We propose a single-step procedure for the synthesis of 8-oxo-10-sulfanylpyrido[4',3':4,5]thieno[3,2-d]pyrimidines, annulated with pyran, cyclohexane, or cyclopentane rings. The alkylation of these compounds in aqueous DMF solution of KOH at room temperature was shown to proceed regioselectively and led to the formation of S-substituted products. Amino- and alkoxy-substituted derivatives of tetracyclic thieno[3,2-d]pyrimidines were synthesized. The antimicrobial activity of the obtained compounds was studied on Grampositive staphylococci and Gram-negative rods.
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The pyrimidine ring is a part of many natural and synthetic compounds, while pyridine derivatives and condensed systems containing pyridine rings have antiinflammatory, analgesic, and antibacterial properties.1 – 4 The preparation of tricyclic pyrido[4',3':4,5]thieno[3,2-d]-pyrimidines from 3-amino-2-cyano(ethoxycarbonyl)thieno-[2,3-b]pyridines has been described in the literature, and these compounds show antitumor, antiviral, and antimicrobial effects.5 – 12 The biological importance of condensed pyrimidine derivatives has motivated significant interest towards the synthesis of new pyrido[4',3':4,5]thieno[3,2-d]-pyrimidine derivatives annulated with pyran, cyclohexane, and cyclopentane rings.
In this work, we continued the synthetic studies of functionalized tetracyclic thieno[3,2-d]pyrimidines by focusing on the methods for preparing derivatives of the respective heterocycles. Previously we have reported a two-stage method for the synthesis of 8-oxo-10-thioxothieno[3,2-d]-pyrimidines 4a–e: in reactions of 1-amino-2-ethoxycarbonylthieno[2,3-b]pyridines 1a–e with benzoylisothiocyanate, involving the formation of N,N'-disubstituted thioureas 2a–e as intermediates, which were subsequently cyclized in the presence of alkali.13 We also described a more efficient onestep procedure14 for the synthesis of compounds 4b,d by a reaction of 1-amino-2-carbamoylthieno[2,3-b]pyridines 3b,d with carbon disulfide in the presence of pyridine. In that case, potassium hydroxide solution in ethanol was selected as base for the synthesis of compounds 4a–e from aminoamides 3a–e,15 allowing to increase the yields of target products to 90–95% (Scheme 1).
Scheme 1
We found that alkylation of 8-oxo-10-thioxothieno[3,2-d]-pyrimidines 4a–e in aqueous DMF solution of KOH at 20–22°C occurred regioselectively with the formation of S-alkyl derivatives 5a–j. The regioselectivity of this reaction was explained by the greater polarizability of sulfur atom, compared to the nitrogen and oxygen atoms.16
The signals of S-methyl and S-methylene group protons were observed in 1H NMR spectra of compounds 5a–j at the ranges of 2.60–2.62 and 3.22–4.90 ppm, respectively, while 13C NMR signals of these groups were at 13.0–13.5 ppm (compounds 5a,f,g,j) and 31.1–38.5 ppm (compounds 5b–e,h,i), confirming the formation of S-alkylated products.17
The treatment of S-alkyl derivatives 5a,b,f,i,j with phosphorus oxychloride further gave 10-alkylsulfanyl-8-chlorothieno[3,2-d]pyrimidines 6a,c–f (Scheme 2). The preparation of compound 6b was described previously.18
Scheme 2
The reactions of compounds 6a–f with amines provided 5,8-diamino-substituted 10-alkylsulfanylthieno[3,2-d]pyrimidines 7a–k, while treatment with sodium alkoxide in the appropriate alcohol gave the 8-alkoxy derivatives 8a–f (Scheme 3). The signals of NH group in 1H NMR spectra of compounds 7a,c,d,f,h were observed in the range of 7.30–8.09 ppm, while the signals of OCH3, OCH2, and OCH groups in spectra of compounds 8a–f were observed in the range of 4.16–5.61 ppm.
Scheme 3
The antimicrobial activity of compounds 5a–j, 7a–k, and 8a–f was studied by the agar diffusion assay.19 Experiments were performed with Gram-positive staphylococci (Staphylococcus aureus 209P, JC-1) and Gram-negative rods (Shigella dysenteriae flexneri 6858, Escherichia coli 0-55). The studies showed that compounds 5b,h, 7a,d,e,h, and 8c,d,f had weak activity against all tested microbial strains: the diameters d of growth inhibition zones were 10–15 mm (Table 1). The indicated compounds were significantly less active than the reference drug furazolidone (d 24–25 mm).20
Thus, as a result of our studies, an efficient method has been developed for the preparation of 8-oxo-10-sulfanylpyrido[4',3':4,5]thieno[3,2-d]pyrimidines annulated with saturated rings, and 90–95% yields were achieved.
Reaction conditions were found for alkylation of the latter compounds with various alkyl halides, enabling good regioselectivity. Functionalized derivatives of condensed pyrido[4',3':4,5]thieno[3,2-d]pyrimidines were synthesized and biological activity of the obtained compounds was evaluated, allowing to identify compounds with antimicrobial effects on the bacterial strains Staphylococcus aureus 209p, JC-1, Shigella dysenteriae flexneri 6858, and Escherichia coli 0-55, opening possibilities for further search of potential antimicrobial agents among this type of compounds.
Experimental
IR spectra were recorded for Nujol mulls on a Nicolet Avatar 330 FT-IR spectrometer. 1H and 13C NMR spectra were acquired on a Varian Mercury Vx 300 instrument (300 and 75 MHz, respectively) in DMSO-d 6, with TMS as internal standard. The assignment of 1H and 13C NMR signals was supported by DEPT, NOESY, and HMQC data when needed (mixing time 1 s). Elemental analysis of the C, H, N, and S content was performed on a Euro EA 3000 Elemental Analyzer. The content of chlorine was determined by the classic Pregl procedure. Melting points were determined on a Boetius micro hot stage. The aminoamides 3a–e were synthesized according to a previously published procedure.15
Preparation of compounds 4a–e (General method). Compound 3a–e (10 mmol) and carbon disulfide (20 ml, 0.33 mol) were added to a solution of KOH (1.68 g, 30 mmol) in EtOH (50 ml). The mixture was refluxed on a water bath at 60–70°C for 24 h. The solution was cooled, the excess of carbon disulfide was removed by distillation and the residue was acidified with dilute acetic acid solution. The obtained precipitate was filtered off, washed with water, and recrystallized from DMSO.
2,2-Dimethyl-5-(pyrrolidin-1-yl)-10-thioxo-1,4,10,11-tetrahydro-2 H -pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno-[3,2- d ]pyrimidin-8(9 H )-one (4a). Yield 5.41 g (92%), light-yellow crystals, mp > 360°C. IR spectrum, ν, cm–1: 1260 (C=S), 1668 (CO), 3427 (2NH). 1H NMR spectrum, δ, ppm: 1.35 (6H, s, 2CH3); 1.92–2.00 (4H, m, 3,4-CH2 pyrrolidine); 3.28 (2H, s, 1-CH2); 3.57–3.65 (4H, m, N(CH2)2 pyrrolidine); 4.75 (2H, s, 4-CH2); 11.04 (1H, br. s, NH); 12.44 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 25.0 (3,4-CH2 pyrrolidine); 26.1 (2CH3); 35.9 (1-CH2); 49.5 (2,5-CH2 pyrrolidine); 59.9 (4-CH2); 68.6 (C-2); 108.9; 112.5; 114.2; 140.0; 140.1; 156.0; 156.1; 160.2 (C-8); 174.6 (C-10). Found, %: C 55.72; H 5.25; N 14.48; S 16.47. C18H20N4O2S2. Calculated, %: C 55.65; H 5.19; N 14.42; S 16.51.
2,2-Dimethyl-5-(morpholin-4-yl)-10-thioxo-1,4,10,11-tetrahydro-2 H -pyrano[4'',3'':4',5']pyrido[3',2':4,5]-thieno[3,2- d ]pyrimidin-8(9 H )-one (4b). Yield 3.84 g (95%), light-yellow crystals, mp > 360°C. 1H NMR spectrum, δ, ppm: 1.35 (6H, s, 2CH3); 3.18–3.27 (4H, m, N(CH2)2 morpholine); 3.37 (2H, s, 1-CH2); 3.72–3.81 (4H, m, O(CH2)2 morpholine); 4.64 (2H, s, 4-CH2); 11.25 (1H, br. s, NH); 12.59 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 26.1 (2CH3); 35.8 (1-CH2); 49.5 (3,5-CH2 morpholine); 59.2 (4-CH2); 66.0 (2,6-CH2 morpholine); 69.5 (C-2); 108.4; 113.5; 118.9; 140.7; 143.3; 156.9; 157.2; 159.4 (C-8); 175.6 (C-10). Found, %: C 53.52; H 4.93; N 13.97; S 15.72. C18H20N4O3S2. Calculated, %: C 53.45; H 4.98; N 13.85; S 15.85.
5-(Pyrrolidin-1-yl)-10-thioxo-1,2,3,4,10,11-hexahydropyrimido[4',5':4,5]thieno[2,3- c ]isoquinolin-8(9 H )-one (4c). Yield 3.26 g (91%), yellow crystals, mp > 360°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.66–1.77 (2H, m, 2-CH2); 1.86–2.00 (6H, m, 3-CH2, 3,4-CH2 pyrrolidine); 2.71 (2H, br. t, J = 5.8, 4-CH2); 3.35 (2H, br. t, J = 6.3, 1-CH2); 3.58–3.65 (4H, m, N(CH2)2 pyrrolidine); 10.48 (1H, br. s, NH); 12.43 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 20.9 (2-CH2); 22.0 (3-CH2); 25.2 (3,4-CH2 pyrrolidine); 26.0 (4-CH2); 27.1 (1-CH2); 49.8 (2,5-CH2 pyrrolidine); 108.3; 113.0; 117.7; 140.3; 143.1; 156.3; 159.4; 159.5 (C-8); 174.3 (C-10). Found, %: C.88; H 5.12; N 15.72; S 17.76. C17H18N4OS2. Calculated, %: C 56.96; H 5.06; N 15.63; S 17.89.
5-(Morpholin-4-yl)-10-thioxo-1,2,3,4,10,11-hexahydropyrimido[4',5':4,5]thieno[2,3- c ]isoquinolin-8(9 H )-one (4d). Yield 3.41 g (91%), white crystals, mp 313–315°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.68–1.79 (2H, m, 2-CH2); 1.87–2.00 (2H, m, 3-CH2); 2.68 (2H, br. t, J = 5.9, 4-CH2); 3.21–3.32 (4H, m, N(CH2)2 morpholine); 3.45 (2H, br. t, J = 6.7, 1-CH2); 3.72–3.81 (4H, m, O(CH2)2 morpholine); 10.70 (1H, br. s, NH); 12.59 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 21.4 (2-CH2); 22.0 (3-CH2); 26.2 (4-CH2); 26.8 (1-CH2); 49.8 (3,5-CH2 morpholine); 66.2 (2,6-CH2 morpholine); 108.3; 113.1; 118.1; 141.3; 145.1; 154.3; 157.8; 159.2 (C-8); 174.8 (C-10). Found, %: C.61; H 4.90; N 14.88; S 17.21. C17H18N4O2S2. Calculated, %: C 54.52; H 4.84; N 14.96; S 17.13.
4-(Morpholin-4-yl)-9-thioxo-2,3,9,10-tetrahydro-1 H cyclopenta[4',5']pyrido[3',2':4,5]thieno[3,2- d ]pyrimidin-7-(8 H )-one (4e). Yield 3.24 g (90%), gray crystals, mp > 360°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.08–2.20 (2H, m, 2-CH2); 2.95 (2H, t, J = 7.2, 3-CH2); 3.43 (2H, t, J = 7.3, 1-CH2); 3.51–3.57 (4H, m, N(CH2)2 morpholine); 3.71–3.77 (4H, m, O(CH2)2 morpholine); 11.49 (1H, br. s, NH). 12.43 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 2 (2-CH2); 29.2 (3-CH2); 34.1 (1-CH2); 47.9 (3,5-CH2 morpholine); 66.3 (2,6-CH2 morpholine); 108.6; 112.1; 115.2; 139.8; 140.0; 156.1; 156.3; 159.6 (C-7); 178.4 (C-9). Found, %: C 53.40; H 4.53; N 15.46; S 17.68. C16H16N4O2S2. Calculated, %: C 53.31; H 4.47; N 15.54; S 17.79.
Preparation of compounds 5a–j (General method). DMF (25 ml) and compound 4a–e (5 mmol) were added to a solution of KOH (0.28 g, 5 mmol) in water (2.5 ml). The mixture was treated by dropwise addition of the appropriate alkyl halide (5 mmol) solution in ethanol (15 ml). The mixture was stirred for 5 h at room temperature. The obtained crystals were filtered off and recrystallized from 2:1 mixture of EtOH and DMF.
2,2-Dimethyl-10-methylsulfanyl-5-(pyrrolidin-1-yl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']pyrido-[3',2':4,5]-thieno[3,2- d ]pyrimidin-8(9 H )-one (5a). Yield 1.95 g (97%), white crystals, mp > 360°C. IR spectrum, ν, cm–1: 1652 (CO), 3420 (NH). 1H NMR spectrum, δ, ppm: 1.30 (6H, s, 2CH3); 1.84–1.91 (4H, m, 3,4-CH2 pyrrolidine); 2.60 (3H, s, SCH3); 3.35 (2H, s, 1-CH2); 3.56–3.62 (4H, m, N(CH2)2 pyrrolidine); 4.81 (2H, s, 4-CH2); 12.85 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 13.1 (SCH3); 25.1 (2CH3); 26.4 (3,4-CH2 pyrrolidine); 37.8 (1-CH2); 49.6 (2,5-CH2 pyrrolidine); 60.1 (4-CH2); 68.7 (C-2); 114.8; 116.4; 141.4; 152.4; 152.5; 156.3; 157.6; 158.2 (C-8); 160.0 (C-10). Found, %: C 56.76; H 5.56; N 13.83; S 15.81. C19H22N4O2S2. Calculated, %: C 56.69; H 5.51; N 13.92; S 15.93.
10-Benzylsulfanyl-2,2-dimethyl-5-(morpholin-4-yl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']pyrido[3',2':4,5]-thieno-[3,2- d ]pyrimidin-8(9 H )-one (5b). Yield 2.25 g (98%), white crystals, mp 314–315°C. 1H NMR spectrum, δ, ppm: 1.17 (6H, s, 2CH3); 3.15–3.21 (4H, m, N(CH2)2 morpholine); 3.34 (2H, s, 1-CH2); 3.72–3.76 (4H, m, O(CH2)2 morpholine); 4.59 (2H, s, SCH2); 4.65 (2H, s, 4-CH2); 7.23–7.36 (3H, m, H Ph); 7.43–7.47 (2H, m, H Ph); 13.10 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 26.6 (2CH3); 33.8 (SCH2); 37.0 (1-CH2); 49.9 (3,5-CH2 morpholine); 59.2 (4-CH2); 66.1 (2,6-CH2 morpholine); 69.3 (C-2); 119.4; 119.8; 127.2 (C-4 Ph); 128.3 (C-3,5 Ph); 128.4 (C-2,6 Ph); 136.9 (C-1 Ph); 142.9; 151.8; 157.8; 157.9; 158.0; 158.9 (C-8); 159.1 (C-10). Found, %: C 60.62; H 5.35; N 11.22; S 13.10. C25H26N4O3S2. Calculated, %: C 60.71; H 5.30; N 11.33; S 12.97.
10-Butylsulfanyl-2,2-dimethyl-5-(morpholin-4-yl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno-[3,2- d ]pyrimidin-8(9 H )-one (5c). Yield 2.25 g (98%), white crystals, mp > 360°C. 1H NMR spectrum, δ, ppm (J, Hz): 0.92 (3H, t, J = 7.3, CH2CH 3); 1.30 (6H, s, 2CH3); 1.39–1.51 (2H, m, SCH2CH2); 1.67–1.77 (2H, m, CH2CH3); 3.16–3.21 (4H, m, N(CH2)2 morpholine); 3.22 (2H, t, J = 7.4, SCH2); 3.41 (2H, s, 1-CH2); 3.72–3.77 (4H, m, O(CH2)2 morpholine); 4.68 (2H, s, 4-CH2); 12.99 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 13.5 (CH2CH 3); 21.6 (CH2); 26.8 (2CH3); 29.9 (CH2); 31.1 (SCH2); 37.0 (1-CH2); 49.9 (3,5-CH2 morpholine); 59.2 (4-CH2); 66.1 (2,6-CH2 morpholine); 69.4 (C-2); 115.0; 117.9; 119.4; 119.8; 142.8; 157.8; 158.3; 158.9 (C-8); 159.1 (C-10). Found, %: C 57.46; H 6.17; N 12.04; S 13.81. C22H28N4O3S2. Calculated, %: C 57.37; H 6.13; N 12.16; S 13.92.
2-{[2,2-Dimethyl-5-(morpholin-4-yl)-8-oxo-1,4,8,9-tetrahydro-2 H -pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno-[3,2- d ]pyrimidin-10-yl]sulfanyl}- N -phenylacetamide (5d). Yield 2.58 g (96%), light-yellow crystals, mp > 360°C. 1H NMR spectrum, δ, ppm: 1.13 (6H, s, 2CH3); 3.12–3.20 (4H, m, N(CH2)2 morpholine); 3.67–3.76 (4H, m, O(CH2)2 morpholine); 3.31 (2H, s, 1-CH2); 4.23 (2H, s, SCH2); 4.60 (2H, s, 4-CH2); 6.99–7.06 (1H, m, H Ph); 7.24–7.32 (2H, m, H Ph); 7.52–7.58 (2H, m, H Ph); 10.19 (1H, br. s, NH); 13.14 (1H, br. s, 9-NH). 13C NMR spectrum, δ, ppm: 26.5 (2CH3); 36.8 (SCH2); 38.7 (1-CH2); 49.8 (3,5-CH2 morpholine); 59.0 (4-CH2); 66.0 (2,6-CH2 morpholine); 69.5 (C-2); 119.1 (C-3,5 Ph); 119.5; 119.8; 123.3 (C-4 Ph); 128.7 (C-2,6 Ph); 138.8 (C-1 Ph); 138.9; 143.1; 152.0; 157.7; 158.8; 158.9 (C-8); 159.1 (C-10); 164.8 (CH2 CO). Found, %: C 58.16; H 5.10; N 13.15; S 12.10. C26H27N5O4S2. Calculated, %: C 58.08; H 5.06; N 13.03; S 11.93.
10-Allylsulfanyl-2,2-dimethyl-5-(morpholin-4-yl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno-[3,2- d ]pyrimidin-8(9 H )-one (5e). Yield 2.09 g (94%), white crystals, mp 288–290°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.31 (6H, s, 2CH3); 3.17–3.25 (4H, m, N(CH2)2 morpholine); 3.43 (2H, s, 1-CH2); 3.74–3.81 (4H, m, O(CH2)2 morpholine); 3.88 (2H, dt, J = 6.6, J = 1.2, SCH2); 4.67 (2H, s, 4-CH2); 5.15 (1H, dq, J=.0, J = 1.2) and 5.34 (1H, dq, J = 17.0, J = 1.2, CH=CH 2); 6.04 (1H, ddt, J = 17.0, J = 10.0, J = 6.6, CH=CH2); 12.75 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 26.4 (2CH3); 32.6 (SCH2); 37.0 (1-CH2); 49.9 (3,5-CH2 morpholine); 59.2 (4-CH2); 66.0 (2,6-CH2 morpholine); 69.0 (C-2); 117.2 (CH=CH 2); 118.8; 120.2; 132.8 (CH=CH2); 141.2; 142.3; 151.4; 156.9; 157.8; 158.6 (C-8); 159.4 (C-10). Found, %: C 56.62; H 5.49; N 12.71; S 14.34. C21H24N4O3S2. Calculated, %: C 56.73; H 5.44; N 12.60; S 14.43.
10-Methylsulfanyl-5-(pyrrolidin-1-yl)-1,2,3,4-tetrahydropyrimido[4',5':4,5]thieno[2,3- c ]isoquinolin-8(9 H )-one (5f). Yield 1.73 g (93%), light-yellow crystals, mp > 360°C. 1H NMR spectrum, δ, ppm: 1.61–1.72 (2H, m, 2-CH2); 1.76–1.93 (6H, m, 3,4-CH2 pyrrolidine, 3-CH2); 2.60 (3H, s, SCH3); 2.67–2.74 (2H, m, 4-CH2); 3.39–3.47 (2H, m, 1-CH2); 3.53–3.61 (4H, m, N(CH2)2 pyrrolidine); 12.81 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 13.0 (SCH3); 22.1 (2-CH2); 25.1 (3,4-CH2 pyrrolidine); 25.4 (3-CH2); 26.0 (4-CH2); 26.8 (1-CH2); 49.7 (2,5-CH2 pyrrolidine); 113.7; 115.4; 141.2; 151.8; 152.3; 155.6; 157.4; 158.5 (C-8); 161.0 (C-10). Found, %: C 58.13; H 5.45; N 14.92; S 17.14. C18H20N4OS2. Calculated, %: C 58.04; H 5.41; N 15.04; S 17.22.
10-Methylsulfanyl-5-(morpholin-4-yl)-1,2,3,4-tetrahydropyrimido[4',5':4,5]thieno[2,3- c ]isoquinolin-8(9 H )-one (5g). Yield 1.85 g (95%), white crystals, mp > 360°C. 1H NMR spectrum, δ, ppm: 1.70–1.80 (2H, m, 2-CH2); 1.85–1.96 (2H, m, 3-CH2); 2.62 (3H, s, SCH3); 2.68–2.74 (2H, m, 4-CH2); 3.19–3.24 (4H, m, N(CH2)2 morpholine); 3.75–3.80 (4H, m, O(CH2)2 morpholine); 3.51–3.57 (2H, m, 1-CH2); 12.85 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 13.0 (SCH3); 20.8 (2-CH2); 21.9 (3-CH2); 26.0 (4-CH2); 26.7 (1-CH2); 49.6 (3,5-CH2 morpholine); 65.7 (2,6-CH2 morpholine); 113.2; 115.7; 141.4; 152.1; 153.5; 156.4; 157.6; 158.2 (C-8); 160.5 (C-10). Found, %: C 55.73; H 5.15; N 14.33; S 16.41. C18H20N4O2S2. Calculated, %: C 55.65; H 5.19; N 14.42; S 16.51.
5-(Morpholin-4-yl)-10-[(2-oxo-2-phenylethyl)sulfanyl]-1,2,3,4-tetrahydropyrimido[4',5':4,5]thieno[2,3- c ]-isoquinolin-8(9 H )-one (5h). Yield 2.29 g (93%), white crystals, mp 274–275°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.18–1.27 (2H, m, 2-CH2); 1.49–1.58 (2H, m, 3-CH2); 2.57 (2H, t, J = 5.9, 4-CH2); 3.09 (2H, t, J = 6.4, 1-CH2); 3.14–3.21 (4H, m, N(CH2)2 morpholine); 3.71–3.78 (4H, m, O(CH2)2 morpholine); 4.90 (2H, s, SCH2); 7.52–7.58 (2H, m, H Ph); 7.61–7.68 (1H, m, H Ph); 8.05–8.11 (2H, m, H Ph); 12.97 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 20.9 (2-CH2); 21.8 (3-CH2); 25.8 (4-CH2); 26.8 (1-CH2); 38.5 (SCH2); 49.5 (3,5-CH2 morpholine); 65.9 (2,6-CH2 morpholine); 115.6; 120.4; 121.4; 127.8 (C-3,5 Ph); 128.2 (C-2,6 Ph); 132.8 (C-4 Ph); 135.4 (C-1 Ph); 145.5; 151.7; 156.3; 157.6; 158.4 (C-8); 160.9 (C-10); 190.4 (CH2CO). Found, %: C 60.87; H 4.96; N.49; S 13.10. C25H24N4O3S2. Calculated, %: C 60.95; H 4.91; N 11.37; S 13.02.
10-Benzylsulfanyl-5-(morpholin-4-yl)-1,2,3,4-tetrahydropyrimido[4',5':4,5]thieno[2,3- c ]isoquinolin-8(9 H )-one (5i). Yield 2.21 g (95%), white crystals, mp 325–327°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.61–1.84 (4H, m, 2,3-CH2); 2.67 (2H, t, J = 5.3, 4-CH2); 3.16–3.22 (4H, m, N(CH2)2 morpholine); 3.40 (2H, t, J = 5.8, 1-CH2); 3.72–3.79 (4H, m, O(CH2)2 morpholine); 4.55 (2H, s, SCH2); 7.23–7.38 (3H, m, H Ph); 7.43–7.47 (2H, m, H); 13.06
(1H, br. s, NH). 13C NMR spectrum, δ, ppm: 21.5 (2-CH2); 22.0 (3-CH2); 26.0 (4-CH2); 26.9 (1-CH2); 34.0 (SCH2); 49.7 (3,5-CH2 morpholine); 66.1 (2,6-CH2 morpholine); 120.3; 122.3; 127.2 (C-4 Ph); 128.4 (C-3,5 Ph); 128.5 (C-2,6 Ph); 136.7 (C-1 Ph); 146.2; 152.1; 155.5; 157.4; 157.8; 158.2 (C-8); 161.5 (C-10). Found, %: C 61.95; H 5.26; N 12.18; S 13.71. C24H24N4O2S2. Calculated, %: C 62.04; H 5.21; N 12.06; S 13.80.
9-Methylsulfanyl-4-(morpholin-4-yl)-2,3-dihydro-1 H cyclopenta[4',5']pyrido[3',2':4,5]thieno[3,2- d ]pyrimidin-7(8 H )-one (5j). Yield 1.80 g (96%), white crystals, mp > 360°C. 1H NMR spectrum, δ, ppm (J,Hz): 2.06–2.16 (2H, m, 2-CH2); 2.60 (3H, s, SCH3); 2.95 (2H, t, J = 7.2, 3-CH2); 3.34 (2H, t, J = 7.5, 1-CH2); 3.47–3.53 (4H, m, N(CH2)2 morpholine); 3.70–3.76 (4H, m, O(CH2)2 morpholine); 12.87 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 13.5 (SCH3); 25.1 (2-CH2); 30.5 (3-CH2); 30.9 (1-CH2); 47.9 (3,5-CH2 morpholine); 66.1 (2,6-CH2 morpholine); 113.2; 117.5; 140.2; 151.9; 154.3; 155.6; 156.7; 158.6 (C-7); 163.6 (C-9). Found, %: C 54.61; H 4.79; N 14.87; S 17.02. C17H18N4O2S2. Calculated, %: C 54.52; H 4.84; N 14.96; S 17.13.
Preparation of compounds 6a,c–f (General method). A mixture of compound 5a,b,f,i,j (5 mmol), phosphorus oxychloride (25 ml, 0.268 mol), and pyridine (1.3 ml, 16 mmol) was refluxed for 6 h. The excess of phosphorus oxychloride was removed by distillation, the residue was quenched with ice water (50 ml) and neutralized with aqueous ammonia solution. The obtained crystals were filtered off, washed with water, and recrystallized from a 4:1 mixture of CHCl3 and EtOH.
8-Chloro-2,2-dimethyl-10-methylsulfanyl-5-(pyrrolidin-1-yl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']pyrido-[3',2':4,5]thieno[3,2- d ]pyrimidine (6a). Yield 1.71 g (81%), light-yellow crystals, mp 224–226°C. 1H NMR spectrum, δ, ppm: 1.35 (6H, s, 2CH3); 1.96–2.02 (4H, m,,4-CH2 pyrrolidine); 2.60 (3H, s, SCH3); 3.36 (2H, s, 1-CH2); 3.66–3.73 (4H, m, N(CH2)2 pyrrolidine); 4.84 (2H, s, 4-CH2). 13C NMR spectrum, δ, ppm: 13.8 (SCH3); 25.1 (3,4-CH2 pyrrolidine); 27.6 (2CH3); 36.5 (1-CH2); 50.1 (2,5-CH2 pyrrolidine); 60.3 (4-CH2); 68.6 (C-2); 115.6; 118.4; 121.5; 144.9; 151.7; 159.2; 160.5; 160.4 (C-8); 165.2 (C-10). Found, %: C 54.30; H 5.09; N 13.15; S 15.33; Cl 8.51. C19H21ClN4OS2. Calculated, %: C 54.21; H 5.03; N 13.31; S 15.23; Cl 8.42.
8-Chloro-2,2-dimethyl-10-methylsulfanyl-5-(morpholin-4-yl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']pyrido[3',2':4,5]-thieno[3,2- d ]pyrimidine (6b).18 White crystals, mp 261–262°C. 1H NMR spectrum, δ, ppm: 1.34 (6H, s, 2CH3); 2.53 (3H, s, SCH3); 3.16–3.27 (4H, m, N(CH2)2 morpholine); 3.51 (2H, s, 1-CH2); 3.73–3.81 (4H, m, O(CH2)2 morpholine); 4.64 (2H, s, 4-CH2). 13C NMR spectrum, δ, ppm: 13.6 (SCH3); 27.3 (2CH3); 36.9 (1-CH2); 48.4 (3,5-CH2 morpholine); 60.2 (4-CH2); 66.9 (2,6-CH2 morpholine); 68.4 (C-2); 115.7; 118.0; 121.7; 145.4; 151.7; 159.3; 160.6; 161.0 (C-8); 165.2 (C-10). Found, %: C 52.45; H 4.56; N 12.74; S 14.56. C19H21ClN4O2S2. Calculated, %: C 52.23; H 4.84; N 12.82; S 14.67.
10-Benzylsulfanyl-8-chloro-2,2-dimethyl-5-(morpholin-4-yl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']pyrido[3',2':4,5]-thieno[3,2- d ]pyrimidine (6c). Yield 1.90 g (74%), white crystals, mp 247–248°C. 1H NMR spectrum, δ, ppm: 1.27 (6H, s, 2CH3); 3.28–3.37 (4H, m, N(CH2)2 morpholine); 3.34 (2H, s, 1-CH2); 3.75–3.82 (4H, m, O(CH2)2 morpholine); 4.50 (2H, s, SCH2); 4.64 (2H, s, 4-CH2); 7.18–7.32 (3H, m, H Ph); 7.40–7.46 (2H, m, H Ph). 13C NMR spectrum, δ, ppm: 27.4 (2CH3); 34.1 (SCH2); 36.2 (1-CH2); 47.8 (3,5-CH2 morpholine); 60.1 (4-CH2); 66.8 (2,6-CH2 morpholine); 69.9 (C-2); 116.4; 119.7; 126.5 (C-4 Ph); 128.3 (C-3,5 Ph); 129.1 (C-2,6 Ph); 138.4 (C-1 Ph); 145.9; 151.4; 157.9; 158.2; 159.7; 160.4 (C-8); 165.1 (C-10). Found, %: C 58.40; H 4.96; N 10.84; S 12.58; Cl 6.83. C25H25ClN4O2S2. Calculated, %: C 58.52; H 4.91; N 10.92; S 12.50; Cl 6.91.
8-Chloro-10-methylsulfanyl-5-(pyrrolidin-1-yl)-1,2,3,4-tetrahydropyrimido[4',5':4,5]thieno[2,3- c ]isoquinoline (6d). Yield 1.51 g (77%), yellow crystals, mp 216–217°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.71–1.79 (2H, m, 2-CH2); 1.86–1.94 (2H, m, 3-CH2); 1.95–2.01 (4H, m, 3,4-CH2 pyrrolidine); 2.61 (3H, s, SCH3); 2.77 (2H, br. t, J = 5.9, 4-CH2); 3.48 (2H, br. t, J = 6.4, 1-CH2); 3.65–3.72 (4H, m, N(CH2)2 pyrrolidine). 13C NMR spectrum, δ, ppm: 13.9 (SCH3); 21.1 (2-CH2); 22.2 (3-CH2); 25.1 (3,4-CH2 pyrrolidine); 27.1 (4-CH2); 27.4 (1-CH2); 50.0 (2,5-CH2 pyrrolidine); 115.1; 117.6; 121.1; 145.9; 151.4; 158.9; 160.3; 160.7 (C-8); 167.0 (C-10). Found, %: C 55.38; H 4.96; N 14.22; S 16.52; Cl 9.16. C18H19ClN4S2. Calculated, %: C 55.30; H 4.90; N 14.33; S 16.40; Cl 9.07.
10-Benzylsulfanyl-8-chloro-5-(morpholin-4-yl)-1,2,3,4-tetrahydropyrimido[4',5':4,5]thieno[2,3- c ]isoquinoline (6e). Yield 1.79 g (74%), light-yellow crystals, mp 246–248°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.72–1.78 (2H, m, 2-CH2); 1.87–1.96 (2H, m, 3-CH2); 2.74 (2H, t, J = 5.8, 4-CH2); 3.25–3.34 (4H, m, N(CH2)2 morpholine); 3.51 (2H, t, J = 6.3, 1-CH2); 3.77–3.85 (4H, m, O(CH2)2 morpholine); 4.52 (2H, s, SCH2); 7.13–7.22 (3H, m, H Ph); 7.43–7.51 (2H, m, H Ph). 13C NMR spectrum.: 21.2 (2-CH2); 22.1 (3-CH2); 26.9 (4-CH2); 27.2 (1-CH2); 34.0 (SCH2); 47.9 (3,5-CH2 morpholine); 66.7 (2,6-CH2 morpholine); 121.6; 121.8; 126.8 (C-4 Ph); 128.5 (C-3,5 Ph); 128.8 (C-2,6 Ph); 138.2 (C-1 Ph); 145.6; 151.8; 158.0; 158.4; 159.5; 160.1 (C-8); 164.7 (C-10). Found, %: C 59.78; H 4.84; N 11.71; S 13.17; Cl 7.25. C24H23ClN4OS2. Calculated, %: C 59.67; H 4.80; N 11.60; S 13.28; Cl 7.34.
7-Chloro-9-methylsulfanyl-4-(morpholin-4-yl)-2,3-dihydro-1 H -cyclopenta[4',5']pyrido[3',2':4,5]thieno[3,2- d ]-pyrimidine (6f). Yield 1.63 g (83%), white crystals, mp 250–251°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.16–2.26 (2H, m, 2-CH2); 2.62 (3H, s, SCH3); 3.03 (2H, t, J = 7.3, 3-CH2); 3.43 (2H, t, J = 7.6, 1-CH2); 3.63–3.70 (4H, m, N(CH2)2 morpholine); 3.73–3.80 (4H, m, O(CH2)2 morpholine). 13C NMR spectrum, δ, ppm: 13.9 (SCH3); 24.6 (2-CH2); 27.8 (3-CH2); 28.9 (1-CH2); 47.8 (3,5-CH2 morpholine); 66.4 (2,6-CH2 morpholine); 114.6; 117.8; 125.3; 146.4; 151.6; 159.2; 160.5; 160.8 (C-7); 166.7 (C-9). Found, %: C 52.03; H 4.40; N 14.34; S 16.21; Cl 9.13. C17H17ClN4OS2. Calculated, %: C 51.96; H 4.36; N 14.26; S 16.32; Cl 9.02.
Preparation of compounds 7a–k (General method). Compound 6a–f (3 mmol) in n-BuOH (40 ml) was treated with the appropriate amine (12 mmol). The mixture was refluxed for 8 h. The crystals that formed after cooling were filtered off, washed with water, ethanol, and recrystallized from a 1:1 mixture of CHCl3 and EtOH.
2,2-Dimethyl-10-methylsulfanyl- N -(pyridin-3-ylmethyl)-5-(pyrrolidin-1-yl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']-pyrido[3',2':4,5]thieno[3,2- d ]pyrimidin-8-amine (7a). Yield 1.20 g (81%), light-yellow crystals, mp 211–212°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.34 (6H, s, 2CH3); 1.93–2.01 (4H, m, 3,4-CH2 pyrrolidine); 2.49 (3H, s, SCH3); 3.45 (2H, s, 1-CH2); 3.59–3.65 (4H, m, N(CH2)2 pyrrolidine); 4.73 (2H, d, J=.9, NHCH2); 4.77 (2H, s, 4-CH2); 7.25 (1H, dd, J = 7.7, J = 4.8, H-5 Py); 7.77 (1H, ddd, J = 7.7, J = 1.9, J = 1.6, H-4 Py); 7.87 (1H, br. t, J = 5.9, NH); 8.40 (1H, dd, J = 4.8, J = 1.6, H-6 Py); 8.58 (1H, d, J = 1.9, H-2 Py). 13C NMR spectrum, δ, ppm: 13.4 (SCH3); 25.0 (3,4-CH2 pyrrolidine); 26.3 (2CH3); 37.3 (1-CH2); 41.1 (NHCH2); 49.5 (2,5-CH2 pyrrolidine); 60.1 (4-CH2); 68.5 (C-2); 105.9; 113.9; 116.2; 122.8 (C-4(5) Py); 135.2 (C-3 Py); 135.6 (C-5(4) Py); 141.6; 146.7 and 148.3 (C-2,6 Py); 155.4; 155.5; 156.3; 159.3 (C-8), 166.1 (C-10). Found, %: C60.83; H 5.79; N 17.19; S 13.10. C25H28N6OS2. Calculated, %: C 60.95; H 5.73; N 17.06; S 13.02.
2,2-Dimethyl-10-methylsulfanyl-8-(morpholin-4-yl)-5-(pyrrolidin-1-yl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']-pyrido[3',2':4,5]thieno[3,2- d ]pyrimidine (7b). Yield 1.10 g (78%), light-yellow crystals, mp 215–216°C. 1H NMR spectrum, δ, ppm: 1.34 (6H, s, 2CH3); 1.91–2.03 (4H, m, 3,4-CH2 pyrrolidine); 2.53 (3H, s, SCH3); 3.46 (2H, s, 1-CH2); 3.59–3.64 (4H, m, N(CH2)2 pyrrolidine); 3.74–3.80 (4H, m, N(CH2)2 morpholine); 3.84–3.90 (4H, m, O(CH2)2 morpholine); 4.79 (2H, s, 4-CH2). 13C NMR spectrum, δ, ppm: 13.5 (SCH3); 25.1 (3,4-CH2 pyrrolidine); 26.5 (2CH3); 37.0 (1-CH2); 48.6 (3,5-CH2 morpholine); 49.7 (2,5-CH2 pyrrolidine); 59.8 (4-CH2); 66.5 (2,6-CH2 morpholine); 68.9 (C-2); 107.8; 115.6; 118.4; 142.1; 154.7; 156.5; 157.2; 158.4 (C-8), 165.8 (C-10). Found, %: C 58.64; H 6.25; N 14.78; S 13.49. C23H29N5O2S2. Calculated, %: C 58.57; H 6.20; N 14.85; S 13.60.
2,2-Dimethyl-10-methylsulfanyl-5-(morpholin-4-yl)- N -(2-phenylethyl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']-pyrido[3',2':4,5]thieno[3,2- d ]pyrimidin-8-amine (7c). Yield 1.30 g (83 %), white crystals, mp 189–190°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.35 (6H, s, 2CH3); 2.56 (3H, s, SCH3); 2.99 (2H, t, J = 7.5, NHCH2CH 2); 3.17–3.24 (4H, m, N(CH2)2 morpholine); 3.53 (2H, s, 1-CH2); 3.70–3.76 (2H, m, NHCH 2); 3.76–3.82 (4H, m, O(CH2)2 morpholine); 4.68 (2H, s, 4-CH2); 7.11–7.20 (1H, m, H Ph); 7.21–7.28 (4H, m, H Ph); 7.47 (1H, br. t, J = 5.5, NH). 13C NMR spectrum, δ, ppm: 13.5 (SCH3); 26.6 (2CH3); 34.9 (NHCH2); 37.0 (1-CH2); 41.9 (CH2Ph); 50.0 (3,5-CH2 morpholine); 59.1 (4-CH2); 66.0 (2,6-CH2 morpholine); 69.1 (C-2); 107.8; 118.5; 120.0; 125.4 (C-4 Ph); 127.7 (C-3,5 Ph); 128.3 (C-2,6 Ph); 139.2 (C-1 Ph); 142.8; 154.6; 155.7; 158.5; 158.6 (C-8); 166.6 (C-10). Found, %: C 62.25; H 6.05; N 13.54; S 12.37. C27H31N5O2S2. Calculated, %: C 62.16; H 5.99; N 13.42; S 12.29.
N -Hexyl-2,2-dimethyl-10-methylsulfanyl-5-(morpholin-4-yl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']pyrido[3',2':4,5]-thieno[3,2- d ]pyrimidin-8-amine (7d). Yield 1.20 g (80%), white crystals, mp 231–232°C. 1H NMR spectrum, δ, ppm (J, Hz): 0.91 (3H, t, J = 6.6, CH2CH 3 ); 1.28–1.45 (6H, m, CH3(CH 2)3); 1.34 (6H, s, 2CH3); 1.61–1.71 (2H, m, NHCH2CH 2); 2.52 (3H, s, SCH3); 3.15–3.25 (4H, m, N(CH2)2 morpholine); 3.46–3.56 (4H, m, NHCH 2 , 1-CH2); 3.74–3.84 (4H, m, O(CH2)2 morpholine); 4.68 (2H, s, 4-CH2); 7.30 (1H, br. t, J = 5.4, NH). 13C NMR spectrum, δ, ppm: 13.4 (CH2 CH3); 13.6 (SCH3); 22.0 (CH2CH3); 26.1 (CH2); 28.7 (CH2); 31.0 (CH2); 26.6 (2CH3); 37.0 (1-CH2); 40.1 (NHCH2); 50.0 (3,5-CH2 morpholine); 59.1 (4-CH2); 66.0 (2,6-CH2 morpholine); 69.0 (C-2); 107.7; 118.5; 120.0; 142.8; 154.4; 155.8; 158.5 (C Ar, C-8); 166.5 (C-10). Found, %: C 59.93; H 6.98; N 13.81; S 12.67. C25H35N5O2S2. Calculated, %: C 59.85; H 7.03; N 13.96; S 12.78.
10-Benzylsulfanyl-2,2-dimethyl-8-(4-methylpiperazin-1-yl)-5-(morpholin-4-yl)-1,4-dihydro-2 H -pyrano-[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2- d ]pyrimidine (7e). Yield 1.40 g (81%), white crystals, mp 206–207°C. 1H NMR spectrum, δ, ppm: 1.21 (6H, s, 2CH3); 2.30 (3H, s, NCH3); 2.46–2.55 (4H, m, N(CH2)3 piperazine); 3.16–3.22 (4H, m, N(CH2)2 morpholine); 3.41 (2H, s, 1-CH2); 3.75–3.80 (4H, m, O(CH2)2 morpholine); 3.89–3.96 (4H, m, N(CH2)2 piperazine); 4.44 (2H, s, SCH2); 4.64 (2H, s, 4-CH2); 7.15–7.29 (3H, m, H Ph); 7.37–7.43 (2H, m, H Ph). 13C NMR spectrum, δ, ppm: 26.4 (2CH3); 34.3 (SCH2); 37.1 (1-CH2); 45.2 (NCH3, 3,5-CH2 piperazine); 49.8 (3,5-CH2 morpholine); 54.1 (2,6-CH2 piperazine); 59.0 (4-CH2); 65.9 (2,6-CH2 morpholine); 68.9 (C-2); 107.1; 118.7; 118.8; 126.2 (C-4 Ph); 127.7 (C-3,5 Ph); 127.8 (C-2,6 Ph); 137.8 (C-1 Ph); 143.1; 156.4 (C-10); 156.6; 156.9; 158.3; 159.1 (C-8). Found, %: C 62.36; H 6.25; N 14.69; S 11.03. C30H36N6O2S2. Calculated, %: C 62.47; H 6.29; N 14.57; S 11.12.
N -Benzyl-10-benzylsulfanyl-2,2-dimethyl-5-(morpholin-4-yl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']pyrido[3',2':4,5]-thieno[3,2- d ]pyrimidin-8-amine (7f). Yield 1.45 g (83%), white crystals, mp 195–196°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.23 (6H, s, 2CH3); 3.17–3.22 (4H, m, N(CH2)2 morpholine); 3.42 (2H, s, 1-CH2); 3.75–3.81 (4H, m, O(CH2)2 morpholine); 4.40 (2H, s, SCH2); 4.66 (2H, s, 4-CH2); 4.76 (2H, d, J = 5.7, NHCH 2); 7.14–7.31 (6H, m, H Ph); 7.33–7.40 (4H, m, H Ph); 8.09 (1H, br. t, J = 5.7, NH). 13C NMR spectrum, δ, ppm: 26.4 (2CH3), 34.2 (SCH2); 36.9 (1-CH2); 43.5 (NHCH2); 49.9 (3,5-CH2 morpholine); 59.0 (4-CH2); 65.9 (2,6-CH2 morpholine); 68.9 (C-2); 118.5; 119.8; 126.0; 127.6 (4CH Ph); 127.8 (2CH Ph); 127.9 (4CH Ph); 138.2 (C Ph); 139.2 (C); 142.8; 154.7; 155.8; 156.8; 158.6 (C-8); 158.7(C-10). Found, %: C 65.77; H 5.76; N 11.91; S 10.86. C32H33N5O2S2. Calculated, %: C 65.84; H 5.70; N 12.00; S 10.99.
N -Butyl- N -ethyl-10-methylsulfanyl-5-(pyrrolidin-1-yl)-1,2,3,4-tetrahydropyrimido[4',5':4,5]thieno[2,3- c ]isoquinolin-8-amine (7g). Yield 1.00 g (73%), light-yellow crystals, mp 119–120°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.01 (3H, t, J = 7.3, CH2CH 3 ); 1.30 (3H, t, J = 7.0, NCH2CH 3 ); 1.38–1.51 (2H, m, CH 2 CH3); 1.66–1.78 (4H, m, 2,3-CH2); 1.84–1.91 (2H, m, 4-CH2); 1.91–1.99 (4H, m, 3,4-CH2 pyrrolidine); 2.51 (3H, s, SCH3); 2.71 (2H, t, J = 5.9, 1-CH2); 3.52–3.62 (6H, m, NCH2CH 2, N(CH2)2 pyrrolidine); 3.64–3.71 (2H, m, NCH 2CH2); 3.76 (2H, q, J = 7.0, NCH 2CH3). 13C NMR spectrum, δ, ppm: 13.4 (NCH2CH3); 13.5 (SCH3); 19.5 (CH2 CH3); 21.6 (2-CH2); 22.3 (3-CH2); 25.1 (3,4-CH2 pyrrolidine); 27.2 (4-CH2); 27.4 (1-CH2); 30.7 (CH2); 40.1 (CH2); 43.2 (CH2); 48.0 (CH2); 49.7 (2,5-CH2 pyrrolidine); 104.0; 116.5; 117.3; 145.3; 155.7; 157.4; 158.0; 159.8 (C-8); 165.1 (C-10). Found, %: C 63.37; H 7.26; N 15.24; S 14.17. C24H33N5S2. Calculated, %: C 63.26; H 7.30; N 15.37; S 14.07.
N -(2-Furylmethyl)-10-methylsulfanyl-5-(pyrrolidin-1-yl)-,2,3,4-tetrahydropyrimido[4',5':4,5]thieno[2,3- c ]isoquinolin-8-amine (7h). Yield 1.00 g (74%), light-yellow crystals, mp 159–160°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.70–1.79 (2H, m, 2-CH2); 1.84–1.92 (2H, m, 3-CH2); 1.92–1.99 (4H, m, 3,4-CH2 pyrrolidine); 2.53 (3H, s, SCH3); 2.71 (2H, t, J = 5.7, 4-CH2); 3.49–3.65 (6H, m, N(CH2)2 pyrrolidine, 1-CH2); 4.70 (2H, d, J = 5.6, NHCH2); 6.25–6.32 (2H, m, H-3,4 Fur); 7.39 (1H, dd, J = 1.7, J = 0.7, H-5 Fur); 7.66 (1H, br. t, J = 5.6, NH). 13C NMR spectrum, δ, ppm: 13.5 (SCH3); 21.5 (2-CH2); 22.4 (3-CH2); 25.1 (3,4-CH2 pyrrolidine); 27.1 (4-CH2); 27.2 (1-CH2); 36.7 (NHCH2); 49.8 (2,5-CH2 pyrrolidine); 106.2; 106.6 (CH Fur); 109.8 (CH Fur); 117.2 (2C); 140.7 (CH Fur); 145.2; 152.5; 155.4; 155.8; 158.4; 159.6 (C-8); 165.7 (C-10). Found, %: C 61.25; H 5.64; N 15.42; S 14.34. C23H25N5OS2. Calculated, %: C 61.17; H 5.58; N 15.51; S 14.20.
10-Benzylsulfanyl-5-(morpholin-4-yl)-8-(pyrrolidin-1-yl)-1,2,3,4-tetrahydropyrimido[4',5':4,5]thieno[2,3- c ]isoquinoline (7i). Yield 1.29 g (83%), white crystals, mp 198–200°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.69–1.79 (2H, m, 2-CH2); 1.81–1.91 (2H, m, 3-CH2); 2.01–2.10 (4H, m, 3,4-CH2 pyrrolidine); 2.70 (2H, t, J = 5.2, 4-CH2); 3.17–3.24 (4H, m, N(CH2)2 morpholine); 3.53 (2H, t, J = 6.5, 1-CH2); 3.74–3.80 (4H, m, O(CH2)2 morpholine); 3.83–3.91 (4H, m, N(CH2)2 pyrrolidine); 4.41 (2H, s, SCH2); 7.14–7.28 (3H, m, HPh); 7.37–7.42 (2H, m, H Ph). 13C NMR spectrum, δ, ppm: 21.8 (2-CH2); 22.3 (3-CH2); 24.6 (4-CH2); 25.1 (3,4-CH2 pyrrolidine); 26.8 (1-CH2); 34.5 (SCH2); 47.5 (2,5-CH2 pyrrolidine); 49.8 (3,5-CH2 morpholine); 66.0 (2,6-CH2 morpholine); 108.9; 117.8; 118.6; 126.7 (C-4 Ph); 127.5 (C-3,5 Ph); 127.9 (C-2,6 Ph); 137.8 (C-1 Ph); 143.6; 157.4; 158.3; 158.7; 159.2 (C-8); 166.1 (C-10). Found, %: C 65.08; H 5.99; N 13.67; S 12.28. C28H31N5OS2. Calculated, %: C 64.96; H 6.04; N 13.53; S 12.39.
9-Methylsulfanyl-4-(morpholin-4-yl)-7-(pyrrolidin-1-yl)-2,3-dihydro-1 H -cyclopenta[4',5']pyrido[3',2':4,5]thieno[3,2- d ]-pyrimidine (7j). Yield 1.03 g (80%), cream-colored crystals, mp 241–242°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.00–2.10 (4H, m, 3,4-CH2 pyrrolidine); 2.12–2.24 (2H, m, 2-CH2); 2.52 (3H, s, SCH3); 2.95 (2H, t, J = 7.2, 3-CH2); 3.47 (2H, t, J = 7.5, 1-CH2); 3.47–3.52 (4H, m, N(CH2)2 morpholine); 3.73–3.78 (4H, m, O(CH2)2 morpholine); 3.82–3.89 (4H, m, N(CH2)2 pyrrolidine). 13C NMR spectrum, δ, ppm: 13.5 (SCH3); 25.1 (2-CH2); 25.2 (3,4-CH2 pyrrolidine), 31.4 (3-CH2); 31.7 (1-CH2); 49.4 (2,5-CH2 pyrrolidine); 49.8 (3,5-CH2 morpholine); 65.9 (2,6-CH2 morpholine); 106.8; 117.5; 123.6; 152.1; 156.4; 156.9; 157.3; 158.4 (C-7); 165.8 (C-9). Found, %: C 59.08; H 5.83; N 16.49; S 14.88. C21H25N5OS2. Calculated, %: C 58.99; H 5.89; N 16.38; S 15.00.
9-Methylsulfanyl-4,7-bis(morpholin-4-yl)-2,3-dihydro-1 H -cyclopenta[4',5']pyrido[3',2':4,5]thieno[3,2- d ]pyrimidine (7k). Yield 1.11 g (83%), light-pink crystals, mp 240–241°C. 1H NMR spectrum, δ, ppm: 2.14–2.25 (2H, m, 2-CH2); 2.55 (3H, s, SCH3); 2.98 (2H, t, J = 7.2, 3-CH2); 3.48 (2H, t, J = 7.4, 1-CH2); 3.49–3.55 (4H, m, 4-N(CH2)2 morpholine); 3.73–3.81 (8H, m, 7-N(CH2)2 morpholine, 4-morpholine). 13C NMR spectrum, δ, ppm: 13.5 (SCH3); 25.1 (2-CH2); 31.5 (3-CH2); 31.9 (1-CH2); 45.5 (3,5-CH2 4-(morpholin-4-yl)); 47.4 (3,5-CH2 7-(morpholin-4-yl)); 65.8 (2,6-CH2 4-(morpholin-4-yl)); 65.9 (2,6-CH2 7-(morpholin-4-yl)); 106.3; 117.0; 123.8; 152.6; 156.6; 156.7; 157.9; 158.6 (C-7); 166.1 (C-9). Found, %: C 56.98; H 5.72; N 15.88; S 14.32. C21H25N5O2S2. Calculated, %: C 56.86; H 5.68; N 15.79; S 14.46.
Preparation of compounds 8a–f (General method). Compound 6a–e (2 mmol) was added to sodium ethoxide solution obtained from sodium metal (46 mg, 2 mmol) and anhydrous ethanol (15 ml). The mixture was refluxed for 10 h. The crystals that formed after cooling were filtered off and washed with water, then recrystallized from a 1:2 mixture of CHCl3 and EtOH.
8-Ethoxy-2,2-dimethyl-10-methylsulfanyl-5-(pyrrolidin-1-yl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']pyrido[3',2':4,5]-thieno[3,2- d ]pyrimidine (8a). Yield 0.66 g (77%), light-yellow crystals, mp 188–189°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.35 (6H, s, 2CH3); 1.49 (3H, t, J = 7.1, OCH2CH3); 1.95–2.00 (4H, m, 3,4-CH2 pyrrolidine); 2.58 (3H, s, SCH3); 3.43 (2H, s, 1-CH2); 3.62–3.67 (4H, m, N(CH2)2 pyrrolidine); 4.61 (2H, q, J=.1, OCH2CH3); 4.80 (2H, s, 4-CH2). 13C NMR spectrum, δ, ppm: 13.5 (SCH3); 14.1 (CH2CH3); 25.0 (3,4-CH2 pyrrolidine); 26.5 (2CH3); 37.1 (1-CH2); 49.8 (2,5-CH2 pyrrolidine); 59.2 (4-CH2); 62.7 (CH2CH3); 68.8 (C-2); 108.7; 115.9; 116.1; 142.8; 156.6; 156.8; 158.5; 161.2 (C-8), 166.3 (C-10). Found, %: C 58.49; H 6.15; N.15; S 14.78. C21H26N4O2S2. Calculated, %: C 58.58; H 6.09; N 13.01; S 14.89.
8-Methoxy-2,2-dimethyl-10-methylsulfanyl-5-(morpholin-4-yl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']pyrido[3',2':4,5]-thieno[3,2- d ]pyrimidine (8b). Yield 0.68 g (79%), white crystals, mp 209–210°C. 1H NMR spectrum, δ, ppm: 1.35 (6H, s, 2CH3); 2.61 (3H, s, SCH3); 3.22–3.28 (4H, m, N(CH2)2 morpholine); 3.49 (2H, s, 1-CH2); 3.76–3.81 (4H, m, O(CH2)2 morpholine); 4.16 (3H, s, OCH3); 4.70 (2H, s, 4-CH2). 13C NMR spectrum, δ, ppm: 13.7 (SCH3); 26.1 (2CH3); 37.0 (1-CH2); 49.7 (3,5-CH2 morpholine); 54.2 (OCH3); 59.4 (4-CH2); 66.1 (2,6-CH2 morpholine); 68.9 (C-2); 108.6; 119.5; 120.3; 143.7; 155.6; 156.4; 157.5; 158.8 (C-8); 166.1 (C-10). Found, %: C 55.60; H 5.64; N 12.83; S 14.97. C20H24N4O3S2. Calculated, %: C 55.53; H 5.59; N 12.95; S 14.83.
8-Isopropoxy-2,2-dimethyl-10-methylsulfanyl-5-(morpholin-4-yl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']pyrido[3',2':4,5]-thieno[3,2- d ]pyrimidine (8c). Yield 0.71 g (77%), white crystals, mp 219–220°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.35 (6H, s, 2CH3); 1.49 (6H, d, J = 6.2, CH(CH 3)2); 2.59 (3H, s, SCH3); 3.22–3.28 (4H, m, N(CH2)2 morpho-line); 3.49 (2H, s, 1-CH2); 3.76–3.82 (4H, m, O(CH2)2 morpholine); 4.68 (2H, s, 4-CH2); 5.61 (1H, sept, J = 6.2, OCH). 13C NMR spectrum, δ, ppm: 13.5 (SCH3); 25.1 (CH(CH3)2); 26.7 (2CH3); 37.1 (1-CH2); 49.8 (3,5-CH2 morpholine); 59.3 (4-CH2); 66.0 (2,6-CH2 morpholine); 65.7 (OCH); 69.0 (C-2); 108.4; 118.7; 121.4; 141.6; 153.8; 156.6; 158.2; 158.7 (C-8); 166.4 (C-10). Found, %: C 57.45; H 6.19; N 12.27; S 13.84. C22H28N4O3S2. Calculated, %: C 57.37; H 6.13; N 12.16; S 13.92.
10-Benzylsulfanyl-8-ethoxy-2,2-dimethyl-5-(morpholin-4-yl)-1,4-dihydro-2 H -pyrano[4'',3'':4',5']pyrido[3',2':4,5]-thieno[3,2- d ]pyrimidine (8d). Yield 0.84 g (80%), white crystals, mp 178–179°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.25 (6H, s, 2CH3); 1.50 (3H, t, J = 7.0, OCH2CH3); 3.21–3.26 (4H, m, N(CH2)2 morpholine); 3.38 (2H, s, 1-CH2); 3.75–3.80 (4H, m, O(CH2)2 morpholine); 4.48 (2H, s, SCH2); 4.63 (2H, q, J = 7.0, OCH2CH3); 4.65 (2H, s, 4-CH2). 7.17–7.30 (3H, m, H Ph); 7.39–7.45 (2H, m, H Ph). 13C NMR spectrum, δ, ppm: 14.0 (CH2CH3); 26.4 (2CH3); 34.5 (SCH2); 37.0 (1-CH2); 49.8 (3,5-CH2 morpholine); 59.1 (4-CH2); 62.5 (CH2CH3); 65.9 (2,6-CH2 morpholine); 68.9 (C-2); 109.9; 118.6; 118.8; 126.3 (C-4 Ph); 127.8 (C-3,5 Ph); 127.9 (C-2,6 Ph); 137.3 (C-1 Ph); 142.9; 157.3; 159.1; 159.8; 162.4 (C-8); 166.1 (C-10). Found, %: C 62.13; H 5.72; N 10.63; S 12.35. C27H30N4O3S2. Calculated, %: C 62.04; H 5.79; N 10.72; S 12.27.
8-Ethoxy-10-methylsulfanyl-5-(pyrrolidin-1-yl)-1,2,3,4-tetrahydropyrimido[4',5':4,5]thieno[2,3- c ]isoquinoline (8e). Yield 0.71 g (88%), yellow crystals, mp 206–207°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.49 (3H, t, J = 7.0, OCH2CH3); 1.71–1.80 (2H, m, 2-CH2); 1.86–1.93 (2H, m, 3-CH2); 1.93–2.00 (4H, m, 3,4-CH2 pyrrolidine); 2.59 (3H, s, SCH3); 2.74 (2H, t, J = 5.9, 4-CH2); 3.54 (2H, t, J = 6.3, 1-CH2); 3.60–3.66 (4H, m, N(CH2)2 pyrrolidine); 4.60 (2H, q, J = 7.0, OCH2CH3). 13C NMR spectrum, δ, ppm: 13.6 (SCH3); 14.0 (CH2CH3); 21.3 (2-CH2); 22.4 (3-CH2); 25.0 (3,4-CH2 pyrrolidine); 26.8 (4-CH2); 27.1 (1-CH2); 49.7,5-CH2 pyrrolidine); 62.4 (CH2CH3); 113.7; 115.8; 119.4; 143.6; 152.8; 157.5; 159.4; 160.5 (C-8), 166.1 (C-10). Found, %: C 59.90; H 6.10; N 14.08; S 16.14. C20H24N4OS2. Calculated, %: C 59.97; H 6.04; N 13.99; S 16.01.
10-Benzylsulfanyl-8-ethoxy-5-(morpholin-4-yl)-1,2,3,4-tetrahydropyrimido[4',5':4,5]thieno[2,3- c ]isoquinoline (8f). Yield 0.78 g (79%), white crystals, mp 236–237°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.50 (3H, t, J = 7.1, OCH2CH 3); 1.71–1.81 (2H, m, 2-CH2); 1.84–1.95 (2H, m, 3-CH2); 2.66–2.74 (2H, m, 4-CH2); 3.22–3.30 (4H, m, N(CH2)2 morpholine); 3.45–3.54 (2H, m, 1-CH2); 3.74–3.83 (4H, m, O(CH2)2 morpholine); 4.47 (2H, s, SCH2); 4.62 (2H, q, J = 7.1, OCH 2CH3); 7.17–7.32 (3H, m, H Ph); 7.38–7.46 (2H, m, H Ph). 13C NMR spectrum, δ, ppm: 14.0 (CH2CH3); 22.1 (2-CH2); 22.4 (3-CH2); 26.8 (4-CH2); 27.1 (1-CH2); 34.4 (SCH2); 49.7 (3,5-CH2 morpholine); 62.4 (CH2CH3); 65.8 (2,6-CH2 morpholine); 108.7; 118.5; 118.8; 126.4 (C-4 Ph); 127.7 (C-3,5 Ph); 127.8 (C-2,6 Ph); 137.4 (C-1 Ph); 142.7; 157.1; 159.4; 160.2; 162.8 (C-8); 166.5 (C-10). Found, %: C 63.46; H 5.78; N 11.46; S 13.14. C26H28N4O2S2. Calculated, %: C 63.39; H 5.73; N 11.37; S 13.02.
Part of this study was performed with financial support from the State Committee of Science at the Ministry of Education and Science of the Republic of Armenia and Russian Foundation for Basic Research within the framework of joint scientific programs 15RF-027 and 15-53-05064/15, respectively.
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Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2016, 52(5), 337–345
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Paronikyan, E.G., Dashyan, S.S., Minasyan, N.S. et al. Synthesis of 10-alkylsulfanyl-substituted pyrido-[4',3':4,5]thieno[3,2-d]pyrimidines annulated with pyran, cyclohexane, and cyclopentane rings. Chem Heterocycl Comp 52, 337–345 (2016). https://doi.org/10.1007/s10593-016-1887-6
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DOI: https://doi.org/10.1007/s10593-016-1887-6