Inhibitors of Prostaglandin Endoperoxide Synthases
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 8 1701
(bs, 2H NH2), 7.6 (d, 1H, ArH), 7.5 (t, 1H, ArH), 7.2 (t, 1H,
ArH), 7.0 (d, 1H, ArH), 4.3 (t, 2H, CH2), 3.1 (t, 2H, CH2); EIMS
M+ 182 (40), 164 (32), 133 (100). Anal. (C9H12ClNO3) C, H,
N.
8.41 mmol), and the reaction mixture was stirred at 0 °C for
1 h and subsequently at room temperature for 2 h. The
reaction mixture was diluted with cold water and treated
dropwise with cold 10% NaOH until a pH of 9 was obtained.
The aqueous solution was extracted with Et2O (3 × 60 mL).
The combined ether extracts were dried (Na2SO4) and filtered,
and the solvent was removed in vacuo to afford a white solid
which was recrystallized from CH3OH/Et2O to yield pure 40
as a crystalline white solid in 69% yield: mp 161-162 °C; 1H
NMR (CDCl3) δ 5.6 (bs, 1H, NH), 3.3 (q, 2H, CH2N), 2.2 (t, 2
H, methylene adjacent to CO), 1.7 (m, 2H, methylene), 1.3-
1.6 (m, 12H, methylenes); EI-MS M+ 169 (100), 125 (65), 112
(67).
10-Am in o-1-d eca n oic Acid H yd r och lor id e Sa lt (48‚
HCl). A reaction mixture containing 40 (0.1 g, 0.6 mmol) in
5 mL of concentrated HCl was heated in a sealed tube at 100
°C for 4 days. The reaction mixture was cooled and diluted
with water to precipitate unreacted starting material. The
mixture was filtered, and the aqueous solution was evaporated
in vacuo. The residue was recrystallized from CH3OH/Et2O
to afford 48‚HCl as a white crystalline solid (30 mg, 20%): mp
157-159 °C; 1H NMR (DMSO-d6) δ 7.7 (bs, 2H, NH2), 2.77 (q,
2H, CH2 adjacent to NH2), 2.2 (t, 2H, CH2 adjacent to COOH),
1.49 (m, 4H, methylenes), 1.24 (complex multiplet, 10H,
methylenes); FAB-MS 188 (MH+ - HCl). Anal. (C10H22ClNO2)
C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of N-(Ca r boxy-
h ep tyl)m a leim id e Der iva tives. A reaction mixture con-
taining the appropriate maleic anhydride (1.25 mmol) and
8-aminocaprylic acid (55, 1.25 mmol) in 25 mL of glacial acetic
acid was refluxed for 10 h. The reaction mixture was cooled,
and acetic anhydride (2 mL) was added to the reaction mixture
which was refluxed for an additional 2 h. The solvent was
removed under reduced pressure, and the residue was chro-
matographed on silica gel and eluted with 40% EtOAc/hexane
to afford the desired maleimide which was recrystallized from
80% EtOH.
N-(Ca r b oxyh ep t yl)-3-b r om om a leim id e (56) was ob-
tained in 61% yield: mp 92-94 °C; 1H NMR (CDCl3) δ 6.6 (s,
1H, olefinic H), 3.5 (t, 2H, NCH2), 2.3 (t, 2H, CH2 adjacent to
COOH), 1.2-1.6 (m, 10H, methylenes); GC-EIMS (tempera-
ture program: 100-320 °C with a temperature ramp of 15
°C/min for 15 min) showed a single peak with tR ) 9.1 min;
m/z 317 (79Br, M•+) (10), 319 (81Br, M•+ + 2) (10), 190 (90), 123
(89), 55 (100). Anal. (C12H16BrNO4) C, H, N.
Ma lea m ic Acid (2). An aqueous solution of the (amino-
ethoxy)benzoic acid hydrochloride salt (38‚HCl, 0.72 g, 3.3
mmol) in 10 mL of water was neutralized with aqueous
potassium carbonate. The aqueous solution was evaporated
under pressure, and the resultant solid in 20 mL of glacial
acetic acid was treated with maleic anhydride (1, 0.32 g, 3.3
mmol). The reaction mixture was stirred overnight, and the
precipitated solid was filtered, washed with water, and dried.
The crude product was recrystallized from EtOH/H2O to afford
2 in 64% yield: mp 161-162 °C; 1H NMR (DMSO-d6) δ 9.3
(bs, 1H, NH), 7.4-7.7 (m, 2H, ArH), 7.0-7.3 (m, 2H, ArH),
6.4 (d, 1H, olefinic H), 6.2 (d, 1H, olefinic H), 4.2 (t, 2H, CH2),
3.6 (t, 2H, CH2); FABMS MH+ 280 (70), 262 (60), 164 (98),
133 (100). Anal. (C13H12NO6) C, H, N.
2-[2-(N-Ma leim id o)eth oxy]ben zoic Acid (19). A reaction
mixture containing 2 (730 mg, 2.6 mmol) in 8 mL of acetic
anhydride and sodium acetate (132 mg, 1.61 mmol) was heated
at 90 °C for 2 h. The reaction mixture was cooled and diluted
with water. The aqueous solution was extracted with Et2O
(3 × 25 mL). The combined organic solution was washed with
brine and then with water. The organic solution was dried
(MgSO4) and filtered, and the solvent was evaporated to afford
a yellow oil. The yellow oil was chromatographed on silica
gel and eluted with EtOAc/hexanes to afford essentially pure
19 as a white solid which was further recrystallized from
ethanol (0.21 g, 31%): mp 145-147 °C; 1H NMR (CDCl3) δ
8.2 (d, 1H, C6-H, ArH), 7.5-7.6 (t, 1H, C5-H, ArH), 7.2-7.3 (t,
1H, C4-H, ArH), 7.0 (d, 1H, C2-H, ArH), 6.7 (s, 2H, olefinic H),
4.4 (t, 2H, CH2), 4.2 (t, 2H, CH2); FABMS MH+ 262 (26), 244
(84), 124 (99), 79 (100). Anal. (C13H11NO5) C, H, N.
Seba cic Acid Ch lor id e Mon om eth yl Ester (43).
A
reaction mixture containing sebacic acid monomethyl ester (41,
0.5 g, 2.31 mmol) and thionyl chloride (0.55 g, 4.62 mmol) was
warmed to 50 °C and allowed to stir at that temperature for
3 h. The excess thionyl chloride was removed under reduced
pressure to afford essentially pure 43 as a colorless oil (0.54
g, 98%): 1H NMR (CDCl3) δ 3.64 (s, 3H, OCH3), 2.84 (t, 2H,
CH2 adjacent to COCl), 2.28 (t, 2H, methylene adjacent to
COOCH3), 1.28-1.7 (complex multiplet, 12 H, methylenes).
Un d eca n ed ioic a cid ch lor id e m on om eth yl ester (44)
was obtained in 96% yield: 1H NMR (CDCl3) δ 3.7 (s, 3H,
OCH3), 2.81 (t, 2H, methylene adjacent to COCl), 2.3 (t, 2H,
methylene adjacent to COOCH3), 1.24-1.8 (complex multiplet,
14 H, methylenes).
9-Isocya n o-1-m eth yln on a n oa te (45). To a solution of the
above acid chloride (43, 0.54 g, 2.31 mmol) in 10 mL of dry
xylene was added sodium azide (0.15 g, 2.34 mmol) and this
reaction mixture was heated under reflux for 2 h. The
insoluble residue was filtered off and the solvent was removed
under reduced pressure to afford 45 as a semisolid material
(0.47g, 97%): 1H NMR (CDCl3) δ 3.54 (s, 3H, OCH3), 3.26 (t,
2H, methylene adjacent to NCO), 2.3 (t, 2H, methylene
adjacent to COOCH3), 1.28-1.7 (complex multiplet, 12H,
methylenes).
N-(Ca r boxyh ep tyl)-3,4-d ich lor om a leim id e (57) was ob-
tained in 75% yield: mp 95-97 °C; 1H NMR (CDCl3) δ 3.6 (t,
2H, NCH2), 2.3 (t, 2H, CH2 adjacent to COOH), 1.24-1.63 (m,
10H, methylenes); GC-EIMS (temperature program: 100-
320 °C with a temperature ramp of 15 °C/min for 15 min)
showed a single peak with tR ) 9.1 min; m/z 307 (35Cl, M•+
)
(20), 309 (37Cl, M•+ + 2) (13), 311 (M•+ + 4), 178 (90), 123 (89),
55 (100). Anal. (C12H15Cl2NO4) C, H, N.
N-(Ca r b oxyh ep t yl)-3-p h en ylm a leim id e (58) was ob-
tained in 50% yield: mp 85-87 °C; 1H NMR (CDCl3) δ 7.9 (m,
2H, ArH), 7.4 (m, 3H, ArH), 6.7 (s, 1H, olefinic H), 3.55 (t, 2H,
NCH2), 2.3 (t, 2H, CH2 adjacent to COOH), 1.24-1.66 (m, 10H,
methylenes); GC-EIMS (temperature program: 100-320 °C
with a temperature ramp of 15 °C/min for 15 min) showed a
single peak with tR ) 7.6 min; m/z 297 (M - 18) (25), 186 (100),
103 (85), 91 (60), 55 (60). Anal. (C18H21NO4) C, H, N.
N-(Ca r boxyh ep tyl)-3,4-d ip h en ylm a leim id e (59) was ob-
tained in 32% yield: mp 110-111 °C; 1H NMR (CDCl3) δ 7.46
(m, 4H, ArH), 7.32 (m, 6 H, ArH), 3.62 (t, 2H, NCH2), 2.33 (t,
2H, CH2 adjacent to COOH), 1.24-1.66 (m, 10H, methylenes);
FAB-MS 392 (MH+). Anal. (C24H25NO4) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of Ha loa ceta m i-
d oca p r ylic Acid An a logs. A reaction mixture containing
8-aminocaprylic acid (55, 1.9 mmol) in 2 mL of 1 M NaOH at
0 °C was treated with the appropriate haloacetyl halide (2
mmol) dropwise, and the reaction mixture was stirred under
nitrogen overnight. The reaction mixture was diluted with
water and acidified with 1 N HCl. The aqueous solution was
extracted with Et2O (3 × 20 mL), the combined organic
solution was washed with water, dried (Na2SO4), and filtered,
and the solvent was removed in vacuo. The resultant oil was
Meth yl 10-isocya n od eca n oa te (46) was obtained in 97%
yield: 1H NMR (CDCl3) δ 3.6 (s, 3H, OCH3), 3.36 (t, 2H,
methylene adjacent to NCO), 2.3 (t, 2H, methylene adjacent
to COOCH3), 1.28-1.7 (complex multiplet, 14H, methylenes).
9-Am in o-1-n on a n oic Acid Hyd r och lor id e (47‚HCl). A
reaction mixture containing crude 45 (0.47 g, 2.2 mmol) in 4
mL of concentrated HCl was heated under reflux for 2.5 h.
The reaction mixture was cooled, and the solvent was removed
under reduced pressure to afford the crude hydrochloride salt
of 47 which was purified by recrystallization from CH3OH/
Et2O to afford the desired product as a white crystalline solid
1
in 64% yield: mp 133-134 °C; H NMR (DMSO-d6) δ 2.74 (t,
2H, methylene adjacent to NH2), 2.15 (t, 2H, methylene
adjacent to COOH), 1.2-1.52 (complex multiplet, 12H, meth-
ylenes). Anal. (C9H20ClNO2) C, H, N.
Aza cyclou n d eca n -2-on e (40). To a reaction mixture
containing cyclodecanone (39, 1 g, 6.4 mmol) in 10 mL of
concentrated H2SO4 at 0 °C was added sodium azide (0.54 g,