Research Article, J Pharm Sci Emerg Drugs Vol: 4 Issue: 2
Synthesis, Antiproliferative Activity of Nitrile Containing Pyranes and 1,2,5,6,7,8-Hexahydroquinoline-3,3,4,4-TetraÑarbonitriles
| Vladimir P Sheverdov1*, Maksim A Mar’yasov1, Vera V Davydova1, Oleg E Nasakin1 and Konstantin A Lyssenko2 | |
| 1Chuvash State University, Cheboksary- 428015, Russia | |
| 2AN Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Science, Russia | |
| Corresponding author : Vladimir P Sheverdov
Chuvash State University,Cheboksary-428015, Russia E-mail: sheverdovvp@yandex.ru |
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| Received: October 24, 2016 Accepted: November 02, 2016 Published: November 09, 2016 | |
| Citation: Sheverdov VP, Mar’yasov MA, Davydova VV, Nasakin OE, Lyssenko KA (2016) Synthesis, Antiproliferative Activity of Nitrile Containing Pyranes and 1,2,5,6,7,8-Hexahydroquinoline-3,3,4,4-Tetraсarbonitriles. J Pharm Sci Emerg Drugs 4:2. doi: 10.4172/2380-9477.1000114 |
Abstract
lMethyl 6-Amino-3-acyl-4-aryl-5-cyano-4H-pyran-2-carboxylates, 9-aryl-12-imino-10,11 dioxatricyclo-[5.3.2.01,6]-dodecan-7,8,8- tricarbonitriles, 2-R-1,2,5,6,7,8-hexahydroquinoline-3,3,4,4- tetraсarbonitriles were synthesized. The antiproliferative activity of obtained compounds was investigated. At a concentration of 10 μM test substances activity higher than that of the drug busulfan and cisplatin showed a compounds containing in its composition fragment of ethyl 1,1,2,2-tetracarbonitrile - 2-R-1,2,5,6,7,8- hexahydroquinoline-3,3,4,4-tetraсarbonitriles.
Keywords: Pharmacophore; Ethyl 1,1,2,2-tetracarbonitrile fragment;Tetracyanoethylene; Antipro-liferative activity
Keywords |
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| Pharmacophore; Ethyl 1,1,2,2-tetracarbonitrile fragment; Tetracyanoethylene; Antipro-liferative activity | |
Introduction |
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| Cancer remains one of the most serious diseases of mankind. Cancer is a leading cause of death worldwide. According to forecasts, the number of deaths from cancer in the world will continue to grow in 2030 to reach 13.1 million deaths (WHO database: Globocan, 2012). In this regard, the synthesis and investigation of antitumor activity of oxygen- and nitrogen-containing heterocyclic compounds is an urgent task for medicinal chemistry [1-3]. | |
| Despite the advent of new anticancer drugs, their clinical effectiveness is insufficient, and the spectrum of cancers that are sensitive to chemotherapy is limited. In this regard, it does not lose relevance of the question to find new chemical compounds with anti-tumour properties as the basis for further development of more effective drugs. The main criteria for the selection of the new compounds are unique chemical structure, a new mechanism of action, selective cytotoxicity availability for production, | |
| Cyano containing compounds are attracting special attention at present in the search for new antitumor agents. Thus, the cyanogenetic glucosides linamarin, lotaustralin, heterodentrin, dhurrin, amygdalin, and tetraphyllin A, which were isolated from seeds and pits of certain plants of the family Rosaceae, subfamily plum, are used in experimental oncology [4]. | |
| Cyanogenic glucosides have been reported in more than 2,650 species of higher plants distributed over 130 families. The most famous cyanogenic glucoside is amygdalin. It was first isolated in 1830 by French chemists [5] and has been used as an anticancer agent in Russia in 1845 [6]. The first use of amygdalin in the United States in the treatment of cancer occurred in the early 1920s [7]. | |
| Several drugs containing cyano groups are already used in medical practice to battle on-cological diseases. These are the antiandrogens bicalutamide, anastrozole, letrozole and the anti-biotic toyocamycin. Creation and opening of new pharmacophore groups, particularly for cancer chemotherapy, is the major problem in the theory of medicines, since they are now read by the amount. | |
| Known publications on the subject statement hold only high biological activity of some compounds due to complex combinations usually heterocyclic fragments and any functional groups. No clear pattern in studying the effect of known and possible pharmacophore groups on the biological activity of organic compounds. | |
| According to the analysis of the literature [8-11], the study of antitumour activity of the cyano-containing compounds is carried out by many groups of researchers; however, these data are not systematized yet, because the study of anti-tumour activity, as a rule, is carried out on non-large number (1-4) cell lines, while there are about 200 cell lines. | |
| We believe that one of the most promising areas of search for new antitumor agents is a synthesis and study of properties of multifunctional cyano-containing compounds. The most promising objects are probably multifunctional heterocyclic compounds. The analysis of drugs in late development or in the market shows that 68% of them are heterocyclic [12] hence it is not surprising that research on the synthesis of multi-functionalized heterocyclic compounds has received significant attention in the recent years. Our researches in this area focused on the study of properties of cyanosubstituted multifunctional carbocyclic and heterocyclic compounds, derived from tetracyanoethylene [13], 2-arylidene malononitriles [14], 4-oxoalkane-1,1,2,2-tetracarbonitriles [15]. Reactions of these compounds are usually unique and accompanied by complicated multi-step molecular level processes in simple synthesis methods. | |
Results and Discussion |
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| Chemistry | |
| Pyranes are an important class of heterocycles because the pyrane fragment present in great variety of natural products and biologically active compounds. The article [16] noted that pyranes have many pharmacological properties and play important roles in biochemical processes, include a selective inhibitor of excitatory amino acid transporter subtype 1, IKCa channel blockers, A3 adenosine receptor antagonists as potential anti-inflammatory agents, and proapoptotic activity against cancer cells (administered alone or in combination with chemo- and radio-therapy). In addition, they can be used as cognitive enhancers for the treatment of neuro-degenerative diseases. | |
| Pyranes derivatives occupy an important place in the realm of medicinal chemistry because of their biological and pharmacological properties as anticancer [17], cytotoxic [18], anti-HIV [19-21], anti-inflammatory [22], anti-malarial [23], antimicrobial [24], anti-hyperglycemic and anti-dyslipidemic [25]. Synthesis of cyanosubstituted pyranes is an urgent task [26-29]. | |
| Methyl 6-amino-3-acyl-4-aryl-5-cyano-4H-pyran-2-carboxylates 1, we prepared by reacting 2 - arylidenemalononitriles with methyl- 2,4-dioxobutanoates (Scheme 1). The reaction yield of 50-90%. | |
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Scheme 1: Scheme 1 |
| Ar=3,4,5-(MeO)3C6H2 (a, b, c), 4-MeOOCC6H4 (d), 2-F-6- ClC6H3 (e); R=Me (a), 2-Fu (b), 3,4- (MeO)2C6H3 (c), 4-BrC6H4 (d), 3,4-(MeO)2C6H3 (e). | |
| Synthesis of Methyl 6-amino-3-acyl-4-aryl-5-cyano-4H-pyran-2- carboxylates1. Reagents and conditions: 2 – arylidenemalononitrile, methyl-2,4-dioxobunoate, ethyl acetate solvent, presence of base (triethylamine or morpholine, diethylamine, piperidine), r.t. for 12- 24 hours. | |
| A promising area of synthesis of cyanopyrans is reaction of 1-(2-oxocyclohexyl)-1,1,2,2-ethanetetracarbonitrile with aldehydes. Interaction proceeds at room temperature in propanol-2 water. 9-R-12- amino-10,11-dioxatricyclo[5.3.2.01,6]dodekan-7,8,8-tricarbonitriles 2 formed in yields of 50-90% according to Scheme 2. We used 3,4,5-trimethoxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde, methyl 4-formylbenzoate, 4-(dimethylamino) benzaldehyde, citral. | |
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Scheme 2: Scheme 2 |
| R =3,4,5-(MeO)3C6H2 (a), 3-MeO-4-HOC6H3 (b), 4-MeOOCC6H4 (c), 4-(CH3)2NC6H4 (d), 2,6-dimethylheptadiene-1,5 (e). | |
| Synthesis of 9-R-12-amino-10,11-dioxatricyclo[5.3.2.01,6] dodekan-7,8,8-tricarbonitriles 2. Reaction and conditions: 1-(2-oxocyclohexyl)-1,1,2,2-ethanetetracarbonitrile, aldehyde, propanol-2 – water solvent, stirring, r.t. for 40 min - 1 h. | |
| For nitrogen containing heterocyclic compounds we synthesized 1,3,5-substituted 2,4-diazapentadiens-1,4 3. (Scheme 3). According to the data of X-ray diffraction data (XRD) for 3а (Figure 1) three parts of aldehyde react with two part of ammonia. | |
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Scheme 3: Scheme 3 |
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Figure 1: General view of 3a in representation of non-hydrogen atoms by probability ellipsoids of atomic displacements (p=50%). |
| R =4-MeOC6H4 (a), 2-Thienyl (b), i-C3H7 (c), 2-Cl-6-FC6H3 (d). | |
| Synthesis of 1,3,5-substituted 2,4-diazapentadiens-1,4 3. Reagents and conditions: aldehyde, ethanol, aqueous ammonia, r.t. for 20-24 h. | |
| 2-R-1,2,5,6,7,8-hexahydroquinoline-3,3,4,4-tetraсarbonitriles 4 we got the reaction of 1-(2-oxocyclohexyl)-1,1,2,2- ethanetetracarbonitrile with 1,3,5-substituted 2,4-diazapentadiens-1,4 3 (Scheme 4). Quinolines 4 obtained in yield of 50-69%. For 4d the structure was confirmed by XRD (Figure 2). | |
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Scheme 4: Scheme 4 |
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Figure 2: General view of one of the independent molecules of 4d in representation of non-hydrogen atoms by probability ellipsoids of atomic displacements (p=50%). |
| The quinoline ring system is an important structural unit in naturally occurring quinoline alkaloids, and synthetic analogues with interesting biological activities. Therefore, the development of new and efficient synthetic routes to the quinoline ring system is of interest in medicinal chemistry (Scheme 4). | |
| R=4-MeOC6H4 (a), 2-Thienyl (b), i-C3H7 (c), 2-Cl-6-FC6H3 (d). | |
| Synthesis of 2-R-1,2,5,6,7,8-hexahydroquinoline-3,3,4,4- tetraсarbonitriles 4. Reagents and conditions: 2,4-diazapentadiene-1,4 3, 1-(2-oxocyclohexyl)-1,1,2,2-ethanetetracarbonitrile, glacial acetic acid solvent, r.t. for 5-10 min. | |
| Biological evaluation | |
| In vitro anti-proliferative activity: Tests of anti-tumour activity of the synthesized compounds were performed at the National Cancer Institute (USA) in Maryland under the program NCI-60 Cell Single Dose Screen (http://dtp.cancer.gov/btp/ivclsp.html). In vitro research model this allows for standardized experimental conditions and quickly repeated episodes. Studies are conducted on 60 cell lines derived from solid human tumours of the lung, colon, brain, ovary, kidney, prostate, breast, melanoma, and leukaemia. | |
| It is found that the investigated for antitumor activity of substances 2-R-1,2,5,6,7,8-tetrahydroquinoline-3,3,4,4-tetracarbonitriles 4 is the most promising for further studies (Table 1). At a concentration of 10 μM compounds has a significant inhibition of tumour cell growth. | |
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Table 1: Results of the study of antiproliferative activity of the compounds at a concentration of 10 �?µM*. |
| The results show that the 2-R-1,2,5,6,7,8-hexahydroquinoline- 3,3,4,4-tetracarbonitriles 4 are most active against leukaemia. Thus, the 2-R-1,2,5,6,7,8-hexahydroquinoline-3,3,4,4-tetracarbonitriles 4 at a concentration of 10 μM are much more active as compared with known anticancer drugs such as cisplatin, busulfan and other cyanoderivatives of quinoline (NCI data-base, Table 2). The maximum average value of inhibition of leukaemia cell lines for compound 4a is 59.31% and 98.88%. The average value of inhibition of leukaemia cell lines for compound 4d is 63.19. | |
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Table 2: Antiproliferative activity of synthesized compounds and quinoline��?s derivatives (NCI database)*. |
| Only those compounds which are composed of ethyl 1,1,2,2-tetracarbonitrile fragment have the highest antiproliferative activity. We have previously synthesized 2-methyl-5-R-3,4- dihydro-2H-cyclopenta[e][1,2,4]triazin-6,6,7,7-tetrakarbonitriles, 1-(dialkylamino)-4-R-6-oksopiperidin-2,2,3,3-tetrakarbonitriles, 3-(2,2-dialkilhydrazono)-5-R-cyclopentane-1,1,2,2-tetracarbonitriles and their analogues [30]. It has been shown that compounds containing in their structure the fragment of ethyl-1,1,2,2-tetrakarbonitrile [30] have the highest antitumor activity. | |
| For comparison, the analogue of 3-(2,2-dialkilhydrazono)-5- R-cyclopentane-1,1,2,2-tetracarbonitriles, 2-cyclopentylidene-1,1- dimethyl (NSC 126436) does not contain carbonitrile groups and antitumor activity is absent (National Cancer Institute database United States (https://dtp.cancer.gov/databases_tools/data_search.htm).We believe that compounds containing ethyl-1,1,2,2- tetracarbonitrilefragment have alkylating action on tumour cells as confirmed by the model reactions of ethyl 1,1,2,2-tetracarbonitrile containing test compounds with nucleophiles [32,33]. In these processes cyano groups interact with nucleophiles under the action of catalysts proceed under mild conditions for a few seconds. In this combination when cyano groups are located at position 1,1,2,2 they are most active and able to inhibit tumour cell growth by alkylation of DNA. Restructuring ethyl-1,1,2,2-tetracarbonitrilefragment compounds considered leads to complete loss of antitumor activity [30,31]. Ethyl-1,1,2,2-tetracarbonitrile fragment behaves as a pharmacophore. | |
Conclusion |
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| The studies of the properties of 1,1,2,2-tetracyano-substituted carbocyclic and heterocyclic carbonitriles are the most promising, because we believe that this fragment is a pharmacophore alkylating mode of action. 2-R-1,2,5,6,7,8-hexahydroquinoline-3,3,4,4- tetraсarbonitriles prove to be most effective against leukaemia, lung, colon, ovarian, kidney and breast cancer. | |
Experimental |
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| Biological activity | |
| Test substances are typically dissolved in DMSO: glycerol (9:1 ratio) and adjusted to a concentration of 10 μM or 15 mg/ml (https:// dtp.cancer.gov/discovery_development/nci-60/handling.htm). A known number of tumour cells are dispersed into a 96-well plate for 24 hrs to settle, and then the drug is added for 48 h at 37°C in an atmosphere containing 5% CO2, 95% air with a relative humidity of 100%. Cell growth was stopped by adding 50 μl of cold 50% trichloroacetic acid and incubating the mixture for 60 min at 4°C. Microplates were washed 5 times with cold water and dried in air. They were added to each well 100 μl solution of 0.4% sulforhodamine B (SRB) in 1% acetic acid and the mixture was kept at room temperature for 10 minutes. After staining, unbound dye remaining and dead cells were removed by washing 5x with 1% acetic acid. Microplates were air dried. Bound dye was then dissolved in 200 μl of 10 mM (10-2 M) aqueous solution of this (hydroxymethyl) aminomethane (Trizma base) and absorption was read in an automatic microplate photometer at a wavelength of 515 nm. To add a reagent and microplate washing instruments used BioTek ELx405 and Titertek Zoom. Determination of the optical density of SRB dye was carried out on the universal microplate photometer Teacan Sunrise reader. | |
| The percentage of tumour cell growth (GP) when the inhibition (TD<T0) was calculated by the formula: GP=[(TD - T0)/T0] • 100% where TD-mean optical density of tumour cells at the end of the test; T0-the average optical density of tumour cells at the initial time, prior to the addition of the test substance. The results for the one dose assay are reported as growth relative to the no-drug control and relative to the time zero number of cells. This allows detection of both growth inhibition and lethality (https://dtp.cancer.gov/discovery_ development/nci-60/methodology.htm). | |
| Synthesis | |
| Materials and methods: All reagents were purchased from commercial suppliers and were used without further purification. Melting point was determined on an Electrothermal 9100 melting point apparatus (Weiss-Gallenkamp, Loughborough, UK). The course of reactions and purity of products were monitored by TLC on Silufol UV-254 plates (detection using UV light, I2, vapour, and thermal decomposition). IR-spectra were recorded from thin layers (mineraloil mull) on an FSM-1201 instrument. PMR and 13C NMR spectra were recorded in DMSO-d6 with TMS internal standard on a Bruker DRX-500 spectrometer at the operating frequency 500.13 MHz for 1H and 125.76 MHz for 13C. Molecular weights were determined in a Finnigan MAT Incos-50 instrument (electron-impact, 70 eV). Elemental analyses agreed with those calculated. | |
| General procedure for the preparation of 6-amino-3-acyl-4-aryl- 5-cyano-4H-pyran-2-carboxylates 1a-1e: To a suspension of methyl 2,4-dioxobutanoate (2 mmol) in 5 ml of ethyl acetate there was added 2-arilidenmalononitrile (2.1 mmol) and a drop of piperidine (triethylamine or morpholine, diethylamine) was stirred to dissolve the reagents. The mixture was kept at room temperature for 12-24 hours (control by TLC). After the reaction, ethyl acetate was distilled off un-der vacuum. The residue was recrystallized from 2-propanol. | |
| Methyl 3-Acetyl-6-amino-5-cyano-4-(3,4,5-trimetoxyphenyl)-4Hpyran- 2-carboxylate (1a): Yield: 72.2%, m.p. 191-193оС. IR νmax(cm-1): 3447, 3331 (N-H stretching), 2190 (C≡N stretching), 1735 (C=O stretching), 1593 (С=C stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 1.90 (s, 3H, CH3CO), 3.47 (s, 3H, COOCH3), 3.77 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 4.41 (s, 1H, pyran), 6.51 (s, 1H, H-2 Ar), 6.53 (s, 1H, H-6 Ar), 7.17 (s, 2H, NH2). | |
| 13C NMR (150 MHz, DMSO−d6) δ (ppm): 192.04, 159.51, 153.11, 152.78, 148.31, 136.36, 128.72, 123.43, 119.93, 110.54 (CN), 110.04, 105.48, 59.77, 55.78, 55.70, 55.34, 54.75, 52.46, 42.65, 40.11, 39.90, 39.69, 39.48, 39.27, 39.07, 38.86. | |
| MS:m/z (Irel,%): 388.13 [M]+, found 388. | |
| Anal Calcd for C19H20N2O7: C, 58.76; H, 5.19; N, 7.21; Found: C, 58.73; H, 5.24; N, 7.18. | |
| Methyl 6-amino-5-cyano-3-(furan-2-carbonyl)-4-(3,4,5-trimethoxyphenyl)- 4H-pyran-2-carboxylate (1b): Yield: 80.7%, m.p. 237-239 °С. IR νmax(cm-1): 3421, 3334 (N-H stretching), 2193 (C≡N stretching), 1735 (C=O stretching),1595 (С=C stretching) | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 7.91 (d, J=10.0 Hz, 1H, 2-Fu), 7.17 (d, J=10.0 Hz, 1H, 2-Fu), 7.16 (m, 1H, 2-Fu), 7.16 (s, 1H, C6H2), 6.63 (s, 1H, C6H2), 6.45 (s, 2H, NH2), 4.51 (s, 1H, pyran), 3.68 (s, 3H, CH3COO), 3.59 (s, 3H, OCH3), 3.57 (s, 3H, OCH3), 3.56 (s, 3H,OCH3). | |
| 13C NMR (150 MHz, DMSO-d6) δ (ppm): 179.05, 160.10, 158.83, 152.77, 151.72, 148.13, 137.33, 136.76, 136.46, 123.40, 119.27, 112.72 (CN), 105.49, 104.91, 59.87, 55.84, 55.46, 52.71, 41.97, 40.11, 39.69, 38.85. | |
| MS: m/z (Irel, %): 440.12 [M]+, found 440. | |
| Anal Calcd for C22H20N2O8: C, 60.00; H, 4.58; N, 6.36; Found: C,60.07; H, 4.52; N,6.31. | |
| Methyl 6-amino-5-cyano-3-(3,4-dimethoxybenzoyl)-4-(3,4,5- trimethoxyphenyl)-4H-pyran-2-carboxylate (1c): Yield: 89.0%, m.p. 218-221 °С IR νmax(cm-1): 3436, 3297 (N-H stretching), 2194 (C≡N stretching ), 1736 (C=O stretching), 1594 (С=C stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 7.20 (s, 2H, NH2), 7.07 (s, 1H, C6H3), 7.06 (d, J=10.0 Hz, 1H, C6H3), 6.91 (d, J=10.0 Hz, 1H, C6H3), 6.39 (d, J=10.0 Hz, 1H, C6H3), 6.37 (d, J=10.0 Hz, 1H, C6H3), 4,43 (s, 1H, pyran), 3.83 (s, 3H, CH3COO), 3.78 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.65 (s, 3H, OCH3),3.52 (s, 3H, OCH3), 3.50 (s, 3H, OCH3). | |
| 13C NMR (150 MHz, DMSO-d6) δ (ppm): 192.04, 159.51, 153.11, 152.78, 148.31, 136.36, 128.72, 123.43, 119.93, 110.54, 110.04, 105.48,59.77, 55.78, 55.70, 55.34, 54.75, 52.46, 42.65, 40.11, 39.90, 39.69, 39.48, 39.27, 39.07, 38.86. | |
| MS: m/z (Irel, %): 510.16 [M]+, found 510. | |
| Anal Calcd for C26H26N2O9: C, 61.17; H, 5.13; N, 5.49; Found: C, 61.13; H, 5.18; N, 5.45. | |
| Methyl 6-amino-3-(4-bromobenzoyl)-5-cyano-4-(4- (methoxycarbonyl)phenyl)-4H-pyran-2-carboxylate (1d): Yield: 81.9%, m.p. 235-237 оС. Yield: 89.0%, m.p. 218-221°С. IR νmax(cm-1): 3336, 3261 (N-H stretching), 2203 (C≡N stretching ), 1740 (C=O stretching), 1658, 1593 (С-C stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 7.97 (d, J=10.0 Hz,1H, C6H4), 7.95 (d, J=10.0 Hz, 1H, C6H4), 7.75 (d, J=10.0 Hz, 1H, C6H4), 7.72 (d, J=10.0 Hz, 1H, C6H4), 7.70 (d, J=10.0 Hz, 1H, C6H4), 7.68 (d, J=10.0 Hz, 1H, C6H4), 7.39 (d, J=10.0 Hz, 1H, C6H4), 7.38 (d, J=10.0 Hz, 1H, C6H4), 7.26 (s, 2H, NH2), 5.01 (s, 1H, pyran), 4.66 (s, 3H, CH3COO), 4.59(s, 3H,OCH3). | |
| 13C NMR (150 MHz, DMSO-d6) δ (ppm): 192.07, 161.71, 158.23, 130.61, 130.33, 129.88, 129.56, 128.81, 128.31, 127.65, 116.93, 65.36, 63.26, 52.13, 42.83, 40.10, 39.90, 39.69, 39.48, 39.27, 39.06, 38.85. | |
| MS:m/z (Irel, %): 496.03 [M]+, found 497. | |
| Anal Calcd for C23H17BrN2O6: C, 55.55; H, 3.45; N, 5.63; Found: C,55.59; H, 3.41; N,5.67. | |
| Methyl 6-amino-4-(2-chloro-6-fluorophenyl)-5-cyano-3-(3,4- dimethoxybenzoyl)-4H-pyran-2-carboxylate (1e): Yield: 54.0%, m.p.178-180 оС. IR νmax(cm-1): (N-H stretching), (C≡N stretching ), 1738 (C=O stretching), 1655,1594 (С-C stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 7.40 (s, 1H, C6H3), 7.38 (s, 1H, C6H3), 7.36 (s, 1H, C6H3), 7.21 (s, 1H, C6H3), 7.20 (d, J=10.0 Hz, 1H, C6H4), 7.02 (d, J=10.0 Hz, 1H, C6H4), 6.99 (s, 2H, NH2), 5.15 (s, 1H, pyran), 3.82 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.51 (s, 3H, CH3COO). | |
| 13C NMR (150 MHz, DMSO-d6) δ (ppm): 189.96, 159.95, 159.84, 153.55, 148.70, 130.63, 130.53, 128.15, 125.47, 123.19, 118.97, 115.73, 110.96, 109.60, 55.75, 55.39, 52.62, 40.11, 39.90,39.69, 39.49, 39.07, 38.86. | |
| MS: m/z (Irel, %): 472.08 [M]+, found 472. | |
| Anal Calcd for C23H18ClFN2O6: C, 58.42; H, 3.84; N, 5.92; Found: C, 58.39; H, 3.88; N, 5.97. | |
| General procedure for the preparation of 9-R-12-imino-10,11- dioxatricyclo[5.3.2.01,6]dodekan-7,8,8-tricarbonitriles 2a-2e: To a suspension of 1-(2-oxocyclohexyl)-1,1,2,2-ethanetetracarbonitrile (2 mmol) in 20 ml mixture of propanole-2 water (1:1) added corresponding aldehyde (2.1 mmol) and stirred to dissolve the reagents and the subsequent formation of a precipitate at room temperature (40min-1h). The precipitate was filtered off and recrystallized from 2-propanol. | |
| 12-imino-9-(3,4,5-trimetoxyphenyl)-10,11-dioxatricyclo [5.3.2.01,6]dodekan-7,8,8-tricarbonitrile (2a): Yield: 81.5%, m.p. 173-175 оС. IR νmax(cm-1): 3283 (N-H stretching), 2253(C≡N stretching ), 1594 (С-C stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.78 (s, 1H, NH), 7.21 (d, J=10.0 Hz, 1H, C6H2), 7.18 (d, J=10.0 Hz, 1H, C6H2), 5.64 (s, 1H,pyran), 3.83 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 1.94 (m, 2H, CH2), 1.82 (dd, J=12.0 Hz, 5.8 Hz, 1H, CH), 1.73-1.68 (m, 2H, CH2), 1.65-1.62 (m, 2H, CH2), 1.61-1.42 (m, 2H, CH2). | |
| 13C NMR (150 MHz, DMSO-d6) δ (ppm): 191.43, 165.26, 141.89, 130.05, 129.83, 129.78, 129.36, 128.11, 126.57, 120.13, 106.75, 74.21, 61.19, 52.53, 52.49, 52.14, 39.90, 39.69, 39.47, 24.15, 23.51, 20.63. | |
| MS: m/z (Irel, %): 422.16 [M]+, found 422. | |
| Anal Calcd forC22H22N4O5: C, 62.55; H, 5.25; N, 13.26; Found: C, 62.59; H, 5.21; N, 13.31. | |
| 9-(4-hydroxy-3-metoxyphenyl)-12-imino-10,11-dioxatricyclo [5.3.2.01,6]dodekan-7,8,8-tricarbonitrile (2b): Yield: 63.0%, m.p. 154-156 оС. IR νmax(cm-1): 3259 (N-H stretching), 2257(C≡N stretching ), 1596 (С-C stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.96 (s, 1H, OH), 9.69 (s, 1H, NH), 6.89 (s, 1H, C6H3), 6.84 (s, 1H, C6H3), 6.79 (s, 1H, C6H3), 5.58 (s, 1H, pyran), 3.86 (s, 3H, OCH3), 1.95 (m, 2H, CH2), 1.81 (dd, J=12.0 Hz, 5.8 Hz, 1H, CH), 1.76-1.66 (m, 2H, CH2), 1.64-1.60 (m, 2H, CH2), 1.58-1.0 (m, 2H, CH2). | |
| 13C NMR (150 MHz, DMSO-d6) δ (ppm):191.84, 163.81, 143.13, 129.98, 129.74, 129.57, 129.32, 128.03, 126.48, 120.11, 106.59, 61.17, 52.24, 39.89, 39.67, 39.49, 27.21, 24.37, 23.43, 20.59. | |
| MS:m/z (Irel, %): 378.13 [M]+, found 378. | |
| Anal Calcd for C20H18N4O4: C, 63.48; H, 4.79; N, 14.81; Found: C, 63.52; H, 4.73; N,14.84; | |
| 12-imino-9-(4-(methoxycarbonyl)phenyl)-10,11-dioxatricyclo [5.3.2.01,6]dodekan-7,8,8-tricarbonitrile (2c): Yield: 75.6%, m.p. 195-197 оС. IR νmax(cm-1): 3272 (N-H stretching), 2253(C≡N stretching ),1711(C=O stretching), 1593 (С-C stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.92 (s, 1H, NH), 8.15 (d, J=8.8 Hz, 1H, C6H4), 8.10 (d, J=8.8 Hz, 1H, C6H4), 7.82 (d, J=8.8 Hz, 1H, C6H4), 7.80 (d, J=8.8 Hz, 1H, C6H4), 5.91 (s, 1H, pyran), 3.90 (s, 3H, CH3COO), 1.93 (m, 2H, CH2), 1.79 (dd, J=12.0 Hz, 5.8 Hz, 1H, CH), 1.76-1.70 (m, 2H, CH2), 1.66-1.63 (m, 2H, CH2), 1.31-1.60 (m, 2H, CH2). | |
| 13C NMR (150 MHz, DMSO-d6) δ (ppm): 192.91, 165.73, 142.10, 129.97, 129.79, 129.62, 129.44, 127.99, 126.61, 120.08, 106.82, 74.10, 61.36, 52.37, 39.90, 39.69, 39.48, 27.17, 24.47, 23.40, 20.76. | |
| MS:m/z (Irel, %): 390.13 [M]+, found 390. | |
| Anal Calcd for C21H18N4O4: C, 64.61; H, 4.65; N, 14.35; Found: C, 64.68; H, 4.61; N,14.38. | |
| 9-(4-dimethylaminophenyl)-12-imino-10,11-dioxatricyclo [5.3.2.01,6]dodekan-7,8,8-tricarbonitrile (2d): Yield: 52.0%, m.p. 192-194 оС. IR νmax(cm-1): 3295 (N-H stretching), 2254(C≡N stretching), 1595 (С-C stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.67 (s, 1H, NH), 7.70 (d, J=8.8 Hz, 1H, C6H4), 7.68 (d, J=8.8 Hz, 1H, C6H4), 7.25 (d, J=8.8 Hz, 1H, C6H4), 7.23 (d, J=8.8 Hz, 1H, C6H4), 4.86 (s, 1H, pyran), 3.05 (s, 3H, CH3), 2.95 (s, 3H, CH3), 2.2 1(m, 2H, CH2), 2.13 (dd, J=12.0 Hz, 5.8 Hz, 1H, CH), 1.65 (m, 2H, CH2), 1.63 (m, 2H, CH2), 1.60 (m, 2H, CH2). | |
| 13C NMR (150 MHz, DMSO-d6) δ (ppm):189.81, 177.61, 152.09, 131.50, 128.78, 120.12, 115.69, 113.68, 113.31, 111.44, 111.03, 99.10, 78.24, 55.88, 39.91, 39.70, 39.49, 26.77, 21.81, 21.62, 20.11. | |
| MS: m/z (Irel, %): 375.17 [M]+, found 375. | |
| Anal Calcd for C21H21N5O2: C, 67.18; H, 5.64; N, 18.65; Found: C,67.14; H, 5.69; N,18.68. | |
| 9-(2,6-dimethylhepta-1,5-diene-1-yl)-12-imino-10,11- dioxatricyclo[5.3.2.01,6]dodekan-7,8,8-tricarbonitrile (2e): Yield: 51.09%, m.p. 140-142 оС. IR νmax(cm-1): 3267 (N-H stretching), 2252 (C≡N stretching ), 1717 (C=N stretching), 1674 (С=C stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.75 (s, 1H, NH), 5.35 (d, J=9.0 Hz, 1H, CH), 5.05 (d, J=6.8 Hz, 1H, CH), 4.96 (d, J=9.0 Hz, 1H, CH), 2.85-2.83 (m, 1H, CH), 2.18-1.97 (m, 6H, (CH2)3), 1.77 (s, 3H, CH3), 1.75-1.71 (m, 3H, (CH2)2), 1.65 (s, 3H, CH3), 1.57 (s, 3H, CH3), 1.51-1.44 (m, 1H, CH2), 1.32-1.25 (m, 1H, CH2), 1.08-1.01 (m, 1H, CH2). | |
| 13C NMR (150 MHz, DMSO-d6) δ (ppm): 156.33, 149.00, 132.08, 123.32, 116.36 (CN), 112.75, 110.47 (CN), 110.39 (CN), 107.81, 70.64, 46.23, 40.23, 40.15, 39.73, 39.33, 32.86, 29.98, 25.62, 23.64, 22.07, 21.10, 17.94. | |
| MS: m/z (Irel, %): 378.21 [M]+, found 378. | |
| Anal Calcd for C22H26N4O2: C, 69.82; H, 6.92; N, 14.80; Found: C, 69.77; H, 6.96; N,14.88. | |
| General procedure for the preparation of 1,3,5-substituted 2,4-diazapentadiens-1,4 3a-3b,3d: To a solution of aldehyde (3 mmol) in ethanol (1 ml) added 5 ml aqueous ammonia (25 per cent by weight) at room temperature. Next day the precipitate was filtrated off and recrystallized from ethanol. | |
| 1,3,5-tri(4-metoxyphenyl)-2,4-diazapentadiene-1,4 3a: Yield: 72.11%, m.p. 125-127 оС IR νmax(cm-1): 1631(C=N stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 8.52 (s, 2H, (HC=)2), 7.79-7.76 (d, J=8.8 Hz, 4H, C6H4), 7.39-7.37 (d, J=8.8 Hz, 2H, C6H4), 7.02-7.00 (d, J=8.8 Hz, 4H, C6H4), 6.93-6.91 (d, J=8.8 Hz, 2H, C6H4), 5.84 (s, 1H, CH), 3.80 (s, 6H, (OCH3)2), 3.73 (s, 1H, OCH3). | |
| MS: m/z (Irel, %): 388.18 [M]+, found 388. | |
| Anal Calcd For C24H24N2O3: C, 74.21; H, 6.23; N, 7.21; Found: C, 74.27; H, 6.19; N, 7.25. | |
| 1,3,5-tri(2-thienyl)-2,4-diazapentadiene-1,4 3b: Yield: 63.20%, m.p. 104-106 оС IR νmax(cm-1): 1690(C=N stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 7.77-7.75 (d, J=5.0 Hz, 2H, thiophene), 7.74-7.73 (d, J=4.5 Hz, 1H, thiophene), 7.61 (s, 2H, (HC=)2), 7.49-7.47 (d, J=5.0 Hz, 1H, thiophene), 7.21-7.19 (d, J=7.0 Hz, 1H, thiophene), 7.19-7.17 (m, 2H, thiophene), 7.04-7.01 (m, 1H, thio-phene), 6.82-6.78 (d, J=4.5 Hz, 1H, thiophene), 6.1 (s, 1H, CH). | |
| MS: m/z (Irel, %): 316.02 [M]+, found 316. | |
| Anal Calcd for C15H12N2S3: C, 56.93; H, 3.82; N, 8.85; Found: C, 56.96; H, 3.77; N, 8.89. | |
| 1,3,5-tri(i-propyl)-2,4-diazapentadiene-1,4 3c: To 0.136 g (2 mmol) of aqueous ammonia (25 per cent by weight) added 0.144 g (2 mmol) i-butiraldehyde. The reaction mixture was cooled to hold the temperature at 5-10°С during the addition of the aldehyde. The agitation was then stopped and the reaction mixture allowed settling. The upper layer was leaving from the lower aqueous layer and then distilled under reduced pressure to get the substance. | |
| Yield: 69.35%, b.p. 93-95°С (20 mm). IR νmax (cm-1): 1668(C=N stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 7.56-7.54 (d, J=4.4 Hz, 2H (HC=)2), 3.93-3.92 (d, J=5.7 Hz, 1H, CH), 2.53-2.47 (m, 2H, CH), 1.81-1.78 (m, 1H, CH), 1.04-1.03 (d, J=6.9 Hz, 3H, CH3), 1.02-1.01 (d, J=6.9 Hz, 6H, (CH3)2), 0.92-0.88 (m, 6H, (CH3)2), 0.79-0.77 (d, J=6.8 Hz, 3H, CH3). | |
| MS: m/z (Irel, %): 196.19 [M]+, found 196. | |
| Anal Calcd for C12H24N2: C, 73.41; H, 12.32; N, 14.27; Found: C, 73.38; H, 12.26; N,14.32. | |
| 1,3,5-tri(2-chloro-6-fluorophenyl)-2,4-diazapentadiene 3d: 1H NMR (500 MHz, DMSO-d6) δ (ppm): 8.92 (s, 2H, (HC=)2), 7.57-7.52 (m, 2H, C6H3), 7.44-7.41 (m, 4H, C6H3), 7.37-7.32 (m, 2H, C6H3), 7.28-7.24 (m, 1H, C6H3), 6.85 (s, 1H, CH). | |
| MS: m/z (Irel, %): 455.65 [M]+, found 455. | |
| Anal Calcd for C21H12Cl3F3N2: C, 55.35; H, 2.65; N, 6.15; Found: C, 55.38; H, 2.71; N,6.07. | |
| General procedure for the preparation of 2-R-1,2,5,6,7,8- hexahydro-3,3,4,4-tetraсarbonitriles 4a-4d: To a suspension of 1-(2-oxocyclohexyl)-1,1,2,2-ethanetetracarbonitrile (2 mmol) in 5 ml glacial acetic acid there was added 1,3,5-substituted 2,4-diazapentadiene-1,4 (1 mmol) and it was stirred to dissolve the reagents at room temperature (5-10 min). After the reaction, acetic acid was distilled off under vacuum. The residue was recrystallized from 2-propanol. | |
| 2-(4-methoxyphenyl)-1,2,5,6,7,8-hexahydroquinoline-3,3,4,4- tetracarbonitrile(4a): Yield: 50.3%, m.p. 147-149 оС IR νmax(cm-1): 3372 (N-H stretching), 2247 (C≡N stretching), 1595, 1504(C-C stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 7.32 (d, J=8.8 Hz, 1H, C6H4), 7.30 (d, J=8.8 Hz, 1H, C6H4), 6.98 (d, J=8.8 Hz, 1H, C6H4), 6.97 (d, J=8.8, 1H, C6H4), 3.98 (s, 1H, quinoline), 3.76 (s, 3H, OCH3), 2.40 (s, 1H, NH), 2.04 (m, 2H, CH2), 2.03 (m, 2H, CH2), 1.75 (m, 2H, CH2), 1.72 (m, 2H,CH2). | |
| 13C NMR (150 MHz, DMSO-d6) δ (ppm): 174.11, 159.74, 133.35, 128.52, 128.43, 128.21, 115.20, 114.03, 81.60, 80.27, 56.27, 55.91, 55.15, 40.10, 39.89, 39.69, 39.27, 39.06, 24.75, 22.16. | |
| MS: m/z (Irel, %): 343.14 [M]+, found 343. | |
| Anal Calcd for C20H17N5O: C, 69.96; H, 4.99; N, 20.40; Found: C, 69.91; H, 4.93; N, 20.47. | |
| 2-(2-Thienyl)-1,2,5,6,7,8-hexahydroquinoline-3,3,4,4- tetracarbonitrile (4b): Yield: 68.4 %, m.p. 136-138 оС IR νmax(cm-1): 3345 (N-H stretching), 2244 (C≡N stretching), 1610,1512 (C-C stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 7.21 (s, 1H, thiophene), 7.08 (s, 1H, thiophene), 6.95 (s, 1H, thiophene), 3.54 (s, 1H, quinoline), 2.51 (s, 1H, NH), 2.04 (m, 2H, CH2), 2.00 (m, 2H, CH2), 1.74 (m, 2H, CH2), 1.72 (m, 2H, CH2). | |
| 13C NMR (150 MHz, DMSO-d6) δ (ppm): 184.73, 154.02, 138.69, 129.11, 128.89, 127.78, 127.33, 114.18, 45.01, 40.12, 39.92, 39.71, 39.50, 39.29, 39.08, 24.63, 22.28. | |
| MS: m/z (Irel, %): 319.09 [M]+, found 319. | |
| Anal Calcd for C17H13N5S: C, 63.93; H, 4.10; N, 21.93; Found: C, 63.90; H, 4.14; N,21.89. | |
| 2-isopropyl-1,2,5,6,7,8-hexahydroquinoline-3,3,4,4- tetracarbonitrile (4c): Yield: 53.4%, m.p. 124-126 оС IR νmax(cm-1): 3399 (N-H stretching), 2246 (C≡N stretching), 1595, 1530(C-C stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 2.87-2.79 (m, 1H, CH), 2.54 (s, 1H, NH), 2.40-2.37 (m, 1H, CH2), 2.29-2.25 (m, 1H, CH2), 2.14-2.08 (m, 1H, CH2), 1.79-1.75 (d, J=14.0 Hz, 1H, CH), 1.31-1.26 (m, 1H, CH2), 1.24-1.20 (m, 1H, CH2), 1.19-1.13 (m, 1H, CH2), 1.11- 1.09 (d, J=6.6, 2H, (CH3)2), 1.07-1.03 (m, 1H, CH2), 0.95-0.90 (m, 1H, CH2). | |
| MS: m/z (Irel, %): 279.15 [M]+, found 279. | |
| Anal Calcd for C16H17N5: C, 68.79; H, 6.13; N, 25.07; Found: C, 68.77; H, 6.10; N, 25.11. | |
| 2-(2-chloro-6-fluorophenyl)-1,2,5,6,7,8-hexahydroquinoline- 3,3,4,4-tetracarbonitrile (4d): Yield: 65.8 %, m.p. 151оС IR νmax(cm-1): 3389 (N-H stretching), 2246 (C≡N stretching) 1660, 1605(C-C stretching). | |
| 1H NMR (500 MHz, DMSO-d6) δ (ppm): 8.64 (s, 1H, NH), 7.73- 7.69 (m, 1H, C6H3), 7.59-7.49 (m, 2H, C6H3), 2.54 (s, 1H, CH), 2.46- 1.40 (m, 8H, (CH2)4). | |
| MS: m/z (Irel, %): 365.80 [M]+, found 366. | |
| Anal Calcd for C19H13ClFN5: C, 62.39; H, 3.58; N, 19.15; Found: C, 62.33; H, 3.63; N,19.18. | |
| X-Ray diffraction study | |
| X-ray diffraction analysis was carried out with: Stoe diffractometer (CuKα-radiation, (λ =1.54086 Å) with Pilatus100K detector at 298K for 3a; 2) SMART APEX II CCD (MoKα-radiation, λ=0.71073 Å) at 120 K for 4d. Details of data collection and structure refinement for 3a and 4d are presented in Table 3 CCDC-1483887 (3A) and 1506765 (4d) and contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. | |
|
Table 3: Crystal data and structure refinement parameters for 3a and 4d. |
Acknowledgments |
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| This work was supported by the Russian Science Foundation (project no. 15-13-10029). | |
References |
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