Antinociceptive effects of N-acyloctahydropyrido[3,2,1-ij][1,6] naphthyridine in mice: Structure-activity relation study of matrine-type alkaloids part II

Article abstract of DOI:10.1248/bpb.26.375

N-Acyloctahydropyrido[3,2,1-ij][1,6]naphthyridines were synthesized as derivatives of matrine-type alkaloids, and the structure-activity relations were examined by the acetic acid-induced abdominal contraction test. The antinociceptive potencies of N-acyl

Full text of DOI:10.1248/bpb.26.375

March 2003
Notes
Biol. Pharm. Bull. 26(3) 375—379 (2003)
375
Antinociceptive Effects of N-Acyloctahydropyrido[3,2,1-ij][1,6]naphthyridine
in Mice: Structure–Activity Relation Study of Matrine-Type Alkaloids
Part II
Seiichi KOBASHI, Masayuki TAKIZAWA, Hajime KUBO, Takayasu YAMAUCHI, and Kimio HIGASHIYAMA*
Faculty of Medicinal Chemistry, Hoshi University; 4–41, Ebara 2-chome, Shinagawa-ku, Tokyo 142–8501, Japan.
Received August 28, 2002; accepted November 14, 2002
N-Acyloctahydropyrido[3,2,1-ij][1,6]naphthyridines were synthesized as derivatives of matrine-type alka-
loids, and the structure–activity relations were examined by the acetic acid-induced abdominal contraction test.
The antinociceptive potencies of N-acyloctahydropyrido[3,2,1-ij][1,6]naphthyridines were significantly lower than
those of (ꢀ)-matrine. The antinociceptive effects of N-benzyloctahydropyrido[3,2,1-ij][1,6]naphthyridines are ap-
proximately 5.6 to 6.5 times less than those of N-benzoyloctahydropyrido[3,2,1-ij][1,6]naphthyridine. These find-
ings suggest that the amide group of matrine-type alkaloids is an essential functional group that influences an-
tinociceptive potency. The antinociceptive effect of 4c was markedly antagonized by pretreatment with Naloxone,
and that of 3c partially so.
Key words structure–activity relationship; antinociception; matrine
We reported previously that (ꢀ)-matrine 1, a typical ma- [1,6]naphthyridines 8 and 9 were made from 3c and 4c to
trine-type lupine alkaloid produced by some Sophora plants confirm the pharmacophore prediction. The antinociceptive
(Leguminosae), has antinociceptive properties identical to effects of these compounds were tested with the acetic acid-
those of pentazocine, and these are mediated mainly through induced abdominal contraction test (writhing test) to clarify
activation of k-opioid receptors and partially through m-opi- structure–activity relations.
oid receptors.1) (ꢀ)-Allomatrine 2, which is the C-6 epimer
Synthesis 1-Benzyl-4-piperidone 5 was bisalkylated
of 1, also has antinociceptive properties, its potency is one- with acrylonitrile via the Stork enamine synthesis.7) A mix-
third the potency of 1. The effects of (ꢀ)-allomatrine are me- ture of bis- and monoalkylated compounds was hydrogenated
diated only through activation of k-opioid receptors.2) The with 20% palladium hydroxide on carbon to the correspond-
structure–activity relation of this antinociceptive effect is of ing amine 6 in 62% yield. We determined that both 3- and 5-
interest because the structure of the matrine-type alkaloids cyanoethyl groups were cis configuration, because six peaks
differs from the structures of conventional k-opioid receptor were observed by 13C-NMR spectra. The amine 6 was acy-
agonists such as ethylketocyclazocine, U-50,488,3,4) and lated with acetic anhydride (7a: RꢁMe, 92%), pentanoyl
TRK-8205) (Chart 1). The matrine-type alkaloids may serve chloride (7b: RꢁBu, 94%), and benzoyl chloride (7c: RꢁPh,
as k-opioid receptor agonist drugs that are more selective 67%) in the presence of triethylamine. Reductive cycliza-
and lack the undesirable morphine-like side effects of exist- tion8,9) of 7a—c was accomplished with 5% palladium on
ing drugs. We reported previously in our study of antinoci- carbon in glacial acetic acid at room temperature under a hy-
ceptive effects of 1-acyl-4-dimethylaminopiperidines that the drogen pressure (5 atm) to give compounds 3a—c in 12 to
amide group of (ꢀ)-matrine 1 is essential for antinociceptive 19% yields and 4a—c in 8 to 11% yields (Chart 3). We de-
potency.6) The N-acyloctahydropyrido[3,2,1-ij][1,6]naph- termined the structure of 3a—c and 4a—c by comparing
thyridines 3a—c and 4a—c were synthesized as derivatives those chemical shifts of 10b position on 13C-NMR spectra.
of the matrine-type alkaloids. They included the amide group Compounds 3c and 4c were reduced with lithium aluminum
and the A, B, and C rings of matrine-type alkaloids because hydride, to give amines 8 and 9 in 81 and 83% yields, respec-
they were predicted to comprise the pharmacophore for tively (Chart 4).
the antinociceptive effect. N-Benzyloctahydropyrido[3,2,1-ij]-
Acetic Acid-Induced Abdominal Contraction Assay
Chart 1
∗ To whom correspondence should be addressed. e-mail: kimio@hoshi.ac.jp
© 2003 Pharmaceutical Society of Japan

376
Vol. 26, No. 3
Fig. 1. Dose–Response Lines for the Antinociceptive Effect of s.c. Ad-
ministration of (ꢀ)-Matrine 1 (ꢀ), (ꢀ)-Allomatrine 2 (ꢁ), 3a (ꢂ), 3b (ꢃ),
3c (ꢄ) in the Acid-Induced Abdominal Contraction Assay in Mice
Chart 2
Each point represents the meanꢃS.E. of 10 mice.
Fig. 2. Dose–Response Lines for the Antinociceptive Effect of s.c. Ad-
ministration of (ꢀ)-Matrine 1 (ꢀ), (ꢀ)-Allomatrine 2 (ꢁ), 4a (ꢂ), 4b (ꢃ),
4c (ꢄ) in the Acid-Induced Abdominal Contraction Assay in Mice
Reagents and reaction conditions: (i) pyrrolidine, benzene, reflux 48 h; (ii) acryloni-
trile, EtOH reflux 48 h; (iii) 25% AcOH rt 1 h; (iv) H2/20% Pd(OH)2–C, EtOH rt 24 h;
(v) Ac2O or RCOCl or RCOCl (RꢁBu, Ph), Et3N, CH2Cl2 0 °C 1 h; (vi) H2/5% Pd–C,
AcOH 5 atm rt 48 h.
Each point represents the meanꢃS.E. of 10 mice.
Chart 3
Fig. 3. The Antinociceptive Effect of s.c. Administration of Amide Com-
pounds 3c and 4c in the Acid-Induced Abdominal Contraction Assay in
Mice
Reagents and reaction conditions: (i) LiAlH4, THF reflux 2 h.
Char 4
∗∗∗ pꢄ0.001 versus the corresponding amine compounds 8 and 9. Each column rep-
resents the mean with S.E. of 10 mice in each group.
(Writhing Test) and Data Analysis For writhing test and
data analysis refer to our previous work.6) Opioid receptor
antagonist Naloxone (1 mg/kg, i.p.) was dissolved in saline,
and administered 30 min before each drug.
mice (Fig. 2). The ED50 values (mg/kg with 95% confidence
limits) were 56.0 mg/kg (25.5—86.5) for 4a, 40.5 mg/kg
(28.4—52.5) for 4b, and 8.6 mg/kg (0.7—107.1) for 4c. All
drugs with the amide group produced dose-dependent inhibi-
tion of the writhing response in mice. The antinociceptive
potencies of 8 and 9 (100 mg/kg) were significantly lower
than those of the corresponding amides 3c and 4c (Fig. 3).
The antinociceptive effect of 4c was markedly antagonized
by pretreatment with Naloxone, and that of 3c was partially
antagonized (Fig. 4).
RESULTS
Compounds 3a—c (doses of 10—100 mg/kg, s.c.) pro-
duced dose-dependent inhibition of the writhing response in
mice (Fig. 1). The ED50 values (mg/kg with 95% confidence
limits) were 35.6 mg/kg (ꢂ127.9—199.2) for 3a, 24.7 mg/kg
(ꢂ81.8—171.3) for 3b, and 37.5 mg/kg (15.7—59.3) for 3c.
Compounds 4a—c (doses of 10—100 mg/kg, s.c.) also pro-
duced dose-dependent inhibition of the writhing response in

March 2003
377
cis-3,5-Dicyanoethyl-4-oxo-piperidine, 6 A mixture of
the piperidone 5 (10.02 g, 52.94 mmol) and pyrrolidine
(15.30 g, 215.12 mmol) in benzene (50 ml) was refluxed with
a dean-stark trap for 48 h. The solvent was evaporated and
the residue was dissolved in anhydrous EtOH (50 ml). Acry-
lonitrile (11.20 g, 226.16 mmol) was added to the solution
and the reaction mixture was refluxed for 48 h. The solvent
was evaporated, and the residue was dissolved in 25% AcOH
(50 ml) and stirred at room temperature for 1 h. The solution
was extracted with CH2Cl2 and the extract was washed with
5% HCl and 5% NaOH. The organic phase was dried over
anhydrous sodium sulfate, filtered, and evaporated to give the
crude product, which was difficult to purify. To a solution of
the crude product in EtOH (50 ml) was added Pd(OH)2 on
carbon (2.0 g, 20% w/w), hydrogenated at atmospheric pres-
sure at room temperature for 24 h. Catalyst was filtered
off, and solvent was evaporated. The residue was puri-
fied by chromatography on silica gel (CH2Cl2/MeOH/28%
NH4OHꢁ100 : 9 : 1) to give the title compound as a pale yel-
Fig. 4. Effects of Naloxone on the Antinociceptive Effects of 3c and 4c
(100 mg/kg, s.c.) in mice
Naloxone (1 mg/kg) was injected i.p. 30 min before the injection of 3c and 4c. Each
column represents the mean with S.E. of 10 mice in each group. ∗ pꢄ0.05,
∗∗∗ pꢄ0.001 versus the respective group.
DISCUSSION
1
low oil (6.74 g, 32.84 mmol, 62%): H-NMR (CDCl3) d:
The present experiments show that compounds 3a—c and
4a—c, which include the amide group and the A, B, and C
rings of matrine-type alkaloids, produced dose-dependent an-
tinociception in mice. The antinociceptive effects of 3c and
4c are approximately 5.6 to 6.5 times greater than those of 8
and 9. These findings showed that the amide group of (ꢀ)-
matrine 1 is essential for antinociceptive potency.
1.40—1.55 (2H, m), 1.97 (1H, s), 2.03—2.16 (2H, m),
2.45—2.51 (4H, m), 2.57—2.65 (4H, m), 3.49 (2H, dd,
Jꢁ6.9, 12.8 Hz). 13C-NMR (CDCl3) d: 15.0, 22.3, 51.1, 54.0,
119.7, 210.0. IR (Film) cmꢂ1; 1700 (CꢁO), 2240 (C¤N),
3330 (NH). HR-MS m/z: Found 205.1191 (Calcd for
C11H15N3O 205.1215).
cis-1-Acetyl-3,5-dicyanoethyl-4-oxo-piperidine, 7a To
a solution of the amine 6 (5.36 g, 26.11 mmol) and triethyl-
amine (10.22 g, 101.0 mmol) in CH2Cl2 (25 ml), cooled to
0 °C under nitrogen, was added acetyl chloride (3.98 g,
50.70 mmol). The reaction mixture was stirred at 0 °C for
2 h, then sat. K2CO3 was added, the organic layer was sepa-
rated, and the aqueous layer was extracted with CH2Cl2. The
organic layer was washed with 10% HCl, dried over anhy-
drous (Na2SO4) and concentrated in vacuo. The residue was
purified by silica gel chromatography (CH2Cl2/MeOH/28%
NH4OHꢁ100 : 9 : 1) and gave the title compound as a pale
The antinociceptive effect of 4c was markedly antagonized
by pretreatment with naloxone. It was clarified that alloma-
trine derivative 4c produced the antinociceptive effect mainly
through the activation of opioid receptor, while that of 3c
was partially antagonized by pretreatment with naloxone.
Like the above, it was determined that matrine derivative 3c
produced the antinociceptive effect partially through the acti-
vation of opioid receptor.
The antinociceptive potency of compounds 3c and 4c,
which contain a benzoyl group, is greater than that of the
other synthesized compounds 3a—b and 4a, b. Thus, ma-
trine derivatives with greater potencies may be developed by
improving the lipophilicity with an acyl group. The antinoci-
ceptive potencies of 3a—c and 4a—c are greater than those
of the 1-acyl-4-dialkylaminopiperidines, which have only the
C ring of 1.5) It is conceivable that the antinociceptive po-
tency of the latter compounds depends on the lipophilicity of
the molecule and on the distance of the amide from the ter-
tiary amino groups. We obtained some useful information re-
garding structure–activity relations in this study, but we
failed to identify any compound with an antinociceptive po-
tency greater than that of 1.
1
yellow oil (5.91 g, 23.90 mmol, 92%): H-NMR (CDCl3) d:
1.50—1.70 (2H, m), 1.99—2.21 (2H, m), 2.22 (3H, s),
2.45—2.75 (7H, m), 3.08 (1H, dd, Jꢁ12.0, 13.2 Hz), 4.17
(1H, ddd, Jꢁ2.8, 6.0, 13.2 Hz), 4.96 (1H, ddd, Jꢁ2.8, 6.0,
12.1 Hz). 13C-NMR (CDCl3) d: 14.0, 20.5, 21.3, 21.6, 45.5,
47.1, 47.5, 50.0, 118.8, 168.2, 207.1. IR (Film) cmꢂ1; 1640
(amide CꢁO), 1710 (CꢁO), 2240 (C¤N). HR-MS m/z:
Found 248.1415 (Mꢀ1) (Calcd for C13H18N3O 2248.1399).
cis-1-Pentanoyl-3,5-dicyanoethyl-4-oxo-piperidine, 7b
As described for the preparation of 7a, the amine 6 (2.90 g,
14.13 mmol) was acylated with pentanoyl chloride (2.46 g,
20.40 mmol) and triethylamine (4.31 g, 42.59 mmol) in
CH2Cl2 (15 ml), and purified by silica gel chromatography
(CH2Cl2/MeOH/28% NH4OHꢁ180 : 9 : 1): colorless crystal,
MATERIALS AND METHODS
1
yield 3.86 g (94%); mp 93 °C. H-NMR (CDCl3) d: 0.96
General High-resolution MS (HR-MS) were measured
at 70 eV using a direct inlet system on a JEOL D300 spec-
trometer. 1H-NMR (270 MHz) and 13C-NMR (67.8 MHz)
spectra were recorded using tetramethylsilane (TMS) as an
internal standard with a JEOL JNM-LA270 spectrometer. IR
spectra were measured with a JASCO FT/IR-200 spectrome-
ter. Column chromatography was carried out on Silica gel 60
(100—210 mm, Kanto Chemical Co., Inc.), Wako gel C-300
(45—75 mm, Wako Pure Chemical Industries, Ltd.), and
Lichrospher Si 60 (40—63 mm, Merck).
(3H, t, Jꢁ7.3 Hz), 1.34—1.48 (2H, m), 1.56—1.73 (4H, m),
2.11—2.18 (4H, m), 2.41—2.73 (7H, m), 3.04 (1H, t,
Jꢁ12.4 Hz), 4.21 (1H, d, Jꢁ12.4 Hz), 4.98 (1H, d,
Jꢁ10.2 Hz). 13C-NMR (CDCl3) d: 13.2, 14.4, 21.6, 21.7,
21.7, 26.6, 32.0, 46.0, 47.5, 48.0, 49.6, 118.8, 171.0, 207.3.
IR (KBr) cmꢂ1; 1630 (amide CꢁO), 1710 (CꢁO), 2240
(C¤N). HR-MS m/z: Found 289.1791 (Calcd for C16H23N3O2
289.1790).
cis-1-Benzoyl-3,5-dicyanoethyl-4-oxo-piperidine, 7c As

378
Vol. 26, No. 3
1
described for the preparation of 7a, the amine 6 (4.18 g,
20.36 mmol) was acylated with benzoyl chloride (4.36 g,
31.02 mmol) and triethylamine (6.21 g, 61.37 mmol) in
CH2Cl2 (20 ml), and purified by silica gel chromatography
(CH2Cl2/MeOH/28% NH4OHꢁ180 : 9 : 1): colorless crystal,
yield 4.36 g (67%); mp 100 °C. (1H-NMR was unanalyzable
by the rotation obstacle of Ph group.) 13C-NMR (CDCl3) d:
14.0, 21.6, 46.5, 47.5, 49.7, 51.4, 118.7, 126.2, 128.0, 129.7,
134.0, 169.5, 207.1. IR (KBr) cmꢂ1; 1640 (amide CꢁO),
1720 (CꢁO), 2240 (C¤N). HR-MS m/z: Found 309.1503
(Calcd for C18H19N3O2 309.1477).
4b: H-NMR (CDCl3) d: 0.88—1.03 (5H, m), 1.27—1.45
(5H, m), 1.54—l.68 (8H, m), 1.9—2.02 (2H, m), 2.20 (1H,
dd, Jꢁ4.13 Hz), 2.33 (2H, dt, Jꢁ3.8, 7.5 Hz), 2.72 (1H, dd,
Jꢁ11.4, 13.3 Hz), 2.86 (2H, d, Jꢁ11.5 Hz), 3.70 (1H, ddd,
Jꢁ2.3, 3.5, 13.3 Hz), 4.58 (1H, ddd, Jꢁ2.3, 3.5, 13.0 Hz).
13C-NMR (CDCl3) d: 13.4, 21.8, 24.1, 26.8, 27.5, 32.1, 38.7,
39.6, 45.8, 50.0, 55.5, 70.6, 170.1. IR (Film) cmꢂ1; 1645
(amide CꢁO). HR-MS m/z: Found 264.2215 (Calcd for
C16H28N2O 264.2202).
all trans-2-Benzoyloctahydropyrido[3,2,1-ij][1,6]naph-
thyridine, 3c, all cis-2-Benzoyloctahydropyrido[3,2,1-
ij][1,6]naphthyridine, 4c As described for the preparation
of 3a and 4a, the dinitrile 7c (3.90 g, 12.61 mmol) was hy-
drogenated with Pd–C (2.0 g, 5% w/w) in AcOH (130 ml),
and purified by silica gel chromatography (CH2Cl2/MeOH/
28% NH4OHꢁ140 : 9 : 1): yielded matrine-type derivative 3c
(520 mg, 1.83 mmol, 15%) and allomatrine-type derivative
4b (380 mg, 1.34 mmol, 11%) as colorless crystals.
all trans-2-Acetyloctahydropyrido[3,2,1-ij][1,6]naphthyri-
dine, 3a, all cis-2-Acetyloctahydropyrido[3,2,1-ij][1,6]-
naphthyridine, 4a Palladium on carbon (1.5 g, 5% w/w)
was added to a solution of dinitrile 7a (3.06 g, 12.37 mmol)
in AcOH (240 ml) and the mixture was hydrogenated at 4.5
atm and room temperature for 48 h. The suspension was fil-
tered off, and the solvent was evaporated. The residue was di-
luted with CH2Cl2, and the organic phase was washed with
aqueous NaOH (10% w/v). The organic phase was dried over
anhydrous NaSO4 and evaporated, and the residue was puri-
fied by chromatography on silica gel (CH2Cl2/MeOH/28%
NH4OHꢁ140 : 9 : 1) to give matrine-type derivative 3a as a
pale yellow oil (319 mg, 1.43 mmol, 12%) and allomatrine-
type derivative 4a as a pale yellow oil (223 mg, 1.03 mmol,
8%).
3c: mp 115 °C. (1H-NMR was unanalyzable by the rotation
obstacle of Ph group.) 13C-NMR (CDCl3) d: 21.1, 27.5, 27.6,
35.4, 36.6, 41.5, 47.2, 57.0, 62.9, 126.6, 128.2, 129.2, 136.3,
170.0. IR (KBr) cmꢂ1; 1630 (amide CꢁO). HR-MS m/z:
Found 284.1873 (Calcd for C18H24N2O 284.1889).
4c: mp 100 °C. (1H-NMR was unanalyzable by the rotation
obstacle of Ph group.) 13C-NMR (CDCl3) d: 23.8, 27.2, 38.6,
39.5, 46.3, 51.9, 55.3, 70.4, 126.0, 127.6, 128.7, 135.3,
169.0. IR (KBr) cmꢂ1; 1630 (amide CꢁO). HR-MS m/z:
Found 284.1908 (Calcd for C18H24N2O 284.1889).
1
3a: H-NMR (CDCl3) d: 1.43—1.79 (10H,m), 1.90—2.00
(1H, m), 2.09 (3H, s), 2.09—2.11 (2H, m), 2.79 (2H, d,
Jꢁ12.7 Hz), 3.01 (1H, dd, Jꢁ12.5, 12.9 Hz), 3.32 (1H, ddd,
Jꢁ1.7, 4.3, 12.9 Hz), 3.57 (1H, t, Jꢁ12.9 Hz), 4.24 (1H, ddd,
Jꢁ1.7, 4.3, 12.5 Hz). 13C-NMR (CDCl3) d: 20.9, 21.1, 27.4,
27.5, 35.2, 36.3, 40.7, 46.0, 56.7, 56.8, 62.6, 168.3. IR (Film)
cmꢂ1; 1645 (amide CꢁO). HR-MS m/z: Found 222.1715
(Calcd for C13H22N2O 222.1732).
all trans-2-Benzyldecahydropyrido[3,2,1-ij][1,6]naph-
thyridine, 8 To a solution of lithium aluminum hydride
(LiAlH4) (59 mg, 1.55 mmol) in tetrahydrofuran (THF)
(2 ml) was added the solution of the amide 3c (0.32 mg, 1.13
mmol) in THF (1 ml), and then refluxed under nitrogen at-
mosphere for 2 h. The reaction mixture was quenched with
water, and the solvent was evaporated. The residue was dis-
solved in CH2Cl2, washed with saturated K2CO3 and brine,
dried over Na2SO4, and the solvent was evaporated. The
residue was purified by silica gel column chromatography
(CH2Cl2/MeOH/28% NH4OHꢁ190 : 9 : 1), gave matrine-type
1
4a: H-NMR (CDCl3) d: 0.92—1.02 (2H, m), 1.31 (1H, t,
Jꢁ9.6 Hz), 1.39—1.51 (2H, m), 1.65—1.73 (6H, m), 1.98—
2.03 (2H, m), 2.08 (3H, s), 2.21 (1H, dd, Jꢁ12.2, 13.2 Hz),
2.77 (1H, dd, Jꢁ12.2, 13.1 Hz), 2.86 (2H, d, Jꢁ11.3 Hz),
3.65 (1H, ddd, Jꢁ2.3, 3.8, 13.2 Hz), 4.56 (1H, ddd, Jꢁ2.3,
3.8, 13.2 Hz). 13C-NMR (CDCl3) d: 21.4, 24.5, 28.0, 28.1,
39.2, 40.1, 46.4, 51.5, 56.1, 56.2, 71.2, 168.6. IR (Film)
cmꢂ1; 1640 (amide CꢁO). HR-MS m/z: Found 222.1707
(Calcd for C13H22N2O 222.1732).
1
derivative 8 as a pale yellow oil (0.25 g, 81%). H-NMR
(CDCl3) d: 1.26—1.54 (6H, m), 1.66—2.03 (7H, m), 2.38—
2.55 (4H, m), 2.77 (2H, dm, Jꢁ10.9 Hz), 3.53 (2H, s),
7.22—7.34 (5H, aromatic). 13C-NMR (CDCl3) d: 21.9, 28.2,
29.3, 35.7, 53.4, 57.3, 63.1, 63.3, 126.7, 128.0, 129.0, 138.9.
HR-MS m/z: Found 270.2106 (Calcd for C18H26N2
270.2096).
all cis-2-Benzyldecahydropyrido[3,2,1-ij][1,6]naphthyri-
dine, 9 As described for the preparation of 8, the amide 4c
(0.34 g, 1.20 mmol) was reduced with LiAlH4 (60 mg,
1.56 mmol), and purified by silica gel column chromatogra-
phy (CH2Cl2/MeOH/28% NH4OHꢁ90 : 9 : 1): colorless crys-
all trans-2-Pentanoyloctahydropyrido[3,2,1-ij][1,6]naph-
thyridine, 3b, all cis-2-Pentanoyloctahydropyrido[3,2,1-
ij][1,6]naphthyridine, 4b As described for the preparation
of 3a and 4a, the dinitrile 7b (2.93 g, 10.12 mmol) was hy-
drogenated with Pd–C (2.0 g, 5% w/w) in AcOH (200 ml),
and purified by silica gel chormatography (CH2Cl2/MeOH/
28% NH4OHꢁ140 : 9 : 1): yielded matrine-type derivative 3b
as a pale yellow oil (517 mg, 1.96 mmol, 19%) and alloma-
trine-type derivative 4b as a pale yellow oil (298 mg,
1.13 mmol, 11%).
1
tal, yield 0.27 g (83%); mp 82 °C. H-NMR (CDCl3) d: 0.90
(1H, ddd, Jꢁ4.9, 11.9, 11.9 Hz), 0.94 (1H, ddd, Jꢁ4.9, 11.9,
11.9 Hz), 1.10 (1H, t, Jꢁ9.1 Hz), 1.53—1.77 (10H, m), 1.94
(2H, ddd, Jꢁ4.1, 11.2, 11.2 Hz), 2.76 (1H, dm, Jꢁ9.4 Hz),
2.83 (1H, dm, Jꢁ11.2 Hz), 3.46 (2H, s), 7.20—7.31 (5H,
aromatic). 13C-NMR (CDCl3) d: 24.8, 28.6, 39.2, 56.3, 59.2,
62.9, 71.5, 126.8, 128.1, 129.0, 138.3. HR-MS m/z: Found
270.2150 (Calcd for C18H26N2 270.2096).
1
3b: H-NMR (CDCl3) d: 0.93 (3H, m), 1.29—1.70 (14H,
m), 1.95 (2H, dd, Jꢁ10.7, 11.4 Hz), 2.18 (1H, br), 2.32 (2H,
t, Jꢁ8.7 Hz), 2.79 (2H, d, Jꢁ10.7 Hz), 3.00 (1H, dd, Jꢁ12.5,
13.0 Hz), 3.37 (1H, d, Jꢁ9.4 Hz), 3.54 (1H, dd, Jꢁ12.4,
12.5 Hz), 4.26 (1H, d, Jꢁ13.0 Hz). 13C-NMR (CDCl3) d:
13.3, 20.6, 21.8, 26.9, 27.1, 32.1, 35.0, 36.1, 40.3, 44.7, 56.3,
62.2, 170.1. IR (Film) cmꢂ1; 1630 (amide CꢁO). HR-MS
m/z: Found 264.2219 (Calcd for C16H28N2O 264.2202).
Acknowledgements This work was supported in part by

March 2003
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a grant from the Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan.
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