ar = C6H 5 (a), Ar = 3,4-(MeO)2C6H3 (b). OCH3 H 3CO
H3CO CN
R''
CN
H 3CO
CN
NH2
R''
H 3CO
+ CN
NH2
H3CO
N NC 4a-c
NC
CN
4: R'' = CN (a), R'' = COOEt (b), R'' = CONH 2 (c).
Scheme 1. Synthesis of 6-substituted polycarbonitrile derivatives of 3-azabicyclo[3.1.0]hexane.
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in a mixture of i-PrOH (3 mL) and H2SO4 solution (3 mL, 10%) was refluxed for 5 min and cooled. The resulting precipitate was filtered off and rinsed with H2O and i-PrOH. Yield 0.209 g (79%). mp 221 – 222°C. IR spectrum, nmax, cm– 1: 1716 (C=O), 2265 (CºN), 3066 (C–H), 3213 (NH). PMR (DMSO-d6), d, ppm: 5.18 (s, 1H, C-H), 7.63 – 7.79 (m, 3H), 8.21 (d, J 8.2 Hz, 2H, C6H5), 12.15 s (s, 1H, NH). Mass spectrum, m/z (Irel, %): 265 (100), 160 (35). C14H7N3O3. Compound 2b was prepared analogously. 6-(3,4-Dimethoxybenzoyl)-2,4-dioxo-3-azabicyclo[3.1.0]hexane-1,5-dicarbonitrile (2b). Yield 83%. mp 210 – 211°C. IR spectrum, nmax, cm– 1: 1715 (C=O), 2276 (CºN), 3071 (C–H)
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