Scientific paper
Synthesis and Structural Characterization of Pyrazino[1,3]diazepines, as a New Ring System
Mohamed Attia Waly
Faculty of Science (Damiatta), Chemistry Department Mansoura University, Egypt * Corresponding author: E-mail: mohamedwalz7@yahoo.com
Received: 03-05-2007
Abstract
Pyrazino[1,3]diazepine represents a new ring system and was synthesized via annulation of the diazepine ring onto the preformed pyrazine derivatives. These compounds were synthesized as potential non-peptide, small-molecule IL-8 receptor antagonists. Different new pyrazine derivatives were also prepared for the syntheses of these new ring systems.
Keywords: Guanidine nitrate; S-methylisothiourea sulphate; pyrazine; dimethylacetylene dicarboxylate; non-peptide small-molecule IL-8 receptor antagonists.
1. Introduction
Diarylureas 1, 2 and 2-amino-3-heteroaryl quinoxa-lines 3 depicted below are found to be specific non-peptide, small-molecule antagonists of the interleukin (IL) receptor.1,2,3,4 Herein we describe a synthesis of the new pyrazino[1,3]diazepine ring systems 4 and 5 as potential non-peptide, small-molecule IL-8 receptor antagonists.
2. Results and Discussion
In our strategy, the [1,3]diazepine nucleus was built onto the preformed piperazine derivatives. Guanidine nitrate and S-methylisothiourea sulphate were employed as the sources of nitrogen atoms in [1,3] diazepine syntheses.
For the syntheses of pyrazino[1,3]diazepine derivatives of the structure 4, reaction of the bromomethylcar-boethoxypyrazines 6 or 13 with either guanidine nitrate (7) or S-methylisothiourea sulphate (8), in the presence of potassium carbonate, afforded the pyrazino[1,3]diazepine derivatives 11 and 16, or 12 and 17, rather than the alternative tautomers 9 and 14 or 10 and 15, respectively (Scheme 1). The 1H NMR spectra for the products 11 and 16 showed the presence of two different kinds of activated enamine protons (NH2 and NH protons), instead of the amide NH protons. In addition, the 13C NMR spectra for compounds 11, 12, 16 and 17 showed for the 5-C signals with upfield chemical shift, namely at 5 197.7, 198.4, 201.0 and 199.3 ppm, respectively. These data revealed the amidate5 not amidic nature for these compounds and supported the existence of the tautomers 11, 12, 16 and 17, respectively. The S-methylthio derivatives 12 and 17 showed SMe protons at 5 2.24 and 2.20 ppm.
Compounds 6 and 13 were prepared by condensation of the 1,2-diamino derivatives with ethyl-a-bromoa-cetoacetate6 in tetrahydrofuran (THF) and potassium carbonate to pyrazine derivatives 18 and 18a, respectively. During the separation of the latter compounds we found
Ac	Ac 0	Ac O
Rl N^CH2Br NH2	ethanol R/ N V-N	R( N "NH
Ac	Ac	Ac
6,13	7,8	9,10,14,15	11,12,16,17
Scheme 1
Compound	R1	R2	Yield (%)	Compound	R1	R2	Yield (%)
6	H	-	65	11	H	NH2	64
13	Me	-	75	12	H	SMe	60
7	-	NH2	-	14	Me	NH2	-
8	-	SMe	-	15	Me	SMe	-
9	H	NH2	-	16	Me	NH2	52
10	H	SMe	-	17	Me	SMe	70
that they were soluble in water and poorly extracted into organic solvents. In addition, they decomposed on standing, so they were diacetylated with acetic anhydride and zinc to compounds 20 and 20a, respectively (Scheme 2). The 2-C amino group of 1,2-diaminopropane moiety is sterically more hindered than the 1-C amino group, so we proposed that it would add to a carbonyl carbon of the ethyl-a-bromoacetoacetate and produce 5-methylpyrazi-ne derivative 18a, rather than its alternative isomer 19 (Scheme 2). Bromination of compounds 20 and 20a with N-bromosuccinimide7 in the presence of dibenzoylperoxi-de as a catalyst in carbon tetrachloride afforded the bro-momethyl pyrazine derivatives 6 and 13, respectively.
The fused tricyclic ring systems containing pyrazi-no-pyrimido[1,3]diazepine moiety (i.e. 22 or 23) were
synthesized in a similar procedure, by direct condensation of bromomethyl pyrazines 6 and 13 with 2-amino-4,6-di-methylpyrimidine 21 (method a). A different procedure (method b) involved condensation of acetylacetone with the aminopyrazino[1,3]diazepines 11 or 16 (Scheme 3).
The other pyrazinodiazepine isomer 5 was prepared as shown in Scheme 4. For this, the 1,2-diamine compound reacts with dimethylacetylene dicarboxylate8 to yield the amide pyrazine derivatives 24 and 25, via addition of one amino group to the triple bond and condensation of the other one with the ester group, which is present on the same side. The 1H NMR spectra of compounds 24 and 25 showed the presence of vinylic proton signals as singlet at 5 5.28 and 5.17 ppm, respectively, in addition to two different NH protons. The structure of 5-
NH,
Br\^C02Et
H,N
Me O
R = H, Me
Ac
N ,C02Et
XX
THF/Na2C03
XX
Or
N CH3
H18; R = H 18a: R = Me
acetic anhydride and zinc
Ac
NBS/CCU
N-^C02Et
R N cH2Br di benzoyl peroxide FT ^CH3
Ac
Ac
N^C03EtMe N c03Et
.X
N CH,
i J
H
19
Scheme 2
6; R=H, 13; R = Me
20; R= H, 59% 20a; R = Me, 63%
Scheme 3
methylpyrazine derivative 25 was confirmed by 2D NMR (COSY). The 1-NH, at 5 3.34 ppm, makes a weak interaction with 6-C-0-hydrogen at 5 3.45 ppm, this illustrating the presence of a CH2 moiety in the piperazine ring beside 4-NH, and confirming the proposed structure 25. Reaction of the amide carbonyl group of compounds 24 and 25 with phosphorous oxychloride gave the chloro derivatives 26 and 27, respectively. The 1H NMR spectra for latter compounds showed the disappearance of both NH and vinylic protons (in contrast with the starting materials 24 and 25) and the presence of allylic activated methylene protons at 5 2.55 and 2.35 ppm, which revealed the existence of the tautomeric forms 26 and 27. IR absorption showed the upfield carbonyl ester at a frequency of 1720 cm1 and disappearance of the amide car-bonyl absorption. Condensation of the chloroester derivatives 26 and 27 with guanidine nitrate yielded the ami-nopyrazino[1,3]diazepines 28 and 29, respectively. Both compounds 28 and 29 showed the presence of two different signals for enaminic protons (NH2 and NH) in their 1H NMR spectra. In addition, further condensation of the
chloro derivatives 26 and 27 with S-methylisothiourea sulphate provided the methylthiopyrazino[1,3]diazepine derivatives 30 and 31, respectively. The 13C NMR spectra for compounds 28, 29, 30 and 31 also showed the upfield shift of 4-C for carbonyl group at 5 205.6, 203.1, 210.4 and 209.2 ppm, respectively. The 1H NMR spectra for the methylthio pyrazino-diazepines 30 and 31, revealed the presence of the SMe protons at 5 2.22 and 2.15 ppm, respectively.
3. Conclusion
In conclusion, we have presented a facile route to pyrazino[2,3-e][1,3]diazepin-5-one derivatives 11, 12, 16 and 17 and pyrazino[2,3-d][1,3]diazepin-4(5H)-one derivatives 28, 29, 30 and 31 with amidate functions starting from the condensation of haloester and guanidine or S-methylisothiourea. Moreover, pyrazino[1,3]diazepine derivatives 11, 16, 28 and 29 with aminal functional group will open access for further structure-activity studies.
Scheme 4
4. Experimental
Silica gel plates (Merck F, 254) and silica gel 60 (Merck, 70-230 mesh) were used for TLC and column chromatography, respectively. Melting points were determined on a Gallenkamp melting point apparatus. Microanalyses were performed with a Perkin-Elmer 260 elemental analyzer for C, H, and N, and the results were within ±0.4% of the theoretical values. The IR spectra were recorded with a Perkin-Elmer 1420 spectrometer in nujol mulls for the solids and mixed with KBr in case of liquids, , wavenumbers are expressed in cm-1, of maximum absorption peaks. The 1H NMR spectra were recorded with Varian EM 390 instrument at 200 MHz, the two dimensional spectra (1H-1H COSY) were taken at 500 MHz and 13C NMR at 50 MHz. The chemical shifts are reported in 5 (ppm). All the exchangeable protons were confirmed by the addition of D2O. Beside standard abbreviations, dm is used for double multiplets.
Ethyl 1,4-diacetyl-1,4,5,6-tetrahydro-3-methylpyrazi-ne-2-carboxylate (20).
1,2-Diaminoethane (0.6 g, 0.01 mol) in tetrahydro-furan (5 mL) was added to a solution of ethyl-a-bromoa-cetoacetate (2.09 g, 0.01 mol) in tetrahydrofuran (20 mL) and sodium carbonate (3.0 g) at -20 °C during 15 min. The reaction mixture was stirred for 4 h, then the temperature was raised and the room temperature was mantained for 8 h. The reaction mixture was filtered, dried over anhydrous sodium sulphate and evaporated in vacuo. The crude material was dissolved in acetic anhydride (30 mL) and zinc (5 g) was added and reaction mixture was reflu-xed for 6 h. The reaction mixture was poured in water (50 mL), extracted with chloroform, washed with water (3 x 20 mL), dried over anhydrous sodium sulphate and evaporated in vacuo to give crude product 20. It was purified on column chromatography (ethyl acetate: petroleum ether 10%) and recrystallized from ethyl acetate to give pure product 20 (1.5 g, 59%). Mp 190 °C. IR vmax 1640 (C=O, amide), 1690 (C=O, vinyl ester). 1H NMR (CDCl3) 5 1.2-1.3 (3H, t, J = 7.1 Hz, CO2CH2CH3), 1.75 (3H, s, 3-CH3), 2.12 (3H, s, CH3, 4-NCOCH3), 2.43 (3H, s, 1-NCOCH3), 3.12-3.43 (4H, m, 5-CH2, 6-CH2), 4.13 (2H, q, J = 7.1 Hz, CO2CH2CH3). 13C NMR 5 171.1, 170.0, 169.2, 126.2, 110.3, 65.5, 49.3, 48.1, 22.0, 22.1, 15.7, 13.6. Anal. Calcd for C12H18N2O4 (254.282): C, 56.68; H, 7.13; N, 11.02. Found: C, 56.75; H, 7.22; N, 11.12.
Ethyl 1,4-diacetyl-1,4,5,6-tetrahydro-3,5-dimethylpy razine-2-carboxylate (20a).
The same procedure as described for compound 20, yielding 1.7 g of 20a (63%). Mp 143-146 °C. IR v 1710 (C=O, ester), 1650 (C=O, acetyl) cm-1. 1H NMR (CDCl3) 5 1.27 (6H, m, CO2CH2CH3, 5-CH3), 2.01 (3H, s, 4-NCOCH3), 2.10 (3H, s, 1-NCOCH3), 2.80 (3H, s, 3-CH3), 3.40-3.67 (2H, 2 x m, J = 6.1 Hz, J= 10.1 Hz, 6-CH2), 3.7
(2H, q, J = 7.1 Hz, CO2CH2CH3), 3.80 (1H, m, J = 10.1 Hz, 5-H). 13C NMR 5 171.7, 170.7, 170.2, 125.2, 105.5, 64.2, 63.2, 47.5, 23.2, 22.4,18.4, 15.5, 13.3. Anal. Calcd for C13H20N2O4 (268.309): C, 58.19; H, 7.51; N, 10.44. Found3 C, 582.43; H, 7.32; N, 10.11.
Ethyl 1,4-diacetyl-3-(bromomethyl)-1,4,5,6-tetrahydro pyrazine-2-carboxylate (6)
A mixture of allylic compound 20 (2.54 g, 0.01 mol), N-bromosuccinimide (2.1 g, 0.012 mol) and diben-zoyl peroxide (0.01 g, catalyst) in carbon tetrachloride (20 mL) was irradiated with a lamp (60 W) for 8 h. Cold water (50 mL) and chloroform (50 mL) were added and the organic layer was separated, washed with cold water (3 x 20 mL), dried over anhydrous sodium sulphate and evaporated in vacuo to give pure product 6 (2.1 g, 65%). Mp 110 °C. IR vmax 1640 (CO, amide), 1700 (CO, ester). 1H-NMR (DMSO-d6) 5 1.2-1.3 (3H, t, J = 7.1 Hz, CO2CH2CH3), 2.12 (3H, s, 1-NCOCH3), 2.23 (3H, s, 4-NCOCH3), 3.12-3.43 (4H, m, 5-CH2, 6-CH2), 3.9 (2H, s, CH2Br), 4.13 (2H, q, J = 7.1 Hz, CO2CH2CH3). 13C NMR 5 1820.2, 172.4, 170.7, 140.4, 136.3, 70.7, 50.5, 50.3, 34.2, 30.1, 24.2, 16.6. Anal. Calcd for C12H17BrN2O4 (333.178): C, 43.26; H, 5.14; Br, 23.98; N, 8.41. Found: C, 43.44; H, 5.20; Br, 24.00; N, 8.54.
Ethyl 1,4-diacetyl-3-(bromomethyl)-1,4,5,6-tetrahydro -5-methylpyrazine-2-carboxylate (13).
The same procedure as described for compound 6, yielding 2.6 g of 13 (75%). Mp 116 °C. IR v 1720 (C=O, ester), 1660 (C=O, acetyl) cm-1. 1H NMR (DMSO-d6) 5 1.33 (6H, m, CO2CH2CH3, 5-CH3), 2.22 (3H, s, 4-NCOCH3), 2.25 (3H, s, 1-NCOCH3), 3.34-3.45 (2H, 2 x m, J = 61 Hz, J = 10.1 Hz, 6-CH2), 3.88 (2H, q, J = 7.1 Hz, CO2CH2CH3) 4.00 (1H, m, 5-H), 4.30 (2H, s, CH2Br).13C NMR 5 177.8, 173.2, 171.0, 139.0, 133.2, 69.22, 64.2, 48.8, 33.4, 28.8, 23.2, 20.1, 16.2. Anal. Calcd for C13H19BrN2O4 (347.205): C, 44.97; H, 5.52; Br, 23.01; N, 8.07. Found: C, 45.23; H, 5.32; Br, 23.25; N, 8.25.
Methyl 2-(3-oxopiperazin-2-ylidene)acetate (24).
A solution of dimethylacetylene dicarboxylate (7.1 g, 0.05 mol) in absolute ethanol (20 mL) was added to a solution of 1,2-diaminoethane (3.0 g, 0.05 mol) in absolute ethanol (20 mL) dropwise during 30 min with stirring at room temperature. The reaction mixture was further stirred for 4 h and the white precipitate was filtered off. The product was crystallized from ethanol to give pure piperazino-ester derivative 24 (6.8 g, 80%). Mp 170 °C. IR v 3450 (sh., NH), 1705 (C=O, ester), 1675 (C=O, amide) cm-1. 1H NMR (DMSO-dg) 5 3.38-3.48 (4H, m, 5-CH2 6-CH2), 3.63 (3H, s, CO2CH3), 5.28 (1H, s, vinylic), 8.42 (1H, br, 4-NH, exch.), 8.51 (1H, br, 1-NH, exch.). Anal. Calcd for C7H10N2O3 (170.166): C, 49.41; H, 5.92; N, 16.46. Found: C, 49.63; H, 6.15; N, 16.26.
Methyl 2-(5-methyl-3-oxopiperazin-2-ylidene)aceta te (25).
The same procedure as described for compound 24, yielding 7.4 g of 25 (84%). Mp 205-207 °C. IR v 3450 (sh., NH), 1700 (C=O, ester), 1680 (C=O, amide) cm-1. 1H-NMR (DMSO-d6, 500 MHz) 5 1.05 (3H, d, J = 7.1 Hz, CH3), 2.92 (1H, t, J= 6.1 Hz, 6-Ha), 3.34 (1H, br, 1-NH, exch.), 3.36-3.45 (1H, dd, J = 6.1 Hz, J = 10.1 Hz, 6-Hp), 3.52 (3H, s, CO2CH3), 3.57 (1H, m, 5-H), 5.17 (1H, s, vinylic), 8.28 (1H, br, 4-NH, exch.). 13C NMR 5 170.8, 165.5, 158.5, 110.5, 54.3, 63.3, 50.5, 19.5. Anal. Calcd for C8H12N2O3 (184.192): C, 52.17; H, 6.57; N, 15.21. Found: C, 52.33; H, 6.72; N, 15.43.
Methyl 2-(3-chloro-5,6-dihydropyrazin-2-yl)acetate (26).
A mixture of the oxopiperazino-acetate derivative 24 (1.7 g, 0.01 mol), phosphorus oxychloride (5 mL, excess) and triethylamine (10 mL, excess) in acetonitrile (20 mL) was stirred at room temperature for 1 h. It was reflu-xed for 4 h and after cooling poured into cold water and the yellowish white precipitate was separated. The precipitate was triturated with diethyl ether (5 x 10 mL) to give the pure product 26 (1.1 g, 61%). Mp 80-82 °C. IR v 3400 (sh., NH), 1720 (C=O, ester) cm-1. 1H-NMR (CDCl3) 5 2.55 (2H, s, CH2CO2Me), 3.44-3.56 (4H, 2 x m, 5-CH2, 6-CH2), 3.85 (3H, s, CO2CH3). 13C NMR 5 175.5, 173.3, 171.2, 60.6, 59.3, 52.5, 32.6. Anal. Calcd for C7H9ClN2O2 (188.612): C, 44.58; H, 4.81; Cl, 18.80; N, 14.85. Found: C, 44.88; H, 4.58; Cl, 18.63; N, 15.22.
Methyl 2-(3-chloro-5,6-dihydro-5-methylpyrazin-2-yl) acetate (27).
The same procedure as described for compound 26, yielding 1.6 g of 27 (78%). Mp 105-110 °C. IR v 3400 (sh., NH), 1716 (C=O, ester) cm-1. 1H NMR (CDCl3) 5 1.35 (3H, d, J = 7.1 Hz, 5-CH3), 2.35 (2H, s, CH2CO2Me), 3.20 (1H, m, J = 6.1 Hz, 6-Ha), 3.60 (1H, m, J = 10.1 Hz, 6-Hp), 3.80 (3H, s, CO2CH3), 4.65 (1H, m, 5-H). 13C NMR 5 174.3, 173.1, 170.7, 59.0, 58.6, 50.5, 32.0, 20.3. Anal. Calcd for C8H11ClN2O2 (202.638): C, 47.42; H, 5.47; Cl, 17.50; N 13.82. Found: C, 47.66; H, 5.23; Cl, 17.30; N, 13.43.
General procedure for the reaction between pyrazinoha loester and guanidine nitrate or S-methylisothiourea
sulphate.
A mixture of pyrazino-haloester (0.01 mol), guanidine nitrate (1.22 g, 0.01 mol), or S-methylisothiourea sulphate (1.88 g, 0.01 mol) and potassium carbonate (3.0 g, 0.03 mol) in absolute ethanol (30 mL) were refluxed for 8 h. The obtained mixture was poured into cold water (75 mL) and the precipitate was filtered off. The pure material was obtained by recrystalization from ethanol (90%).
1,4-Diacetyl-7-amino-1,2,3,4,8,9-hexahydropyrazino [2,3-e][1,3]diazepin-5-one (11).
Yielding 1.7 g of 11 (64%). Mp 173-180 °C. IR v 3350 (br, NH2), 1690 (C=O, C-5), 1650 (C=O, acetyl, N-4), 1640 (C=O, acetyl, N-1) cm-1. 1H NMR (DMSO-d6) 5
2.02	(3H, s, 1-NCOCH3), 2.10 (3H, s, 4-NCOCH3), 3.22-3.44 (4H, 2 x m, 2-CH2, 3-CH2), 4.45 (2H, s, 9-CH2), 7.45 (2H, br, exch., 7-NH2), 7.65 (1H, br, exch., 8-NH). 13C NMR 5 197.7, 171.0, 170.6, 165.6, 135.5, 115.5, 51.6, 51.4, 40.4, 22.8, 21.4. Anal. Calcd for C11H15N5O3 (265.269): C, 49.81; H, 5.70; N, 26.40. Found: C, 50.10;
H,	5.66; N, 26.23.
I,4-Diacetyl-7-amino-1,2,3,4,8,9-hexahydro-2-methyl pyrazino[2,3-e][1,3]diazepin-5-one (16).
Yielding 1.54 g of 16 (52%). Mp 220-225 °C. IR v 3350 (br, NH2), 1685 (C=O, C-5), 1640 (C=O, acetyl, N-4), 1635 (C=O, acetyl, N-1) cm-1. 1H NMR (DMSO-d6) 5
1.3	(3H, d, J = 7.1 Hz, 2-CH3), 2.00 (3H, s, 1-NCOCH3), 2.10 (3H, s, 4-NCOCH3), 3.335-3.50 (2H, 2 x m, 3-CH32), 4.10 (1H, m, 2-H), 4.32 (2H, s, 9-CH2), 7.50 (2H, br, exch., 7-NH2), 7.60 (1H, br, exch., 8-NH). 13C NMR 5 201.0, 170.5, 168.9, 165.5, 134.5, 116.4, 60.6, 46.8, 40.2, 22.5, 21.2, 18.2. Anal. Calcd for C12H17N5O3 (279.295): C, 51.60; H, 6.14; N, 25.08. Found: C, 51.50; H, 6.33; N, 25.32.
2-Amino-7,8-dihydro-1H-pyrazino[2,3-d][1,3]diazepin -4(5H)-one (28).
Yielding 0.8 g of 28 (45%). Mp 215-218 °C. IR v 3300 (br, NH2), 1680 (C=O, C-4) cm-1. 1H NMR (DMSO-d6) 5 2.85 (2H, s, 5-CH2), 3.50-3.75 (4H, 2 x m, 7-CH2, 8-CH2), 7.48 (2H, br, exch., 2-NH2), 7.85 (1H, br, exch., 1-NH). 13C NMR 5 205.6, 171.5, 170.4, 168.1, 55.2, 50.3, 30.3. Anal. Calcd for C7H9N5O (179.179): C, 46.92; H, 5.06; N, 39.09. Found: C, 46.(51; H, 5.32; N, 39.29.
2-Amino-7,8-dihydro-8-methyl-1H-pyrazino[2,3-d][1, 3]diazepin-4(5H)-one (29).
Yielding 0.96 g of 29 (50%). Mp 240-245 °C. IR v 3300 (br, NH2), 1680 (C=O, C-4) cm-1. 1H NMR (DMSO-d6) 5 1.33 (3H, d, J = 7.1 Hz, 8-CH3), 2.80 (2H, s, 5-CH2), 3.20-3.40 (2H, 2 x m, J = 6.1 Hz, J = 10.1 Hz, 7-CH2), 4.10 (1H, m, J = 10.1 Hz, 8-H), 7.50 (2H, br, exch., 2-NH2), 7.60 (1H, br, exch., 1-NH).13C NMR 5 203.1,
168.3,	166.7, 169.5, 60.2, 48.1, 29.8, 20.3. Anal. Calcd for C8H11N5O (193.206): C, 49.73; H, 5.74; N, 36.25. Found: C 49.60; H, 5.55; N, 36.45.
1,4-Diacetyl-1,2,3,4,8,9-hexahydro-7-(methylt-hio)pyrazino[2,3-e][1,3]diazepin-5-one (12).
Yielding 1.77 g of 12 (60%). Mp 170 °C. IR v 3350 (sh., NH), 1692 (C=O, C-5), 1654 (C=O, acetyl, N-4), 1645 (C=O, acetyl, N-1) cm-1. 1H NMR (DMSO-d6) 5 2.00 (3H, s, 1-NCOCH3), 2.11 (3H, s, 4-NCOCH3), 2.24 (3H, s, SCH3), 3.20-3.40 (4H, m, 2-CH2, 3-CH2), 4.33 (2H, s, 9-CH2), 7.75 (1H, br., exch., 8-NH).13C NMR 5
198.4,	170.8, 170.3, 170.1, 166.1, 137.2, 51.5, 51.0, 42.4,
21.3, 22.7, 15.3. Anal. Calcd for C12H16N4O3S (296.345): C, 48.64; H, 5.44; N, 18.91; S, 10.82. Found: C, 48.33; H, 5.34; N, 18.66; S, 10.63.
1,4-Diacetyl-1,2,3,4,8,9-hexahydro-2-methyl-7-(methylthio)pyrazino[2,3-e][1,3]diazepin-5-one (17).
Yielding 2.2 g of 17 (70%). Mp 195 °C. IR v 3350 (sh., NH), 1690 (C=O, C-5), 1640 (C=O, acetyl, N-1), 1635 (C=O, acetyl, N-4) cm1. 1H NMR (DMSO-d6) 5 1.28 (3H, d, J = 7.1 Hz, 2-CH3), 2.07 (3H, s, 1-NCOCH3), 2.12 (3H, s, 4-NCOCH3), 2.20 (3H, s, SCH3), 3.30-3.445 (2H, 2 x m, 3-CH2), 4.20 (1H, m, 2-H), 4.52 (2H, s, 9-CH2), 7.73 (1H, t»r, exch., 8-NH). 13C NMR 5 199.3, 170.9, 169.2, 168.1, 135.1, 116.8, 60.9, 47.1, 41.4, 21.5, 22.6, 18.3, 15.2. Anal. Calcd for C13H18N4O3S (310.372): C, 50.31; H, 5.85; N, 18.05; S, 10.33. Found: C, 50.51; H, 5.66; N, 18.11; S, 10.23.
7,8-Dihydro-2-(methylthio)-1#-pyrazino[2,3-d][1,3] diazepin-4(5.ff)-one (30).
Yielding 1.26 g of 30 (60%). Mp 210-212 °C. IR v 3400 (sh., NH), 1685 (C=O, C-4) cm-1. 1H NMR (DMSO-d6): 5 2.22 (3H, s, SCH3), 2.65 (2H, s, 5-CH2), 3.35-3.65 (4H, 2 x m, 7-CH2, 8-CH2), 4.66 (2H, s, 5-CH2), 8.66 (1H, br, exch., 1-NH).13C NMR 5 210.4, 170.2, 169.2, 166.6, 59.1, 48.8, 29.3, 15.3. Anal. Calcd for C8H10N4OS (210.256): C, 45.70; H, 4.79; N, 26.65; S, 15.25. Found: C, 45.34; H, 4.54; N, 26.76; S, 15.33.
7,8-Dihydro-8-methyl-2-(methylthio)-1.ff-pyrazino[2, 3-rf][1,3]diazepin-4(5tf)-one (31).
Yielding 1.48 g of 31 (66%). Mp 230-233 °C. IR v 3400 (sh, NH), 1660 (C=O, C-4) cm-1. 1H NMR (DMSO-d6) 5 1.33 (3H, d, J = 7.1 Hz, 8-CH3), 2.15 (3H, s, SCH3), 2.55 (2H, s, 5-CH2), 3.11-3.33 (2H, 2 x m, J = 6.1 Hz, / = 10.1 Hz, 7-CH2), 4.00 (1H, m, J = 10.1 Hz, 8-H), 7.88 (1H, br, exch., 1-NH).13C NMR 5 209.2, 168.0, 167.5, 165.8, 59.3, 48.0, 28.1, 20.1, 15.1. Anal. Calcd for C9H12N4OS (224.283): C, 48.20; H, 5.39; N, 24.98; S, 149.30. Found: C, 48.43; H, 5.40; N, 24.77; S, 14.35.
1,4-Diacetyl-8,10-dimetyhl-1,2,3,4,11-pentahydropyra zino[2,3-e]-pyrimido[1,2-aJ[1,3]diazepm-5-one (22).
Method a. Fusion of the pyrazinobromoester derivative 6 (0.9 g, 0.003 mol) with 2-amino-4,6-dimethylpyri-midine (0.34 g, 0.003 mol) was carried out in an oil bath (140 °C) for 3 h. The residue was then dissolved in absolute ethanol (5 mL) and poured into a cold solution of sodium carbonate. The precipitate was collected and recry-stallized from mixture of N,N-dimethylformamide and water (3:1) to give pure product 22 (0.44 g, 45%). Mp >300 °C. IR v 1680 (C=O, C-5), 1660 (C=O, acetyl, N-4), 1650 (C=O, acetyl, N-1) cm-1. 1H NMR (DMSO-d6) 5 1.72 (3H, s, 10-CH3), 1.92 (3H, s, 8-CH3), 2.11 (3H, s, 1-NCOCH3), 2.20 (3H, s, 4-NCOCH3), 3.33-3.54 (4H, dm, 2-CH2, 3-CH2), 4.82 (2H, s, 11-CH2), 6.54 (1H, s, 9-
H).13C NMR 5 202.4, 177.8, 176.1, 171.8, 169.3, 162.3, 138.2, 118.1, 105.5, 50.3, 49.9, 44.5, 25.2, 23.5, 21.4, 21.1. Anal. Calcd for C16H19N5O3 (329.354): C, 58.35; H, 5.81; N, 21.26. Found: C, 58.55; H, 6.00; N, 21.30.
Method b. Fusion of the aminopyrazino-diazepine derivative 11 (1.33 g, 0.005 mol) with acetylacetone (0.5 g, 0.005 mol) and anhydrous sodium acetate (1.65 g, 0.02 mol) was carried out in an oil bath (140 °C) for 8 h. The residue was then dissolved in absolute ethanol (8 mL) and poured into cold water. The precipitate was collected and recrystallized from mixture of N,N-dimethyl-formamide and water (3 : 1) to give pure product identical to the compound 22 (same TLC and IR, 0.98 g, yield 60%).
1,4-Diacetyl-2,8,10-trimetyhl-1,3,4,11-tetrahydropyra-zino[2,3-e]-pyrimido[1,2-a] [1,3]diazepin-5-one (23).
Same procedures as for compound 22; method a gave 0.56 g (55%) of the compound 23, whereas the method b gave 1.0 g (63%) of the same compound 23 (TLC and IR). Mp >300 °C. IR v 1680 (C=O, C-5), 1660 (C=O, acetyl, N-4), 1650 (C=O, acetyl, N-1) cm-1. 1H NMR (DMSO-d6) 5 1.13 (3H, d, J = 7.1 Hz, 2-CH3), 1.68 (3H, s, 10-CH3), 6.90 (3H, s, 8-CH3), 2.00 (3H, s, 1-NCOCH3), 2.10 (3H, s, 4-NCOCH3), 3.30-3.40 (2H, dm, 3-CH2), 4.12 (1H, m, 2-H), 4.80 (2H, s, 11-CH2), 6.44 (1H, s, 9-H). 13C NMR 5 200.2, 175.8, 175.5, 171.3, 170.3, 169.9, 136.2, 116.6, 101.2, 60.6, 47.5, 42.5, 24.8, 22.5, 21.0, 20.8, 18.1. Anal. Calcd for C17H21N5O3 (343.38): C, 59.46; H, 6.16; N, 20.40. Found: C, 59.50; H, 6.10; N, 20.33.
5. References
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Povzetek
S pripajanjem diazepinskega obroča na že v naprej pripravljene pirazinske derivate so bili sintetizirani nekateri novi pi-razino[1,3]diazepinski ciklični sistemi. V ta namen so bili pripravljeni različni novi, kot tudi že znani, pirazinski derivati. Produkti bi morda lahko učinkovali kot nepeptidni antagonisti IL-8 receptorjev z majhno molekulsko maso.