Frakdon. (150 ml) wird verworfen. Der kristalline Verdampfungsriickstand der 2. Frak- tion (450 ml) wird aus C2H5OH unter Zugabe von Akbvkohle kristallisiert.
^ Eswird analog 3.7.3 gearbeitet, wobei eine doppelte Menge Ausgangsprodukt (10, 3,2 g) eingesetzt wird, die Reaktionsdauer 4 h betragt und zur Extraktion | CH2C12 verwendet wird. Aus der waBrigen Phase wird 45,0% des Ausgangs1 produktes 10 zuruckerhalten. Aus dem CH 2C12-Auszug wird 10a auf folgende j Weise isoliert. Der Auszug wird auf ein Volumen von 10 ml eingeengt und an einer Saule (80 g S i02, 0 3 cm) mit CH 2C12 chromatographiert. Die 1. Frakdon (150 ml) wird verworfen. Der kristalline Verdampfungsriickstand der 2. Fraktion (450 ml) wird aus C 2H 5OH unter Zugabe von Akbvkohle kristallisiert. Man erhalt 10a, C 7H 8N 40 6 (244,2); fast farblose dicke Nadeln vom Schmp. 109-111 °C; Ausbeute: 1,1 g (= 41,3%). ‘H-NMR (6, ppm): 7,90 (H-5, s), 5,23 (N-CH2, s), 4,32 ( 0 - C H 2, q, J = 7 Hz), 1,32 (CH3, t, J = 7 Hz); 'H-NMR (6,ppm,DMSO-d6):8,75 (H-5,s), 5,41 (N - CH2,s),4,23 (O - CH 2,q,J — 7 Hz), 1,23 (CH3, t, J = 7 Hz), 13C-NMR (6, ppm): 166,2 (C = 0), 142,1 (C-4), 141,1 (0-2), 126,7 (C-5), 62,0 ( 0 - C H 2, 51,4 ( N - C H 2), 13,9 (CH3). 3.9, Priifung a u f a n tib a k te rie lle W irk u n g Analog [4] 3.10. Priifung a u f fu n g izid e W irk u n g Die Priifung der fungiziden Eigenschaften von 4a, 5a-4c, 5c, 6a, 7a und 7b erfolgte auf einer mit der folgenden Losung getrankten Perlit-Unterlage: 0,5 g KC1,0,3 g K 2H P 0 4, 0,5 g M gS0 4 • 7H 20 , 2,0 g N a N 0 3, 0,7 g KH 2P 0 4, 30,0 g Malzextrakt und 1000 ml H 20 , wobei auf 100 g Perlit-Unterlage 270 g dieser Losung gebraucht wurde. Cellulosestreifen (4 x 4 cm, Whatman 2) wurden mit den Losungen (C 2H 5OH) der untersuchten Imidazolderivate in den Konzentrationen 1,0; 0,5; 0,25; 0,125; und 0,0625% impragniert, bei Raumtemperatur getrocknet und auf dem oben beschriebenen und sterielen Nahrboden in Petrischalen ( 0 120, Schichtdicke 5 mm) mit einem Tropfen Sporenaufschwemmung des folgenden Pilzartengemisches beimpft: Aspergillus niger (van Tieghem), Aspergillus terreus (Thom), Aureobasidium pullulans [(de Barry) Arnauld], Paeciliomyces varioti (Bainier), Penicillium funiculosum (Thom), Penicillium ochrochloron (Biourge), Scopuliaropsis brevicalis [(Sacc) Bain] und Trichoderma viride (Pers. ex Fr). Die mit Hilfe der Zahlkammer nach Thoma bestimmte Konzentration der Sporenaufschwemmung war konstant und betrug 107 in 1ml. Die Versuche erfolgten fur jede gepriifte Verbindung und Konzentration in je 6 parallel durchgefuhrten Proben. Das Wachstum des Myzels und die Sporenbildung wurde bei einer Temperatur von 28 °C (+ 1 °C) und relativen Luftfeuchte des Priifraumes von 90% (± 5%) liber einen Zeitraum von 21 d beobachtet. Die folgende Bewertungsskala wurde angewendet: Vollige Hemmungdes Myzelwachstums —0; Myzelbewuchs der Perlit-Oberflache bis 25% ohne Sporenbildung —1; Myzelbewuchs im Bereich von 25 -50% mit vereinzel. ter Sporenbildung —2; Myzelbewuchs der Perlit-Oberflache bis 70% mit
—5. Die erzielten Ergebnisse sind in Tabelle 3 zusammengestellt. Die Priifung der fungiziden Eigenschaften der Verbindungen 8c, 9c und 10a gegenuber den in Tabelle 4 vermerkten Pilzarten erfolgte analog [4]. Es wurde die oben beschriebene Bewertungsskala angewendet.
Die Arbeit wurde im Rahmen der Programme R.P.TI.13. und IV.8.2. durchgefuhrt.
4 33. Mitt.: Pharmazie 47 258 (1992)
Literatur 1 Wrzeciono, U.; Pietkiewicz, K.; Jobke, E.; Michalska, W .: Pharmazie 33, 264 (1978) 2 Wrzeciono, U.; Pietkiewicz, K.; Niew^glowska, W.; Michalska, W .: ibid. 34, 20 (1979) 3 Lutomski, K .: Material u. Organismen 21,213 (1986) und dort zit. Literatur 4 Zaprutko, L.; Gajdzinski, M .; Michalska, W.; Pietkiewicz, K.; Lutoms ki, K.; Lukaszewski, Z.; Wrzeciono, U.: Pharmazi 44, 817 (1989) 5 Skwarski, D.; Sobiak, S.: Pol. J. Chem. 57, 551 (1983) 6 Boyer, J. H.: Nitroazoles. The C-Nitro Derivatives of Five-Membered N- and N,0-Heterocycles, S. 109, VCH Publishers Inc., Deerfield Beach, Florida 1986 und dort zit. Lit. 7 Nagarajan, K.; Sudarsanam, V .; Parthasarathy, P. C.; Arya, V. P.; Shenoy, S. J.: Indian J. Chem. 218, 1006 (1982) 8 McKillop, A.; Wright, D. E.; Podmore, M. L.; Chambers, R. K .: Tetra hedron 39, 3797 (1983) 9 Patsch, R .: Antibiotika - Ratgeber, S. 15, Gustav Fischer Verlag, Jena 1975 10 Fargher, R. G.; Pyman, F. L.: J. Chem. Soc. 115, 217 (1919) 11 Novikov, S. S.; Chmielnickij, L. J.; Lebiediev, O. W.; Sievostjanova, W. W.; Episzyna, L. W.: Khim. Geterocikl. Soedin. 6, 503 (1970) 12 Sharnin, G. P.; Fassakhov, R. Ch.; Orlov, P. P.: SU 458 553 (1975); ref.: C.A. 82, 156316m (1975) 13 M^kosza, M.: Synteza organiczna, S. 240, Panstwowe Wydawnictwo Naukowe, Warszawa 1972 Eingegangen am 6 . Mai 1991
Prof. Dr. hab. Urszula Wrzeciono ul. Grunwaldzka 6 60-780 Poznan Polen
Pharmaceutical Institute1 and Department of Natural and Biologically Active Compounds2, Faculty of Chemistry, Perm University, Perm, Russia
Synthesis and a n tim icro b ia l a ctiv ity of new 5 -aryl-2 -hyd roxy-3(2 H )-pyrrolinone d erivative s3 V.O. KOZMINYKH1 4, N. M. IGIDOV1, E. N. KOZMINYKH1, Z. N. SEMENOVA 1 and YU. S. ANDREICHIKOV 2
” :l 1
The synthesis of some 1-substituted 5-aryl-2-hydroxy2-methoxycarbonylmethyl-3(2H)-pyrrolinones is described. The results of microbiological screening are given. They indicate that 2-methylene-3(2H)-furanone and 2-hydroxy-3(2H)-pyrrolinone derivatives exhibit a rather low antimicrobiological activity.
'0 1C
b(
и 3
Synthese und antimikrobielle Wirkung neuer 5-Aryl-2hydroxy-3 (2H)-pyrrolinon-Derivate
j ^ ’fe
Die Darstellung einiger in 1-Stellung substituierter 5-Aryl-2-hydroxy-2-methoxycarbonylmethyl-3(2H)pyrrolinone wird beschrieben. Die antimikrobielle Testung der Titelverbindungen und der als Ausgangs-
[. Pharmazie 47 (1992), H. 4
verbindungen eingesetzten 3(2H)-Furanone wies nur schwache Wirkungen aus. 1. Introduction Recently we described the synthetic approaches for several 2-substitued l,5-diaryl-2-hydroxy-3(2H)-pyrrolinones obtain ed by recyclization of 2-alkoxycarbonylmethylene-5-aryl3(2H)-furanones on treatment with arylamines [1-4]. A few reports on this class of compounds are known [5-9] and no bioactivity data was earlier obtained. Our interest in the chemical transformations and the utility of 2-hydroxy-3(2H)pyrrolinones as potential medicinal agents promted additional work in this area. In the present work we report the synthesis 261
The structure of the new 2-hydroxy-3(2H)-pyrrolinones 8,9, 15-21 was confirmed by elemental analysis and spectral datiy It is interesting that the reaction of arylideneimines witl 5-methyl-3(2H)-furanones proceeds without recylization and the corresponding 2-arylidene-5-styryl-3(2H)-furanones an formed [12]. The antimicrobial activity was once observed in the series a 2-alkoxycarbonylmethylene-5-aryl-3(2H)-furanones [10]. Ac cording to these data the furanones 1-22 were evaluated foi their in vitro antimicrobial effect against Gram positive coo: (Staphylococcus aureus 209 P) and Gram negative rod (Escherichia coli M 17) according to a reported procedure [13] The results of biological tests of the investigated compound ars shown in Table 2. The MIC values indicate that 1 methylene-3 (2H)-furanone and 2-hyd roxy-3(2H)-pyrrolino ne derivatives exhibited a rather low antimicrobial activitj
of some 1-substituted 5-aryl-2-hydroxy-2-methoxycarbonylmethyl-3(2H)-pyrrolinones, their characteristics, and the re sults of a microbiological screening. 2. Investigations, results and discussion When the readily available (Z)-5-aryl-2-methoxycarbonylmethylene-3(2H)-furanones 1-7 [3,10,11] were allowed to react with one equivalent of Schiff bases (method A), o-aminophenol (method B) or o-phenylenediamine (method C) by refluxing in ethanol the corresponding substituted 2-hydroxy-3(2H)pyrrolinones 8-10, 15-21 were formed (Scheme). Some data of these compounds are listed in Table 1. The synthesis of l,5-diaryl-2-hydroxy-2-methoxycarbonylmethyl-3-(2H)-pyrrolinones 10-14 and 22 was described in previous reports [2-4]. Scheme 1
R2 's — 4 -R -H 4 Cr
—С
f
0
A r - C H = N - R 3 (A )
H
У=с
4
3
+
'е о о с н з
R-nh2
4
(В о г С )
- ^
с
R2
1 2 3 4 5 6 7 8 9 10 11
H
H H H H
[10, 11] [10, 11] [10, 11]
Br
[3] [3] [3]
Table 1
1-Substituted 5-a ryl-2-hydroxy-2-methoxycarbonylmethyl-3(2H)-pyrrolinones
C om pound
Cl CH 3 CH 3 CH3o H
CH 3 CH3 CH3o
R3
R ef.
M .p. (dec.) [ Cl (solvent)
12 13 14 15 16 17 18 19 20 21 22
[11]
Cl Cl H H H H
C6H 5 c 6H 5 4 -CH3 —C6H4 4 -CH 3 — C 6H 4
Yield
^
H c h 2- c o o c h 3
8 - 21
R1
c h 3o
V
R3
1-7
CH 3
Д
[2 ] [2]
M e th o d
1%]
F o rm u la (m o lecu lar m ass)
R1
R2
R3
R ef.
CH 3 CH 3 CH30 CH 3 CH30
Cl
4-CH 3 — C 6H 4 4-CH30 — C6H 4 4 -CH 3O — C6H 4 C6H 5 - C H 2 C 6H 5 - C H 2 2-HO — C6H4 2-HO — C 6H 4 2-HO — C6H 4 2-HO—C6H 4 2-H2N — C6H 4 2-H2N —C6H 4
[3] [3] [3]
H
CH 3 CH 3O Cl H
CH 3
Br
Cl H H H H H H H H
[4 ]
A nalysis calcd ./fo u n d C
H
N
(323.35)
70.58 70.72
5.30 5.12
4.33 4.47
149-150 (C2H5OH)
76
180-181 (CH3COCH3)
84
A
C20H 19NO 4 (337.36)
71.20 71.44
5.68 5.71
4.15 4.28
172-173 (C2H5OH)
80
A
C j i H ,,N O j
(351.40)
71.78 71.90
6.02 6.13
3.99 4.07
15
119-120 (C2H5OH)
72
A
C21H21NO, (351.40)
71.78 71.63
6.02 6.14
3.99 4.10
16
122-123 (CH3CN)
55
A
c 21H21NO, (367.40)
68.65 68.56
5.76 5.81
3.81 3.76
17
187-188 (CH3CN)
68
В
c
19h 1vn o .
67.25 67.21
5.05 5.09
4.12 4.23
203-204 (CH3CN)
77
67.98 67.87
5.42 5.46
3.96 4.03
192-193 (CH3CN)
59
65.03 65.17
5.18 5.09
3.79 3.64
198-199 (C6H5CH3)
63
61.05 61.12
4.31. 4.28
3.74 3.69
164-165
65
67.45 67.30
5.36 5.45
8.28 8.12
8 9 10
18 19
20 21
1 C ,H ,0 H /H ,0 )
A
c
19h 17n o 4
(339.35) В
c 20h
19n o .
(353.37) В
C 2 o H l9 N 0 6
(369.37) в
c
19h 16c i n o 5
(373.79) C
c
19h 18n 2o 4
(338.36)
lene-3(2H)-furanones and 1-substituted 5-aryl-2-hydroxy-2-methoxycarbonylmethyl-3(2H)-pyrrolinones Com pound
1 2 3 4 5
6 7
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
M inim um in h ib ito ry c o n c e n tra tio n (M IC ) [|ig/m l] S. aureus P-209
E. coli M 17
63 500 500 250 31 125 2 50 in a c tiv e in a c tiv e 1000 500 2 50 2 50 1000 in a c tiv e 1000
in a c tiv e
1000 1000 1000 1000 1000 1000
500 500 in a c tiv e in a c tiv e 500 500 in a c tiv e 1000 1000 in a c tiv e 500 500 1000 in a c tiv e 1000 1000 1000 1000 1000 1000 in a c tiv e
Of all the compounds examined, 5 from furanone and 12 from pyrrolinone series were found to have the maximum antimicrobial effect on the S. aureus strains.
3. Experimental Elemental analyses were carried out in the Laboratory for Microanalysis of Perm Pharmaceutical Institute. IR spectra were recorded on a UR-20 spectro meter. ‘H NMR spectra were taken on a RS-60 spectrometer using CDC13 as a solvent and HMDS as an internal standard. Mass spectra were recorded on a Varian MAT-311 spectrometer at an electron energy of 70 eV. TLC on silica gel plates Silufol® UV-254 was used to follow the reactions and to check the purity of the products; eluens: C 6H 6/(C 2H 5)20 (3 : 2), C 6H 6/(C 2H 5)20 / CH3COCH3 (10 : 9 : 1). IR and ‘H NMR data are available on request to the authors. 3.1. 5 -A ry l-2 -m e th o x y c a rb o n y lm e th y le n e -3 (2 H )-fu ra n o n e s 1-7 and l,5 -d ia ry l-2 -h y d ro x y -2 -m e th o x y c a rb o n y lm e th y l-3 (2 H )pyrrolinones 10-13, 21 These compounds were obtained according to standard methods [2-4; 10,11].
(VR Mb (m/z, relative ion intensity ”/o): 331 izi.s) ivi ■ , ju v ijj . ij М-ССГ+, 306 (6.0) M-CHjO"1*, 278(3.0) M-CH 30 - C C P +, 264 (5.7) М -С И зО -С И зС О "^, 236(100.0) M-CH 3O C O -C H 2CO"' +, 235 (5.8) 4CH 3C„H 4 - C( = NC 6H 5) - CH = C = CP + , 208 (43.3) M-CH3OCO - CH2CO - C C P +, 194 (22.7) 4-CH 3C 6H4C = NC 6H 5n +, 119 (16.5) 4-CH 3C 6H4C = CP+, 117 (13.2) 4-CH 3C 6H4C = Nn +', 116 (22.4) 4-CH 3C 6H4C ^ C H "14 , 115 (24.0) 4-CH 3C 6H4C = CU +. 3.3. R e a c tio n of 1-4 w ith o -a m in o p h e n o l (m eth o d B) A mixture of 1-4 (0.005 mol) and o-aminophenol (0.005 mol) in C 2H 5OH (80 ml) was refluxed for 1 h. The solid after evaporating the solvent was recrystallized from C 6H 5CH 3 or CH3CN to give pale yellow crystals of 17-20, respectively. l-o-Hydroxyphenyl-2-hydroxy-2-methoxycarbonylmethyl-5-p-tolyl-3 (2H)pyrrolinone (18): MS (m/z): 353 M-1®, 335 M-H 20 "l+ , 325 М-ССГ +, 322 M-CHjO"1*, 280 M-CH 3O —CH 2COn +, 252 M-CH 3O C O -C H 2COn+, 210 M-4-CH 3C 6H4C = C —C = On+, 116 4-CH 3C 6H4C = CHn+ . 3.4. S y n th e sis of 1-o -a m in o p h e n y l-2 -h y d ro x y -2 -m e th o x y c a rb o n y lm e th y l-5 -p h e n y l-3 (2 H )-p y rro lin o n e (21; m eth o d C) A mixture of 1 (0.01 mol) and o-phenylenediamine (0.01 mol) in C 2H 5OH (80 ml) was refluxed for 15 min. The solid after evaporating the solvent was washed by C 6H 6(2 x 50 ml) and then by hot (50 60 °C) C 2H 5OH (50 ml). The C 2H 5OH solution was filtered, evaporated to 1/2 of its volume and left for crystallization. Light orange crystals were collected by filtration and recry stallized from C 2H 50 H /H 20 (3 : 1) to give 21. 3 Part 9: Chemistry of 2-methylene-3(2H)-furanone derivatives; Part 8 : Khim.Farm. Zh., in press 4 The correspondence should be adressed to Dr. V. O. Kozminykh see below.
References 1 Andreichikov, Yu. S.; V. O. Kozminykh; N. M. Igidov; E. N. Kozminykh: Vth International Symposium on Furan Chemistry, Abstracts, p. 127, Riga 1988 2 Andrechikov, Yu. S.; V. O. Kozminykh: Zh. Org. Khim. 25, 618 (1989) 3 Kozminykh, V. О.; E. N. Kozminykh; Yu. S. Andreichikov: Khim. Heterocikl. Soedin. 1989, 1034 4 Idem: ibid. 1990, 277 5 Weigele, M.; J. F. Blount; J. P. Tengi; R. C. Czajkowski; W. Leimgruber: J. Am. Chem. Soc. 94, 4052 (1972) 5 Weigele, M.: J. P. Tengi; S. de Bernardo; R. Czajkowski; W. Leimgruber: J. Org. Chem. 41, 388 (1976). 7 Gelin, S.; R. Gelin: ibid. 44, 808 (1979) 8 Chantegrel, B.; S. Gelin: J. Heterocycl. Chem. 15, 1215 (1978) 9 Kozminykh, V. O.; Yu. S. Andreichikov: Khim. Heterocikl. Soedin. 1988, 1698 10 Andreichikov, Yu. S.; V. O. Kozminykh: SU 1077 891 (1982) 11 Andreichikov, Yu. S.; V. O. Kozminykh; E. N. Manelova: Zh. Org. Khim. 21, 402 (1985) 12 Chantegrel, B.; S. Gelin: Synthesis 1981, 45 13 Andreichikov, Yu. S.; D. D. Nekrasov; S. G. Pitirimova; A. S. Zachs; M. I. Korsheninnikova; P. N. Plaksina; Z. N. Semenova; V. A. Kopeykin: Khim.Farm. Zh., 23, 946 (1989)
3.2. Reaction of 1-3 w ith Schiff bases (m eth o d A) A mixture of 1 or 2 and benzylidene phenylimine, or 2 and benzylidene p-tolylimine, or 2 or 3 and p-methoxybenzylidene benzylimine taken in equimolar quantities (0.005 mol) and solved in C 2H 5OH (100 ml) was refluxed for 2 h. The solid mass after evaporating the solvent was recrystallized from C2H5OH, CH 3COCH 3, or CH3CN to give bright yellow crystals of 8-10,15,16, respectively.
Pharmazie 47 (1992), H. 4
Received July 4, 1991
Prof. Dr. Yu. S. Andreichikov Perm University, Bukireva Str. 15 Dr. V. O. Kozminykh Post Box 52 614051 Perm-51 Russia
263
