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Synthesis of Substituted 3-Hydroxy-1H5H-pyrido[12-a]-benzimidazol-1-ones as Possible Antimicrobial and Antineoplastic Agents.

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317f84
3-Hydroxy-IH,SH-pyrido[l,2-n]benzimidazol-l
-ones
951
11 P. M. Quan und L. D. Quin, J. Org. Chem. 31, 2487 (1966).
12 W.-H. Giindel, Z. Naturforsch. 28b,471 (1973); H.-W. Gundel, B. Buecher und I. Hagedorn, Z.
Naturforsch. 296, 556 (1974); Rontgenstruktur eines Tetrameren: M. Martinez-Ripoli, F. H.
Cano, S. Garcia-Blanco, S. Martinez-Carrera und W.-H. Gundel, Acta Crystallogr. Sect. 833,
494 (1977).
[Ph 8371
Arch. Pharm. (Weinheim) 317, 951-958 (1984)
Synthesis of Substituted 3-Hydroxy-lH,SH-pyrido[ 1,2-a]benzimidazol-1-ones as Possible Antimicrobial and Antineoplastic
Agents
Farid S. G. Soliman'), Samia M. Rida"),El-Sayed A. M. Badawy") and Thomas
Kappe*b)
a) Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria,
A.R. Egypt
Abteilung fiir Organische Synthese, Institut fiir Organische Chemie, Karl-FranzensUniversitat, Heinrichstr. 28, A-8010Graz, bterreich
b,
Eingegangen am 18. August 1983
Syntheses of the title compounds 3 as possible antimicrobial and antineoplastic agents were achieved
by reacting the active malonates 1 with the benzimidazoles 2a,b. On the other hand, reaction of lc,d
with 2-methylbenzimidazole(2c)yielded the imidazoquinolinonesh , b . Four compounds in the series
3 displayed in vitro antibacterial and antifungal activities.
Synthese von substituierten 3-Hyclroxy-~~,5~-pyriao[l,2-a]benzimidPz
pls potentieUe
antimilwbielle und antioeoplastischeWirlrstoffe
Die Synthese der Titelverbindungen 3 als potentielle antimikrobielle und antineoplastische
Wirkstoffe wurde durch Kondensation der aktiven Malonester 1 mit den Benzimidazolen 2a,b
erreicht. Im Gegensatz dam reagieren lc,d mit 2-Methyl-benzimidazol (k)
zu den Imidazochinolonen h , b . Vier Verbindungen der Struktur 3 zeigten in vitro antibakterielle und fungizide
Wirkungen.
Many derivatives of benzimidazole are known to possess antibacterial, antifungal as well as
anticancer potencies'). Looking for other advantageous structural modificationsof benzimidazolesof
potential antimicrobial and anticancer activities, the synthesis of some 2,4-disubstituted 3hydroxy-IH,5H-pyrido[1,2-a]benzimidazol-l-ones
3 was designed. This approach was initiated from
the fact that the desired compounds have certain structural features in common with natural and
03654233/84/11114951 $ 02.50/0
8 Verlag Chemie GmbH, Weinheim 1984
952
Soliman, Ria& Badawy and Kappe
Arch. Pharm.
synthetic purines. Additional impetus arose from the observation that the tricyclic systems 3 and the
potent antimicrobial, antiviral and anticancer agent "3-deazag~anine"~)comprise a 6-amino2-pyridone residue within their structures. A survey of the literature') indicated that the adopted
system is with unexplored pharmacotoxicologicalproperties.
Compounds 3aA (table 1)were prepared in good yields by reacting equimol. quantities
of monosubstituted bis 2,4,6-trichlorophenylmalonates 1with 2-cyanomethyl-benzimidazole (2a) or ethyl 2-benzimidazoleacetate (2b) in boiling bromobenzene. The reaction
involves the interaction between a ketene-carboxylate intermediate'), generated in situ
from 1on thermolysis, and the 1,f-binucleophiliccenters of 2. Acid hydrolysis of the cyano
compound 3a afforded the corresponding 4-carboxamide derivative 3i.
la: R' = C2H,
l b : R1 = n-C,H,
2a: R~ = CN
Ic:
Z C : R2 = H
t b : R2 = C02C2H5
R' = CH(CH3),
Id: R' = CH,C,H,
le: H' = CsH,
I
3a-h: R-Key see Table 1
3i: R' = c~H,; R~ = CONH,
OH
R2 . H
: Q&JcH'CyJ1
/
3
HO
E
C
H
3
H
5
c1
The mass spectrometric data of the cyano derivatives3a,b,d are recorded in table 2. In spectra of the
three compounds reveal intense molecular ion peaks. The base peak of the spectra of 3s and 3b is the
ion at m/e 238 which results by loss of CH, from the molecular ion of the former compound, or C3H,
from the latter. An important ion which appears in all the spectra is the one at d e 184.It is originated
by loss of CH3CH,C=C=0, C,H,C=C=O or Cd-I,C=C=O associated with hydrogen transfer from
3a,3b or 3d,resp. All the spectra show a fragment at m/e 65 which might be formulated as +CH(CN)2.
In the spectrum of 3d phenyketene ( d e 118)constituted the base peak, and in the spectrum of 3b an
ion corresponding to M-GHS at m/e 252 is observed.
In contrast, condensing l c with an equimol. amount of 2c at 200-220" for 1h led to the
imidazo-quinolinone4a, instead of the structuralisomer of 3 (with Rz = H). The exclusion
of the pyridobenzimidazolestructure was based on the 'H-NMR spectrum which showed
the C-2 CH, singlet at 6 = 2.8 ppm. Referring to the literature, another analog, namely 4b
has been prepared from 2c and bis-2,4-dichlorophenyl malonate6). However, no
spectroscopicdata were available to support its ring structure. In order to provide a further
proof of the imidazoquinolone structure of our compound 4a and the previously described
analog4b,we have repeated the synthesisof the latter using now the trichlorophenyl ester
Id and obtained the same compound 4b,the structure of which coincided with its 'H-NMR
CN
C4H9
C6H5CH2 CN
C6H5
3b
3c
3d
~~
86.7
79.4
67.9
90
Yield
%
Ethanol/
Water
Recryst.
Solvent
295
Ethanol/
decomp. Water
275-216 Ethanol/
Water
255-257 Ethanol/
decomp. Water
300
"C
M.P.
C18H11N3O2. 2 H z 0
(337.2)
C19H13N302
(315.3)
C16H15N302
(281.3)
C14H11N3O2. H 2 0
(271.3)
Molecular
Formula
64.1
64.5
72.4
72.6
62.0
62.4
4.5
4.2
4.2
4.2
4.8
4.8
Calc.
Found
C
H
c-9).
'H-NMR (DMSO-d,) of 3c: 6 (ppm) = 4.0 (s, CHz- benzyl); 7.0-7.6 (m, 8 aromatic H); 8.5 (dd, H a t
H); 8.6 (dd, J = 2 + 7Hz, H at C-9).
* bm = Broad-medium; bw = broad-weak; s = strong; w = weak.
'H-NMR (DMSO-d,) of 3a: 6 (ppm) = 1.1 (t, J = 7Hz,CH3); 2.6 (4,CH2); 7.1-7.65 (m, 3 aromatic
CN
CN
C2H5
R2
3a
pound
Com- R1
Table 1:2,4-Dkubstituted 3-Hydroxy-1H,JH-pyrido[l,2-a]benrimidazol-l
-ones 3*3i
12.5
12.4
3600-2900 bw (OH, NH);
2220 s (CN); 1650 s (CO);
1590 w; 1530 m (C=C and
aromatics).
3500-2500 bm (OH, NH,
CH); 2220 s (CN), 1650 (CO);
1590 w; 1530 m (C=C and
aromatics).
3500-2500 bm (OH, NH,
CH); 2220 s (CN), 1650 s ((20);
1590 w; 1550 s (C=C and
aromatics).
14.9
14.7
13.3
13.3
3600-2500 bm (OH, NH, CH);
2220s (CN); 1650 s (CO);
1585 w, 1535 s (C=C and
aromatics).
IR (KBr) cm-'*
15.5
15.5
N
62.0
62.2
4.8
4.8
4.6
45
5.0
4.9
MS of 3:m/e 271 (M+, 43).
'H-NMR (DMSO-4) of%: 6 (ppm) = 1.6 (t, J = 7Hz,CH,); 3.75 (s, CH2- benzyl); 4.45 (9, CH2ethyl); 7.0-7.7 (m, 8 aromatic H); 8.55 (dd, H at C-9).
275
Benzene/
(demmp.) Ethanol
C14H13N303
(271.3)
CONH2 Almost
quant
3i
C2H5
CZOH16N204
(348.4)
3h
69.0
69.2
69.6
69.7
C21H18N204
(362.4)
3g
6.1
5.9
5.4
5.2
64.0
64.0
c16H i d 2 0 4
(300.3)
Calc.
Found
C
H
Molecular
Formula
65.9
65.9
Acetic
acid
Acetic
acid
Reayst.
Solvent
C18HZON204
(328.4)
236
COOC~HS53
C4H9
3f
MP.
OC
COOC2H5Almost 173
quant.
Yield
%
CzH~
R2
3e
pound
Com- R1
Table 1 (continued)
155
15.4
8.O
8.O
7.1
7.7
8.5
8.5
9.3
9.2
N
3240 m (OH, NH, CH); 1690
m; 1650 m (CO); 1620 m;
1560 s shouldered at 1580
(amide II band, C=C and aromatics).
3400-2200 bm (OH, NH,
CH); 1650 shouldered at 1630
(CO); 1600 w;1530 m (C=C
and aromatics).
3500-2300 bm (OH, NH,
CH); 1700 s and 1650 s (CO);
1550 w (C=C and aromatics).
3500-2500 bm (OH, NH,
CH); 1650 s shouldered at 1630
((20);1600 w;1530 m (C=C
and aromatics).
3600-2600 bm (OH, NH,
CHI; 1650 s shouldered at 1630
(CO); 1600 w,1530 m (C=C
and aromatics).
IR (KBr) cm-1*
317/84
3-Hydroxy-1H,5H-~vrido/l,2-alben~imidazol-l
-ones
955
Table2 Mass spectrometric Data of some 2,4-Disubstituted3-Hydroxy-lH,5H-pyrido[l,2-a]benzimidazol-1-ones(3)
m/e Values (Relative Abundance %)
Compound
3a
254 (8, M + 1);253 (37, M
; 239 (13); 238 (1003M-CH3); 220 (10);210 (10);
)
'
184 (8, M-CHJ-CH?-C=C=O); 168 ( 6 ) ;156 (10); 155 (7); 149 (211,129 (7); 103
(5); 102 (6); 91 (6, C%H4NH?);88 ( 5 ) ; 87 (7); 85 (6); 82 (15); 81 (13); 90 (15);
78 ( 5 ) ; 77 ( 5 ) ; 76 ( 5 ) ; 72 (5); 71 ( 5 ) ; 70 (60); 69 ( ~ ~ , C H ~ - C H Z - & C = O67) ; (6);
65 (5, ifH(CN)z); 64(4); 61 (5); 60 (5); 59 (5),58 (15); 57 (15); 56 (7); 55 (10);
53 (5);51 ( 5 ) .
3b
282 (6, M+1); 281 (48, M?); 264 (5); 253 (7); 252 (7, M - C2H5); 240 (7); 239
(50); 238 (100, M - C3H7); 225 ( 5 ) ; 210 (10); 184 (10, M - C4H9-&=0);
183 (9); 182 (5); 157 (10); 156 (10); 155 (10); 149 (10); 129 (8); 109 (4); 103 (7);
102 (7); 97 (6, C4Hg-&C=O); 91 (6, C6H4NH:); 90 ( 5 ) ; 85 ( 5 ) ; 83 (7); 82 ( 5 ) ;
91 (6); 77 (6); 76 (5);71 (8); 69 (8); 65 (5,6H(CN)2); 59 (8); 58 (45); 57 (14);
56 ( 5 ) ; 55 (14); 53 ( 5 ) ; 51 (5).
3d
302 (16, M + 1); 301 (70, M?); 244 (10); 238 (18); 185 (9); 184 (144,
M - C~HS-&C=O); 183 (23); 156 (25); 155 (9); 151 (11);149 (10); 137 (6);
129 (11); 123 (8); 122 (5); 119 (11); 118 (100, C6H5-CH=C=O?); 109 (9); 105 ( 5 ) ;
1-3 (12); 102 (8); 97 (6); 91 (6, C6H4NH?); 90 (16); 89 (10); 77 (10); 76 (5);
71 (9); 65 (8,6H(CN)2); 64 (8); 63 (9); 58 (12); 57 (12); 5 5 (10); 51 (6).
spectrum. In addition, we were able to isolate 2-methylbenzimidazole - 2,4,6trichlorophenol(1:1) adduct 5 from the reaction mixture. The identity of 5 was affirmed by
m. p., elementary analysis, IR and mass spectral data which were identical with those
recorded for a sample prepared by us by the interaction of equimol. amounts of 2c and
2,4,6-trichlorophenol in methanol. In the mass spectrum the adduct does not show the
parent ion peak. It is cleaved to its components, the 2-methylbenzimidazoleion at d e 132
which constitutes the base peak of the spectrum and the 2,4,64richlorophenolion at d e
196(of w l ) . The fragmentationpattern of the former ion is identical to that reported for 2c
itself".
Antimicrobial Screening
Compounds 3b,d,f,h were screenedfor in vitro activity against two bacteria:Staphylococcusaureus
and Escherichia coli and one fungus: Candida albicans; using the following agar diffusion method').
Sterile nutrient agar (ascoid) was melted and allowed to cool to 48".Each lOOml of the medium was
inoculated with 1ml of 24 h broth-culture and transferred to sterile Petri-dishesof 15 cm diameter,
each receiving 50 ml. The media were then allowed to cool and cups of 8 m m diameter were cut in the
agar. Each cup was filled with three drops of a solution of a different compound dissolved in DMF at a
conc. of 0,2mg/mI. The dishes were incubated at 37" for 24h and the resulting inhibition zones were
measured. A control for the solvent was included for each organism. The inhibition zones obtained
are recorded in table 3.
All the compounds are considered, in vitro, active against E. coli and C. albicans since
they showed acceptable values of inhibition zones (14-17mm) at the adopted conc. level
956
Arch. Pharm.
Soliman, Rida, Badawy and Kappe
(0,2mg/ml DMF). On t h e other hand, 3d was the only compound which showed an
inhibitory effect on
S. aureus.
Table 3: Inhibition Zones in mm Exhibited by some 2,4-Disubstituted 3-Hydroxy-lH,5H-pyrido[1,2-a]-benzimidazol-l -ones 3
Compound
3b
3d
3f
3h
S. aureus
NCTC* 4163
___
12
___
___
E. coli
C. albieans
NCTC* 5933
3501 **
15
17
14
15
15
16
15
14
* National collection type culture.
** Obtained from the Institute of Microbiology, Gottingen, West Germany.
Antineoplastic Screening
Compound 3d was screened against P 388 lymphotic leukemia in mice according to a standard
protocolg)+).Median survival time was taken as the activity parameter for tumor evaluation. A
compound is considered active in this system if the ratio of the median survival time for treated to
control mice (T/C) is 1 120 %. The compound did not reach this value when tested by a three dose
assay at 200,100 and 50 mgkg body weight; intraperitoneal injection using hydroxypropylcelluloseas
vehicle.
The authors are grateful to Dr. G. G. Tuwil, Ass. Prof. of Pharmaceutical Microbiology, Faculty of
Pharmacy, University of Alexandria, for antimicrobial screening. They also thank the staff of the
Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute,
Bethesda, Maryland, USA, for the anticancer test report.
Experimental Part
M.P.: uncorr.; ZR: Perkin Elmer 421; 'H-NMR: Varian EM 360,6 (ppm) with TMS as int. stand.;
MS: Varian-Mat 111 (80eV), peaks below 5 % of the base peak are omitted; Elementary Analysis:
CHN-Automat Carlo Erba 1106.
2,4-Disubstituted 3-Hydroxy-1H,SH-pyrido[l,2-a]benzimidazol-l
-ones (3a-h)
A solution of 2 mmole of the appropriate 1") and 2 m o l e of 2a or 2b in 15ml of bromobenzene was
refluxed for 30-45min during which the product partly was separated. After cooling, the solid was
filtered, washed with benzene, dried and crystallized from the proper solvent (see tablel).
Compounds 3s and 3d crystallized with one or two moles of water.
+)
Conducted by the National Cancer Institute, Bethesda, Maryland, USA.
317/84
3-Hydroxy-1H,5H-pyrido[l,2-a]benzimidazol-l
-ones
957
2-Ethyl-3-hydroxy-1-0x04
H,SH-pyrido[l,2-a]benzimidazole-4-carboxamide
(3i)
0,2 g of 3s was dissolved in a mixture of 14ml ethanol, 8 ml of water and 8 ml of conc. sulfuric acid and
refluxed for 6 h. The product obtainedon coolingwas washed with water, dried and recrystallized(see
table 1).
6-Hydroxy-S-bopropyl-2-methyl-4H-imidazo[4,5,1
-ij]quinolin-4-one(4a)
An intimate mixture of 1,7g (3.76mmole) ldo)and 0,49 g (3.76 mmole) k was placed in an oil bath at
210-220" for 1h. After cooling the dark reddish-brownsolidified mass was triturated with benzene and
the insoluble product w& filtered, washed with benzene and dried. It was recrystallized from a
benzene-ethanol mixture as white crystals, m.p. 271-272"; yieldOJ8g (19.8 %), C14H14N202(242.3)
Calcd.: N 11.6; Found: N 11.3. IR (KBr): 3400 (OH), 3200-2200 with multiple splits (CH), 1715
(CO), l640,159Ocm-' (C=C and aromatics). 'H-NMR (DMSO-d6): 6 (ppm) = 1.3 (d; J = 7Hz, 2
CH3-isopropyl),2.8 (s; CH3 at C-2), 3.4 (4; CH-isopropyl), 7.3-7.9 (m, 2 aromatic H), 8.5 (dd; J =
2/7Hz, H at C-7).
5-Benzyl-6-hydroxy-2-methyl-4H-irnidazo[4,5,1
-i,j]quinolin-4-one(4)
Amixtureof2.38g(4.3mmole)ld'o)and0,57g(4.3mmole)2cwasheatedinanoilbathat2000for2h.
After cooling, the semi solid product was digested with 4Oml of acetone and set aside overnight. The
deposited yellow product was washed with acetone and dried. It was recrystallized from a
benzene-ethanol mixture (lit.'? from bromobenzene), m. p. 278-281" (lit.') m.p.: 276277'); yield
0,32g (25,6%), CigH,4NZO2 (290.3) Calcd.: C 74.5 H 4.86 N 9.6; Found: C 74.0 H 4.98 N 9.4 IR
(C=C and
(KBr): 3500 (OH), 3000-2000 with multiple splits (CH), 1705 (CO), 1630,1595,1580~~'
aromatics). - 'H-NMR (DMSO-d,): 6 (ppm) = 2.75 (s; CH3 at C-2), 3.8 (s, CH2-benzyl),6.65-7.90
(m;7 aromatic H), 8.5 (dd, J = mHz,H at C-7).
2-Methylbenzimidazole- 2,4,6-trichlorophenol(1:1) adduct (5)
The combined acetone filtrate and washings from 4a or 4b were concentrated i. vac. and the oily
residue was treated with benzene - light petroleum (W)
mixture. The adduct obtained on
refrigeration was filtered and recrystallized from aqueous ethanol as colorless prisms, m. p. 155",
undepressed on admixture with an authentic specimen, prepared by mixing equimol. solutions of 2.c
and 2,4,6-trichlorophenoI in the minimum amount of hot methanol; yield 0,3g (21%).
C8H8N2.C6H3C120(329.7) Calcd.: C51.OH3.4C132.3N 8.5; Found: C50.9H3.4 C132.2N8.4.-1R
(KBr): 3420 (OH), 3100-2100 (NH,CH), l620,158Ocm-' (C=C and aromatics). - MS: m/e values
(relative abundance %), 200 (21), 199(S), 198(57), 197 ( S ) , 196 (62), 162 (lo), 160(U), 134(16), 133
(lo), 132 (100), 131 (62), 104 (S), 99 (ll), 98 (6), 97 (20), 92 (6), 67 (6), 66 (13), 65 (8), 64 (8), 63
(11).
Referencea
1 Literature survey: El-SayedA. M . Badawy,M. Pharm. Thesis, Faculty of Pharmacy, University of
Alexandria, Egypt.
2 S. K. Kim, D. G. Bartholomew, L. B. Allen, R. K. Robins, G. R. Revankar, and P. Dea, J. Med.
Chem. 21, 853 (1978).
3 T. A. Khawaja, L. Kigwawa, R. B.Meyer, and R. K. Robins, Proc. Am. Assoc. Cancer Res. 16,
162 (1975).
4 P.P. Saunders, L.Y. Chao, R.K. Robins, and T.L. Loo, Molecular Pharmacol. 15, 691
(1979).
958
Eiden und Wanner
Arch. Pharm.
5 E. Ziegler, C h i d a 24, 62 (1970).
6 E. Ziegler, H. Junek, E. Nolken, K. Gelfert, and R. Salvador, Monatsh. Chem. 92, 815
(l%l).
7 Q.N. Porter and J. Baldas, Mass Spectrometry of Heterocyclic Compounds, p.457, WileyInterscience, New York 1971.
8 S.R. Jain and A. Rar, Planta Med. 20, 118 (1971).
9 R. I. Geran, N. H. Greenberg, M. M. MacDonald, A. M.Schumacher, and B. J. Abbott, Cancer
Chemother. Rep., Part3,3, 1 (1972); Screening Data Summary, Interpretation and Outline of
Current Screen, Instruction Booklet 14, National Cancer Institute, Bethesda 1977.
10 Th. Kappe, Monatsh. Chem. 98, 874 (1967).
[Ph 8381
Arch. Pharm. (Weinheim) 317, 95&962 (1984)
Tetrahydro-3-pyranon als Baustein zur Pyrano[3,2-6]pyranSynthesel)
Fritz Eiden* und Klaus Th. Wanner
Institut fiir Pharmazie und Lebensmittelchemie der Universitat Miinchen, SophienstraSe 10,
8000 Miinchen2
Eingegangen am 29. August 1983
Das aus dem Pyranon 2 gewonnene Enamin 4 setzt sich mit Diketen (6) zum Pyrano[3,2-b]pyranon7
um. Mit 1,3-Dimethylbarbitursaure(10)entsteht das Pyranyliden-Derivat11.Reaktion von 7bzw. 11
mit Ammoniak oder primaren Aminen fiihrt zu den Pyrano-pyridin-Derivaten 8 , 9 , U n und Ub.
Synthesis of ~ o [ 3 , 2 - b ] p y r a nfrom Tetrahydro-3-pyr~ooae~)
The enamine 4, obtained from the pyranone 2, reacts with diketene (6)to yield the pyrano[3,2blpyranone 7. Reaction with 1,3dimethylbarbituric acid (10) results in the formation of the
pyranylidene derivative 11. Reaction of 7 or 11 with ammonia or primary amines leads to the
formation of the pyranopyridine derivatives 8 , 9 , l2a and Ub.
Die Pyrano[3,2-b]pyran-Struktur(1)findet man bei einer Reihe von Naturstoffen: z. B. bei den
Peltogynolen (u. a. in Peltogyne porphyrocardia)’), bei den Clausmarinen (in Clausena pentaphylla)3), bei den Brevetoxinen (in Gymnodinium breve)4) oder den Herbicidinen (aus Streptomyces
saganonensis)’).
036S6233/84/1111-0958 S 02.5OlO
0 Verlag Chemie GmbH, Weinhein 19134
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1h5h, synthesis, ones, antineoplastic, antimicrobials, pyridon, agenti, possible, substituted, hydroxy, benzimidazole
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