Studies on antiplatelet agents from natural safrole. II. Synthesis and pharmacological properties of novel functionalized oxime O-benzylether derivatives

DOI: 10.1016/S0031-6865(99)00014-X

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Pharmaceutica Acta Helvetiae p. 19 - 28 (1999)

Update date:2022-08-11

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Authors:

De A. Reis, Andre L.

Ormelli, Claudia B.

Miranda, Ana L.P.

Fraga, Carlos A.M.

Barreiro, Eliezer J.

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Article abstract of DOI:10.1016/S0031-6865(99)00014-X

In an ongoing research program aiming at the synthesis and pharmacological evaluation of new possible prototype candidates exploring the molecular hybridation and bioisosterism principles for molecular designing, we describe in this paper the design and synthesis of a series of new functionalized oxime O-benzylethers (4a-b) and (14a-b) as antiplatelet agents based on the inhibition of arachidonic acid (AA) cascade enzymes. For the synthesis of these new bioactive derivatives we used safrole (5), a Brazilian abundant natural product, as starting material. The platelet anti-aggregating evaluation of these oxime O-benzylether compounds (4a-b) and (14a-b) in model induced by ADP, collagen and AA, has permitted to evidence an antithrombotic profile to these new derivatives, being the most active the derivative methyl [[3,4-methylenedioxyphenyl]methylene]amino]oxy]-4-methylenephenylacetic acid (14a). Copyright (C) 1999 Elsevier Science B.V.

Full text of DOI:10.1016/S0031-6865(99)00014-X

Pharmaceutica Acta Helvetiae 74 1999 19–28

www.elsevier.comrlocaterpharmactahelv

Studies on antiplatelet agents from natural safrole

II. Synthesis and pharmacological properties of novel functionalized

oxime O-benzylether derivatives

a,b

Andre L. de A. Reis , Claudia B. Ormelli , Ana L.P. Miranda , Carlos A.M. Fraga ,

a,b,)

Eliezer J. Barreiro

(

)

Laboratorio de AÕaliac¸ao e Sıntese de Substancias BioatiÕas LASSBio, http:rrwww.ufrj.brr; pharmarlassbio , Faculdade de Farmacia,

UniÕersidade Federal do Rio de Janeiro, PO Box 68.006, ZIP 21944-970, Rio de Janeiro, RJ, Brazil

^bInstituto de Quımica, UniÕersidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

Received 8 March 1999; received in revised form 25 June 1999; accepted 7 July 1999

Abstract

In an ongoing research program aiming at the synthesis and pharmacological evaluation of new possible prototype candidates

exploring the molecular hybridation and bioisosterism principles for molecular designing, we describe in this paper the design and

synthesis of a series of new functionalized oxime O-benzylethers 4a–b and 14a–b as antiplatelet agents based on the inhibition of

Ž .

arachidonic acid AA cascade enzymes. For the synthesis of these new bioactive derivatives we used safrole 5 , a Brazilian abundant

natural product, as starting material. The platelet anti-aggregating evaluation of these oxime O-benzylether compounds 4a–b and

14a–b in model induced by ADP, collagen and AA, has permitted to evidence an antithrombotic profile to these new derivatives, being

the most active the derivative methyl 3,4-methylenedioxyphenyl methylene amino oxy -4-methylenephenylacetic acid 14a . q 1999

Keywords: Platelet aggregation; Oxime O-benzylethers derivatives; Safrole in synthesis

1. Introduction

TPant and new N-phenylpyrazole oxime-O-benzylether

. Ž

TXSirTPant Fig. 1 . In our continuing studies, we syn-

thesized a new class of conformationally restricted PAF

derivatives 2a–b Muri et al., 1998 , designed as dual

During an ongoing research program to identify new

lead compounds with antiplatelet activity, acting at AA

cascade level, we described in previous papers, the anti-ag-

Ž .

antagonists candidates

belonging to the 2-oxabi-

gregating profile of new arylsulfonamides derivatives 1a–

cyclo 3.3.0 octane and tested them for their antiplatelet

. Ž

Lima et al., 1999 , synthesized from natural safrole as

effects Pec¸anha et al., 1998 Fig. 1 . These novel an-

tiplatelet agents presented important biological profile,

where the most active derivative was represented by com-

)

. Ž

pound 1a Lima et al., 1999 .

Corresponding author. Laboratorio de Avaliac¸ao

e Sıntese de

Following these efforts, we wish to describe in this

report, the synthesis and antiplatelet properties of novel

Substancias Bioativas LASSBio, http:rrwww.ufrj.brr ; pharmar

lassbio , Faculdade de Farmacia, Universidade Federal do Rio de Janeiro,

PO Box 68.006, ZIP 21944-970, Rio de Janeiro, RJ, Brazil. Tel.:

q55-21-280-1784, ext. 238; fax: q55-21-260-2299 or 273-3890; E-mail:

eliezer@pharma.ufrj.br

oxime O-benzylether derivatives 4a–b , structurally

planned as dual TXSirTPant. candidates, synthesized from

¹Taken, in part, from the M.Sc. Thesis of ALAR; this paper represents

Ž .

safrole 5 , an abundant Brazilian natural product, occur-

ring in the Sassafras oil, as starting material Fig. 1 .

the contribution a 38 from LASSBio, UFRJ Br. .

PII: S0031-6865 99 00014-X

(

)

A.L. de A. Reis et al.rPharmaceutica Acta HelÕetiae 74 1999 19–28

Fig. 1.

. Ž

The design of these new derivatives 4a–b Fig. 1 ,

maintained in order to assure the ionic site for binding

with TP and TXS, as presented in numerous dual an-

considered the 1,3-benzodioxole ring, present in the natu-

Ž .

ral starting material 5 , as a hydrogen-bonding acceptor

tiplatelet agents Jin and Hopfinger, 1994; Albuquerque et

site, as well explore the presence of the oxygen atom a

al., 1995 . The interphenylene nature of this acidic chain,

Fig. 1 as an equivalent site to coordinate with the Fe-heme

presents in TXS, mimicking the nitrogen-containing ring

Ž . Ž

corresponding to a phenyl acetic acid residue, was intro-

duced as a conformational restriction tool in order also to

prevents the metabolic b-oxidation process that reduce the

of ridogrel 6 De Clerck et al., 1989a,b; Bossche et al.,

. Ž

1992 a , Fig. 1 . The compound 4a was planned by

introduction of a second aromatic ring, correspondent to a

hydrophobic unit, which could be essential, due to its

lipophilic properties, to present a dual profile Fig. 1 . In

addition, to compare the contribution of this second aro-

matic ring in the antiplatelet activity, the corresponding

length of fatty acid-like chains Schulz, 1991 .

2. Experimental

2.1. Chemistry

nor-phenyl derivative 4b was also prepared. In all these

Melting points were determined with a Thomas–Hoover

apparatus and are uncorrected. Proton magnetic resonance

derivatives 4a–b , the carboxylic acid end-chain was

(

)

A.L. de A. Reis et al.rPharmaceutica Acta HelÕetiae 74 1999 19–28

Ž¹

H NMR , unless otherwise stated, was determined in

CHOH ppm; IR Film : 3405 n O0-H , 1245 and 1038

deuterochloroform containing ca. 1% tetramethylsilane as

internal standard with a Brucker AC 200 at 200 MHz.

Carbon magnetic resonance C NMR was determined in

the same spectrometer described above at 50 MHz, using

n C–O cm ; MS mrz : 228 M , 100% , 211 17% ,

151 50% , 123 75% , 105 65% .

Ž¹³

(

)

( )

2.3. 3,4-Methylenedioxyphenyl phenylmethanone 10

(

)

deuterochloroform as internal standard. Infrared IR spec-

tra were obtained with Nicolet-205 spectrophotometers by

using potassium bromide plates or neat films on sodium

Takeuchi et al., 1995

To a solution of 0.60 g 2.63 mmol of alcohol deriva-

Ž .

chloride plates. Ultraviolet UV spectra were determined

tive

in 10 ml of dry THF were added 3.60 g of

in methanol solution on a Shimadzu UV-1601 spectro-

previously thermo-activated MnO₂. Next, the reaction mix-

ture was refluxed for 30 min, then filtered in a Celite

packed column. The filtrate was concentrated at reduced

photometer. The mass spectra MS were obtained by

electron impact with a GCrVG Micromass 12 spectrome-

ter.

pressure to furnish 0.41 g 70% of the benzophenone

The progress of all reactions was monitored by tlc

which was performed on 2.0 cm=6.0 cm aluminum sheets

derivative 10 , as a white solid, mp 49–538C; H NMR

200 MHz : d 7.73 2H, dt, H-2 , 7.60–7.40 3H, m, H-3

precoated with silica gel 60 HF-254, Merck to a thick-

ness of 0.25 mm. The developed chromatograms were

viewed under ultraviolet light. For column chromatography

and H-4 , 7.37 1H, dd, J_6y5s8 Hz and J_6y2s2 Hz,

H-6 , 7.35 1H, d, J_6y2s2 Hz, H-2 , 6.85 1H, d, J_6y5

8 Hz, H-5 ppm; C NMR 50 MHz : d 195.0 C5O ,

Merck silica gel 70–230 mesh was used. Solvents used

in the reactions were generally redistilled prior to use and

151.4 C-4 , 147.8 C-3 , 138.0 C-1 , 131.8 C-4 , 131.7

C-1 , 129.5 C-3 , 128.1 C-2 , 126.7 C-6 , 109.8 C-5 ,

107.5 C-2 , 101.7 OCH₂O ppm; IR KBr : 1642 n

C5O , 1236 and 1039 n C–O cm ; MS mrz : 226

M , 46% , 149 100% , 121 15% , 105 33% , 77

stored over 3–4 A molecular sieves. Reactions were gener-

ally stirred under a dry nitrogen atmosphere. The usual

work-up means that the organic extracts prior to concentra-

tion, under reduced pressure, were treated with a saturated

aqueous sodium chloride solution, referred to as brine,

dried over anhydrous sodium sulfate and filtered.

50% .

(

)

2.4. 3,4-Methylenedioxyphenyl phenylmethanone oxime

) (

(

)

7a Furniss et al., 1989

(

)

( ) (

2.2. 3,4-Methylenedioxyphenyl phenylmethanol 9 Klix

)

et al., 1995

To a mixture containing 0.70 g 3.10 mmol of the

ketone derivative 10 , 0.64 g 9.30 mmol of hydroxyl-

amine hydrochloride, 10 ml of ethanol and 2 ml of water,

were added slowly 0.62 g 15.5 mmol of NaOH, under

vigorous stirring. The reaction mixture was refluxed for 30

min, then neutralized with a 1 M aqueous HCl solution and

extracted with dichloromethane 3=30 ml . The organic

extracts were joined and evaporated under reduced pres-

sure to give 0.47 g 64% of an 1.1:1 E – Z diastere-

omeric mixture of oxime derivative 7a , as a white solid,

To a suspension of 0.43 g 18.00 mmol of pre-activated

magnesium in 5 ml of dry THF containing a catalytic

iodine crystal, was added 1.8 ml 2.82 g; 18.00 mmol of

dry bromobenzene. The reaction mixture was stirred until

total consumption of the magnesium turnings and then a

solution of 0.90 g 6.00 mmol of aldehyde 8 in 4 ml of

dry THF was added, dropwise, at 08C. The reaction mix-

ture was stirred at room temperature for 40 min, then

poured in an ice-water mixture, neutralized with 4% aq.

HCl and extracted with diethyl ether 3=30 ml . The

organic extracts were submitted at usual work-up to give

crude residue, which was purified by column chromatogra-

phy on neutral alumina, using a hexanes:dichloromethane

Ž .

Ž . Ž .

mp 143-48C; H NMR 200 MHz : d 7.50–7.26 6H, m,

H-2 , H-3 , H-4 and OH , 7.06 1H, dd, J_6y5s2 Hz and

Ž ..

_5y2-1 Hz, H-5 Z , 7.01 1H, t, J_6y2s1 Hz and

Ž .. Ž .

_5y2-1 Hz, H-2 Z , 6.89 2H, m, H-6

and H-2

E , 6.84 1H, dd, J_6y5s8 Hz and J_6y2s2 Hz, H-6

Ž ..

gradient from 100:0 to 0:100, to give 0.82 g 60% of the

diarylmethanol derivative 9 , as a brownish oil; H NMR

200 MHz : d 7.38–7.22 5H, m, H-2 , H-3 and H-4 ,

E , 6.72 1H, dd, J_6y5s8 Hz and J_5y2s1 Hz, H-5

Ž .

Ž .. Ž .. Ž ..

E , 6.02 2H, s, OC H₂O Z , 5.97 2H, s, OC H₂O E

Ž ..

ppm; C NMR 50 MHz : d 157.5 C5N Z , 157.2

C5N E , 148.7 C-4 Z , 148.1 C-4 E , 147.7 C-3

Ž ..

6.87–6.82 2H, m, H-2 and H-6 , 6.76 1H, d, J_6y5s8.0

Ž ..

Hz, H-5 , 5.92 s, 2H, OC H₂O , 5.73 s, 1H, C HOH ,

Z , 147.3 C-3 E , 136.3 C-1 Z , 132.7 C-1 E ,

Ž ..

2.42 br, 1H, D₂O exangeable, OH ppm; C NMR 50

MHz : d 147.7 C-3 , 146.9 C-4 , 143.7 C-1 , 137.9

C-1 , 128.4 C-3 , 127.4 C-4 , 126.2 C-2 , 119.9

C-6 , 108.0 C-5 , 107.1 C-2 , 100.9 OCH₂O , 75.9

130.2 C-1 E , 129.3 C-4 E , 129.0 C-4 Z , 128.9

C-3 E , 128.2 C-3 Z , 128.1 C-2 E , 127.9 C-2

^XŽ ..

Ž ..

Ž .. Ž .. Ž .. Ž ..

Z , 125.9 C-1 Z , 123.6 C-6 Z , 122.7 C-6 E ;

Ž .. Ž .. Ž ..

110.0 C-2 Z , 108.1 C-2 E , 107.8 C-5 E , 107.4

(

)

A.L. de A. Reis et al.rPharmaceutica Acta HelÕetiae 74 1999 19–28

Ž .. Ž

Ž ..

C-5 Z , 101.2 OCH₂O ppm; IR KBr : 3294

J_6y5s8 Hz and J_6y2s2 Hz, H-6 E , 6.70 1H, d,

Ž ..

O–H , 1500 and 1487 n C5N , 1232 and 1040 n C–O

J_6y5s8 Hz, H-5 E , 5.96 2H, s, OC H₂O Z , 5.92

cm^y1; MS mrz : 241 M , 100% , 224 63% , 122

Ž ..

2H, s, OC H₂O E , 3.97 3H, s, OC H₃E , 3.92 3H,

Ž ..

44% , 77 30% ; UV MeOH : l 295.0 ´, 5520 , 224.0

s, OC H₃

Ž ..

ppm; C NMR 50 MHz : d 156.3 C5N

Ž .. Ž .. Ž ..

´, 15 900 nm.

Z , 156.1 C5N E , 148.7 C-4 Z , 148.0 C-4 E ,

Ž ..

147.8 C-3 Z , 147.4 C-3 E , 136.8 C-1 Z , 133.6

(

) (

Ž ..

2.5. 3,4-Methylenedioxybenzaldehyde oxime 7b Furniss

et al., 1989

C-1 E , 130.8 C-1 E , 129.1 C-4 , 128.6 C-3

)

Ž ..

E , 128.1 C-3 Z , 128.0 C-2 , 126.0 C-1 Z ,

Ž ..

123.6 C-6 Z , 122.7 C-6 E , 110.1 C-2 Z , 108.0

Ž ..

To a mixture containing 0.45 g 3.00 mmol of alde-

C-2 E , 107.8 C-5 E , 107.6 C-5 Z , 101.2

Ž .

Ž ..

hyde 8 , 0.31 g 4.50 mmol of hydroxylamine hydrochlo-

ride, 7 ml of ethanol and 1.5 ml of water, were added

slowly 0.60 g 15.0 mmol of NaOH, under vigorous

stirring. The reaction mixture was refluxed for 5 min, then

poured in 10 ml of a 1 M aqueous HCl solution. The

resulting precipitate was filtered out, washed with 10 ml of

OCH₂O , 62.3 OCH₃Z , 62.2 OCH₃

ppm; MS

mrz : 255 M , 76% , 224 100% , 121 20% , 77

35% .

[[[(

)

2.7. Methyl 4- 3,4-methylenedioxyphenyl phenylmethyl-

]

(

) (

ene amino oxy methyl phenyl acetate 14a adapted from

)

water and air dried, furnishing 0.25 g 51% of the desired

Seebach et al., 1994

oxime derivative 7b , as a white solid, mp 1088C; ¹H

NMR 200 MHz : d 8.87 1H, br, OH , 8.06 1H, s, H

An 80% suspension of sodium hydride in mineral oil

0.06 g, 2 mmol was washed with dry n-hexane until a

white pale solid was obtained which was suspended in 1

ml of dry DME. Then, a solution of 0.066 g 0.27 mmol

of the oxime derivative 7a in 2 ml of dry DME was

added dropwise and the reaction mixture was refluxed

under stirring for 30 min. After this time, a solution of

C5N , 7.17 1H, d, J_6y2s2 Hz, H-2 , 6.96 1H, dd,

J_6y5s8 Hz and J_6y2s2 Hz, H-6 , 6.79 1H, d, J_6-2s2

Hz, H-5 , 5.98 2H, s, OC H₂O ppm; ¹³C NMR 50

MHz : d 149.9 C5N , 149.2 C-4 , 148.1 C-3 , 126.0

C-1 , 123.0 C-6 , 108.2 C-5 , 105.6 C-2 , 101.3

OCH₂O ppm; IR KBr : 3225 n O–H , 1499 n C5N ,

1256 and 1035 n C–O cm^-1; MS mrz : 165 M ,

0.10 g 0.43 mmol of 4-bromomethylphenylacetic acid

100% , 149 4% , 122 40% ; UV MeOH : l 306.5 ´,

12 in 2 ml of dry DME was added and the reaction was

additionally refluxed for 18 h, then poured into an ice–

8390 , 268.0 ´, 12 290 , 223.0 ´, 14 110 nm.

water mixture containing 2 ml of an 10% aqueous HCl

(

)

2.6. 3,4-Methylenedioxyphenyl phenylmethanone oxime,

) (

solution and extracted with ethyl ether 5=15 ml . The

organic extracts were submitted at usual work-up, furnish-

ing a crude residue which was next treated with an ethereal

(

)

O-methyl ether 11 adapted from Seebach et al., 1994

An 80% suspension of sodium hydride in mineral oil

diazomethane solution Monson, 1971 . The obtained mix-

ture was purified by silica gel column chromatography,

0.050 g, 1.66 mmol was washed with dry n-hexane until

a white pale solid was obtained which was suspended in 1

using hexanes:EtOAc as eluent gradient, 100:0 to 94:6 ,

to give 0.035 g 58% of the ketone derivative 10 , 0.005

Ž .

ml of dry DME. Then, a solution of 0.044 g 0.18 mmol

Ž .

of the oxime derivative 7a in 2 ml of dry DME was

g 8% of the precursor oxime derivative 7a and 0.031 g

Ž . Ž .

added dropwise and the reaction mixture was refluxed

28% of an 1:1 E – Z diastereomeric mixture of methyl

under stirring for 30 min. After this time, 0.1 ml 1.6

ester derivative 14a , as brownish solid, mp 80-848C; H

NMR 200 MHz : d 7.50–7.20 9H, m, H-2 , H-3 , H-4 ,

mmol of methyl iodide was added at room temperature.

After 5 min, the reaction mixture was poured into an

ice–water mixture containing 2 ml of an 10% aqueous HCl

H-2 , H-3 , 7.10 1H, dd, J_6y5s2 Hz and J_5y2-1 Hz,

Ž ..

H-5 Z , 6.91 1H, dd, J_6y2s;1 Hz and J_5y2-1 Hz,

Ž .. Ž . Ž ..

solution and extracted with ethyl ether 3=15 ml . The

organic extracts were submitted at usual work-up, furnish-

ing a crude oily residue which was purified by silica gel

H-2 Z , 6.82 2H, m, H-6 Z and H-2 E , 6.79 1H,

Ž ..

dd, J_6y5s8 Hz and J_6y2s2 Hz, H-6 E , 6.69 1H, dd,

Ž ..

J_6y5s8 Hz and J_5y2s1 Hz, H-5 E , 5.99 2H, s,

Ž .. Ž ..

column chromatography, furnishing 0.012 g 33% of the

OC H₂O Z , 5.94 2H, s, OC H₂O E , 5.21 2H, s,

Ž .. Ž ..

benzophenone derivative 10 and 0.026 g 57% of the an

1.1:1 E – Z diastereomeric mixture of the desired oxyme

methylether 11 , as a dark yellow oil; H NMR 200

MHz : d 7.50–7.26 6H, m, H-2 , H-3 , H-4 and OH ,

OC H₂Ar E , 5.16 2H, s, OC H₂Ar Z , 3.67 6H, s,

Ž . Ž .

Ž .

Ž ..

Ž .

COOC H₃E and Z , 3.61 4H, s, ArC H₂C5O E and

Ž ..

ppm; C NMR 50 MHz : d 171.9 C5O , 156.6

Ž .. Ž .. Ž ..

C5N Z , 156.4 C5N E , 148.6 C-4 Z , 147.8

Ž ..

7.10 1H, d, J_6y5s2 Hz, H-5 Z , 6.90 1H, br, H-2

C-4 E , 147.6 C-3 Z , 147.1 C-3 E , 137.1 C-1

Ž .. Ž . Ž ..

Ž ..

Z , 6.82 2H, m, H-6 Z and H-2 E , 6.81 1H, dd,

Z , 136.9 C-1 E , 136.6 C-1 Z , 133.3 C-1 E ,

(

)

A.L. de A. Reis et al.rPharmaceutica Acta HelÕetiae 74 1999 19–28

Ž ..

133.2 C-4 Z , 133.1 C-4 E , 130.5 C-1 E ,

of 1 N aqueous LiOH solution. The resulting mixture was

stirred at room temperature for 7 h then neutralized with 1

129.17 C-3 , 129.12 C-4 , 129.0 C-2 , 128.6 C-3

E , 128.2 C-3 Z , 128.1 C-2 E , 128.0 C-2 Z ,

Ž ..

N aqueous HCl ca. 3 ml until pH 4 and extracted with

Ž .. Ž .. Ž ..

126.6 C-1 Z , 123.6 C-6 Z , 122.7 C-6 E , 110.0

Ž .. Ž .. Ž ..

diethyl ether 3=10 ml . The organic extracts were joined

and submitted at usual work-up to give 0.020 g 90% of

the respective acid derivative 4a , as a viscous brownish

oil; H NMR 200 MHz : d 7.50–7.18 10H, m, H-2 ,

C-2 Z , 107.9 C-2 E , 107.7 C-5 E , 107.5 C-5

Ž .. Ž ..

Z , 101.1 OCH₂O , 76.1 OCH₂Ar Z , 75.9

Ž ..

OCH₂Ar E , 52.0 COOC H₃, 40.8 ArC H₂CsO

ppm; MS mrz : 403 M , 49% , 372 100% , 121 18% ,

H-3 , H-4 , H-2 , H-3 , CO₂H , 7.08 1H, d, J_6y5s;1

Ž ..

77 38% .

Anal. Calcd. for C₂₄H₂₁NO₅: C, 71.44; H, 5.25; N,

3.47. Found: C, 71.53; H, 5,17; N, 3.55.

Hz, H-5 Z , 6.88 1H, t, J_6y2s;1 Hz and J_5y2-1

Ž .. Ž . Ž ..

Hz, H-2 Z , 6.81 2H, m, H-6 Z and H-2 E , 6.80

Ž ..

1H, dd, J_6y5s8 Hz and J_6y2s2 Hz, H-6 E , 6.68

Ž ..

1H, dd, J_6y5s8 Hz and J_5y2s1 Hz, H-5 E , 5.90

[[[(

)

]

2.8. 4-

3,4-Methylenedioxyphenyl methylene amino

) (

Ž ..

2H, s, OC H₂O Z , 5.86 2H, s, OC H₂O E , 5.13 2H,

Ž .. Ž ..

]

(

oxy methyl phenylacetic acid 4b adapted from Seebach

s, OC H₂Ar E , 5.08 2H, s, OC H₂Ar Z , 3.55 4H, s,

)

et al., 1994

Ž .

Ž ..

ArC H₂CsO E and Z ppm; C NMR 50 MHz : d

Ž ..

176.1 C5O , 156.8 C5N Z , 156.6 C5N E , 148.7

Ž .. Ž .. Ž ..

An 80% suspension of sodium hydride in mineral oil

0.12 g, 5 mmol was washed with dry n-hexane until a

white pale solid was obtained which was suspended in 1

C-4 Z , 147.9 C-4 E , 147.8 C-3 Z , 147.3 C-3

Ž ..

E , 137.5 C-1 Z , 137.3 C-1 E , 136.8 C-1 Z ,

Ž ..

133.6 C-1 E , 132.7 C-4 Z , 132.6 C-4 E , 130.8

ml of dry THF. Then, a solution of 0.166 g 1 mmol of

Ž ..

C-1 E , 129.2 C-4 and C-3 , 129.1 C-2 , 128.6 C-3

the oxime derivative 7b in 2 ml of dry THF was added

dropwise and the reaction mixture was refluxed under

stirring for 30 min. After this time, a solution of 0.298 g

Ž ..

E , 128.3 C-3 Z , 128.1 C-2 E , 128.0 C-2 Z ,

Ž .. Ž .. Ž ..

126.9 C-1 Z , 123.7 C-6 Z , 122.8 C-6 E , 110.1

Ž .. Ž .. Ž ..

C-2 Z , 108.0 C-2 E , 107.8 C-5 E , 107.7 C-5

Ž .. Ž ..

Ž .

1.30 mmol of 4-bromomethylphenylacetic acid 12 in 4

Z , 101.2 OCH₂O , 76.2 OCH₂Ar Z , 76.0

Ž ..

ml of dry THF was added and the reaction was addition-

ally refluxed for 1.5 h, then poured into an ice–water

mixture containing 5 ml of an 10% aqueous HCl solution

and extracted with dichloromethane 3=20 ml . The or-

ganic extracts were submitted at usual work-up, furnishing

OCH₂Ar E , 40.6 ArC H₂CsO ppm; IR Film :

3447 n O–H , 1709 n C5O , 1487 n C5N , 1237 and

1038 n C–O cm

Anal. Calcd. for C₂₃H₁₉NO₅: C, 70.93; H, 4.92; N,

3.60. Found: C, 71.03; H, 4.98; N, 3.55.

0.190 g 61% of the acid derivative 4b , as a white solid,

mp 154–1568C; H NMR 200 MHz : d 8.05 1H, s,

HC5N , 7.37 2H, d, Js8 Hz, H-3 , 7.28 2H, d, Js8

[[[(

)

2.10. Methyl 4-

3,4-methylenedioxyphenyl methy-

) (

Hz, H-2 , 7.26 1H, s, CO₂H , 7.19 1H, d, J_6y2s2 Hz,

]

(

lene amino oxy methyl phenylacetate 14b Teixeira et

H-2 , 6.93 1H, dd, J_6y5s8 Hz and J_6y2s2 Hz, H-6 ,

)

al., 1998

6.78 1H, d, J_6y5s8 Hz, H-5 , 6.00 2H, s, OC H₂O ,

5.15 2H, s, OC H₂Ar , 3.65 2H, s, ArC H₂CsO ppm;

A solution of 0.070 g 0.22 mmol of the acid 4b in 5

ml of methanol, containing two drops concentrated sulfuric

acid, was refluxed for 2 h, then poured into an ice–water

mixture. The precipitate formed was filtered out, washed

with 5 ml of a 5% aqueous sodium bicarbonate solution

C NMR 50 MHz : d 172.7 C5O , 148.9 C-4 , 148.8

C5N , 147.8 C-3 , 136.0 C-1 , 134.7 C-4 ; 129.4

C-3 , 128.3 C-2 , 126.1 C-1 , 122.9 C-6 , 108.5 C-5 ,

105.3 C-2 , 101.5 OCH₂O , 75.1 OCH₂Ar , 40.4

ArC H₂CsO ppm; IR KBr : 3444 n O–H , 1703 n

C5O , 1603 n C5N , 1256 and 1033 n C–O cm

MS mrz : 313 M , 14% , 149 100% , 121 6% , 77

14% .

Anal. Calcd. for C₁₇H₁₅NO₅: C, 65.16; H, 4.83; N,

4.47. Found: C, 65.23; H, 4,87; N, 4.55.

and air-dried, to give 0.062 g 86% of the corresponding

;

methyl ester derivative 14b , as a white solid, mp 70-718

C; H NMR 200 MHz : d 8.05 1H, s, HC5N , 7.38

2H, d, Js8 Hz, H-3 , 7.28 2H, d, Js8 Hz, H-2 ,

7.19 1H, d, J_6y2s2 Hz, H-2 , 6.93 1H, dd, J_6y5s8

Hz and J_6y2s2 Hz, H-6 , 6.78 1H, d, J_6y5s8 Hz,

H-5 , 6.00 2H, s, OC H₂O , 5.15 2H, s, OC H₂Ar , 3.70

[[[(

)

]

2.9. 4-

3,4-Methylenedioxyphenyl phenylmethylene

) (

3H, s, COOC H₃, 3.65 2H, s, ArC H₂C5O ppm; ¹³C

]

(

amino oxy methyl phenylacetic acid 4a Barrow et al.,

NMR 50 MHz : d 171.8 C5O , 149.0 C-4 , 148.5

)

1995

C5N , 148.0 C-3 , 136.3 C-1 , 133.5 C-4 , 129.2

To a solution of the 0.023 g 0.057 mmol of the methyl

ester derivative 14a in 7 ml of acetone were added 4 ml

C-3 , 128.5 C-2 , 126.4 C-1 , 122.8 C-6 , 108.1 C-5 ,

105.6 C-2 , 101.2 OCH₂O , 75.8 OCH₂Ar , 51.9

(

)

A.L. de A. Reis et al.rPharmaceutica Acta HelÕetiae 74 1999 19–28

COOCH₃, 40.8 ArC H₂CsO ppm; IR KBr : 1731 n

500=g for 10 min, at room temperature, and platelet

count was adjusted to 5=10⁸plateletsrml.

C5O , 1500 n C5N , 1260 and 1043 n C–O cm

MS mrz : 327 M , 33% , 296 100% , 149 63% .

;

Platelet aggregation was monitored by the turbidimetric

Ž .

Anal. Calcd. for C₁₈H₁₇NO₅: C, 66.03; H, 5.24; N,

method Born and Cross, 1963 in a Chrono-Log aggre-

4.28. Found: C, 66.11; H, 5,27; N, 4.35.

gometer. PRP 400 ml was incubated at 378C for 1 min

with continuous stirring at 900 rpm and then stimulated

Ž . Ž

saline , arachidonic acid AA — 200 mM in ethanol or

2.11. Pharmacology

with ADP 5 mM in distilled water , collagen 5 mgrml in

Blood was collected from rabbits by puncture of the

central ear artery into 3.8% sodium citrate 9:1 vrv .

Platelet-rich plasma PRP was prepared by centrifugation,

U-46619 3 mM in ethanol .

. Ž

The new oxime derivatives 4a–b , 14a–b and the

vehicle 0.5% DMSO, 2 ml were added to the PRP

Ž .

Scheme 1. a aq. 3N KOH, n-BuOH, reflux, 3 h, 98%; b i: O₃–O₂, AcOH, y108C, 4 h; ii: Zn, AcOH, 08C, 2 h; 78%; c PhMgBr, THF, r.t., 40 min.,

Ž . Ž . . Ž .

60%; d MnO₂, THF, reflux, 30 min, 70%; e NH₂OHPHCl, NaOH, EtOH, H₂O, reflux; 30 min, 64% 7a ; 5 min, 94% 7b ; f i: NaH, DME, 30 min;

Ž . . Ž .

ii: para-BrCH₂C₆H₄CH₂COOH 12 , DME, r.t.

Ž .

THF, r.t. 10 h, 85%; l CH₃OH, H₂SO₄, reflux, 2 h, 86%.

reflux, 18 h; g i: CH₂N₂, Et₂O, r.t.; ii: chromatographic purification SiO₂, 28% two steps ; h

Ž .

LiOH, acetone, r.t., 4 h, 90%; i i: NaH, DME, reflux, 30 min; ii: CH₃I, r.t., 5 min, 57%; j i: NaH, THF, 30 min; ii: para-BrCH₂C₆H₄CH₂COOH 12 ,

Ž .

(

)

A.L. de A. Reis et al.rPharmaceutica Acta HelÕetiae 74 1999 19–28

Table 1

Diastereomer ratio and chemical shift of the 1,3-benzodioxole ring hydrogens from ¹H NMR spectra of the E - and Z -ketoxime derivatives 7a–b and

ErZ ratio^b

ppm

–OCH₂O–

Compound

Ž .

1.1:1

100:0

5.97

5.92

5.98

6.02

5.96

–

6.89

6.82^c

7.17

7.01

6.90

–

6.72

6.70

6.79

7.06

7.10

–

6.84

6.81

6.96

6.89

6.82^c

–

^aDetermined by relative integration of methylenedioxy singlet signals.

^bPerformed in CDCl₃at 200 MHz.

Ž .

The signals corresponding to the hydrogens E –Ha and Z –Hb appears together in a multiplete at d 6.82 ppm.

Ž .

cursor of the desired oxime 7a , was next treated with the

phenyl Grignard reagent Klix et al., 1995 furnishing the

samples 5 min before addition of the aggregating agent.

The DMSO used as vehicle did not have either pro- or

Ž .

antiplatelet aggregation activity. Indomethacin 10 mM , a

classical cyclooxygenase inhibitor, was used as standard.

The platelet aggregation was expressed as percentage of

aggregation for ADP, AA, U-46619 and as the maximum

aryl-benzylic alcohol 9 , in high yield Scheme 1 . The

next step of the planned synthetic route to access the new

oxime 7a , was the MnO₂oxidation Takeuchi et al.,

Ž .

1995 of the benzylic alcohol 9 , to produce the corre-

sponding aryl-ketone 10 . Treatment of the aryl–ketone

Ž .

rate of aggregation slope for collagen. Data were ana-

lyzed statistically by Student’s ‘‘t’’ test for a p value of

-0.05 and are expressed as mean"S.D. for n experi-

ments in triplicate.

derivative 10 , with hydroxylamine gave the desired oxime

. Ž

Ž .

7a Furniss et al., 1989 . The oxime 7a was obtained as

Ž .

1.1:1 mixture of diastereomers E and Z , as indicated

by the relative integration of singlets refereed to meth-

ylenedioxy hydrogens in H NMR spectra Table 1 . The

diastereomer attribution was made in agreement with pre-

3. Results and discussion

vious paper of Karabatsos and His 1967 and by relative

3.1. Chemistry

comparison of the its H NMR signals with those of the

. Ž

diastereomerically pure nor-phenyl derivative 7b Table

Ž .

The target new oximes O-benzylethers derivatives 4a–

1 . Additionally, the stereochemical assignment of 7a

b were synthesized by using the methodology illustrated

was aided by nOe experiment on the correspondent methyl

Ž .

ether derivative 11 , obtained by treatment of the sodium

in Scheme 1. Our synthetic approach to these new com-

pounds identify the functionalized arylketone-oxime 7a

and the 3,4-methylenedioxybenzaldehyde-oxime 7b as

the key intermediates. These compounds can be easily

obtained from the natural product used as starting-material

Ž .

salt of the diastereomeric mixture of oximes 7a with

Ž .

5 by exploring a well-known synthetic sequence from

this laboratory Barreiro and Lima, 1992; Barreiro et al.,

1985 Scheme 1 , including the basic isomerization of

safrole 5 double bond, followed by ozonolysis cleavage

. Ž

Ž .

with reductive work-up furnishing the corresponding 3,4-

Ž .

methylenedioxybenzaldehyde 8 . The aldehyde 8 , pre-

Fig. 2.

Table 2

Effect of oxime O-benzylether derivatives 4a–b and 14a–b on in vitro platelet aggregation of citrated rabbit platelet-rich plasma induced by arachidonic acid, ADP, collagen and U-46619

C^amM

n^b

Arachidonic Acid 200 mM

n^b

ADP 5 mM

n^b

Collagen 5 mgrml

Aggregation Inhibition

n^b

U-46619 3 mM

Compounds

Aggregation Inhibition

Aggregation

Inhibition

Aggregation

Inhibition

Ž .

slope

Control

Indomethacin

–

100

68.9"5.1

–

32.5"2.5

–

25.3"0.5

23.2"1.2

–

1.2

22.1

28.6^U

–

19.7

24.0

–

8.7"0.5

–

4.7"1.6

0.7"0.7

–

52.7"4.3

–

48.6"4.2

48.0"4.6

–

100.0^U

21.8

86.2^U

26.7

1.4

94.8^U

46.0^U

91.9^U

–

1.9

7.8

8.9

–

53.9"5.5

9.5"4.1

50.5"6.5

67.9"3.5

64.9"6.7

56.0"4.6

14a

–

14b

5.8

26.1"0.6

24.7"1.2

6.7"1.3

4.6"1.6

23.0

18.7

47.1^U

–

^aCsconcentration.

^bnsnumber of independent experiments carried out in triplicate.

p-0.05 compared to appropriate control Student’s ‘‘t’’ test .

(

)

A.L. de A. Reis et al.rPharmaceutica Acta HelÕetiae 74 1999 19–28

methyl iodide Scheme 1 . For instance, irradiation of the

4b , in models induced by AA and collagen Table 2 .

(

)

OCH₃protons of the major isomer of the compound 11

Compound 4b did not shown any significant activity for

all agonists studied.

at d 3.97 ppm in the ¹H NMR spectrum, showed a

positive nOe effect into ortho-hydrogens present in phenyl

Compound 14a was the most active one. It inhibited

strongly the platelet aggregation induced by AA and colla-

gen, by 86.2% and 91.9% respectively, and while also

inhibited the ADP induced aggregation, by 28.6%. The

IC₅₀obtained from AA induced aggregation of the com-

Ž .

group Table 1 , indicating the relative configuration E .

The key-step for access to new oxime O-benzylether

4a was the O-benzylation of the oxime 7a . This step

was accomplished by treatment sodium salt of oxime

Ž .

derivative 7a , prepared from treatment with NaH in THF

pound 14a was 81.5 mM Table 2 .

at room temperature, with para-bromophenylacetic acid

12 at reflux, to produce the corresponding acid 4a , in

appropriated yield Seebach et al., 1994 . In fact, the

O-alkylation of benzophenone-like oximes can produce a

In addition, compound 14a inhibited the second wave

of aggregation induced by ADP on human PRP data not

Ž .

shown .

Compounds 4a and 14b presented a similar activity.

Both compounds inhibited moderately the platelet aggrega-

mixture of N,O-alkylation products Grigg et al., 1990 .

For instance, in the alkylation of benzophenone-oxime

tion induced by collagen 46% 4a vs. 47.1% 14b and

.x Ž

7a , we are able to detect by tlc the formation of sec-

. Ž

AA 21.8% 4a vs. 18.7% 14b Table 2 .

ondary nitrone derivative 13 Smith and Robertson, 1962

Compounds 4a and 14a did not inhibited the platelet

Fig. 2 and also the recovery of 58% yield of the corre-

aggregation induced by U-46619 Table 2 , suggesting that

the anti-aggregating activity presented by these compounds

is not probably through antagonism of TP receptors.

These results stand out the relevance, to the antiplatelet

profile, of the presence of a second phenyl unit at the

oxime moiety, characterized by pattern benzophenone-

sponding aryl–ketone derivative 10 .

In order to obtain the desired O-benzylated product

4a , in good purity degree, we are obligated to esterify

them with diazomethane followed by carefully chromato-

graphic purification. This procedure gave the pure corre-

Ž .

sponding methyl esters 14a , as a mixture of E - and

oxime of compound 14a , just as described in the lead

Ž .

Z -diastereomers. The basic hydrolysis of the methyl

ester 14a with an aqueous LiOH solution in acetone

Barrow et al., 1995 at room temperature regenerated the

compound ridogrel 6 . Curiously, the results obtained

from this study seems to indicate that the interphenylene

acidic chain present in compound 14a prevents the TPant

profile as shown the data using U-46619 Table 2 , con-

trasting with the lead compound 6 . In addition, the more

pronounced activity of the methyl ester 14a can be

probably due to its less effective plasmatic protein binding

in comparison with the corresponding acid derivative 4a

desired acid compound 4a , in 90% yield. The nor-aryl

Ž .

oxime O-benzylether derivative 4b was prepared from

Ž . Ž

the aldehyde 8 Scheme 1 by oximation with hydroxyl-

Ž .

amine, to produce pure E -diastereomer of 7b , which

after O-benzylation with 12 , using the same experimental

conditions, gives the acid 4b in good yield.

Kragh-Hansen, 1981 .

Finally, in order to compare the antiplatelet profile of

Finally, the results described herein demonstrated an

planned acid derivatives 4a–b with the corresponding

important antithrombotic profile for compound 14a , sug-

gesting an activity at the TXS level.

methyl esters 14a–b , we submitted the acid 4b to

classical Fisher’s esterification conditions Teixeira et al.,

1998 , to obtain the ester 14b , in 86% yield.

4. Conclusions

3.2. Pharmacology

The synthetic route described herein represents an use-

The antithrombotic activity of these novel oxime O-

ful method to access the new antiplatelet oxime O-benzyl-

(

)

benzylethers 4a–b and its corresponding methyl ester

ether derivatives 4a and 14a , exploring the 3,4-methyl-

derivatives 14a–b were evaluated by their ability to

inhibit platelet aggregation of rabbit platelet-rich plasma

PRP induced by either adenosine diphosphate ADP, 5

mM , collagen 100 mM , arachidonic acid AA, 200 mM

enedioxybenzophenone oxime 7a as a key intermediate

and safrole 5 as starting material. The antiplatelet profile

of these new compounds identify the new compound 14a

as inhibitor of the platelet aggregation induced by arachi-

donic acid presenting an IC₅₀s81.5 mM. These results

indicated that the compounds 4a–b and 14a–b repre-

sents a new class of antiplatelet agents, possessing a new

molecular pattern, synthesized from Brazilian abundant

Ž .

and U-46619 3 mM , a stable TP agonist. The results of

(

)

(

)

the antiplatelet profile of 4a–b and 14a–b are dis-

played in Table 2.

In this series, methyl esters 14a and 14b were more

active than the corresponding acid derivatives 4a and

Ž .

natural product safrole 5 .

(

)

A.L. de A. Reis et al.rPharmaceutica Acta HelÕetiae 74 1999 19–28

Furniss, B.S., Hannaford, A.J., Smith, P.W.G. and Tatchel, A.R., 1989.

Acknowledgements

Vogel’s Textbook of Practical Organic Chemistry. Longman Scien-

tific and Technical, London, p. 1049.

We are grateful to the CNPq a52.0033r96-5 and

Grigg, R., Markandu, J., Surendrakumar, S., 1990. Tandem nucleophilic

substitution-1,3-dipolar cycloaddition reactions of oximes with alkyl

halides and dipolarophiles. Tetrahedron Lett. 31, 1191–1194.

Jin, B., Hopfinger, A.J., 1994. A proposed common spatial pharma-

cophore and the corresponding active conformations of some TxA₂

receptor antagonists. J. Chem. Inf. Comput. Sci. 34, 1014–1018.

Karabatsos, G.J., His, N., 1967. Structural studies by nuclear magnetic

ressonance: XI. Conformations and configurations of oxime O-methyl

ethers. Tetrahedron 23, 1079–1095.

Klix, R.C., Cain, M.H., Bhatia, A.V., 1995. Synthesis of 5,6-methylen-

edioxy-1-tetralone. An aryl Grignard approach from guaiacol. Tetra-

hedron Lett. 36, 6413–6414.

Kragh-Hansen, U., 1981. Molecular aspects of ligand binding to serum

albumin. Pharmacol. Rev. 33, 17–53.

Lima, L.M., Brito, F.F., Ormerlli, C.B., Miranda, A.L.P., Fraga, C.A.M.,

Barreiro, E.J., 1999. Synthesis and antiplatelet evaluation of novel

aryl-sulfonamide derivatives, from natural safrole. Pharm. Acta Helv.

73, 281–292.

Monson, R.S., 1971. Advanced Organic Synthesis. Academic Press, New

York, pp. 59–60 and 155–156.

Muri, E.M.F., Barreiro, E.J., Fraga, C.A.M., 1998. Synthesis of new

benzylic ethers of oximes derived from 1-phenyl-pyrazole com-

pounds. Synth. Commun. 28, 1299–1321.

Pec¸anha, E.P., Fraga, C.A.M., Sant’Anna, C.M.R., Miranda, A.L.P.,

Barreiro, E.J., 1998. Synthesis and pharmacological evaluation of a

new class of bicyclic phospholipids, designed as platelet activating

factor antagonists. Il Farmaco 53, 327–336.

FUJB BR. for the financial support of this work and to

CNPq and CAPES BR. for fellowships ALAR, ALPM,

CAMF and EJB . The authors also thanks the Analytical

Center of NPPN UFRJ, BR for spectrocospopic data.

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Studies on antiplatelet agents from natural safrole. II. Synthesis and pharmacological properties of novel functionalized oxime O-benzylether derivatives

DOI: 10.1016/S0031-6865(99)00014-X

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