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F. Parra-Ruiz et al. / European Journal of Medicinal Chemistry 46 (2011) 4980e4991
for 2 h. The solvent was evaporated at reduced pressure and the
solid dissolved in dichloromethane. The NaBr salt was filtered and
the reaction product isolated by solvent evaporation at reduced
pressure. NM was obtained as a white solid. The reaction yield was
reduced pressure, giving the monomer HK as a waxy solid with
a reaction yield of 99%. 1H NMR (300 MHz, CDCl3)
(ppm): 7.70e7.56
(m, 3H, Ar), 7.52e7.39 (m, 2H, Ar), 7.40e7.21 (m, 3H, Ar), 7.11 (t, 1H,
d
J
¼
7.4 Hz, Ar), 6.10 (s, 1H, COCH3
¼
CHaH), 5.63 (s, 1H,
99%. 1H NMR (300 MHz, CDCl3)
d
(ppm): 10.71 (s, 1H, NH), 8.13 (d,
OCOCH3 ¼ CHbH), 4.59 (s, 2H, NþCH2), 4.06 (s, 2H, CO2CH2), 3.75e3.32
(m þ s, 9H, ArCH CO2ꢀ, NþCH2eCH2e(CH2)13eCH3), NþMe2), 1.90 (s,
3H, OCOCCH3), 1.70 (m, 2H, NþCH2eCH2e(CH2)13eCH3), 1.60e1.1 (m,
29H, NþCH2eCH2e(CH2)13eCH3, ArCHCH3COꢀ2 , 0.84 (t, J ¼ 6.6 Hz,
1H, J ¼ 7.3 Hz, Ar), 7.84e7.55 (m, 4H, Ar), 7.55e7.37 (m, 2H, Ar),
7.37e7.20 (m, 1 H, Ar), 7.07 (d, 1H, J ¼ 8.4 Hz, Ar), 6.93 (t, 1H,
J ¼ 7.4 Hz, Ar), 6.85 (d, 1H, J ¼ 7.9 Hz, Ar), 6.45 (t, 1H, J ¼ 7.0 Hz, Ar),
6.13 (d, 1H, J ¼ 8.4 Hz, Ar), 5.93 (s, 1H, COCCH3 ¼ CHaH), 5.40 (s, 1H,
OCOCCH3 ¼ CHbH), 4.75 (s, 2H, NþCH2), 4.52 (s, 2H, ArCH2), 3.76 (s,
2H, CO2CH2), 3.08 (s, 6H, NþMe2), 2.18 (s, 3H, ArCH3), 1.72 (s, 3H,
NþCH2e(CH2)14eCH3).13C NMR (75 MHz, CDCl3)
d (ppm): 197.3,180.4,
166.2, 145.2, 137.2, 137.1, 135.0, 132.4, 132.1, 130.1, 128.7, 128.1, 127.7,
127.3, 65.3, 62.1, 58.1, 51.8, 48.3, 31.8, 29.6, 29.5, 29.4, 29.3, 29.2, 26.2,
OCOCCH3). 13C NMR (75 MHz, CDCl3)
d
(ppm): 175.6, 166.9, 146.7,
22.8, 22.6,19.3,18.2,14.0. IR (
O),1496 and 1449(n CeC inthearomaticringand alkyl groups). HRMS
n n n C]
max/cmꢀ1): 29557 ( NþR4),1718 (
137.3, 136.4, 135.1, 134.2, 134.1, 133.1, 132.8, 131.3, 131.1, 129.4, 129.3,
128.9, 127.9, 127.8, 127.6, 127.1, 124.4, 120.4, 117.7, 113.2, 69.9, 62.9,
(ESIþ) m/z [Mþ] for C24H48O2, 382.3680, found, 382.3694. HRMS (ESIꢀ)
m/z [MꢀHꢀ] for C14H10Cl2NO2, 294.0094, found, 294.0088.
58.5, 50.8, 20.9, 18.5. IR (n n n C]O),
max/cmꢀ1): 3059 ( NþR4), 1718 (
1496 and 1449 (n CeC in the aromatic ring and alkyl groups). HRMS
(ESIþ) m/z [Mþ] for C19H24NO2, 298.1802, found, 298.1806.
2.4. Polymerization reactions
2.3.5. N,N-dimethyl-N-(2-methylenenaphthyl)-N-(2-
methacryloyloxyethyl) ammonium ketoprofenate (NK)
The polymers poly-BM, poly-BK, poly-BI, poly-NK, poly-HK were
obtained in DMF solution (1M) at 50 ꢁC, using AIBN (0.5 wt-% with
respect to monomer) as a free radical initiator, and reaction time of
24 h to render high conversion polymers. At the end of the reaction,
the medium was dialyzed in distilled water; the solid was lyophi-
lized and dried until constant weight under vacuum.
To a solution of NBrꢀ (1.32 mmol) in chloroform (20 mL) SK
(1.32 mmol) was added at room temperature and the solution
stirred for 2 h. The suspension was filtered and the solvent evap-
orated at reduced pressure giving the monomer NK as a white solid
with a reaction yield of 99%. 1H NMR (300 MHz, CDCl3)
d (ppm):
8.10 (s, 1H, Ar), 8.01e7.60 (m, 5H, Ar), 7.60e7.28 (m, 6H, Ar),
7.28e7.16 (m, 2H, Ar), 7.12 (d, 1H, J ¼ 7.4 Hz, Ar), 6.96 (t, 1H,
J ¼ 7.8 Hz, Ar), 6.02 (s, 1H, COCCH3 ¼ CHaH), 5.51 (s, 1H,
OCOCCH3 ¼ CHbH), 5.26 (s, 2H, ArCH2), 4.60 (s, 2H, CO2CH2), 4.11 (s,
2H, NþCH2), 4.0 (c, 1H, J ¼ 6.8 Hz, CH), 3.31 (s, 6H, NþMe2), 1.80 (s,
3H, OCOCCH3), 1.13 (d, J ¼ 6.8 Hz, CHCH3). 13C NMR (75 MHz, CDCl3)
2.4.1. Poly-BM
1H NMR (400 MHz, CDCl3)
d
(ppm): 7.92 (d, 1H, J ¼ 8.0 Hz,
Ar), 7.50e7.20 (m, 5H, Ar), 7.18 (d, 1H, J ¼ 7.7 Hz, Ar), 7.0 (d, 2H,
J ¼ 8. Hz, Ar), 6.59 (t, 1H, J ¼ 7.7 Hz, Ar), 6.15 (d, 1H, J ¼ 8.2 Hz,
Ar), 4.80 (bs, 2H, ArCH2), 4.57 (bs, 2H, NþCH2), 3.82 (bs, 2H,
CO2CH2), 3.04 (bs, 6H, NþMe2), 2.27 (s, 3H, ArCH3), 1.16 (bs, 3H,
d
(ppm): 197.3, 181.2, 166.2, 145.4, 137.1, 137.0, 134.9, 133.9, 133.7,
132.7,132.4, 132.1, 130.1, 129.2, 129.0, 128.7, 128.4, 128.0, 127.7, 127.6,
127.7, 126.9, 124.2, 68.8, 62.2, 58.0, 50.1, 48.5, 19.3, 18.2. IR ( max/
CeC in the
OCOCCH3). 13C NMR (100 MHz, CDCl3)
d (ppm): 176.3, 173.4,
n
145.4, 135.8, 135.7, 132.5, 131.0, 130.8, 130.3, 129.7, 128.6, 128.5,
128.3, 127.1, 126.3, 120.0, 116.8, 116.3, 113.1, 112.6, 68.5, 61.6, 58.5,
49.0, 44.7, 19.6.
cmꢀ1): 2968 ( NþR4), 1722 (
n n C]O), 1481 and 1445 (n
aromatic ring and alkyl groups). HRMS (ESIþ) m/z [Mþ] for
C19H24NO2, 298.1802, found, 248.1806.
2.4.2. Poly-BK
2.3.6. N,N-dimethyl-N-(2-hexadecyl)-N-(2-methacryloyloxyethyl)
ammonium meclofenamate (HM)
1H NMR (400 MHz, CD3OD)
d (ppm): 7.78 (s, 1H, Ar), 7. 67 (d, 1H,
J ¼ 6.5 Hz, Ar), 7.64e7.26, (m, 12H Ar), 4.67 (bs, 2H, ArCH2), 4.50 (s,
2H, NþCH2), 3.88 (s, 2H, CO2CH2), 3.62 (c, 1H, J ¼ 6.6 Hz, CH), 3.09
(bs, 6H, NþMe2), 1.41 (d, 3H, J ¼ 6.7 Hz, CHCH3), 1.14 (bs, 3H,
To a solution of HIꢀ (1.12 mmol) in chloroform (20 mL) SM was
added at room temperature (1.12 mmol) and the solution stirred for
2 h. The suspension was filtered and the solvent evaporated at
reduced pressure giving the monomer HM as a waxy solid with
OCOCCH3). 13C NMR (100 MHz, CD3OD)
d (ppm): 198.7, 181.5, 178.0,
146.3, 138.7, 138.5, 134.3, 133.8, 133.3, 132.0, 131.0, 130.4, 130.0,
129.5, 129.2, 128.9, 128.6, 69.8, 63.5, 60.1, 50.8, 50.3, 46.5, 20.2.
a reaction yield of 99%. 1H NMR (300 MHz, CDCl3)
d (ppm): 10.85 (s,
1H, NH), 8.12 (d, 1H, J ¼ 7.6 Hz, Ar), 7.16 (d, 1H, J ¼ 8.0 Hz, Ar), 6.97
(m, 2H, Ar), 6.54 (t,1H, J ¼ 8.0 Hz, Ar), 6.16 (d,1H, J ¼ 7.6 Hz, Ar), 5.98
(s, 1H, COCCH3 ¼ CHaH), 5.53 (s, 1H, OCOCCH3 ¼ CHbH), 4.42 (s, 2H,
NþCH2), 3.78 (s, 2H, CO2CH2), 3.25 (s, 8H, NþMe2,
NþCH2e(CH2)14eCH3), 2.27 (s, 3H, OCOCCH3), 1.82 (s, 3H, ArCH3),
1.60e1.1 (m, 26H, NþCH2eCH2(CH2)13eCH3), 0.86 (t, J ¼ 6.4 Hz,
2.4.3. Poly-BI
1H NMR (400 MHz, CD3OD)
d (ppm): 7.64e7.34 (bs, 5H, Ar), 7.23
(d, 2H, J ¼ 6.1 Hz, Ar), 6.96 (d, 2H, J ¼ 6.1 Hz, Ar), 4.65 (bs, 2H,
ArCH2), 4.49 (bs, 4H, NþCH2), 3.87 (bs, 2H, CO2CH2), 3.53 (c, 1H,
J ¼ 5.7 Hz, ꢀO2CeCHe(CH3)Ar), 3.07 (bs, 6H, NþMe2), 2.32 (d, 2H,
J ¼ 7.2 Hz AreCH2),1.74 (nona,1H, J ¼ 6.8 Hz, CH2eCHe(CH3)2), 1.36
(d, 2H, J ¼ 5.7 Hz, CHꢀ(CH3)Ar), 1.10 (bs, 3H, OCOCCH3), 0.81 (d, 2H,
NþCH2e(CH2)14eCH3). 13C NMR (75 MHz, CDCl3)
d (ppm): 174.8,
166.7, 146.6, 137.3, 136.6, 135.4, 134.0, 132.6, 131.4, 130.9, 128.0,
127.7, 120.3, 117.7, 113.3, 65.7, 62.6, 58.5, 52.4, 32.3, 30.1, 30.9, 30.0,
(CHꢀ(CH3))2). 13C NMR (100 MHz, CD3OD)
d (ppm): 182.2, 177.6,
29.9, 29.8, 29.6, 26.6, 23.2, 23.1, 21.0, 18.6, 14.6. IR (
3019 ( C]H), 1722 ( C]O), 1500 and
NþR4), 2917 and 2848 (
1453 (
n
max/cmꢀ1):
142.4, 140.0, 134.1, 131.8, 130.1, 129.6, 128.0, 69.5, 63.3, 60.1, 50.5,
46.2, 45.8, 31.1, 22.8, 20.2.
n
n
n
n
CeC in the aromatic ring and alkyl groups). HRMS (ESIþ) m/
z [Mþ] for C24H48NO2, 382.3680, found, 382.3681. HRMS (ESIꢀ) m/z
[MeHꢀ] for C16H13O3, 253.0864, found, 253.0870.
2.4.4. Poly-NK
1H NMR (400 MHz, CDCl3)
d (ppm): 8.02 (s, 1H, Ar), 7.72 (bs, 4H,
Ar), 7.61e7.25 (m, 10H, Ar), 7.20 (bs, 1H, Ar), 4.69 (bs, 6H, ArCH2,
NþCH2, CO2CH2), 3.61 (bs, 1H, CH), 3.12 (bs, 6H, NþMe2), 1.39 (bs,
3H, CHCH3), 1.18 (bs, 3H, OCOCCH3). 13C NMR (100 MHz, CDCl3)
d (ppm): 197.0, 179.6, 176.2, 144.5, 136.7, 136.5, 133.2, 132.2, 132.0,
131.6, 129.2, 128.2, 127.7, 127.4, 127.3, 126.6, 123.9, 68.2, 62.0, 60.0,
49.1, 44.7, 18.8.
2.3.7. N,N-dimethyl-N-(2-hexadecyl)-N-(2-methacryloyloxyethyl)
ammonium ketoprofenate (HK)
To a solution of HIꢀ (1.12 mmol) in chloroform (20 mL) SK
(1.12 mmol) was added at room temperature and the solution stirred
for 2 h. The suspension was filtered and the solvent evaporated at