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Reactions with Khellin and VisnaginFused Chromone Derivatives of Pyridine Pyrazole and Pyrimidinones.

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Khellin and Visnagin Derivalives
Arch. Pharm. (Weinheim) 320,823-829 (1987)
Reactions with Khellin and Visnagin: Fused Chromone Derivatives
of Pyridine, Pyrazole and Pyrimidinones
Abdel-Kerim M. N. Gohar* and G. G. Abdel-Sadek
Department of Chemistry, Faculty of Science, El-Minia University, El-Minia, A.R. Egypt
Eingegangen am 12. Dezember 1986
New azole and azine derivatives with fused chromone groups have been synthesised from the 5-(dicyanomethylene) furobenzopyran derivative 2 with hydrazines, ammonia, amines, thiourea and active methylene reagents.
Reaktionenmit Khellin und Visnagin: Kondensierte Chromonyl-Pyridine, -Pyrazole und -Pyrimidinone
Mehrere neue heterocyclische Chromonyl-Azole und -Azine wurden aus 5-Dicyanomethylenefurochromonen mit Hydrazinen, Ammoniak, Aminen, Thioharnstoff und aktiven Methylenverbindungen synthetisiert.
Furochromones exhibit diverse biological and physiological activities'). Since the days of the ancient
Egyptians, these derivatives are known as antispasmodics for the relief of spasms of of the ureter, bile
duct, gall bladder and bronchial asthma. Moreover, they were used as potent coronary vasodilators').
We have been interested in the synthesis of heterocyclic derivatives of potential biological and medicinal activitieszg3).Here we report on the synthesis of new chromonyl
derivatives utilizing khellin and visnagin. Visnagin (la) or Khellin (lb) react with malononitrile to the corresponding 5-dicyanomethylenefurochromones 2a, b, respectively.
2a, b were used for the synthesis of, otherwise difficult obtainable, furochromone derivatives. 2%b reacted with NH3 to the cyanoamides 3a, b, respectively. The IR spectra
of 3a, b show bands related to CN-, NH2- and C=O-groups. 3a, b were also synthesized by the reaction of la, b with cyanoacetamide. However, 2a, b reacted also with
NH3 in pyridine to yield the furocoumarinopyridines 4a, b, respectively. 4a, b are most
likely formed via addition of NH3 and simultaneous ring opening of compounds 2a, b
followed by recyclization to the isolable imino derivatives 4a, b. For spectral data cf.
Experimental part. Further evidence for structure 4 came from the conversion of 4a
into its oxygen-counter analoge by hydrolysis to compound 5. Moreover, the imino derivative 4b reacted with benzoyl chloride to afford the pyridopyrimidine 6, probably
via reaction with the acid chloride and subsequent loss of water. The IR spectrum of 6
did not reveal any absorption related to NH, or C=O indicating that these groups were
involved in the cyclization step.
Similar to its behaviour towards NH3in pyridine, 2a reacted with benzylamine to afford the iminofurocoumarinopyridine 7. The structure of 7 was established by spectral
data and via its conversion into the corresponding lactone 8 by hydrolyzation (C=O
band at 1700 cm-I).
0365-6233/87/0909-823 S 02.50/0
0 VCH VerlagsgesellschaR mbH, D-6940 Weinheim, 1987
Gohar and Abdel-Sadek
Arch. Pharm.
I 0
Equimol. amounts of both 2a, b and each of hydrazine hydrate or phenyl hydrazine
resulted in the formation of the furochromonyl pyrazoles 9 and 10, respectively.
The synthetic potentiality of 2a, b was further demonstrated through their reaction
with excess of hydrazines. Thus, 2a, b reacted with an excess of hydrazine hydrate
without solvent to the benzofurylpyrazolopyridines12a, b, respectively. 12a, b are assumed t o be formed first via the addition of hydrazine hydrate to 2a, b followed by ring
Khellin and Visnagin Derivatives
0 \
NHNH2' H20
a , R = H
b, R = OCH3
Gohar and Abdel-Sadek
Arch. Pharm.
opening to afford the corresponding phenolic derivatives 1 la, b which cyclise via the
loss of one molecule of hydrazine hydrate to the final isolable 12a, b. Similar to their behaviour towards hydrazine hydrate, 2a, b reacted with phenyl hydrazine under the
same conditions to give the benzofuranyl-pyrazolopyridines 13a, b. The formation of
13a, b is assumed to proceed via the same sequence leading to 12a, b.
2a reacted with thiourea by fusion in the presence of Et,N to afford the furochromonyl-pyrimidinethione 14. 14 was hydrolysed using HCl/EtOH to afford the corresponding furochromonyl-pyrimidinedione thione 15. Furthermore, 15 was synthesised
via the reaction of l a with thiobarbituric acid.
Experimental Part
M. p. s uncorrected. - IR (KBr, cm-I) spectra: Schimadzu 408 spectrophotometer.
spectra (DMSO): 60 MHz Ern-360 instrument.
'H-NMR (6 ppm)
Preparation of 5-(Dieyanomethylene)-5Hjiuro/3,2-glll
lbenzopyran Derivatives (2a, b, 3a, b and 15)
(General Procedure):
Visnagin (la) or Khellin (lb) (0.01 mol), each of malononitrile, cyanoacetamide or thiobarbituric acid
(0.01 mol) and acetic anhydride (25 ml) were heated under reflux for 1 h. The mixture was left to cool, the
excess of acetic anhydride was aspirated off and the residue was washed with 50 ml of hot water to give
2a, b, 3a, b and 15:
4-Methoxy-S-(dicyanomethylene)-7-rnethyl-5H-furo/3,2-gl/llbenzopyran (2a)
Violet crystals from benzene, m.p. 182'; yield ca. 85 %. C,,H,,N,O, (314.2) Ca1c.C 69.1 H 3.6 N 10.2
Found C 69.0 H 3.8 N 10.3 - IR: 2200 (CN); 1640 (C=C). - 'H-NMR: 2.0 (s, 3H, CH,); 4.1 (s, 3H,
OCH,); 7.3 (s, lH, ar-H); 7.5 (d, lH, furan H-3); 8.2 (d, lH, furan H-2).
4,9-Dirnethoxy-5-(dieyanornethylene)-7-methyl-5H-furo [3,2-glll lbenzopyran (2b)
Brown crystals from benzene m.p. 218-220"; yield ca. 80 YO.C,,H,,N,O, (308.2) Calc. C 66.2 H 3.9
N 9.1 Found C 66.3 H 4.0 N 9.2 - IR: 2200 (CN); 1645 (C=C). - 'H-NMR: 2.1 (s, 3H, CH,); 4.0 (s, 6H,
2 OCH,); 6.5 (s, lH, pyran H-3); 7.2 (s, IH, ar-H); 7.45 (d, lH, furan H-3); 8.2 (d, lH, furan H-2).
4-Methoxy-5-l(arninocarbonyl)(cyano)rnethylenel- 7-methyl-5Hzfuro~3,2-gl/l/benzopyran
From ethanol as brown powder m.p. 200-202"; yield ca. 78 %. C,,H,,N,O, (296.2) Calc. C 64.9 H 4.1
N 9.4 Found C 64.8 H 4.3 N 9.4. - IR: 2900 (NH,); 2200 (CN); 1660 (C=O).
4,9-Dimethoxy-5-l(aminocarbonyl)(eyano)methylenel-7-rnethyl-5H-furol3,2-g//llbenzopyran (3b)
Brown powder from CHCI,, m.p. 207-208O: yield ca. 75 %. C,,H,,N,O, (326.2) Calc. C 62.6 H 4.3
N 8.6 Found C 62.4 H 4.5 N 8.7. - IR: 3000 (NH,): 2200 (CNk 1665 (C=O).
From CHCI, as dark powder m.p. > 300"; yield ca. 85 Yo. C,,H,,N,SO, (356.2) Calc. C 57.3 H 3.4
N 7.9 Found C 57.4 H 3.2 N 7.8. - IR: br 1705-1690 (2 C=O). - 'H-NMR: 2.0 (s, 3H, CH,); 3.1 (s, 2H,
NH); 4.0 (s, 3H, OCH,); 6.7 (s, lH, pyran H-3); 7.3 (d, lH, furan H-3); 7.5 (s, lH, ar-H); 8.2 (d, lH,
furan H-2).
Hydrolysis of 2a, b
A mixture of each of 2a, b (0.5 g) and 10 ml of NH,OH (22 %)was heated on the steam-bath for 1-2 h.
The reaction mixture was left to cool and the precipitated 3a and 3b were crystallized from EtOH and
CHCI,, respectively.
Khellin and Visnagin Derivatives
Preparation of SH-Furo13',2': 6,7NI Ibenzopyranol3,4-clpyridineDerivatives @a, b)
2.7 g of 2a of 2b in 50 ml of pyridine was heated under reflux for 1 h after which 10 ml of NH,OH (22 %)
were added. The mixture was refluxed additional 2 h, cooled, the excess of pyridine was evaportated in vaCUO. The residue was triturated with pet. ether (40-60") to give 4a and 4b.
5-Imino-II -methoxy-2-methyl-SH-fur0[3'2':
Reddish-brown powder from benzene m.p. 214-215': yield ca. 75 %. C,,H,,N,O, (295.2) Calc. C 65.1
H 4.4 N 14.2 Found C 65.0 H 4.5 N 14.0. - IR: 3400: 3200 (NH, NH,).
5-Imino-7,1I -dimethoxy-2-methyl-5H-furol3',2':
6,7111 Ibenzopyranol3.4-clpyridine-4-amine(4b)
From CHCI, as brown powder, m.p. > 270"; yield ca. 80 %. C,,H,,N,O, (325.2) Calc. C 62.8 H 4.6
N 12.9 Found C 62.9 H 4.5 N 13.0. - IR: 3350, 3100 (NH, NH,). - 'H-NMR: 2.1 (s, 3H, CH,); 4.0
(s, 6H, 2 OCH,); 7.2 (d, IH, furan H-3); 7.7 (s, br, IH, NH); 7.95 (d, IH, furan H-2); 8.2 (s, IH, pyridine
H-3); 8.6 (s, br, 2H, NH,).
4b (1.4 g), benzoyl chloride (1 ml) and pyridine (8 ml) were heated for 45 min on the steam-bath then the
mixture was diluted with water. The resulting solid was crystallized from EtOH-CHCI, to give 6. m.p.
> 300'; yield ca. 75 %. C,,H,,N,O, (399.3) Calc. C 69.2 H 4.3 N 10.5 Found C 69.3 H 4.2 N 10.6. 'H-NMR: 2.0 (s, 3H, CH,); 4.1 (s, 6H, 2 OCH,); 7.25 (d, IH, furan H-3); 7.4-7.6 (m,5H, ar-H); 7.9 (d,
IH,furan H-2); 8.1 (s, IH, pyridine H-3).
I -methoxy-2-methyl-5H-furol3'.2':6.71/1
A mixture of 2a (2 g) and benzylamine (10 ml) was heated on the steam-bath for 2-3 h, cooled, diluted
with EtOH and the solid product crystallized from CHCI, to give 7, m.p. > 300'; yield ca. 80 %.
C,,H,,N,O, (475.3) Calc. C 75.9 H 5.1 N 8.7 Found C 76.0 H 5.0 N 8.8. - IR: 3300(NH). - 'H-NMR:
2.1 (s, 3H, CH,); 4.0 (s, 3H, OCH,); 4.5 (s, 4H, 2 CH,-); 7.3 (d, IH, furan H-3); 7.4-7.6 (m, 1IH, ar-H);
7.75 (s, br, IH, NH), 7.9 (d, IH, furan H-2); 8.2 (s, IH, pyridine H-3).
Reaction of 2a, b with Hydrazines:
Method A : A mixture of 2a or 2b (0.01 mol) in EtOH (20 ml and hydrazine hydrate or phenyl hydrazine
(0.01 niol) was heated under reflux for 1 h. The mixture was left to cool. The solid products so obtained
were crystallized to give 9a, b and IOa, b:
Brown powder from DMF/H,O, m.p. > 300'; yield 70 %. C,,H,,N,O, (310.2) Calc. C 61.9 H 4.5
N 18.1 Found C 62.0 H 4.4 N 18.0. - IR: 3400,3260 (NH,). - 'H-NMR: 2.15 (s, 3H, CH,); 4.1 (s, 3H,
OCH,); 6.6 (s, IH, pyran H-3); 7.3 (d, lH, furan H-3); 7.5 (s, IH, ar-H); 7.85 (d, IH,furan H-2); 8.45 (s,
br, 4H, 2 NH,).
Dark brown powder from DMF/H,O, m.p. > 300'; yield 65 %. C,,H,,N,O, (340.2) Calc. C 60.0 H 4.7
N 16.5 Found C 59.9 H 4.8 N 16.4.
H-pyrarol-3imine (10a)
Reddish-brown powder from DMF/H,O, m.p. > 300'; yield 60 %. C,,H,,N,O, (386.3) Calc. C 66.3
H 4.7 N 14.5 Found C 66.4 H 4.8 N 14.4.
Arch. Pharm.
Gohar and Abdel-Sadek
4-(4,9-Dimethoq-7-methyl-5Hzfurol3.2-gl/llbenzopyran-5-ylidene)-2,3-dihydro-2-phen~l-4H-pyrazol3-imine (fob)
Brown powder from DMF/H,O, m.p. > 300" yield ca. 65 %. C,,H,,N,O, (416.3) Calc. C 66.3 H 4.8
N 13.5 Found C 66.2 H 4.7 N 13.4.
Method B : A mixture of 2a or Zb (1.4 g) and hydrazine hydrate or phenyl hydrazine (10 ml) was heated
on the steam-bath for 2 h and then diluted with water. Treatment with dilute acetic acid led to the solid
products. 12a, b and 13a, b.
Brown powder from DMF/H,O, m.p. > 270'; yield ca. 75 %. C,,H,,N,O, (309.2) Calc. C 62. I H 4.2
N 18.1 Found C 62.3 H 4.3 N 18.0. - IR: br (3500-3300), 3280, (OH, NH, NH,). - 'H-NMR: 2.1
(s, 3H, CH,); 4.0 (s, 3H, OCH,); 6.6 (s, IH, H-3 pyridine); 6.7 (s, lH, ar-H); 7.0 (d, lH, furan H-3); 7.7
(s, br, lH, NH); 7.8 (d, lH, furan H-2); 7.9 (s, br, 2H, NH,).
5-(1 -Amino-S-methyl-4H-pyrazolol3,4-b1pyridin-7-yl)-4,7-dimethoxy-l-benzofuran-6-ol(l2b)
From DMF/H,O dark-brown powder, m.p. > 270"; yield ca. 70 %. C,,H,5N,0, (339.2) Calc. C 60.2
H 4.4 N 16.2 Found 60.0 H 4.5 N 16.0.
H-pyrazolol3,4-blpyridin7-yl)-4-methoxy-lbenzofurand01 (13a)
From DMF/H,O dark-brown powder, m.p.
H 4.7 N 14.5 Found C 68.5 H 4.6 N 14.6.
> 280"; yield ca. 74 %. C,,HI8N,O,
(386.3) Calc. C 68.4
Brown powder from DMF/H,O, m.p. > 270'; yield ca. 65 YO.C,,H,,N,O, (416.3) Calc. C 66.3; H 4.8
N 13.5 Found C 66.1 H 4.9 N 13.4.
Ibenzopyran-5-ylidene)pyrimidine-2thione (14)
A solid mixture of 2a (1.4 g), thiourea (0.6 g) and Et,N (3 drops) was heated on the hot plate for 15 min.
The mixture melted and the reaction product started to precipitate. The solid thus formed was triturated
with EtOH to give 13 as dark-brown powder from DMF/H,O, m.p. > 300O; yield ca. 80%.
C,,H,,N,SO, (354.2) Calc. C 57.6 H 4.0 N 15.8 Found C 57.7 H 4.1 N 15.7. - IR: 3450,3400(NHZ).lH-NMR: 2.1 (s, 3H, CH,); 4.15 (s. 3H. OCH,): 6.6 (s. IH. pyran H-3); 7.2 (d, IH, furan H-3): 7.4
(s, lH, ar-H); 7.85 (d, lH, furan H-2): 8.2 (s. br. 4H. 2 NH,).
Hydrolysis of 4a, I and 14 (General Procedure):
A solution of each of 4a, 7 or 14 (1 g) in HCI (2 ml) and EtOH (20 ml) was refluxed for 2 h. The mixture
was allowed to cool and the solid products were collected by filtration to give 5,8 and 15*:
4-Amino-II -methoxy-2-methyl-5H-furol3'.2':6,7111lbenzopyranol3,4-clp.vridin-5-one(5)
From benzene and EtOH as dark-brown crystals , m.p. > 270'; yield ca. 70 %. C , 6 H 1 2 N Z 0(296.2)
Calc. C 64.9 H 4.1 N 9.5 Found C 65.0 H 4.0 N 9.6. - IR: 3420 (NH,); 1700 (C=O).
I -methoxy-2-methyl-5
Hzfuro13',2':6,7111lbenzopyranol3,4-clpyridin-5one (8)
Brown powder from DMF/H,O, m.p. > 300"; yield 75 %. C,,H,,N,O, (369.3) Calc. C 74.8 H 4.6 N 7.6
Found C 74.6 H 4.5 N 7.7. - IR: 3320 (NH); 1700 (C=O).
* I5 showed no depression (mixed m.p.) with a sample obtained by the general procedure mentioned before.
320/8 7
Antiaggregatorische und anticoagulante Oligoamine
1 A. Mustafa ,,Furopyranes and Furopyrones in the Chemistry of heterocyclic compounds", Ed. A.
Weisberger, Interscience publisher, J. Wily and Sons, London (1967) and references cited therein.
2 Y. S. Mohammed, A-K. M. N. Gohar, F. F. Abdel-Latif, and M. Z. A. Badr, Pharmazie 40, 312
3 A-K. M. N. Gohar, F. F. Abdel-Latif, and M. S . El-Katatny, Indian J. Chem. 25B, 404 (1986).
[Ph 2821
Arch. Pharm. (Weinheim) 320, 829-836 (1987)
Antiaggregatorische und anticoagulante Eigenschaften von Oligoaminen, 5. Mitt.
Alicyclische Di- und Triamine
Klaus Rehse. Andrea Carstensen und Hans-Joachim Ernst
Institut fur Pharmazie der Freien Universitat Berlin, Konigin-Luise-Str. 2+4, 1000 Berlin 33
Eingegangen am 15. Dezember 1986
Es wurden 17 Oligoamine aus der Cyclohexan-, Adamantan-, Spiro-[3,3]-heptan- und 9,10-Ethanoanthracenreihe dargestellt. Die durch Collagen induzierte Thrombocytenaggregation wurde von acht Substanzen in Konzentrationen zwischen 2-5 bmol/L halbmaximal gehemmt. Die Gerinnungsfahigkeit von
Blutplasma - dargestellt als Verlangerung der Thromboplastinzeit - wurde von drei Substanzen in Konzentrationen von 50 pmol/L auf 25 % der Norm herabgesetzt. Fur das Spiro-13,3l-heptan-2,6-dimethanamin 16 wird mit Hilfe des 500 MHz-COSY-Spektrums nachgewiesen, daL3 die Cyclobutanringe gefaltet
und die Substituenten equatorial angeordnet sind.
Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines, V:
Alicyclic Diamines and Triamines
Seventeen oligoamines beeing derivatives of cyclohexane, adamantane, spiro[3,3]heptane and 9,IO-ethanoanthracene have been synthesized. Platelet aggregation induced by collagen in vitro is inhibited by eight
of them at IC,, I 5 ymol/L. Three compounds depress the formation of fibrin to 25 96 of normal at a
50 bmol/L concentration. This was indicated by prolongation of the thromboplastin and partial thromboplastin times. The 500 MHz COSY spectrum of a spiro[3,3lheptane-2,6-dimethanamin(16) confirms that
the cyclobutane rings are puckered and that the substituents are in equatorial positions.
Im Zuge unserer Untersuchungen iiber Berinnungsphysiologischaktive Oligoamine haben wir kiirzlich
berichtetl), daL3 die Verkniipfung der Aminfunktion nicht nur iiber aromatische Ringe sondern auch durch
unverzweigtealiphatische Kohlenwasserstoffe bevorzugt mit vier bis sechs C-Atomen ohne WirkungseinbuL3e erfolgen kann.
0 VCH Verlagsgesellschaft mbH,D-6940Weinheim, 1987
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pyridin, pyrazole, visnaginfused, reaction, pyrimidinone, khellin, derivatives, chromone
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