Synthesis of N-Alkaloidacyl Derivatives of Phenothiazine - Springer Link

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2008, Vol. 81, No. 2, pp. 263!267. + Pleiades Publishing, Ltd., 2008. Original Russian Text + I.V. Kulakov, A.A. Ainabaev, O.A. Nurkenov, A.M. Gazaliev, 2008, published in Zhurnal Prikladnoi Khimii, 2008, Vol. 81, No. 2, pp. 274 !277.

ORGANIC SYNTHESIS AND INDUSTRIAL ORGANIC CHEMISTRY

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Synthesis of N-Alkaloidacyl Derivatives of Phenothiazine I. V. Kulakov, A. A. Ainabaev, O. A. Nurkenov, and A. M. Gazaliev Institute of Organic Synthesis and Coal Fuel Chemistry of the Republic of Kazakhstan, Karaganda, Kazakhstan Received May 30, 2007

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Abstract Compounds in which cytisine, anabasine, D-pseudoephedrine, and L-ephedrine fragments are linked to the phenothiazine nitrogen atom via acyl group were synthesized. These compounds are potential drugs, and their activity was confirmed by computer prediction using PASS software. DOI: 10.1134/S1070427208020195

Many S,N-containing heterocyclic compounds exhibit a broad spectrum of biological activity. Fused tricyclic systems occupy a particular place in this series. For example, phenothiazine 1 is very important as insecticide and helminthicide [1]. The toxicity of phenothiazine, like that of many sulfur-containing compounds, is very low.

and antiarrhythmic action [4]. Among more than a thousand of new phenothiazine compounds, certain relationships were revealed between the biological activity and the structure of substituents at the N atom and in the cyclic system. 10-Aminopropionyl derivatives proved to be the most active, and lengthening or shortening of the acylalkyl chain decreased the activity [5]. However, despite a huge number of the phenothiazine derivatives synthesized, compounds combining a tricyclic phenothiazine core with certain physiologically active alkaloids as substituents have not been reported.

The discovery in the 1960s of compounds with a high neuroleptic activity (aminazine, largactil) [2, 3] among 10-aminoalkyl phenothiazine derivatives stimulated their synthesis and comprehensive study. It was also found that 10-aminoacyl phenothiazine derivatives, inactive as neuroleptics, show high cholinoand adrenolytic activity and pronounced antianginal

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O

N

N

3

S

N

OÍCCH2ÄN > > 3!6

OÍCCH2Cl 2

N

< < < N =

776

S

ClCH2COCl

N H 1

Therefore, it was interesting to prepare previously unknown phenothiazine derivatives of certain alkaloids:

HO H H H ; C6H5ÄCÄCÄCH3 ; C6H5ÄCÄCÄCH3 . H HO NÄCH3 NÄCH3

4

5

The starting phenothiazine was prepared by the procedure described in [6]. The alkylation of cytisine, anabasine, L-ephedrine, and D-pseudoephedrine with 10-(2-chloroacetyl)phenothiazine was performed

6


in refluxing toluene in the presence of triethylamine. The target products were purified by column chromatography and by conversion of the hydrochlorides into free bases that are difficultly soluble in water. 263

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Compounds 3! 6 are white or gray crystalline substances readily soluble in the majority of organic solvents. To further study the structure3activity relationship, we also prepared N-alkaloidpropionyl phenothiazine

derivatives, because specifically 10-aminopropionyl phenothiazine derivatives exhibit high cholino- and adrenolytic activity and pronounced antianginal and antiarrhythmic action:

d 68g6 68g6 j68g6 jd dj?C8g8;=;9c6;8g gg gg


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N H 1

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ClCH2CH2COCl

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< < < NH

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OÍCÄCH2CH2Cl 7

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N

O

N

N

8

9

Compounds 8!11 are white or gray crystalline substances melting at lower temperatures than their acetyl analogs. The compounds are soluble in the majority of organic solvents. The yield, physicochemical constants, and analytical data are listed in Table 1. The IR spectra of all the compounds prepared contain, along with bands of the functional groups of alkaloid fragments [n(OH) at 3320 33280 cm!1 for ephedrine alkaloids; n(C=O) of the cytisine core at 1647 cm!1], also a strong absorption band of the carbonyl (amide) group at 167231650 cm!1. The mass spectra of 3! 6 and 8311 contain a peak of the molecular ion M+ with a relative intensity of 5 to 30% and fragment peaks. Their m/z values and relative intensities Irel (%) are given below for compound 4 as an example: 175 (100%), 199 (22%), 132

OÍCÄCH2CH2ÄN > > 8!11

HO H H H ; C6H5ÄCÄCÄCH3 ; C6H5ÄCÄCÄCH3 . H HO NÄCH3 NÄCH3 10

11


(24%), and 44% (58%). These peaks were assigned to the anabasine core >N3CH+2 , phenothiazine, and other fragmentation products. The 1H NMR spectra of 3!11 contain, along with signals of phenothiazine protons (multiplets and doublets at 7.20 37.70 ppm), also signals of protons of the alkaloid fragments, having typical chemical shifts:

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Table 1. Physicochemical constants and elemental analyses of the compounds prepared

ÄÄÄÄÄÄÂÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ ³ ³ ³ Found, % ³ ³ Calculated, % Com- ³ Yield, ³ ÃÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄ´ ÃÄÄÄÄÄÄÄÂÄÄÄÄÄÄÂÄÄÄÄÄÄ mp, C Empirical formula pound ³ % ³ ³ C ³ H ³ N ³ ³ C ³ H ³ N ÄÄÄÄÄÄÅÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÅÄÄÄÄÄÄÅÄÄÄÄÄÄ 3 ³ 75.0 ³ 99 100 ³ 69.38 ³ 4.97 ³ 9.12 ³ C25H23N3O2S ³ 69.91 ³ 5.40 ³ 9.78 4 ³ 62.1 ³ 75 76 ³ 71.30 ³ 5.28 ³ 9.98 ³ C24H23N3OS ³ 71.79 ³ 5.77 ³ 10.47 5 ³ 67.7 ³ 63 64 ³ 70.78 ³ 5.39 ³ 6.42 ³ C24H24N2O2S ³ 71.26 ³ 5.98 ³ 6.93 6 ³ 70.0 ³ 94 95 ³ 70.85 ³ 6.42 ³ 6.38 ³ C24H24N2O2S ³ 71.26 ³ 5.98 ³ 6.93 8 ³ 72.0 ³ 70 72 ³ 69.91 ³ 5.16 ³ 8.96 ³ C26H25N3O2S ³ 70.40 ³ 5.68 ³ 9.47 9 ³ 66.6 ³ 73 74 ³ 71.76 ³ 5.57 ³ 9.62 ³ C25H25N3OS ³ 72.26 ³ 6.06 ³ 10.11 10 ³ 65.0 ³ 63 65 ³ 71.26 ³ 5.78 ³ 6.17 ³ C25H26N2O2S ³ 71.74 ³ 6.26 ³ 6.69 11 ³ 68.0 ³ 69 70 ³ 72.16 ³ 6.70 ³ 6.22 ³ C25H26N2O2S ³ 71.74 ³ 6.26 ³ 6.69 ÄÄÄÄÄÄÁÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÁÄÄÄÄÄÄÁÄÄÄÄÄÄ

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SYNTHESIS OF N-ALKALOIDACYL DERIVATIVES OF PHENOTHIAZINE Table 2. Results of computer prediction of the bioactivity of the compounds synthesized

68gg6 8g8;=;9 C ? 68gg6 g 6 8;g 68g6gg 68gg6 8g8;=;9 C ? 68gg g 6 8; 68g6ggg

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ÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ ³ Pi ³ Expected kind of activity Compound ³ Structural formula ³ Pa ÄÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÄÄÅÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ S ³ 0.930 ³ 0.002 ³ Antismoking ³ ³ ³ 0.900 ³ 0.004 ³ Analeptic N ³ ³ 0.867 ³ 0.003 ³ Respiratory analeptic 3 ³ ³ 0.832 ³ 0.008 ³ Psychotropic C ÍO ³ ³ 0.769 ³ 0.003 ³ Acetylcholine nicotinic agonist N ÄCH2 ³ ³ 0.767 ³ 0.007 ³ Hypothermic ³ ³ 0.755 ³ 0.007 ³ Antiarrhythmic N ³ ³ ³ ³ ³ O ³ ³ ³ S ³ 0.843 ³ 0.011 ³ Convulsant ³ ³ ³ 0.836 ³ 0.005 ³ Hypothermic N ³ ³ 0.816 ³ 0.011 ³ Nootropic 4 ³ ³ 0.788 ³ 0.006 ³ Acetylcholine antagonist OÍC N ³ ³ 0.782 ³ 0.023 ³ Cardiovascular analeptic CH2 ³ ³ 0.756 ³ 0.007 ³ Antiparkinsonian N ³ ³ 0.755 ³ 0.011 ³ Psychotropic ³ ³ ³ ³ ³ ³ ³ ³ S ³ 0.924 ³ 0.006 ³ Spasmolytic ³ C6H5 6 ³ ³ 0.882 ³ 0.028 ³ Hematotoxic N HCÄOH ³ ³ 0.795 ³ 0.007 ³ Cardiodepressant ³ ³ 0.792 ³ 0.007 ³ Antitoxic OÍCÄCH2ÄNÄCÄCH3 H ³ ³ 0.788 ³ 0.007 ³ Antiarrhythmic H3C ³ ³ 0.776 ³ 0.006 ³ Hypertensive ³ ³ 0.784 ³ 0.016 ³ Antineurotoxic ³³ ³ ³³ ³³ S ³ ³ 0.924 ³ 0.002 ³ Antismoking ³ ³ ³ 0.887 ³ 0.007 ³ Psychotropic N ³ ³ 0.859 ³ 0.005 ³ Analeptic C ÍO 8 ³ ³ 0.856 ³ 0.004 ³ Respiratory analeptic N Ä(CH2)2 ³ ³ 0.826 ³ 0.006 ³ Hypothermic ³ ³ 0.819 ³ 0.018 ³ Cardioprotectant N ³ ³ 0.790 ³ 0.007 ³ Antiarrhythmic ³³ O ³ ³³ ³³ ³ S ³ ³ 0.872 ³ 0.005 ³ Hypothermic ³ ³ 0.828 ³ 0.008 ³ Psychotropic N ³ ³ 0.819 ³ 0.018 ³ Cardioprotectant OÍC 9 ³ ³ 0.780 ³ 0.024 ³ Convulsant N ³ ³ 0.759 ³ 0.006 ³ Acetylcholine antagonist (CH2)2 ³ ³ 0.760 ³ 0.015 ³ Nootropic N ³ ³ 0.733 ³ 0.009 ³ Spasmolytic ³ ³ ³ ³ ³ 0.920 ³ 0.006 ³ Spasmolytic ³ ³ ³ 0.869 ³ 0.031 ³ Hematotoxic S C6H5 11 ³ ³ 0.820 ³ 0.011 ³ Antineurotoxic ³ ³ 0.810 ³ 0.007 ³ Cardiodepressant N HCÄOH ³ ³ 0.793 ³ 0.006 ³ Hypertensive OÍCÄ(CH2)2ÄNÄCÄCH3 ³ ³ 0.798 ³ 0.033 ³ Beta-adrenergic-receptor kinase inhibitor H H3C ³ ³ 0.746 ³ 0.007 ³ Antiarrhythmic ÄÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ RUSSIAN JOURNAL OF APPLIED CHEMISTRY

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In particular, in the 1H NMR spectrum of 10-(2-Ncytisinoacetyl)phenothiazine 3, the phenothiazine protons give groups of overlapping multiplets and doublets centered at 7.47 ppm for H = and H > and at 7.25 ppm for H C and H @. The next three low-field signals belong to protons of the pyridine core. The signal at 7.35 ppm corresponds to H 2 (JH 2H 3 ~3.2 Hz). The doublet at 6.23 ppm corresponds to H 1 (JH 1H 2 ~3.6 Hz), and the doublet at 6.05 ppm, to H 3. The next group of lines (a complex multiplet centered at 3.66 ppm) corresponds to the axial and equatorial H 7 protons. The methylene protons of the 3NC=(O)CH2 group are nonequivalent and give two doublets at 3.14 and 3.20 ppm with the coupling constant JH10a H10b = 4.0 Hz. The group of lines in the range 2.6732.85 ppm originates from the H 4 and H 6 protons. The doublets from the H 8 and H 9 protons are situated at 2.42 and 2.32 ppm. The methylene protons H 5 give a pair of doublets centered at 1.68 ppm. The integral curves are consistent with the numbers of protons. To estimate the expected biological activity of the synthesized phenothiazine derivatives, we performed a bioprediction using the PASS software (Prediction of Activity Spectra for Substances) [7]. The results are listed in Table 2 as the expected kinds of activity and coefficients of the probability of the presence (Pa) and absence (Pi) of each kind of activity, ranging from 0 to 1. In the analysis of the predicted activity spectra, we chose the condition Pa > 70%. Analysis of the predicted bioactivity of the new alkaloid-containing phenothiazine derivatives shows that their expected activity combines the physiological activity of both the starting alkaloids and aminoacyl phenothiazine derivatives. With fairly high probability, compounds 3!11 may exhibit antismoking, antiarrhythmic, psychotropic, spasmolytic, analeptic, and nootropic activity. They can be suggested for tests as new effective drugs. EXPERIMENTAL The 1H NMR spectra were recorded on a Bruker DRX500 device operating at 500 MHz from DMSOd6 solutions relative to internal TMS; the IR spectra, on an Avatar-320 FTIR spectrometer from KBr pellets; and the mass spectra, on a Finnigan MAT.INCOS 50 device with direct sample inlet, at an ionizing electron energy of 70 eV. The melting points were determined with a Bo1etius device. The reaction progress and product purity were monitored by thin-layer chromatography on Sorbfil plates in the system ben-

zene3acetone, 1 : 1. The plates were developed with iodine vapor. 10-(2-Cytisinoacetyl)phenothiazine 3. To a mixture of 0.97 g (0.005 mol) of cytisine and 1.38 g (0.005 mol) of 10-(2-choloroacetyl)phenothiazine in 7 ml of toluene, we added 2.02 g (0.02 mol) of triethylamine and refluxed the mixture for 3 h. The precipitate of triethylamine hydrochloride was filtered off, the solvent was removed, and the residue was crystallized from petroleum ether and purified by passing through a column packed with a 1 : 1 blend of Al2O3 and SiO2 (eluent benzene). The dilution of the solution with a threefold volume of hexane resulted in the precipitation of a white crystalline product. 10-(2-N-Cytisinopropionyl)phenothiazine 8 was prepared similarly to 3. 10-(2-N-D-Pseudoephedrinoacetyl)phenothiazine 6. To a mixture of 0.66 g (0.004 mol) of D-pseudoephedrine and 1.11 g (0.004 mol) of 10-(2-chloroacetyl)phenothiazine in 7 ml of toluene, we added 1.21 g (0.012 mol) of triethylamine and refluxed the mixture for 5 h. The precipitate of triethylamine hydrochloride was filtered off. The toluene solution was washed with distilled water and extracted with 10% HCl. The acidic solution was diluted with water, clarified with activated carbon, and alkalized with aqueous ammonia. The precipitate was filtered off and dried in air. 10-(2-N-Anabasinoacetyl)phenothiazine 4, 10-(2N-L-ephedrinoacetyl)phenothiazine 5, 10-(3-N-anabasinopropionyl)phenothiazine 9, 10-(3-N-L-ephedrinopropionyl)phenothiazine 10, and 10-(3-N-D-pseudoephedrinopropionyl)phenothiazine 11 were prepared similarly to 6. CONCLUSIONS (1) Alkylation of physiologically active alkaloids cytisine, anabasine, D-pseudoephedrine, and L-ephedrine with 10-(2-chloroacetyl)phenothiazine and 10-(3chloropropionyl)phenothiazine was performed. (2) The physicochemical constants of the compounds synthesized were determined, and their compositions and structures were confirmed by 1H NMR, IR, and mass spectroscopy. (3) The bioactivity of the synthesized alkaloidcontaining phenothiazine derivatives was evaluated by computer prediction using the PASS program. The results obtained show that it is appropriate to further study these compounds as new effective drugs.


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SYNTHESIS OF N-ALKALOIDACYL DERIVATIVES OF PHENOTHIAZINE

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5. Yakhontov, L.N. and Glushkov, R.G., Sinteticheskie lekarstvennye sredstva (Synthetic Drugs), Moscow: Meditsina, 1983. 6. Pozharskii, A.F., Anisimova, V.A., and Tsupak, E.B., Prakticheskie raboty po khimii geterotsiklov (Practical Works in Chemistry of Heterocycles), Rostov-on-Don: Rostov. Gos. Univ., 1988, p. 21. 7. Sadym, A.V., Lagunin, A.A., Filimonov, D.A., and Poroikov, V.V., Khim.-Farm. Zh., 2002, vol. 36, no. 10, pp. 21 26.

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