Synthesis of 7-β-(N,N-dialkylamino)ethoxy derivatives of natural isoflavones and 4-aryl-3-[2-hydroxy-4-β-(N,N-dialkylamino) ethoxy]phenylpyrazoles based on them

Article abstract of DOI:10.1007/s10600-013-0500-9

7-O-β-(N,N-dialkylamino)ethyl derivatives of formononetin, 2-methylformononetin, and cladrin were synthesized. Their recyclization through the action of hydrazine hydrate was studied. A series of 4-aryl-3-[2-hydroxy-4- β-(N,N-dialkylamino)ethoxy]phenylpyr

Full text of DOI:10.1007/s10600-013-0500-9

Chemistry of Natural Compounds, Vol. 49, No. 1, March, 2013 [Russian original No. 1, January–February, 2013]
SYNTHESIS OF 7-ꢀ-(N,N-DIALKYLAMINO)ETHOXY
DERIVATIVES OF NATURAL ISOFLAVONES AND
4-ARYL-3-[2-HYDROXY-4-ꢀ-(N,N-DIALKYLAMINO)
ETHOXY]PHENYLPYRAZOLES BASED ON THEM
S. P. Bondarenko
UDC 547.814.5
7-O-ꢀ-(N,N-dialkylamino)ethyl derivatives of formononetin, 2-methylformononetin, and cladrin were
synthesized. Their recyclization through the action of hydrazine hydrate was studied. A series of 4-aryl-3-
[2-hydroxy-4-ꢀ-(N,N-dialkylamino)ethoxy]phenylpyrazoles was obtained.
Keywords: formononetin, 2-methylformononetin, cladrin, ethanolamine, pyrazole.
Many effective modern drugs are analogs or derivatives of natural compounds. A significant fraction of new drugs
are currently natural compounds (10%) and their derivatives (29%) [1].
The goal of the present work was to synthesize 7-O-ꢀ-(N,N-dialkylamino)ethyl derivatives of the natural isoflavones
formononetin (1a), 2-methylformononetin (1b), and cladrin (1c) and also 3-[2-hydroxy-4-ꢀ-(N,N-dialkylamino)ethoxy]-phenyl-
4-arylpyrazoles as their recyclization products.
Methods for synthesizing ꢁ-(N,N-dialkylamino)alkoxy derivatives of flavonoids via the reaction of hydroxyflavones
with ꢁ-(N,N-dialkylamino)alkyl halides were described [2–4]. The reaction of amines with ꢁ-haloalkoxyflavonoids [5–8]
and with phenol glycidyl esters [9] were also used to prepare these compounds.
Alkylation by an excess of dibromoethane in DMF in the presence of potash was used to synthesize 7-O-ꢀ-(N,N-
dialkylamino)ethyl derivatives of formononetin, 2-methylformononetin, and cladrin. This enabled 7-(2-bromoethoxy)
derivatives 2a–c to be synthesized.
R
5
R
4
R
4
R
5
N
R
3
Br
N
4''
R
2
HO
O
R
1
O
5
O
O
R
R
1''
2
a
b
c
R
1
1
OH
5'
O
N
3
N
H
1a - c
2a - c
3a,b, 4c, 5a,b, 6c, 7a,b, 8a
9a,b, 10c, 11a,b, 12c, 13a,b, 14a
a: R = R = H, R = OCH ; b: R = CH , R = H, R = OCH ; c: R = H, R = R = OCH
3
1
2
3
3
1
3
2
3
3
1
2
3
3,9: R R = CH CH CH CH CH ; 4,10: R R = CH CH CH(CONH )CH CH
4
5
2
2
2
2
2
4
5
2
2
2
2
2
5,11: R R = CH CH OCH CH ; 6,12: R R = CH CH(CH )OCH(CH )CH
4
5
2
2
2
2
4
5
2
3
3
2
7,13: R R = CH CH N(Ph)CH CH ; 8,14: R R = CH CH N(C H -F-p)CH CH
4
5
2
2
2
2
4
5
2
2
6
4
2
2
a. BrCH CH Br, K CO ; b. HNR R , i-Pr NEt; c. N H
2 4
2
2
2
3
4
5
2
Alkylation of secondary amines by 7-(2-bromoethoxy)isoflavones 2a–c in the presence of base was studied in order
to prepare 7-ꢀ-(N,N-dialkylamino)ethoxy derivatives of the natural isoflavones. As it turned out, the reaction occurred in high
yield if it was carried out in EtOH in the presence of i-Pr NEt. Thus, a series of derivatives of natural isoflavones 3–8 that
2
contained piperidine, piperidinecarboxamide, morpholine, 2,6-dimethylmorpholine, and N-substituted piperazines bound through
a linker to the chromone ring was synthesized.
Natural University of Food Technologies, Ukraine, 01601, Kiev, Ul. Vladimirskaya, 68, e-mail:
sp_bondarenko@ukrpost.ua. Translated from Khimiya Prirodnykh Soedinenii, No. 1, January–February, 2013, pp. 34–37.
Original article submitted September 14, 2012.
©
36
0009-3130/13/4901-0036 2013 Springer Science+Business Media New York

The structures of the synthesized 7-ꢀ-(N,N-dialkylamino)ethoxy derivatives of isoflavones 3–8 were confirmed by
NMR spectroscopy. Thus, PMR spectra of these compounds contained proton resonances of the isoflavone group and the
amine groups.
3,4-Diarylpyrazoles are known to be interesting compounds for biological studies because they exhibit high inhibitory
activity of Hsp90 [10–13]. Furthermore, 3,4-diarylpyrazoles are inhibitors of catechol-O-methyltransferase (COMT) [14] in
addition to cyclooxygenase-2 [15]. Considering this, the development of synthetic methods for the new compounds of this
series was very timely.
Although several approaches to the synthesis of similar pyrazole derivatives were developed, the most convenient
method for preparing 3,4-diarylpyrazoles was recyclization of the chromone ring through the action of hydrazine [10–18].
Recyclization of the synthesized 7-ꢀ-(N,N-dialkylamino)ethoxy isoflavone derivative 3–8 through the action of
hydrazine was studied in order to prepare 4-aryl-3-[2-hydroxy-4-ꢀ-(N,N-dialkylamino)ethoxy]phenylpyrazoles. Electron-
donating methoxyls in ring B of the natural isoflavone derivatives decreased markedly their reactivity toward dinucleophiles,
especially for 2-methylsubstituted isoflavones 3b, 5b, and 7b, recyclization of which through the action of hydrazine occurred
in several hours.
The pyrazole structures of 9–14 were confirmed by PMR spectroscopy. Occurrence of the reaction with opening of
the chromone ring was confirmed by a diamagnetic shift by 0.5–0.8 ppm of the resonances for phenol protons H-4 and H-6 of
the pyrazole products compared with the position of the H-6 and H-8 proton resonances of the starting isoflavones. Furthermore,
the resonance of the H-3(5) proton was observed as two broad singlets of total intensity 1H because of tautomerism of the
pyrazole ring. Also, the exact positions of the pyrazole H-1 and phenol OH-1 substituents could not be located in most
instances because of exchange processes.
Thus, a series of 7-ꢀ-(N,N-dialkylamino)ethoxy derivatives of natural isoflavones in addition to 4-aryl-3-[2-hydroxy-
4-ꢀ-(N,N-dialkylamino)ethoxy]phenylpyrazoles as products of their recyclization were synthesized.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Sorbfil UV-254 (Russia) and Merck plates
(Germany). The eluents were toluene:EtOH mixtures (9:1, 95:5). PMR spectra were measured in CDCl or DMSO-d
3
6
relative to TMS (internal standard) on the ꢂ-scale on a VXR-300 instrument (Varian, 300 MHz). Analytical data of all compounds
agreed with those calculated.
General Method for Preparing 7-(2-Bromoethoxy)isoflavones 2a–c. A solution of 7-hydroxyisoflavone (1a–c,
10 mmol) in DMF (20 mL) was treated with potash (25 mmol) and dibromoethane (50 mmol). The mixture was stirred at 75–
80°C for 2–5 h (end of reaction determined by TLC). The potash was filtered off. The DMF was evaporated in vacuo. The
solid was crystallized from i-PrOH:DMF.
7-(2-Bromoethoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (2a). Yield 58%, C H BrO , mp 178–180°C.
18 15
4
PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 3.79 (3H, s, 4ꢃ-OCH ), 3.84–3.91 (2H, m, CH Br), 4.47–4.54 (2H, m,
6
3
2
3
3
4
4
3
CH O-7), 7.0 (2H, d, J = 9.0, H-3ꢃ, 5ꢃ), 7.12 (1H, dd, J = 8.9, J = 2.5, H-6), 7.21 (1H, d, J = 2.5, H-8), 7.53 (2H, d, J = 9.0,
H-2ꢃ, 6ꢃ), 8.05 (1H, d, J = 8.9, H-5), 8.43 (1H, s, H-2).
2
3
7-(2-Bromoethoxy)-2-methyl-3-(4-methoxyphenyl)-4H-chromen-4-one (2b). Yield 64%, C H BrO , mp 165–
19 17
4
167°C. PMR spectrum (300 MHz, CDCl , ꢂ, ppm, J/Hz): 2.30 (3H, s, CH -2), 3.64–3.74 (2H, m, CH Br), 3.84 (3H, s,
3
3
2
4
3
4ꢃ-OCH ), 4.33–4.43 (2H, m, CH O-7), 6.84 (1H, d, J = 2.3, H-8), 6.92–7.0 (3H, m, H-6, H-3ꢃ, H-5ꢃ), 7.20 (2H, d, J = 8.7,
3
2
3
H-2ꢃ, H-6ꢃ), 8.14 (1H, d, J = 8.6, H-5).
7-(2-Bromoethoxy)-3- (3,4-dimethoxyphenyl)-4H-chromen-4-one (2c). Yield 60%, C H BrO , mp 165–167°C.
19 17
5
PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 3.80 (6H, s, 3ꢃ-OCH and 4ꢃ-OCH ), 3.84–3.91 (2H, m, CH Br), 4.47–
6
3
3
2
3
3
4.54 (2H, m, CH O-7), 7.00 (1H, d, J = 8.2, H-5ꢃ), 7.07–7.27 (4H, m, H-6, H-8, H-2ꢃ, H-6ꢃ), 8.05 (1H, d, J = 9.0, H-5), 8.43
2
(1H, s, H-2).
General Method for Preparing 7-ꢀ-(N,N-Dialkylamino)ethoxy Derivatives of Isoflavones 3a,b, 4c, 5a,b, 6c,
7a,b, 8a. A solution of the appropriate 7-(2-bromoethoxy)isoflavone 2a–c (2 mmol) in EtOH (30 mL) was treated with
secondary amine (2.4 mmol) and di-isopropylethylamine (3 mmol), refluxed for 4–8 h (end of reaction determined by TLC),
cooled, and diluted with H O. The resulting precipitate was filtered off and crystallized from EtOH:H O.
2
2
37

3-(4-Methoxyphenyl)-7-(2-piperidin-1-ylethoxy)-4H-chromen-4-one (3a). Yield 70%, C H NO , mp 122–124°C.
23 25
4
PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 1.31–1.59, 2.38–2.48 (6H, m, 4H, m, piperidine protons), 2.63–2.78
6
3
(2H, m, NCH CH O-7), 3.79 (3H, s, 4ꢃ-OCH ), 4.18–4.26 (2H, m, NCH CH O-7), 6.99 (2H, d, J = 8.7, H-3ꢃ, H-5ꢃ), 7.07
(1H, dd, J = 9.0, J = 2.3, H-6), 7.17 (1H, d, J = 2.3, H-8), 7.53 (2H, d, J = 8.7, H-2ꢃ, H-6ꢃ), 8.02 (1H, d, J = 9.0, H-5), 8.40
(1H, s, H-2).
2
2
3
2
2
3
4
4
3
3
2-Methyl-3-(4-methoxyphenyl)-7-(2-piperidin-1-ylethoxy)-4H-chromen-4-one (3b). Yield 67%, C H NO ,
24 27
4
mp 113–115°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 1.32–1.56, 2.39–2.48 (6H, m, 4H, m, piperidine protons),
6
2.26 (3H, c, CH -2), 2.65–2.72 (2H, m, NCH CH O-7), 3.80 (3H, s, 4ꢃ-OCH ), 4.17–4.24 (2H, m, NCH CH O-7), 6.98 (2H,
3
2
2
3
2
2
3
3
4
4
3
d, J = 8.7, H-3ꢃ, H-5ꢃ), 7.03 (1H, dd, J = 9.0, J = 2.3, H-6), 7.13 (1H, d, J = 2.3, H-8), 7.20 (2H, d, J = 8.7, H-2ꢃ, H-6ꢃ), 7.92
(1H, d, J = 9.0, H-5).
3
1-(2-{[3-(3,4-Dimethoxyphenyl)-4-oxo-4H-chromen-7-yl]oxy}ethyl)piperidine-4-carboxamide (4c). Yield 65%,
C H N O , mp 207–209°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 1.45–1.73, 1.92–2.14, 2.89–3.06 (5H, m,
25 28
2
6
6
2H, m, 2H, m, piperidine protons), 2.66–2.79 (2H, m, NCH CH O-7), 3.79 (6H, s, 3ꢃ-OCH , 4ꢃ-OCH ), 4.19–4.27 (2H, m,
2
2
3
3
3
NCH CH O-7), 6.68–7.27 (7H, m, CONH , H-6, H-8, H-2ꢃ, H-5ꢃ, H-6ꢃ), 8.02 (1H, d, J = 8.9, H-5), 8.50 (1H, s, H-2).
2
2
2
3-(4-Methoxyphenyl)-7-(2-morpholin-4-ylethoxy)-4H-chromen-4-one (5a). Yield 74%, C H NO , mp 156–
22 23
5
158°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.45–2.53, 3.55–3.62 (4H, m, 4H, m, morpholine protons),
6
3
2.70–2.78 (2H, m, NCH CH O-7), 3.79 (3H, s, 4ꢃ-OCH ), 4.21–4.29 (2H, m, NCH CH O-7), 6.99 (2H, d, J = 8.7, H-3ꢃ,
H-5ꢃ), 7.08 (1H, dd, J = 9.0, J = 2.3, H-6), 7.17 (1H, d, J = 2.3, H-8), 7.53 (2H, d, J = 8.7, H-2ꢃ, H-6ꢃ), 8.03 (1H, d, J = 9.0,
H-5), 8.40 (1H, s, H-2).
2
2
4
3
2
2
3
4
3
3
2-Methyl-3-(4-methoxyphenyl)-7-(2-morpholin-4-ylethoxy)-4H-chromen-4-one (5b). Yield 67%, C H NO ,
23 25
5
mp 112–114°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.29 (3H, c, CH -2), 2.44–2.56, 3.56–3.65 (4H, m, 4H,
6
3
m, morpholine protons), 2.72–2.80 (2H, m, NCH CH O-7), 3.82 (3H, s, 4ꢃ-OCH ), 4.16–4.24 (2H, m, NCH CH O-7), 6.93
2
2
3
2
2
3
3
4
4
3
(2H, d, J = 8.7, H-3ꢃ, H-5ꢃ), 6.93 (1H, dd, J = 9.0, J = 2.3, H-6), 6.99 (1H, d, J = 2.3, H-8), 7.14 (2H, d, J = 8.7, H-2ꢃ,
3
H-6ꢃ), 7.92 (1H, d, J = 9.0, H-5).
7-[2-(2,6-Dimethylmorpholin-4-yl)ethoxy]-3-(3,4-dimethoxyphenyl)-4H-chromen-4-one (6c). Yield 73%,
C H NO , mp 107–109°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 1.01–1.15, 1.68–1.80, 2.80–2.89, 3.50–
25 29
6
6
3.64 (6H, 2H, 2H, 2H, 4 m, morpholine protons), 2.68–2.76 (2H, m, NCH CH O-7), 3.80 (6H, s, 3ꢃ-OCH , 4ꢃ-OCH ), 4.21–
2
2
3
3
3
4.29 (2H, m, NCH CH O-7), 6.96–7.24 (5H, m, H-6, H-8, H-2ꢃ, H-5ꢃ, H-6ꢃ), 8.03 (1H, d, J = 9.0, H-5), 8.46 (1H, s, H-2).
2
2
3-(4-Methoxyphenyl)-7-[2-(4-phenylpiperazin-1-yl)ethoxy]-4H-chromen-4-one (7a). Yield 69%, C H N O ,
28 28
2 4
mp 160–162°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.60–2.70, 3.08–3.19 (4H, m, 4H, m, piperazine protons),
6
2.76–2.85 (2H, m, NCH CH O-7), 3.79 (3H, s, 4ꢃ-OCH ), 4.23–4.33 (2H, m, NCH CH O-7), 6.73–6.96 (3H, m, H-2ꢃꢃꢃ,
2
2
3
2
2
3
3
4
H-4ꢃꢃꢃ, H-6ꢃꢃꢃ), 7.00 (2H, d, J = 8.7, H-3ꢃ, H-5ꢃ), 7.10 (1H, dd, J = 8.7, J = 2.0, H-6), 7.17–7.25 (3H, m, H-8, H-3ꢃꢃꢃ, H-5ꢃꢃꢃ),
7.53 (2H, d, J = 8.7, H-2ꢃ, H-6ꢃ), 8.04 (1H, d, J = 8.7, H-5), 8.42 (1H, s, H-2).
3
3
2-Methyl-3-(4-methoxyphenyl)-7-[2-(4-phenylpiperazin-1-yl)ethoxy]-4H-chromen-4-one (7b). Yield 76%,
C H N O , mp 150–152°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.27 (3H, c, CH -2), 2.61–2.90, 3.10–
29 30
2
4
6
3
3.18 (4H, m, 4H, m, piperazine protons), 2.77–2.85 (2H, m, NCH CH O-7), 3.80 (3H, s, 4ꢃ-OCH ), 4.24–4.33 (2H, m,
2
2
3
3
3
4
NCH CH O-7), 6.72–6.96 (3H, m, H-2ꢃꢃꢃ, H-4ꢃꢃꢃ, H-6ꢃꢃꢃ), 6.99 (2H, d, J = 8.7, H-3ꢃ, H-5ꢃ), 7.06 (1H, dd, J = 8.7, J = 2.3,
2
2
3
H-6), 7.15–7.26 (5H, m, H-8, H-2ꢃ, H-6ꢃ, H-3ꢃꢃꢃ, H-5ꢃꢃꢃ), 7.93 (1H, d, J = 8.7, H-5).
3-(4-Methoxyphenyl)-7-{2-[4-(4-fluorophenyl)piperazin-1-yl]ethoxy}-4H-chromen-4-one (8a). Yield 70%,
C H FN O , mp 170–172°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.61–2.70, 3.04–3.12 (4H, m, 4H, m,
28 27
2
4
6
piperazine protons), 2.77–2.85 (2H, m, NCH CH O-7), 3.79 (3H, s, 4ꢃ-OCH ), 4.25–4.32 (2H, m, NCH CH O-7), 6.89–7.07
2
2
3
2
2
3
4
4
3
(6H, m, H-3ꢃ, H-5ꢃ, Nꢃ-C H -F-p), 7.10 (1H, dd, J = 8.7, J = 2.0, H-6), 7.20 (1H, d, J = 2.0, H-8), 7.53 (2H, d, J = 8.7,
H-2ꢃ, H-6ꢃ), 8.03 (1H, d, J = 8.7, H-5), 8.41 (1H, s, H-2).
6
3
4
General Method for Preparing 3-[2-Hydroxy-4-ꢀ-(N,N-dialkylamino)ethoxy]phenyl-4-arylpyrazoles 9a,b, 10c,
11a,b, 12c, 13a,b, 14a. A hot solution of the appropriate isoflavone 3–8 (4.5 mmol) in the minimal amount of EtOH was
treated with hydrazine hydrate (2 mL, 60 mmol, 85%), refluxed for 0.1–2 h (end of reaction determined by TLC), and poured
into H O (100–150 mL). The precipitate was filtered off and crystallized from MeOH.
2
2-[4-(4-Methoxyphenyl)-1H-pyrazol-3(5)-yl]-5-(2-piperidin-1-ylethoxy)phenol (9a). Yield 85%, C H N O ,
23 27
3 3
mp 80–82°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 1.30–1.59, 2.32–2.46 (6H, m, 4H, m, piperidine protons),
6
3
4
2.60–2.69 (2H, m, NCH CH O-5), 3.79 (3H, s, 4ꢃꢃ-OCH ), 3.96–4.07 (2H, m, NCH CH O-5), 6.36 (1H, dd, J = 8.1, J = 2.2,
2
2
3
2
2
38

4
3
3
3
H-4), 6.47 (1H, d, J = 2.2, H-6), 6.85 (2H, d, J = 8.9, H-3ꢃꢃ, H-5ꢃꢃ), 7.00 (1H, d, J = 8.1, H-3), 7.20 (2H, d, J = 8.9, H-2ꢃꢃ,
H-6ꢃꢃ), 7.78 (1H, br.s, H-5ꢃ(3ꢃ)).
2-[5(3)-Methyl-4-(4-methoxyphenyl)-1H-pyrazol-3(5)-yl]-5-(2-piperidin-1-ylethoxy)phenol (9b). Yield 81%,
C H N O , mp 192–194°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 1.29–1.55, 2.32–2.48 (6H, m, 4H, m,
24 29
3
3
6
piperidine protons), 2.15 (3H, c, CH -5ꢃ(3ꢃ)), 2.55–2.42 (2H, m, NCH CH O-5), 3.77 (3H, s, 4ꢃꢃ-OCH ), 3.93–4.03 (2H, m,
3
2
2
3
3
4
4
3
NCH CH O-5), 6.22 (1H, dd, J = 8.6, J = 2.4, H-4), 6.42 (1H, d, J = 2.4, H-6), 6.94 (2H, d, J = 8.4, H-3ꢃꢃ, H-5ꢃꢃ), 7.13 (2H,
d, J = 8.4, H-2ꢃꢃ, H-6ꢃꢃ), 7.13 (1H, d, J = 8.6, H-3), 11.20 (1H, s, OH), 13.00 (1H, br.s, NH).
2
2
3
3
1-(2-{4-[4-(3,4-Dimethoxyphenyl)-1H-pyrazol-3(5)-yl]-3-hydroxyphenoxy}-ethyl)piperidine-4-carboxamide
(10c). Yield 75%, C H N O , mp 104–106°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 1.44–1.73, 1.91–2.12,
25 30
4
5
6
2.86–2.99 (5H, 2H, 2H, 3m, piperidine protons), 2.58–2.70 (2H, m, NCH CH O-5), 3.59, 3.72 (3H, 3H, 2s, 3ꢃꢃ-OCH , 4ꢃꢃ-OCH ),
2
2
3
3
3.98–4.06 (2H, m, NCH CH O-5), 6.22–7.27 (8H, m, CONH , H-3, H-4, H-6, H-2ꢃꢃ, H-5ꢃꢃ, H-6ꢃꢃ), 7.73, 7.94 (1H, 2 br.s,
2
2
2
H-5ꢃ(3ꢃ)).
2-[4-(4-Methoxyphenyl)-1H-pyrazol-3(5)-yl]-5-(2-morpholin-4-ylethoxy)phenol (11a). Yield 84%, C H N O ,
22 25
3 4
mp 63–65°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.40–2.56, 3.52–3.63 (4H, m, 4H, m, morpholine protons),
6
3
4
2.62–2.72 (2H, m, NCH CH O-5), 3.79 (3H, s, 4ꢃꢃ-OCH ), 3.99–4.09 (2H, m, NCH CH O-5), 6.37 (1H, dd, J = 9.0, J = 2.3,
H-4), 6.48 (1H, d, J = 2.3, H-6), 6.85 (2H, d, J = 8.4, H-3ꢃꢃ, H-5ꢃꢃ), 7.01 (1H, d, J = 9.0, H-3), 7.20 (2H, d, J = 8.4, H-2ꢃꢃ,
H-6ꢃꢃ), 7.78 (1H, br.s, H-5ꢃ(3ꢃ)).
2
2
3
2
2
4
3
3
3
5(3)-Methyl-2-[4-(4-methoxyphenyl)-1H-pyrazol-3(5)-yl]-5-(2-morpholin-4-ylethoxy)phenol (11b). Yield 80%,
C H N O , mp 187–189°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.15 (3H, c, CH -5ꢃ(3ꢃ)), 2.40–2.47,
23 27
3
4
6
3
3.52–3.60 (4H, m, 4H, m, morpholine protons), 2.60–2.67 (2H, m, NCH CH O-5), 3.77 (3H, s, 4ꢃꢃ-OCH ), 3.97–4.04 (2H, m,
2
2
3
3
4
4
3
NCH CH O-5), 6.22 (1H, dd, J = 8.7, J = 2.2, H-4), 6.43 (1H, d, J = 2.2, H-6), 6.89 (1H, d, J = 8.7, H-3), 6.92–7.19 (4H,
2
2
m, C H -OMe-p), 11.20 (1H, s, OH), 12.98 (1H, br.s, NH).
6
4
5-[2-(2,6-Dimethylmorpholin-4-yl)ethoxy]-2-[4-(3,4-dimethoxyphenyl)-1H-pyrazol-3(5)-yl]phenol (12c). Yield
76%, C H N O , mp 79–81°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 0.97–1.16, 1.65–1.77, 2.75–2.86,
25 31
3
5
6
3.49–3.64 (6H, 2H, 2H, 2H, 4 m, morpholine protons), 2.58–2.96 (2H, m, NCH CH O-5), 3.72 (6H, s, 3ꢃꢃ-OCH , 4ꢃꢃ-OCH ),
2
2
3
3
3.99–4.09 (2H, m, NCH CH O-5), 6.27–6.58 (2H, m, H-4, H-6), 6.70–7.18 (4H, m, H-3, H-2ꢃꢃ, H-5ꢃꢃ, H-6ꢃꢃ), 7.73, 7.94 (1H,
2
2
2 br.s, H-5ꢃ(3ꢃ)).
2-[4-(4-Methoxyphenyl)-1H-pyrazol-3(5)-yl]-5-[2-(4-phenylpiperazin-1-yl)ethoxy]phenol (13a). Yield 88%,
C H N O , mp 92–94°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.58–2.67, 3.09–3.17 (4H, m, 4H, m,
28 30
4
3
6
piperazine protons), 2.70–2.78 (2H, m, NCH CH O-5), 3.72 (3H, s, 4ꢃꢃ-OCH ), 4.04–4.12 (2H, m, NCH CH O-5), 6.28–6.57
2
2
3
2
2
(2H, m, H-4, H-6), 6.72–7.30 (10H, m, H-3, C H -OMe-p, Nꢃ-C H ), 7.68, 7.92 (1H, 2 br.s, H-5ꢃ(3ꢃ)).
6
4
6 5
5(3)-Methyl-2-[4-(4-methoxyphenyl)-1H-pyrazol-3(5)-yl]-5-[2-(4-phenylpiperazin-1-yl)ethoxy]phenol (13b).
Yield 85%, C H N O , mp 203–205°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.16 (3H, c, CH -5ꢃ(3ꢃ)),
29 32
4
3
6
3
2.58–2.65, 3.08–3.16 (4H, m, 4H, m, piperazine protons), 2.68–2.75 (2H, m, NCH CH O-5), 3.78 (3H, s, 4ꢃꢃ-OCH ), 4.01–
2
2
3
3
4
4
4.10 (2H, m, NCH CH O-5), 6.26 (1H, dd, J = 8.8, J = 2.2, H-4), 6.46 (1H, d, J = 2.2, H-6), 6.72–7.27 (10H, m, H-3,
2
2
C H -OMe-p, Nꢃ-C H ).
6
4
6 5
2-[4-(4-Methoxyphenyl)-1H-pyrazol-3(5)-yl]-5-{2-[4-(4-fluorophenyl)piperazin-1-yl]ethoxy}phenol (14a). Yield
88%, C H FN O , mp 171–173°C. PMR spectrum (300 MHz, DMSO-d , ꢂ, ppm): 2.59–2.67, 3.03–3.13 (4H, m, 4H, m,
28 29
4
3
6
piperazine protons), 2.70–2.79 (2H, m, NCH CH O-5), 3.72 (3H, s, 4ꢃꢃ-OCH ), 4.04–4.12 (2H, m, NCH CH O-5), 6.28–6.56
2
2
3
2
2
(2H, m, H-4, H-6), 6.74–7.26 (9H, m, H-3, C H -OMe-p, Nꢃ-C H -F-p), 7.68, 7.91 (1H, 2 br.s, H-5ꢃ(3ꢃ)).
6
4
6 4
REFERENCES
1.
2.
R. Bade, H.-F. Chan, and J. Reynisson, Eur. J. Med. Chem., 45, 5646 (2010).
L. Betti, M. Floridi, G. Giannaccini, F. Manetti, C. Paparelli, G. Strappaghetti, and M. Botta, Bioorg. Med. Chem., 12,
1527 (2004).
3.
4.
M. Bonesi, R. Tundis, B. Deguin, M. R. Loizzo, F. Menichini, F. Tillequin, and F. Menichini, Bioorg. Med. Chem. Lett.,
18, 5431 (2008).
W. Loewe, S. Witzel, S. Tappmeyer, and R. Albuschat, J. Heterocycl. Chem., 41, 317 (2004).
39

5.
M. Delcanale, G. Amari, E. Armani, M. Lipreri, M. Civelli, E. Galbiati, M. Giossi, P. L. Caruso, P. Crivori, P.-A. Carrupt,
and B. Testa, Helv. Chim. Acta., 84, 2417 (2001).
6.
7.
8.
H.-Q. Li, L. Shi, Q.-S. Li, P.-G. Liu, Y. Luo, J. Zhao, and H.-L. Zhu, Bioorg. Med. Chem., 17, 6264 (2009).
J. C. Jaen, L. D. Wise, T. G. Heffner, T. A. Pugsley, and L. T. Meltzer, J. Med. Chem., 34, 248 (1991).
A. Rampa, A. Bisi, P. Valenti, M. Recanatini, A. Cavalli, V. Andrisano, V. Cavrini, L. Fin, A. Buriani, and P. Giusti,
J. Med. Chem., 41, 3976 (1998).
9.
10.
11.
12.
13.
E. S. C. Wu, J. T. Loch, B. H. Toder, A. R. Borrelli, D. Gawlak, L. A. Radov, and N. P. Gensmantel, J. Med. Chem., 35,
3519 (1992).
K.-M. J. Cheung, T. P. Matthews, K. James, M. G. Rowlands, K. J. Boxall, S. Y. Sharp, A. Maloney, S. M. Roe,
C. Prodromou, L. H. Pearl, G. W. Aherne, E. McDonald, and P. Workmans, Bioorg. Med. Chem. Lett., 15, 3338 (2005).
X. Barril, M. C. Beswick, A. Collier, M. J. Drysdale, B. W. Dymock, A. Fink, K. Grant, R. Howes, A. M. Jordan,
A. Massey, A. Surgenor, J. Wayne, P. Workman, and L. Wright, Bioorg. Med. Chem. Lett., 16, 2543 (2006).
B. W. Dymock , X. Barril, P. A. Brough, J. E. Cansfield, A. Massey, E. McDonald, R. E. Hubbard, A. Surgenor,
S. D. Roughley, P. Webb, P. Workman, L. Wright, and M. J. Drysdale, J. Med. Chem., 48, 4212 (2005).
P. A. Brough, W. Aherne, X. Barril, J. Borgognoni, K. Boxall, J. E. Cansfield, K.-M. J. Cheung, I. Collins,
N. G. M. Davies, M. J. Drysdale, B. Dymock, S. A. Eccles, H. Finch, A. Fink, A. Hayes, R. Howes, R. E. Hubbard,
K. James, A. M. Jordan, A. Lockie, V. Martins, A. Massey, T. P. Matthews, E. McDonald, C. J. Northfield,
L. H. Pearl, C. Prodromou, S. Ray, F. I. Raynaud, S. D. Roughley, S. Y. Sharp, A. Surgenor, D. L. Walmsley,
P. Webb, M. Wood, P. Workman, and L. Wright, J. Med. Chem., 51, 196 (2008).
14.
15.
L. E. Kiss, H. S. Ferreira, L. Torrao, M. J. Bonifacio, P. N. Palma, P. Soares-da-Silva, and D. A. Learmonth,
J. Med. Chem., 53, 3396 (2010).
T. D. Penning, S. W. Kramer, L. F. Lee, P. W. Collins, C. M. Koboldt, K. Seibert, A. W. Veenhuizen, Y. Y. Zhang,
and P. C. Isakson, Bioorg. Med. Chem. Lett., 7 (16), 2121 (1997).
16.
17.
18.
V. Szabo, J. Borda, and V. Vegh, Magy. Kem. Foly., 83 (3), 393 (1977).
V. P. Khilya, A. Aitmambetov, M. Ismailov, and L. G. Grishko, Khim. Prir. Soedin., 554 (1994).
A. Matin, N. Gavande, M. S. Kim, N. X. Yang, N. K. Salam, J. R. Hanrahan, R. H. Roubin, and D. E. Hibbs,
J. Med. Chem., 52, 6835 (2009).
40