Synthesis and SAR of Novel Retinoids
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16 3071
1300, 1280, 1223, 753 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.39
(s, 6H), 1.42 (s, 6H), 2.07 (s, 2H), 3.93 (s, 3H), 7.47 (t, J ) 7.8
Hz, 1H), 7.82 (dt, J ) 7.8, 1.4 Hz, 1H), 8.19 (m, 2H), 9.27 (s,
1H), 9.80 (s, 1H); 13C NMR (67.8 MHz, CDCl3) δ 29.6, 29.7,
40.2, 40.7, 52.3, 53.2, 120.7, 124.3, 125.6, 129.4, 131.0, 137.7
(2×), 142.6, 143.2, 161.7, 166.7, 168.0; MS (EI) m/z 353 (M+,
100), 203 (15), 175 (83); HRMS C20H23N3O3 calcd 353.1739
(M+), found 353.1743.
163.8, 167.3; MS (EI) m/z 367 (M+, 100), 248 (19), 189 (83),
173 (30); HRMS C21H25N3O3 calcd 367.1896 (M+), found
367.1916.
Meth yl 3-[(5,6,7,8-tetr a h yd r o-5,5,8,8-tetr a m eth yl-2-qu i-
n oxa lin yl)ca r boxa m id o]ben zoa te (9p ): mp 107-108 °C;
IR (KBr) 3357 (NH), 2952, 2867, 1716 (CO), 1697 (CO), 1539,
1
1426, 1226, 754 cm-1; H NMR (200 MHz, CDCl3) δ 1.34 (s,
6H), 1.39 (s, 6H), 1.83 (s, 4H), 3.92 (s, 3H), 7.45 (t, J ) 7.9 Hz,
1H), 7.80 (dt, J ) 7.9, 1.1 Hz, 1H), 8.13 (ddd, J ) 7.9, 2.2, 1.1
Hz, 1H), 8.19 (m, 1H), 9.21 (s, 1H), 9.72 (s, 1H); 13C NMR (67.8
MHz, CDCl3) δ 29.8, 30.0, 33.7, 33.8, 37.2, 37.8, 52.3, 120.5,
124.1, 125.6, 129.4, 131.1, 137.7, 140.5, 141.1, 156.7, 161.7,
162.8, 166.7; MS (EI) m/z 367 (M+, 21), 189 (100), 173 (18);
HRMS C21H25N3O3 calcd 367.1896 (M+), found 367.1911.
Dim eth yl 3-[(5,6,7,8-tetr a h yd r o-5,5,8,8-tetr a m eth yl-2-
q u in oxa lin yl)ca r b oxa m id o]isop h t h a la t e (9q ): mp 143-
145 °C; IR (KBr) 3346 (NH), 2961, 2867, 1730 (CO), 1693 (CO),
1539, 1245, 1140, 756 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.35
(s, 6H), 1.40 (s, 6H), 1.84 (s, 4H), 3.95 (s, 6H), 8.46 (t, J ) 1.5
Hz, 1H), 8.59 (d, J ) 1.5 Hz, 2H), 9.23 (s, 1H), 9.80 (br s, 1H);
13C NMR (67.8 MHz, CDCl3) δ 29.7, 30.0, 33.7, 33.8, 37.2, 37.8,
52.5, 124.6, 126.5, 131.5, 138.0, 140.2, 141.1, 156.8, 161.8,
163.1, 165.9; MS (EI) m/z 425 (M+, 13), 189 (100), 173 (20);
HRMS C23H27N3O5 calcd 425.1951 (M+), found 425.1952.
Meth yl 2-ch lor o-4-[(5,6,7,8-tetr ah ydr o-5,5,8,8-tetr am eth -
yl-2-qu in oxa lin yl)ca r boxa m id o]ben zoa te (9r ): mp 159-
161 °C; IR (KBr) 3346 (NH), 2867, 1733 (CO), 1701 (CO), 1576,
Dim eth yl 3-[(5,6-(1,1,3,3-tetr a m eth ylcyclop en ta n o)-2-
p yr a zin yl)ca r boxa m id o]isop h th a la te (9c): mp 168-169
°C; IR (KBr) 2956, 2870, 1730 (CO), 1694 (CO), 1540, 1436,
1
1248, 1240, 756 cm-1; H NMR (200 MHz, CDCl3) δ 1.40 (s,
6H), 1.43 (s, 6H), 2.08 (s, 2H), 3.96 (s, 6H), 8.84 (t, J ) 1.5 Hz,
1H), 8.63 (d, J ) 1.5 Hz, 2H), 9.28 (s, 1H), 9.89 (s, 1H); 13C
NMR (67.8 MHz, DMSO-d6) δ 29.6, 29.7, 40.3, 40.7, 52.5, 53.2,
124.7, 126.6, 131.6, 138.1, 142.3, 143.2, 161.9, 162.4, 166.0,
168.3; MS (EI) m/z 411 (M+, 97), 203 (21), 175 (100); HRMS
C
22H25N3O5 calcd 411.1794 (M+), found 411.1797.
Meth yl 2-ch lor o-4-[(5,6-(1,1,3,3-tetr a m eth ylcyclop en -
ta n o)-2-p yr a zin yl)ca r boxa m id o]ben zoa te (9d ): mp 143.5-
144.5 °C; IR (KBr) 3340 (NH), 2964, 2867, 1728 (CO), 1701
1
(CO), 1581, 1519, 1396, 1252, 1119, 771 cm-1; H NMR (200
MHz, CDCl3) δ 1.39 (s, 6H), 1.41 (s, 6H), 2.07 (s, 2H), 3.91 (s,
3H), 7.75 (dd, J ) 8.4, 2.0 Hz, 1H), 7.56 (d, J ) 2.0 Hz, 1H),
7.94 (d, J ) 8.4 Hz, 1H), 9.26 (s, 1H), 9.83 (s, 1H); 13C NMR
(67.8 MHz, CDCl3) δ 29.6, 29.7, 40.3, 40.7, 52.3, 53.2, 117.3,
121.6, 125.0, 132.9, 135.3, 141.2, 142.1, 143.3, 161.8, 162.3,
165.4, 168.5; MS (EI) m/z 389 (M+ + 2, 22), 387 (M+, 65), 203
(25), 175 (100); HRMS C20H22ClN3O3 calcd 387.1350 (M+),
found 387.1354.
1
1508, 1121, 774 cm-1; H NMR (200 MHz, CDCl3) δ 1.35 (s,
6H), 1.38 (s, 6H), 1.84 (s, 4H), 3.90 (s, 3H), 7.70 (dd, J ) 8.6,
2.3 Hz, 1H), 7.89 (d, J ) 2.3 Hz, 1H), 7.91 (d, J ) 8.6 Hz, 1H),
9.20 (s, 1H), 9.76 (br s, 1H); 13C NMR (67.8 MHz, CDCl3) δ
29.7, 29.9, 33.6, 33.7, 37.2, 37.8, 52.3, 117.1, 121.4, 124.8, 132.8,
135.3, 140.0, 141.1 (2×), 156.8, 161.7, 163.3, 165.3; MS (EI)
m/z 403 (M+ + 2, 31) 401 (M+, 92), 366 (18), 189 (100), 173
(17); HRMS C21H24ClN3O3 calcd 401.1506 (M+), found 401.1514.
Meth yl 4-ch lor o-3-[(5,6,7,8-tetr ah ydr o-5,5,8,8-tetr am eth -
yl-2-qu in oxa lin yl)ca r boxa m id o]ben zoa te (9s): mp 95-97
°C; IR (KBr) 3339 (NH), 2957, 2927, 1722 (s, CO), 1585, 1530,
Meth yl 4-ch lor o-3-[(5,6-(1,1,3,3-tetr a m eth ylcyclop en -
ta n o)-2-p yr a zin yl)ca r boxa m id o]ben zoa te (9e): mp 130-
131 °C; IR (KBr) 3350 (NH), 2965, 2862, 1721 (CO), 1708 (CO),
1
1589, 1531, 1307, 1252, 1259, 759 cm-1; H NMR (200 MHz,
CDCl3) δ 1.40 (s, 6H), 1.41 (s, 6H), 2.08 (s, 2H), 3.93 (s, 3H),
7.64 (d, J ) 8.4 Hz, 1H), 7.78 (dd, J ) 8.4, 2.0 Hz, 1H), 9.27
(s, 1H) 9.28 (d, J ) 2.0 Hz, 1H), 10.59 (s, 1H); 13C NMR (67.8
MHz, CDCl3) δ 29.6, 29.7, 40.2, 40.8, 52.4, 53.1, 121.7, 125.9,
127.9, 129.3, 130.0, 134.6, 142.6, 143.0, 161.7, 162.3, 166.2,
168.2; MS (EI) m/z 389 (M+ + 2, 8), 387 (M+, 22), 352 (100),
203 (5), 175 (58); HRMS C20H22ClN3O3 calcd 387.1350 (M+),
found 387.1345.
Met h yl 4-m et h oxy-3-[(5,6-(1,1,3,3-t et r a m et h ylcyclo-
pen tan o)-2-pyr azin yl)car boxam ido]ben zoate (9f): mp 198-
200 °C; IR (KBr) 3350 (NH), 2964, 2864, 1713 (CO), 1696 (CO),
1606, 1548, 1268, 764 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.39
(s, 6H), 1.40 (s, 6H), 2.06 (s, 2H), 3.89 (s, 3H), 4.01 (s, 3H),
6.95 (d, J ) 8.7 Hz, 1H), 7.85 (dd, J ) 8.7, 2.1 Hz, 1H), 9.20
(d, J ) 2.1 Hz, 1H), 9.26 (s, 1H), 10.42 (s, 1H); 13C NMR (67.8
MHz, CDCl3) δ 29.6, 29.7, 40.1, 40.7, 52.0, 53.2, 56.2, 109.6,
120.8, 123.2, 126.6, 127.1, 143.0, 143.2, 152.2, 161.5, 162.1,
166.9, 167.5; MS (EI) m/z 383 (M+, 100), 352 (22), 203 (6), 190
(17), 175 (56); HRMS C21H25N3O4 calcd 383.1845 (M+), found
383.1849.
1
1304, 1230, 1107 cm-1; H NMR (200 MHz, CDCl3) δ 1.36 (s,
6H), 1.40 (s, 6H), 1.85 (s, 4H), 3.92 (s, 3H), 7.50 (d, J ) 8.4
Hz, 1H), 7.76 (dd, J ) 8.4, 2.4 Hz, 1H), 9.22 (s, 1H), 9.29 (d, J
) 2.4 Hz, 1H), 10.60 (s, 1H); 13C NMR (67.8 MHz, CDCl3) δ
29.7, 29.9, 33.6, 33.9, 37.3, 37.8, 52.4, 121.5, 125.7, 127.6, 129.2,
130.0, 134.6, 140.4, 140.9, 156.9, 161.6, 163.1, 166.1; MS (EI)
m/z 403 (M+ + 2, 10) 401 (M+, 29), 366 (100), 189 (47); HRMS
C
21H24ClN3O3 calcd 401.1506 (M+), found 401.1514.
Meth yl 4-m eth oxy-3-[(5,6,7,8-tetr a h yd r o-5,5,8,8-tetr a -
m eth yl-2-qu in oxa lin yl)ca r boxa m id o]ben zoa te (9t): mp
197-198 °C; IR (KBr) 3350 (NH), 2918, 2867, 1716 (CO), 1694
(CO), 1545, 1129, 1213, 764 cm-1; 1H NMR (200 MHz, CDCl3)
δ 1.36 (s, 6H), 1.39 (s, 6H), 1.85 (s, 4H), 3.89 (s, 3H), 4.01 (s,
3H), 6.96 (d, J ) 8.5 Hz, 1H), 7.85 (dd, J ) 8.5, 2.1 Hz, 1H),
9.20 (d, J ) 2.1 Hz, 1H), 9.21 (s, 1H), 10.48 (s, 1H); 13C NMR
(67.8 MHz, CDCl3) δ 29.7, 29.8, 33.6, 33.9, 37.2, 37.7, 52.0,
56.2, 109.5, 120.4, 123.2, 126.5, 127.2, 140.8, 141.0, 152.0,
156.6, 161.4, 162.5, 166.9; MS (EI) m/z 397 (M+, 100), 366 (23),
190 (71), 189 (50), 173 (17); HRMS C22H27O4N3 calcd 397.2001
(M+), found 397.2003.
Met h yl 3-m et h oxy-4-[(5,6-(1,1,3,3-t et r a m et h ylcyclo-
p en t a n o)-2-p yr a zin yl)ca r b oxa m id o]b en zoa t e (9g): mp
219-219.5 °C; IR (KBr) 3328 (NH), 2963, 2867, 1702 (CO),
1
1697 (CO), 1606, 1545, 1451, 1286, 1278, 761 cm-1; H NMR
Gen er a l Meth od for Meth yl Ester Clea va ge.42 To a
suspension of 1 equiv of methyl benzoates in anhydrous
dimethoxyethane were added 8.6 equiv of potassium tert-
butoxide and 2.2 equiv of water. The suspension was refluxed
for 12 h and then cooled and water added. The aqueous layer
was washed with ether, acidified with concentrated HCl, and
then extracted with ether. The organic phases were combined,
dried (MgSO4), and concentrated in vacuo. Purification was
accomplished by flash chromatography using CH2Cl2/MeOH:
AcOH; 200:4:0.5. Yields varied between 82 and 97%.
4-[(5,6-(1,1,3,3-Tet r a m et h ylcyclop en t a n o)-2-p yr a zin -
yl)ca r boxa m id o]ben zoic a cid (9h ): mp 243.5-245 °C dec;
IR (KBr) 3300 (NH), 3200-2400 (br, COOH), 2964, 2852, 1684
(200 MHz, CDCl3) δ 1.39 (s, 6H), 1.40 (s, 6H), 2.07 (s, 2H),
3.90 (s, 3H), 4.01 (s, 3H), 7.59 (d, J ) 1.6 Hz, 1H), 7.74 (dd, J
) 1.6, 8.4 Hz, 1H), 8.64 (d, J ) 8.4 Hz, 1H), 9.24 (s, 1H), 10.62
(s, 1H); 13C NMR (67.8 MHz, CDCl3) δ 29.6, 29.7, 40.1, 40.7,
52.1, 53.1, 56.3, 111.0, 118.6, 123.5, 125.4, 131.7, 143.0 (2×),
148.2, 161.7, 162.2, 166.8, 167.7; MS (EI) m/z 383 (M+, 100),
352 (20), 203 (7), 190 (15), 175 (67); HRMS C21H25N3O4 calcd
383.1845 (M+), found 383.1848.
Meth yl 4-[(5,6,7,8-tetr a h yd r o-5,5,8,8-tetr a m eth yl-2-qu i-
n oxa lin yl)ca r boxa m id o]ben zoa te (9o): mp 125-126 °C;
IR (KBr) 3350 (NH), 2929, 2867, 1716 (CO), 1712 (CO), 1591,
1
1532, 1275, 768 cm-1; H NMR (200 MHz, CDCl3) δ 1.35 (s,
6H), 1.39 (s, 6H), 1.84 (s, 4H), 3.90 (s, 3H), 7.81 (d, J ) 8.7
Hz, 2H), 8.07 (d, J ) 8.7 Hz, 2H), 9.22 (s, 1H), 9.82 (s, 1H);
13C NMR (67.8 MHz, CDCl3) δ 30.5, 30.7, 34.4, 34.5, 38.0, 38.6,
52.8, 119.7, 126.7, 131.7, 141.1, 141.9, 142.3, 157.5, 162.4,
(s, CO), 1592, 1527, 1297, 1171 cm-1 1H NMR (200 MHz,
;
CDCl3) δ 1.40 (s, 6H), 1.41 (s, 6H), 2.07 (s, 2H), 7.88 (d, J )
8.5 Hz, 2H,), 8.13 (d, J ) 8.5 Hz, 2H), 9.28 (s, 1H), 9.91 (s,