Synthesis and CNS activity of new 3-amino-3-arylpropionic acid derivatives

Article abstract of DOI:10.1211/146080899128734631

The synthesis of new analogues of methylphenidate and modafinil, derived from 3-amino-3-arylpropionic acids, is described. Central pharmacological properties were studied in mice.

Full text of DOI:10.1211/146080899128734631

Pharm. Pharmacol. Commun. 1999, 5: 217±223
# 1999 Pharm. Pharmacol. Commun.
Synthesis and CNS Activity of New 3-Amino-3-arylpropionic
Acid Derivatives
O. RENAULT, J. GUILLON, C. HUARD*, H. MIEL, S. STIEBING, S. LE BOURN, M. BOULOUARD*,
P. DALLEMAGNE AND S. RAULT
Â
Centre d'Etudes et de Recherche sur le Medicament de Normandie, Laboratoire de Pharmacochimie, and
Â
*Laboratoire de Pharmacologie, UFR des Sciences Pharmaceutiques, 1 rue Vaubenard,
14032 Caen Cedex, France
Abstract
The synthesis of new analogues of methylphenidate and moda®nil, derived from 3-amino-
3-arylpropionic acids, is described. Central pharmacological properties were studied in
mice.
Methylphenidate (methyl 2-phenyl-2-(20-piper-
idyl)acetate) is a commonly prescribed stimulant
used in the treatment of attention de®cit hyper-
activity disorder (ADHD) in children and for the
treatment of narcolepsy and depression in adults.
The central stimulant activity of methylphenidate is
attributed to the activation of brain catecholamines
systems (Reigle et al 1981; Rapport et al 1996).
as solvent. Chemical shifts (d ppm) refer to tetra-
methylsilane which was used as an internal refer-
ence. NH2 and OH signals appeared as broad
singlets exchangeable with D2O. Key: t ˆ triplet,
bs ˆ broad singlet, s ˆ singlet, d ˆ doublet,
q ˆ quartet, dd ˆ double doublet, m ˆ multiplet.
Elemental analyses (C, H, N) were performed by
INSA, Rouen, France and agreed with the proposed
structures within Æ0Á3% of the theoretical values.
Moda®nil
(2-diphenylmethylsulphinyl-2-acet-
amide) is a central a-adrenergic agonist which sti-
mulates wakefulness and is the therapeutic
reference in the treatment of idiopathic hypersom-
nia and narcolepsy (Saletu et al 1989; Simon et al
1994, 1996). Its effects are attributed to an inhibi-
tory effect of on g-amino-butyric acid (GABA)-
ergic transmission (Ferraro et al 1996) (Figure 1).
We designed and synthesized some structural
compromises of these two psychostimulants. The
general structure is shown in Figure 1. In-vivo CNS
properties (Morpugo's screening, locomotor activ-
ity and barbituric narcosis) were evaluated in mice.
General procedure for the preparation of
2-methoxycarbonyl-1-arylethylammonium
chlorides (2a±c)
To a suspension of 3-amino-3-arylpropionic acids
(1a±c) (50 mmol) and 100 mL methanol was added
thionylchloride (55 mmol). The reaction mixture
was stirred at room temperature for 30 min. The
methanol was removed under reduced pressure and
the residue was triturated in ethyl ether until crys-
tallization. The precipitate was then ®ltered,
washed with ethyl ether and recrystallized from
propan-2-ol.
2-Methoxycarbonyl-1-phenylethylammonium chlor-
Materials and Methods
ide (2a). White crystals (94%); mp 138ꢀC; IR
(KBr) n: 3250±2600 (NH3 ), 1720 (CO); 1H
‡
Chemical procedures
NMR (d6-DMSO) d: 3Á02 (1H, dd, J ˆ 16Á20 and
9Á20 Hz, H-2b), 3Á27 (1H, dd, J ˆ 16Á20 and
5Á50 Hz, H-2a), 3Á50 (3H, s, CH3), 4Á55 (1H, dd,
J ˆ 9Á20 and 5Á50 Hz, H-1), 7Á37 (3H, m, H-phe-
Melting points were determined on a Ko¯er block
and are uncorrected. IR spectra were recorded on
an Unicam Mattson 1000 spectrometer. 1H and 1H-
COSY NMR spectra were recorded on a Jeol JNM-
LA 400 spectrometer (400 MHz) using d6-DMSO
‡
nyl), 7Á57 (2H, m, H-phenyl), 8Á93 (3H, bs, NH3 ).
Calculated for C10H14ClNO2: C, 55Á68; H, 6Á49; N,
6Á48. Found: C, 55Á59; H, 6Á58; N, 6Á45%.
Correspondence: S. Rault, Centre d'Etudes et de Recherche
Â
sur le Medicament de Normandie, Laboratoire de Pharmaco-
Â
2-Methoxycarbonyl-1-thien-2-ylethylammonium
chimie, UFR des Sciences Pharmaceutiques, 1 rue Vaubenard,
14032 Caen Cedex, France.
chloride (2b). White crystals (98%); mp 130ꢀC; IR

218
O. RENAULT ET AL
(2H, m, H-2eq and H-6eq), 3Á03 (1H, dd, J ˆ 15Á90
and 8Á90 Hz, H-8b), 3Á29 (1H, dd, J ˆ 15Á90 and
5Á40 Hz, H-8a), 3Á54 (3H, s, CH3), 3Á71 (2H, m, H-
2ax and H-6ax), 4Á76 (1H, dd, J ˆ 8Á90 and
5Á40 Hz, H-7), 7Á40 (3H, m, H-phenyl), 7Á59 (2H,
m, H-phenyl). Calculated for C17H23NO6: C, 66Á65;
H, 6Á99; N, 9Á72. Found: C, 66Á91; H, 7Á12; N,
9Á85%.
Figure 1. Structure of methylphenidate, moda®nil and the
general structure of new compounds.
(KBr) n: 3150±2600 (NH3 ), 1730 (CO); 1H NMR
‡
1-(2-Methoxycarbonyl-1-thien-2-yl-ethyl)-piperidi-
(d6-DMSO) d: 3Á09 (1H, dd, J ˆ 15Á70 and
8Á70 Hz, H-2b), 3Á19 (1H, dd, J ˆ 15Á70 and
6Á80 Hz, H-2a), 3Á61 (3H, s, CH3), 4Á87 (1H, dd,
J ˆ 8Á70 and 6Á80 Hz, H-1), 7Á05 (1H, d,
J ˆ 3Á20 Hz, H-30), 7Á31 (1H, dd, J ˆ 4Á90 and
3Á20 Hz, H-40), 7Á57 (1H, d, J ˆ 4Á90 Hz, H-50),
nium oxalate (4b). Beige oil (75%); IR (KBr) n:
1
1730 (COOCH3); H NMR (d6-DMSO) d: 1Á32
(1H, m, H-4ax), 1Á80 (2H, m, H-3eq and H-5eq),
1Á89 (1H, m, H-4eq), 2Á39 (2H, m, H-3ax and H-
5ax), 2Á90 (2H, m, H-2eq and H-6eq), 3Á10 (1H, dd,
J ˆ 16Á20 and 9Á05 Hz, H-8b), 3Á29 (1H, dd,
J ˆ 16Á20 and 5Á40 Hz, H-8a), 3Á54 (3H, s, CH3),
3Á71 (2H, m, H-2ax and H-6ax), 4Á76 (1H, dd,
J ˆ 9Á05 and 5Á40 Hz, H-7), 7Á01 (1H, dd,
J ˆ 4Á80 and 3Á00 Hz, H-4thienyl), 7Á10 (1H, d,
‡
8Á96 (3H, bs, NH3 ). Calculated for C8H12ClNO2S:
C, 43Á34; H, 5Á42; N, 6Á32. Found: C, 43Á21; H,
5Á37; N, 6Á29%.
2-Methoxycarbonyl-1-thien-3-ylethylammonium
J ˆ 4Á80 Hz,
J ˆ 3Á00 Hz,
H-3thienyl),
H-5thienyl).
7Á46
(1H,
Calculated
d,
for
chloride (2c). Beige crystals (87%); mp 120ꢀC; IR
(KBr) n: 3300±2500 (NH3 ), 1720 (CO); 1H NMR
‡
C15H21NO6S: C, 52Á46; H, 6Á16 ; N, 4Á08. Found:
(d6-DMSO) d: 3Á01 (1H, dd, J ˆ 16Á20 and
8Á60 Hz, H-2b), 3Á22 (1H, dd, J ˆ 16Á20 and
5Á70 Hz, H-2a), 3Á55 (3H, s, CH3), 4Á66 (1H, dd,
J ˆ 8Á60 and 5Á70 Hz, H-1), 7Á33 (1H, dd, J ˆ 4Á90
and 0Á95 Hz, H-50), 7Á56 (1H, dd, J ˆ 4Á90 and
2Á90 Hz, H-40), 7Á69 (1H, dd, J ˆ 2Á90 and
C, 52Á71; H, 6Á07; N, 4Á00.
1-(2-Methoxycarbonyl-1-thien-3-yl-ethyl)-piperidi-
nium oxalate (4c). Beige oil (71%); IR (KBr) n:
1
1728 (COOCH3); H NMR (d6-DMSO) d: 1Á32
(1H, m, H-4ax), 1Á80 (2H, m, H-3eq and H-5eq),
1Á89 (1H, m, H-4eq), 2Á39 (2H, m, H-3ax and H-
5ax), 2Á90 (2H, m, H-2eq and H-6eq), 3Á10 (1H, dd,
J ˆ 16Á20 and 9Á05 Hz, H-8b), 3Á29 (1H, dd,
J ˆ 16Á20 and 5Á40 Hz, H-8a), 3Á54 (3H, s, CH3),
3Á71 (2H, m, H-2ax and H-6ax), 4Á76 (1H, dd,
J ˆ 9Á05 and 5Á40 Hz, H-7), 7Á09 (1H, dd,
J ˆ 5Á10 and 1Á00 Hz, H-5thienyl), 7Á53 (1H, dd,
J ˆ 3Á10 and 1Á00 Hz, H-2thienyl), 7Á59 (1H, dd,
J ˆ 5Á10 and 3Á10 Hz, H-4thienyl). Calculated for
C15H21NO6S: C, 52Á46; H, 6Á16 ; N, 4Á08. Found: C,
52Á44; H, 6Á16; N, 4Á21%.
‡
0Á95 Hz, H-20), 8Á85 (3H, bs, NH3 ). Calculated
for C8H12ClNO2S: C, 43Á34; H, 5Á42; N, 6Á32.
Found: C, 43Á40; H, 5Á32; N, 6Á25%.
General procedure for the preparation of
1-(2-methoxycarbonyl-1-aryl-ethyl)-piperidinium
oxalate (4a±c)
To a solution of hydrochloride (2a±c) (10 mmol)
and triethylamine (3 equiv.) in 50 mL methanol was
added 1,5-dibromopentane (1Á1 equiv.). The reac-
tion was heated at 60ꢀC for 36 h with stirring. The
mixture obtained after evaporation in-vacuo was
dissolved in 50 mL CH2Cl2 and the precipitate
Et3NHBr was ®ltered off. The organic layer was
dried over anhydrous Na2SO4 and evaporated to
dryness. The crude product was dissolved in 10 mL
propan-2-ol and oxalic acid (2 equiv.) was added.
After re¯uxing for 2 h and cooling to room tem-
perature the product was ®ltered off and washed
with Et2O to give hygroscopic oils 5a±c.
General procedure for the preparation of
3-carbamoyl-1-(2-methoxycarbonyl-1-arylethyl)
pyridinium chlorides (5a±c)
A solution of 2-methoxycarbonyl-1-arylethyl-
ammonium chlorides 2a±c (50 mmol) in 60 mL dry
methanol was added to a suspension of 1-(2,4-
dinitrophenyl)-3-carbamoylpyridinium
chloride
Â
(50 mmol) prepared by the method of Lettre et al
(1953) in 60 mL dry methanol. Sodium bicarbonate
(50 mmol) and ®ve drops of pyridine (catalyst)
were then added and the reaction mixture was
stirred overnight at room temperature. The pre-
cipitate, 2,4-dinitroaniline and sodium chloride,
was ®ltered off. Ether was added to the ®ltrate and
1-(2-Methoxycarbonyl-1-phenyl-ethyl)-piperidinium
oxalate (4a). Beige oil (78%); IR (KBr) n: 1725
1
(COOCH3); H NMR (d6-DMSO) d: 1Á35 (1H, m,
H-4ax), 1Á79 (2H, m, H-3eq and H-5eq), 1Á86 (1H,
m, H-4eq), 2Á41 (2H, m, H-3ax and H-5ax), 2Á95

NEW 3-AMINO-3-ARYLPROPIONIC ACID DERIVATIVES
219
the resulting precipitate was ®ltered off, washed
with dry ether and recrystallized from methanol-
ether (50:50, v=v).
2pyridine). Calculated for C14H15ClN2O3S: C,
51Á45; H, 4Á63; N, 8Á57. Found: C, 51Á40; H, 4Á68;
N, 8Á56%.
3-Carbamoyl-1-(2-methoxycarbonyl-1-phenylethyl)
pyridinium chloride (5a). Orange crystals (54%);
mp 130ꢀC; IR (KBr) n: 3100 (NH), 1720
General procedure for the preparation of methyl 3-
(3-carbamoyl-4H-pyridin-1-yl)-3-arylpropionates
(6a±c)
1
(COOCH3), 1660 (CONH2); H NMR (d6-DMSO)
d: 3Á54 (3H, s, CH3O), 3Á85 (1H, dd, J ˆ 17Á60 and
6Á00 Hz, H-2a), 4Á22 (1H, dd, J ˆ 17Á60 and
9Á00 Hz, H-2b), 6Á61 (1H, dd, J ˆ 9Á00 and
6Á00 Hz, H-1), 7Á43 (3H, m, H-phenyl), 7Á84 (2H,
m, H-phenyl), 8Á22 (1H, s, NH), 8Á31 (1H, t,
J ˆ 6Á70 Hz, H-5pyridine), 9Á06 (1H, d,
J ˆ 6Á70 Hz, H-4pyridine), 9Á24 (1H, s, NH), 9Á67
(1H, d, J ˆ 6Á70 Hz, H-6pyridine), 10Á15 (1H, s, H-
2pyridine); 13C NMR (d6-DMSO) d: 36Á0 (C-2),
52Á0 (CH3), 70Á4 (C-3), 128Á1 (C-3 and C-5phenyl),
128Á4 (C-4phenyl), 129Á2 (C-2 and C-6phenyl),
129Á8 (C-1pyridine), 134Á1 (C-5pyridine), 135Á9
(C-4pyridine), 143Á7 (C-3pyridine), 145Á1 (C-6pyr-
idine), 145Á7 (C-2pyridine), 162Á3 (CO), 169Á9
(CO). Calculated for C16H17ClN2O3: C, 59Á9; H,
5Á30; N, 8Á73. Found: C, 60Á07; H, 5Á38; N, 8Á92%.
To a solution of 3-carbamoyl-1-(2-methoxy-
carbonyl-1-arylethyl)pyridinium chlorides (5a±c)
(8 mmol) in 300 mL deaerated water and 300 mL
ethyl acetate was added a mixture of sodium
hydrogenocarbonate (80 mmol) and sodium
dithionite (80 mmol). The system was maintained
under an argon stream and was stirred for 2 h. The
organic layer was separated and the aqueous layer
extracted with ethyl acetate (2 6 100 mL). The
combined organic layers were washed with cold
degassed water (2 6 500 mL), dried over magne-
sium sulphate and evaporated under reduced pres-
sure to give 4a±c, which was puri®ed by
chromatography on silica gel using CHCl3
CH3OH (98:2, v=v) as eluent.
Methyl 3-(3-carbamoyl-4H-pyridin-1-yl)-3-phenyl-
propionate (6a). Yellow crystals (53%); mp 45ꢀC;
IR (KBr) n: 3285, 3200 (NH2), 1735 (COOCH3),
3-Carbamoyl-1-(2-methoxycarbonyl-1-thien-2-yl-
ethyl)pyridinium chloride (5b). Orange crystals
(52%); mp 153ꢀC; IR (KBr) n: 3250 (NH), 1705
1
1685 (CONH2); H NMR (d6-DMSO) d: 2Á90 (2H,
1
(COOCH3), 1630 (CONH2); H NMR (d6-DMSO)
m, H-4pyridine), 3Á11 (2H, m, H-2), 3Á59 (3H, s,
CH3O), 4Á56 (1H, m, H-5pyridine), 4Á77 (1H, dd,
J ˆ 8Á10 and 7Á40 Hz, H-3), 6Á02 (1H, d,
J ˆ 8Á00 Hz, H-6pyridine), 6Á62 (2H, bs, NH2),
7Á04 (1H, s, H-2pyridine), 7Á39 (5H, m, H-phenyl);
13C NMR (d6-DMSO) d: 22Á7 (CH2), 36Á7 (CH2),
51Á6 (CH3), 61Á5 (CH), 101Á1 (C-5pyridine), 102Á2
(C-6pyridine), 126Á8 (C-3 and C-5phenyl), 127Á7
(C-2pyridine), 127Á9 (C-3pyridine), 128Á6 (C-2 and
C-6phenyl), 136Á1 (C-4phenyl), 139Á8 (C-1phenyl),
169Á1 (CO), 170Á7 (CO). Calculated for C16H18
N2O3: C, 67Á12; H, 6Á34; N, 9Á78. Found: C,
67Á26; H, 6Á61; N, 9Á80%.
d: 3Á56 (3H, s, CH3O), 3Á90 (1H, dd, J ˆ 15Á80 and
6Á10 Hz, H-2a), 4Á10 (1H, dd, J ˆ 15Á80 and
9Á10 Hz, H-2b), 6Á80 (1H, dd, J ˆ 9Á10 and
6Á10 Hz, H-1), 6Á99 (1H, dd, J ˆ 4Á80 and
3Á20 Hz, H-40), 7Á10 (1H, d, J ˆ 3Á20 Hz, H-30),
7Á70 (1H, d, J ˆ 4Á80 Hz, H-50), 8Á20 (1H, s, NH),
8Á30 (1H, t, J ˆ 7Á10 Hz, H-5pyridine), 9Á09 (1H, s,
H-2pyridine), 9Á21 (1H, d, J ˆ 7Á10 Hz, H-4pyri-
dine), 9Á50 (1H, d, J ˆ 6Á40 Hz, H-6pyridine), 9Á98
(1H, s, NH). Calculated for C14H15ClN2O3S: C,
51Á45; H, 4Á63; N, 8Á57. Found: C, 51Á21; H, 4Á65;
N, 8Á60%.
3-Carbamoyl-1-(2-methoxycarbonyl-1-thien-3-yl-
ethyl)pyridinium chloride (5c). Orange crystals
(63%); mp 158ꢀC; IR (KBr) n: 3360 (NH), 1735
Methyl 3-(3-carbamoyl-4H-pyridin-1-yl)-3-thien-2-
ylpropionate (6b). Yellow oil (69%); IR (KBr) n:
3320, 3290 (NH2), 1695 (COOCH3), 1655
1
1
(COOCH3), 1655 (CONH2); H NMR (d6-DMSO)
(CONH2); H NMR (d6-DMSO) d: 2Á90 (2H, m,
d: 3Á52 (3H, s, CH3O), 3Á81 (1H, dd, J ˆ 17Á50 and
5Á90 Hz, H-2a), 4Á15 (1H, dd, J ˆ 17Á50 and
9Á00 Hz, H-2b), 6Á66 (1H, dd, J ˆ 9Á00 and
5Á90 Hz, H-1), 7Á49 (1H, dd, J ˆ 5Á10 and
1Á00 Hz, H-50), 7Á60 (1H, dd, J ˆ 5Á10 and
2Á90 Hz, H-40), 8Á10 (1H, s, NH), 8Á13 (1H, dd,
J ˆ 2Á90 and 1Á00 Hz, H-20), 8Á28 (1H, t,
J ˆ 6Á40 Hz, H-5pyridine), 9Á04 (1H, d,
J ˆ 6Á40 Hz, H-4pyridine), 9Á20 (1H, s, NH), 9Á62
(1H, d, J ˆ 6Á40 Hz, H-6pyridine), 10Á12 (1H, s, H-
H-4pyridine), 3Á10 (1H, dd, J ˆ 15Á80 and 6Á60 Hz,
H-2a), 3Á13 (1H, dd, J ˆ 15Á80 and 9Á70 Hz, H-2b),
3Á60 (3H, s, CH3O), 4Á60 (1H, m, H-5pyridine),
4Á98 (1H, dd, J ˆ 9Á70 and 6Á60 Hz, H-3), 5Á98 (1H,
d, J ˆ 7Á90 Hz, H-6pyridine), 6Á61 (2H, bs, NH2),
6Á97 (1H, s, H-2pyridine), 6Á99 (1H, dd, J ˆ 4Á80
and 3Á10 Hz, H-4thienyl), 7Á08 (1H, d, J ˆ 4Á80 Hz,
H-3thienyl), 7Á46 (1H, d, J ˆ 3Á10 Hz, H-5thienyl).
Calculated for C14H16N2O3S: C, 57Á52; H, 5Á52; N,
9Á58. Found: C, 57Á69; H, 5Á47; N, 9Á61%.

220
O. RENAULT ET AL
Methyl 3-(3-carbamoyl-4H-pyridin-1-yl)-3-thien-3-
ylpropionate (6c). Yellow oil (71%); IR (KBr) n:
3360, 3230 (NH2), 1730 (COOCH3), 1650
layer was washed twice with water, dried over
magnesium sulphate and evaporated to dryness.
The residue was recrystallized from a mixture of
diethyl ether-petroleum ether (50:50, v=v) to give
9. White crystals (45%); mp 102ꢀC; IR (KBr) n:
3445, 3405 (NH2), 1680, 1660 (CONH2); 1H NMR
(d6-DMSO) d: 2Á91 (2H, dd, J ˆ 14Á90 and
6Á60 Hz, H-2b), 3Á01 (2H, dd, J ˆ 14Á90 and
8Á90 Hz, H-2a), 5Á61 (1H, dd, J ˆ 8Á90 and 6Á60 Hz,
H-3), 5Á98 (2H, dd, J ˆ 1Á95 and 1Á95 Hz, H-b),
6Á84 (2H, dd, J ˆ 1Á95 and 1Á95 Hz, H-a), 6Á89 (1H,
bs, NH), 7Á17 (2H, d, J ˆ 7Á30 Hz, H-20 and H-60),
7Á23 (1H, d, J ˆ 7Á30 Hz, H-40), 7Á29 (2H, t,
J ˆ 7Á30 Hz, H-30 and H-50), 7Á41 (1H, bs, NH).
Calculated for C13H14N2O: C, 72Á87; H, 6Á59; N,
13Á07. Found: C, 72Á62; H, 6Á51; N, 12Á85%.
1
(CONH2); H NMR (d6-DMSO) d: 2Á97 (2H, m,
H-4pyridine), 3Á12 (2H, m, H-2), 3Á66 (3H, s,
CH3O), 4Á63 (1H, m, H-5pyridine), 4Á86 (1H, dd,
J ˆ 7Á90 and 7Á20 Hz, H-3), 6Á03 (1H, d,
J ˆ 8Á00 Hz, H-6pyridine), 6Á64 (2H, bs, NH2),
7Á05 (1H, s, H-2pyridine), 7Á15 (1H, dd, J ˆ 5Á00
and 1Á10 Hz, H-5thienyl), 7Á50 (1H, dd, J ˆ 3Á10
and 1Á10 Hz, H-2thienyl), 7Á57 (1H, dd, J ˆ 5Á00
and 3Á10 Hz, H-4thienyl). Calculated for
C14H16N2O3S: C, 57Á52; H, 5Á52; N, 9Á58. Found:
C, 57Á63; H, 5Á48; N, 9Á80%.
Methyl 3-(5-carbamoyl-3,4-dihydro-2H-pyridin-1-
yl)-3-phenylpropionates (7a)
Compound 6a (5 mmol) and NiCl2, 6H2O (5 mmol)
were dissolved in 40 mL methanol and sodium
borohydride (20 mmol) was added portionwise with
stirring under cooling for 30 min. Stirring was
continued for 4 h at room temperature. After the
removal of methanol by distillation, the black
precipitate was dissolved in 10% hydrochloric acid.
The acidic solution was ®ltered, basi®ed by the
addition of concentrated ammonium hydroxide and
extracted with ethyl acetate. The extract was dried
over magnesium sulphate and evaporated under
reduced pressure. The residue was puri®ed by
chromatography column using CHCl3 CH3OH
(98:2, v=v) as eluent. Yellow crystals (51%); mp
44ꢀC; IR (KBr) n: 3300, 3250 (NH2), 1730
Pharmacology
Animals. Female OF-1 mice (Iffa credo, France),
18±22 g, were used. The animals were allowed free
access to food and water and were housed at room
temperature (20±22ꢀC). All test compounds were
administered via intraperitoneal injection in dis-
tilled water with a drop of Tween 80 solution.
Gross behavioural effects and acute toxicity in mice.
Morpugo's modi®cation (Morpugo 1971) of
Irwin's multi-dimensional screening procedure
was used on groups of four mice to evaluate
drug-induced behavioural effects. The test com-
pounds were administered in log-spaced doses,
and detailed observations of the mice were made
1, 3 and 24 h after treatment. The approximate
LD50 was obtained from the mortality observed
during a 48-h period.
1
(COOCH3), 1685 (CONH2); H NMR (d6-DMSO)
d: 1Á57 (2H, m, H-3pyridine), 2Á02 (2H, m, H-
4pyridine), 2Á74 (1H, m, H-2pyridine), 2Á94 (1H, m,
H-2pyridine), 3Á05 (1H, dd, J ˆ 15Á80 and 7Á00 Hz,
H-2a), 3Á12 (1H, dd, J ˆ 15Á80 and 9Á00 Hz, H-2b),
3Á58 (3H, s, CH3O), 4Á71 (1H, dd, J ˆ 9Á00 and
7Á00 Hz, H-3), 6Á31 (2H, bs, NH2), 7Á33 (6H, m, H-
phenyl and H-6pyridine). Calculated for
C16H20N2O3: C, 66Á65; H, 6Á99; N, 9Á72. Found: C,
66Á91; H, 7Á12; N, 9Á85%.
Locomotor activity. The spontaneous activity of
normal mice was recorded with a photoelectric
actimeter. This apparatus comprises transparent
cages and the activity of the animal is measured
by light beams connected to a photoelectric cell;
the total number of beam-breaks is counted over a
period of 15±30 min after treatment.
3-Phenyl-3-pyrrol-1-ylpropionamide (9)
To a stirred solution of compound 8 (0Á0232 mol) in
100 mL acetone at 0ꢀC, triethylamine (0Á0232 mol)
was added dropwise. After 30 min, ethyl chloro-
formate (0Á0232 mol) was added and the reaction
mixture was stirred at 0ꢀC for 30 min. The pre-
cipitate formed was ®ltered and the ®ltrate was
evaporated to dryness. The oily residue was then
dissolved in 100 mL diethyl ether and ammonia
solution (28%) was added. The reaction mixture
was re¯uxed for 2 h. After cooling, the organic
Barbituric narcosis. Tested compounds were admi-
nistered intraperitoneally 30 min before a hypnotic
1
dose of pentobarbital (50 mg kg , i.p.) or barbital
1
(180 mg kg , i.p.). The parameter quanti®ed was
the sleeping time to abolition of the righting re¯ex
when the mice were placed on their back (Simon et
al 1992).

NEW 3-AMINO-3-ARYLPROPIONIC ACID DERIVATIVES
221
Results and Discussion
Chemistry
During the course of our work concerning the
synthesis of new heterocyclic compounds of
potential therapeutic interest, we recently described
the access to numerous 3-amino-3-arylpropionic
acids 1a±c starting from aldehydes (Dallemagne et
al 1986, 1987 ). The synthetic pathway involved the
Rodionow±Johnson reaction (Rodionow & Mal-
ewinskaja 1926; Johnson & Livak 1936) using
malonic acid and ammonium acetate in an etha-
nolic solution of starting material. Reaction of the
b-amino acids 1a±c in methanol with a stoichio-
metric amount of thionyl chloride led to the 1-aryl-
2-methoxycarbonylethyl ammonium chlorides 2a±
c (Brenner & Huber 1953; Patel & Price 1965;
Langlois et al 1996; Guillon et al 1998). The
methyl 3-aryl-3-piperidin-1-ylpropionates 3a±c
were obtained by condensing the 1-aryl-2-meth-
oxycarbonylethyl ammonium chlorides 2a±c with
1,5-dibromopentane in the presence of triethyla-
mine. The products were obtained as free bases and
then converted into the corresponding oxalates 4a±
c (Juarez et al 1997) (Figure 2).
Figure 3. Reagents: i. 3-carbamoyl-1-(2,4-dinitrophenyl)pyr-
idinium chloride, CH3OH, NaHCO3; ii. Na2S2O4, NaHCO3,
H2O=CH3COOC2H5; iii. NiCl2, 6H2O-NaBH4, CH3OH.
1991, 1994). The reduction of the pyridin ring with
the sodium borohydride±nickelous chloride system
was investigated (Nose & Kudo 1984). The deri-
vative 6a was thus selectively reduced to give the
corresponding methyl 3-(5-carbamoyl-3,4-dihydro-
2H-pyridin-1-yl)-3-phenylpropionate
7a.
The
structure of 7a was con®rmed by two-dimensional
COSY NMR (Figure 3).
The pyridinium salts 5a±c were synthesized
according to the Zincke procedure (Zincke 1903;
Treatment of 1a with 2,5-dimethoxytetra-
hydrofuran in boiling acetic acid, according to the
Clauson-Kaas method (Clauson-Kaas & Elming
1952; Clauson-Kaas & Tyle 1952) led to the pyr-
rolylphenylpropionic acid 8 (Tembo et al 1993).
Reaction of 8 with triethylamine followed by
treatment with ethyl chloroformate and ammonia
gave the amide 9 via the anhydride 10 (Figure 4).
Â
Lettre et al 1953; Tamura et al 1972; Kost et al
1981). The amino group of 2a±c was reacted in
dry methanol with 3-carbamoyl-1-(2,4-dinitro-
phenyl)pyridinium chloride, obtained from nicoti-
Â
namide and 1-chloro-2,4-dinitrobenzene (Lettre et
al 1953), in the presence of sodium bicarbonate and
catalytic amounts of pyridine. The 1,4-dihy-
dropyridines 6a±c were obtained by regioselective
reduction of the pyridinium salts 6a±c with sodium
dithionite in a biphasic system (ethyl acetate±
aqueous sodium bicarbonate) (Pop et al 1990,
Pharmacology
Pharmacological results are given in Table 1.
Locomotor activity. Methylphenidate, the structural
and pharmacological reference, induced a dose-
dependant increase in spontaneous locomotor activ-
Figure 2. Reagents: i. CH3COONH4, CH2(COOH)2,
C2H5OH; ii. CH3OH, SOCl2; iii. Br (CH2)5 Br, (C2H5)3N,
CH3OH; iv. (CH3)2CHOH, HOOC COOH.
Figure 4. Reagents: i. 2,5-dimethoxytetrahydrofuran,
CH3COOH; ii. (C2H5)3N, CH3COCH3, ClCOOC2H5; iii.
(C2H5)2O, NH4OH.

222
O. RENAULT ET AL
Table 1. Pharmacological data of reference and new compounds.
Compound
LD50
(mg kg
Locomotor activity
ED50 Effect
Barbituric narcosis
1
)
Dose of
compound
Sleeping
time with
barbital (%)
Sleeping
time with
pentobarbital (%)
1
(mg kg
)
1
(mg kg
)
Methylphenidate
175
3Á6
Increased
8
16
NT
5
15
115
NT
59Á0
44Á2
NT
71Á5
89Á8
111Á4
NT
122Á5
96Á8
4a
4b
4c
9
175
75
75
900
NE
NE
NE
56
Decreased
Decreased
Decreased
Increased
Decreased
NT
117Á4
108Á4
152Á3**
NT
160
NT, not tested; NE, not established. **P < 0Á01, compared with methylphenidate (Student's t-test).
ity in mice. These results were in accordance with
data of Reigle et al (1981). Methylphenidate ana-
logues 4a±c and 9 exhibited opposite central
effects with depressant effects on spontaneous
locomotor activity. The decrease in activity was
more pronounced with the moda®nil analogue
9 which exhibited a biphasic effect on explora-
tory activity with signi®cant stimulant activity at
particular in relation to GABA interaction, would
be of interest.
References
È
Brenner, M., Huber, W. (1953) Herstellung von a-Aminosaur-
eestern durch Alkoholyse der Methylester. Helv. Chim. Acta
36: 1109±1115
1
lower doses (ED50 ˆ 56 mg kg ) and signi®cant
Clauson-Kaas, N., Elming, N. (1952) The preparation of
pyrroles from furans. Acta Chem. Scand. 6: 867±874
Clauson-Kaas, N., Tyle, Z. (1952) Preparation of cis and trans
2,5-dimethoxy-2-(acetamidomethyl)-2,5-dihydrofuran, of
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depressant property at higher doses (ED50 ˆ
1
160 mg kg ). Other methylphenidate analogues
(5a±c, 6a±c and 7a) were submitted to screening
and locomotor activity studies. Central depressant
activity but not psychostimulant activity was found.
Â
Dallemagne, P., Rault, S., Cugnon de Sevricourt, M., Hassan,
K. M., Robba, M. (1986) Cyclisation de l'acide amino-3
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date were in accordance with those of Simon et al
(1992). Methylphenidate had no effect on pento-
barbital-induced narcosis but decreased barbital-
induced narcosis at the same dose. The new com-
pounds tested had no effect on barbital-induced
narcosis. However, compound 9 (115 mg kg )
induced a signi®cant effect on pentobarbital
induced-narcosis with an increase in sleeping time.
Á
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Conclusions
The analogues of methylphenidate (4a±c) did not
exhibit central-stimulant properties. It seems that
substitution of the piperidin nitrogen was detri-
mental to this pro®le. Overall, 4a±c had a depres-
sive central effect.
Compound 9 (moda®nil analogue) demonstrated
biphasic effects on locomotor activity, with
stimulant effects at lower doses (ED50 ˆ
1
56 mg kg ) and depressive effects at higher doses
1
(ED50 ˆ 160 mg kg ). Moreover, it had a hyp-
Langlois, N., Dahuron, N., Wang, H. S. (1996) Enantioselec-
tive syntheses of (R)-3-phenyl GABA, (R)-baclofen and 4-
arylpyrrolidin-2-ones. Tetrahedron 52: 15117±15126
1
notic effect at doses of 250 mg kg . Further study
of the mechanism of action of compound 9, in