Synthesis and pharmacological evaluation of 5-dialkylaminomethyl-2-amino-2-oxazolines as H1-antagonists

Article abstract of DOI:10.1211/0022357011776315

New 5-dialkylaminomethyl-2-amino-2-oxazolines have been synthezised in two steps from the corresponding dialkylamines. They were evaluated in-vitro as H₁-antagonists. Compounds 1c, 1d and 1j significantly antagonized histamine-induced contraction of guinea-pig trachea with a rightward shift of the concentration-response curve to histamine. Compound 1f, 5-[(4-benzyl-1-piperidinyl)methyl]-2-amino-2-oxazoline, induced an increase in acetylcholine E_max (the maximal response to acetylcholine 10^-3 M) and a shift to the left of the concentration-response curve. The lack of effect of this compound on histamine-induced contraction rules out a non-selective potentiation of the contraction mechanisms. Preliminary structure-activity results were reported partly based on physicochemical results.

Full text of DOI:10.1211/0022357011776315

Atlantic Arc
Medicinal Chemistry
Journal of
Pharmacy and Pharmacology
JPP 2001, 53: 923–927
# 2001 The Authors
Received December 19, 2000
Accepted April 11, 2001
ISSN 0022-3573
Synthesis and pharmacological evaluation of
5-dialkylaminomethyl-2-amino-2-oxazolines as
H1-antagonists
J. J. Bosc, C. Jarry, B. Martinez and M. Molimard
Abstract
New 5-dialkylaminomethyl-2-amino-2-oxazolines have been synthezised in two steps from the
corresponding dialkylamines. They were evaluated in-vitro as H1-antagonists. Compounds 1c,
1d and 1j significantly antagonized histamine-induced contraction of guinea-pig trachea with
a rightward shift of the concentration–response curve to histamine. Compound 1f, 5-[(4-
benzyl-1-piperidinyl)methyl]-2-amino-2-oxazoline, induced an increase in acetylcholine Emax
3
−
(the maximal response to acetylcholine 10 M) and a shift to the left of the concen-
tration–response curve. The lack of effect of this compound on histamine-induced contraction
rules out a non-selective potentiation of the contraction mechanisms. Preliminary struc-
ture–activity results were reported partly based on physicochemical results.
Introduction
For several years we have focused our attention mainly on the chemistry of 2-
amino-2-oxazolines (Jarry et al 1986, Bosc et al 1992). Recently, we reported the
synthesis of 5-[(1-aryl-4-piperazinyl)methyl]-2-amino-2-oxazolines useful either as
synthons (Chaimbault et al 1999, Forfar et al 1999) or as precursors of potentially
active ring-opened compounds (Bosc & Jarry 1998). 5-Aryl-2-amino-2-oxazolines
have been widely investigated for pharmaceutical uses. They are very potent in
suppressing appetite, but they cause CNS stimulation and produce sympatho-
mimetic cardiovascular effects (Poos et al 1963).
EA 2962 Pharmacochimie,
Universite Victor Segalen
Bordeaux 2, 146 rue Leo Saignat,
33076 Bordeaux Cedex, France
In this study, we describe the synthesis of a series of 5-dialkylaminomethyl-2-
amino-2-oxazolines (1a–l; Figure 1). The dialkylamino moiety is either a substituted
piperidinyl, tetrahydropyridinyl, indolinyl or indolyl ring. The general structure of
these compounds is characterized by the presence of pharmacophoric requirements
of H1-receptor antagonists, in comparison with the model recently refined by Ter
Laak et al (Battaglia et al 1999, Van der Goot & Timmerman 2000). They were
evaluated in-vitro for their ability to antagonize histamine-induced contraction of
guinea-pig trachea. Preliminary structure–activity results were reported partly
based on physicochemical results.
J. J. Bosc, C. Jarry
Laboratoire de pharmacologie,
Universite Victor Segalen
Bordeaux 2, 146 rue Leo Saignat,
33076 Bordeaux Cedex, France
B. Martinez, M. Molimard
Correspondence: J. J. Bosc, EA
2962 Pharmacochimie, Universite
Victor Segalen Bordeaux 2, 146
rue Leo Saignat, 33076 Bordeaux
Cedex, France.
923

924
J. J. Bosc et al
Figure 1 Synthesis of 5-dialkylaminomethyl-2-amino-2-oxazolines. Reagents: I, C2H5OH; ii, NaOH, C2H5OH; iii, NaNHCN, CH3OH.
Materials and Methods
was stirred for 15 h, then concentrated under reduced
pressure. The residue was extracted with ether. The
ether phase was washed twice with water and dried.
After evaporation of the solvent, the crude 5-dialkyl-
aminomethyl-2-amino-2-oxazolines (1a–l) were crystal-
lized after trituration with heptane.
Chemical procedures
Microanalyses were carried out at the Service Central
d’Analyse CNRS, Vernaison, France. Melting points
were determined with an SM-LUXPOL Leitz hot-stage
microscope and are uncorrected. The IR spectra were
obtained with a Bruker IFS 25 spectrophotometer. 5-[(2-Ethyl-1-piperidinyl)methyl]-2-amino-2-oxazoline
NMR data were recorded with a Bruker AC-200 spec- (1e)
1
−
trometer. Chemical shifts (δ ppm) and coupling con- White powder (27%); mp 114mC; IR (KBr) ν: 1698 cm
stants (J Hz) were measured using tetramethylsilane as (CN); 1H NMR (CDCl3) δ: 4.84 (s, 2H, NH2), 4.67–4.53
the internal standard.
(m, 1H, CH), 3.70 (dd, 1H, J l 12.0, 8.8, C2-H2a), 3.27
(dd, 1H, J l 12.0, 7.2, C2-H2b), 2.91–2.79, 2.70–2.49,
2.32–2.12, 1.59–1.18 (4m, 13H, CH2 pip, C4-H2,
CH2CH3), 0.79 (t, 3H, J l 7.4, CH3); 13C NMR (CDCl3)
δ: 161 (C1), 78.45 (C3), 62.14, (C4), 56.38 (CH pip),
52.41 (C2), 57.02, 28.91, 24.70, 23.24 (CH2 pip), 24
(CH2CH3), 10.11 (CH3). Calculated for C11H21N3O : C,
62.52; H, 10.02; N, 19.89; Found: C, 62.61; H, 10.10;
N, 19.83%.
General procedure for the preparation of
5-dialkylaminomethyl-2-amino-2-oxazolines (1a–l)
The 1-dialkylamino-2,3-epoxypropanes 2 were obtained
by treating an equimolar mixture (0.5 mol) of dialkyl-
amine and epichlorhydrin in 200 mL of ethanol for 3 h.
After addition of 20 g (0.5 mol) of NaOH, the mixture
was stirred for 15 h. After evaporation of the solvent the
residue was dissolved in ether, filtered, washed with 5[(4-Piperidinyl-1-piperidinyl)methyl]-2-amino-2-
water and dried. After evaporation of the ether, the oxazoline (1g)
residue was distilled at reduced pressure to yield the White powder (18%); mp 38.7mC; IR (KBr) ν:
1
1
−
corresponding1-dialkylamino-2,3-epoxypropane.Com- 1690 cm (CN); H NMR (CDCl3) δ: 4.86 (s, 2H,
pound 2 (0.2 mol) was added drop-wise at 20mC to a NH2), 4.70–4.53 (m, 1H, CH), 3.74 (dd, 1H, J l 12.0,
stirred mixture of monosodium cyanamid salt (12.8 g, 8.9, C2-H2a), 3.27 (dd, 1H, J l 12.0, 7.4, C2-H2b), 2.59
0.2 mol) in 200 mL of methanol. The reaction mixture (dd, 1H, J l 13.5, 8.3, C4-H2a), 2.33 (dd, 1H, J l 13.5,

925
5-Dialkylaminomethyl-2-amino-2-oxazolines as H1-antagonists
3.5, C4-H2b), 2.99–2.93, 2.46–2.40, 2.29–2.20, 1.99–1.93, C2-H2a) ; 3.51 (dd, 1H, J l 12.5, 6.15, C2-H2b), 2.43 (d,
1.72–1.36 (5m, 19H, CH2 pip); 13C NMR (CDCl3) δ: 3H, J l 0.8, CH3); 13C NMR (CDCl3) δ: 160.53
160.8 (C1), 78.06 (C3), 62.75 (CH pip), 62.49 (C4), 53.83 (C1), 136.80, 128.10, 120.71, 119.83, 119.61, 108.80
(C2), 56.56, 27.46, (CH2 pip), 49.99, 26.31, 24.71 (CH2 (C-Ar), 136.49 (ꢀC-CH3), 100.66 (ꢀCH), 78.65 (C3),
pip). Calculated for C14H26N4O : C, 63.12; H, 9.84; N, 55.38 (C4), 46.62 (C2), 12.98 (CH3). Calculated for
21.03; Found: C, 63.11; H, 9.90; N, 21.0%.
C13H15N3O : C, 68.10; H, 6.59; N, 18.33; Found: C,
68.40; H, 6.36; N, 18.30%.
5-[(4-Carboxamide-1-piperidinyl)methyl]-2-amino-2-
oxazoline (1h)
Pharmacological procedures
White powder (17%); mp 202mC; IR (KBr) ν: 1720
(CO), 1668 cm 1 (CN); 1H NMR (d6-DMSO) δ: 7.19 (s,
−
Guinea-pigs of either sex, 250–400 g were killed by a
blow on the head and exsanguinated. Trachea were
rapidly removed and cut into rings. Each set of guinea-
pig airways rings was suspended under an initial tension
of 2 g in Krebs-Henseleit solution, bubbled with 95%
O2–5% CO2 and maintained at 37mC. Changes in force
of contraction were measured isometrically with strain-
gauge amplifiers. Digital signal acquisition enabling
treatment of pharmacological data was performed using
the Mac Lab system and the chart 3.5.6 program
(Phymep, Paris, France). Krebs solution was composed
of (m): NaCl 4.7; CaCl2 1.9; MgSO4 1.2; KH2PO4 1.2;
NaHCO3 25; glucose 11.5.
1H, NH), 6.69 (s, 1H, NH), 5.74 (s, 2H, NH2), 4.62–4.48
(m, 1H, CH), 3.60 (dd, 1H, J l 12.0, 8.9, C2-H2a), 3.15
(dd, 1H, J l 12.0, 7.1, C2-H2b), 2.86–2.82, 2.49–1.83,
1.59–1.41 (3m, 11H, CH2 pip, C4-H2); 13C NMR (d6-
DMSO) δ: 169.3 (CO), 159.9 (C1), 76.5 (C3), 63.2 (C4),
53.75 (C2), 53.34, 28.59 (CH2 pip), 41.68 (CH pip);
Calculated for C10H18N4O2 : C, 53.10; H, 7.96; N, 24.78;
Found: C, 52.81; H, 7.79; N, 24.52%.
5-[(1-Indolinyl)methyl]-2-amino-2-oxazoline (1j)
1
−
White powder (22%); mp 73mC; IR (KBr) ν: 1684 cm
(CN); H NMR (CDCl3) δ: 7.08–6.44 (m, 4H, H-Ar),
1
After 1 h of equilibration with washing every 15 min,
the resting load was between 1 and 2 g. Under these
conditions, the responses obtained were reproducible.
4.82–4.72 (m, 1H, CH), 4.58–4.52 (m, 2H, NH2), 3.84
(dd, 1H, J l 12.1, 8.9, C2-H2a), 3.53–2.93 (m, 7H, C2-
H2b, N-CH2,Ar-CH2); 13C NMR (CDCl3) δ: 160.7 (C1),
152.26, 129.58, 127.31, 124.54, 117.99, 106.75 (C-Ar),
78.93 (C3), 55.81 (C4), 54.56 (N-C5 indol), 53.84 (C2),
28.74 (C6 indol). Calculated for C12H15N3O : C, 66.34;
H, 6.96; N, 19.34; Found: C, 66.30; H, 6.99; N, 19.31%.
Cumulative concentration–response curves to hista-
7
mine dihydrochloride (10 –10 3 ) or acetylcholine
−
−
8
(10 –10 3 ) were performed after 10 min incubations
−
−
with the tested compounds at 10 6 . The Emax and
−
klogEC50 were determined from cumulative concen-
tration response curves. Emax was defined as the maxi-
mal response to histamine or acetylcholine 10 3 .
5-[(1-Indolyl)methyl]-2-amino-2-oxazoline (1k)
−
1
−
White powder (26%); mp 111mC; IR (KBr) ν: 1682 cm
(CN); H NMR (CDCl3) δ: 7.67–7.09 (m, 4H, H-Ar),
klogEC50 was defined as the klog concentration of
acetylcholine or histamine which induces 50% of the
maximal response. Results are expressed as meanp
s.e.m. Statistical comparison with the paired control
was performed using paired Student’s t-test with P !
0.05 being considered significant.
1
7.12 (d, 1H, J l 3.1, ꢀCHa), 6.53 (d, 1H, J l 3.1,
ꢀCHb), 5.03 (s, 2H, NH2), 4.91–4.80 (m, 1H, CH),
4.32–4.19 (m, 2H, C4-H2), 3.80 (dd, 1H, J l 12.4, 8.9,
C2-H2a), 3.47 (dd, 1H, J l 12.4, 6.26, C2-H2b); 13C
NMR (CDCl3) δ: 160.6 (C1), 136.28, 128.58, 121.79,
121.12, 119.67, 109.20 (C-Ar), 128.06 (ꢀCHa), 101.99
(ꢀCHb), 78.7 (C3), 55.44 (C4), 49.52 (C2). Calculated
for C12H13N3O : C, 66.96; H, 6.09; N, 19.52; Found: C,
66.40; H, 6.36; N, 19.31%.
Drugs were acetylcholine chloride and histamine di-
hydrochloride (Sigma, St Louis, MO). Depending on
the requirement, drugs were dissolved in distilled water
or ethanol and then diluted in Krebs solution.
5-[(2-Methyl-1-indolyl)methyl]-2-amino-2-oxazoline
(1l)
Results
1
−
White powder (29%); mp 88mC; IR (KBr) ν 1698 cm
(CN); H NMR (CDCl3) δ: 7.55–7.04 (m, 4H, H-Ar),
Chemistry
1
6.27 (s, 1H, ꢀCH), 4.95 (s, 2H, NH2), 4.93–4.81 (m, For the synthesis of target heterocycles, the reaction
1H, CH), 4.24 (dd, 1H, J l 15.4, 8.3, C4-H2a), 4.11 (dd, sequences outlined in Figure 1 were followed. Treatment
1H, J l 15.4, 4.3, C4-H2b), 3.83 (dd, 1H, J l 12.5, 8.8, of appropriate dialkylamines with epichlorhydrin in

926
J. J. Bosc et al
ethanol led to the 1-dialkylamino-2,3-epoxypropanes, of the concentration–response curve to histamine. This
2, via 1-chloro-3-dialkylaminopropan-2-ols (Heywood antagonism was selective of histamine since no antag-
& Phillips 1958, Jarry et al 1986). The epoxydes, 2, were onistic effect of these compounds on acetylcholine-
converted into the corresponding 5-dialkylamino- induced contraction was observed.
methyl-2-amino-2-oxazolines 1a–l by condensation with
Compound 1f induced an increase in acetylcholine
monosodium cyanamid salt performed in methanol. Emax and a shift to the left of the concentration–response
The IR and NMR spectra of all compounds were in curve. However, the increase of the maximal response to
1
agreement with the proposed structures. In the H acetylcholine induced by 1f makes it unlikely that the
NMR spectra, the protons at C-2 and C-3 formed a potentiation is due to cholinesterase inhibition. Indeed
characteristicABXsystem, theC-5methineHwasfound in that case, only a leftward shift of the acetylcholine
at about 5 ppm.
concentration–response curve is observed without
Different substituents or heterocycle moieties were change in the maximal response. Moreover, the lack of
defined to increase the lipophilicity of the molecules in effect of this compound on histamine-induced contrac-
comparison with the non-substituted compound 1a. On tion rules out a non-selective potentiation of the con-
the other hand, the amidine function in the 2-amino-2- traction mechanisms.
oxazoline ring represents a basic centre predominantly
The other tested 2-amino-2-oxazolines induced no
protonated at physiological pH, capable of an H- change of either acetylcholine or histamine concen-
bonding interaction with any potential receptor. The tration–response curves.
measured pKa values range from 8.81 to 9.75 for the
amidine basic centre (Demontes-Mainard et al 1992).
Discussion
Pharmacology
In terms of structure–activity relationships only pre-
All 5-dialkylaminomethyl-2-amino-2-oxazolines, 1a–l, liminary results were attained, the number of tested
were tested as H1-receptor antagonists. Significant re- compounds being too limited to draw a definitive con-
sults are summarized in Table 1. No effect was observed clusion. No activity was found for the non-substituted
for any compound on baseline tension. Compounds 1c, piperidinyl compound 1a, nor for the related tetra-
1d and 1j significantly antagonized histamine-induced hydropyridine 1i, suggesting an influence of the sub-
contraction of guinea-pig trachea with a rightward shift stitution on the piperidinyl ring. Of the 5-piperidinyl-
Table 1 Effect of 5-dialkylaminomethyl-2-amino-2-oxazolines 1a–l on guinea-pig trachea, determined
7
from the cumulative response curves to histamine (10 –10 3  histamine dihydrochloride) or acetylcholine
−
−
(10 –10 3 ).
8
−
−
Compound
Histamine
Acetylcholine
Emax
klog EC50
Emax
klog EC50
Control
1a
1911p106 (n l 25)
1811p377
1940p280
1389p49*
1508p168*
2392p365
1363p335
1794p239
1958p439
1602p89*
1424p171
1562p273
1160p152
5.36p0.07
5.18p0.12
5.32p0.06
4.99p0.17*
5.08p0.15*
5.57p0.13
5.77p0.31
4.22p0.04
4.06p0.13
5.34p0.11
3.75p0.23*
5.52p0.19
5.35p0.40
2098p173 (n l 28)
2377p406
2774p367
2609p401
2932p266
3324p467
2516p243*
1772p684
1853p321
2931p344
2021p368
1262p302
1464p440
5.55p0.12
5.17p0.37
5.89p0.18
5.03p0.49
5.11p0.42
5.77p0.47
6.65p0.37*
5.59p0.94
4.54p0.54
5.24p0.37
5.50p0.56
5.46p1.14
5.56p0.31
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
*P ! 0.05 vs paired control; n l 6 per group.

927
5-Dialkylaminomethyl-2-amino-2-oxazolines as H1-antagonists
Bosc, J. J., Jarry, C. (1998) 2-Amino-2-oxazolines IX: synthesis and
pharmacological evaluation of N-phenyl-Nh-[1-o3-(1-phenyl-4-
piperazinyl) propane-2-olq]ureas. Arch. Pharm. 331: 291–293
Bosc, J. J., Jarry, C., Carpy, A., Panconi, E., Descas, P. (1992)
Synthesis and antidepressant activity of 5-(1-aryl-4-piperazino)-
methyl-2-amino-2-oxazolines. Eur. J. Med. Chem. 27: 437–442
Chaimbault, C., Bosc, J. J., Jarry, C. (1999) Synthesis, antitumor and
anti-HIV screening of oxazolidines and oxazolidinones derivatives.
Pharm. Pharmacol. Comm. 5: 211–215
methyl-2-amino-2-oxazolines, only a methyl and a ben-
zyl substituent were found to favour antagonism of the
histamine-induced contraction. These results could be
estimated in terms of lipophilicity (1f, log P l 2.38; 1i,
log P l 0.19) (Pehourcq et al 2000). Moreover, the
substitution position on the piperidinyl ring was found
to have influence in the three methyl-substituted isomers
1b, 1c and 1d.
Demontes-Mainard, F., Tranchot, J., Cambar, J., Jarry, C. (1992)
Synthesis of some 5-dialkylaminomethyl-2-amino-2-oxazolines and
evaluation of their diuretic activity. Arch. Pharm. (Weinheim) 325:
193–198
The two related compounds 1k and 1l, on the other
hand, were poorly active, in contrast to their hydro-
genated counterpart 1j, that induced an increase in
acetylcholine Emax and a shift to the left of the concen-
tration–response curve. These results cannot be simply
estimated in terms of lipophilicity.
Forfar, I., Jarry, C., Laguerre, M., Leger, J. M., Pianet, I. (1999)
Reaction between 2-amino-2-oxazoline and N-benzyl-3-ethox-
carbonyl-4-piperinone hydrochloride: a structural investigation.
Tetrahedron 55: 12819–12828
In conclusion, a mild antihistaminic effect of some
5-dialkylaminomethyl-2-amino-2-oxazolines (1a–l) was
noticed during this study. Nevertheless, this was ob-
Heywood, D. L., Phillips, B. (1958) The reaction of epichlorhydrin
with secondary amines. J. Am. Chem. Soc. 80: 1257–1259
Jarry, C., Golse, R., Panconi, E., Creuzet, M. H. (1986) Synthesis and
pharmacological properties of some 5-dialkylaminomethyl-2-
amino-2-oxazolines. Eur. J. Med. Chem. 21: 138–142
served at a relatively too high concentration (10 6 ),
−
compared with other available antihistaminic tools, to
deserve further investigation.
Pehourcq, F., Thomas, J., Jarry, C. (2000) A microscale HPLC
method for the evaluation of octanol–water partition coefficients in
a series of new 2-amino-2-oxazolines. J. Liq. Chrom. & Rel. Technol.
23: 443–453
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