Nonpeptide Cyanoguanidines as HIV PR Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9 1453
gel provided the desired hydrogenated, reduced, or hydro-
genolysis product.
J ) 1.8, 13.6 Hz, 2H), 3.40 (br s, 2H), 3.55-3.65 (m, 4H), 3.94
(br, 2H), 7.16-7.37 (m, 10H); 13C NMR (CDCl3) δ 22.44, 26.18,
32.56, 36.92, 52.83, 66.59, 70.12, 126.83, 128.82, 129.31,
138.42, 162.81; HRMS-CI calcd for C30H43N4O2 [M + H]+
491.3386, found 491.3377. Anal. (C30H42N4O2) C, H, N.
[4R-(4r,5r,6â,7â)]-[H exa h yd r o-5,6-d ih yd r oxy-4,7-b is-
(p h en ylm et h yl)-2H -1,3-d ia zep in -2-ylid en e]u r ea , Q8188
(8a ). To a solution of 6 was added 4 M HCl in dioxane, and
the mixture stirred at room temperature for 15 min. TLC
indicated a complete reaction. The mixture was poured into
saturated sodium bicarbonate and extracted with dichlo-
romethane (3 × 25 mL). The organic layers were combined,
dried over MgSO4, filtered, concentrated, and purified by
chromatography to provide 8a in 35% yield as a white solid:
1H NMR (CDCl3 + CD3OD) δ 2.91 (dd, J ) 6, 12 Hz, 2H), 2.97
(dd, J ) 6, 12 Hz, 2H), 3.38 (br s, 2H), 3.81 (t, J ) 6 Hz, 2H),
4.85 (br s, 4H), 7.12-7.35 (m, 10H); 13C NMR (CDCl3 + CD3-
OD) δ 37.66, 54.18, 68.96, 126.32, 128.11, 128.28, 128.49,
129.19, 137.81, 161.65, 161.72, 161.74, 162.01, 162.03; HRMS-
CI calcd for C20H25N4O3 [M]+ 369.1926, found 369.1914. Anal.
(C20H24N4O3‚HCl) C, H, N.
[4R-(4r,5r,6â,7â)]-[1,3-Bis(cyclop r op ylm et h yl)h exa -
h yd r o-5,6-d ih yd r oxy-4,7-b is(p h en ylm et h yl)-2H -1,3-d ia -
zep in -2-ylid en e]cya n a m id e, Q8239 (8g). The compound 8g
was obtained from 6 by using the general procedure A in 45.9%
yield as a white solid: mp 211.2 °C; [R]D -104.4° (c 1.06,
DMSO); 1H NMR (CDCl3) δ 0.13-0.17 (m, 4H), 0.40-0.60 (m,
4H), 2.65 (dd, J ) 6.6, 14.1 Hz, 2H), 2.89-2.98 (m, 2H), 3.19
(dd, J ) 2.1, 13.5 Hz, 2H), 3.53 (dd, J ) 4.2, 14.1 Hz, 2H),
3.85-3.92 (m, 2H), 4.06 (br, 2H), 7.18-7.36 (m, 10H); 13C NMR
(CDCl3) δ 4.31, 4.52, 4.52, 10.30, 32.51, 59.24, 66.76, 70.30,
116.78, 126.95, 129.02, 129.50, 138.92, 162.89; HRMS-CI calcd
for C28H35N4O2 [M + H]+ 459.2760, found 459.2751. Anal.
(C28H34N4O2‚0.5H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-[H exa h yd r o-5,6-d ih yd r oxy-4,7-b is-
(p h e n ylm e t h yl)-1,3-d i-2-p r op e n yl-2H -1,3-d ia ze p in -2-
ylid en e]cya n a m id e, Q8244 (8b). The compound 8b was
obtained from 6 by using the general procedure A in 43.4%
yield as a white solid: mp 70.2 °C; [R]D +163.4°(c 1.16, DMSO);
1H NMR (CDCl3) δ 1.59 (br s, 2H), 2.71 (dd, J ) 11.4, 13.6 Hz,
2H), 3.17 (dd, J ) 2.6, 13.9 Hz, 2H), 3.38 (dd, J ) 7.7, 14.6
Hz, 2H), 3.67-3.77 (m, 2H), 3.88 (br s, 2H), 4.18 (dd, J ) 6.2,
14.3 Hz, 2H), 5.11 (dd, J ) 1.1, 8.4 Hz, 2H), 5.15 (d, J ) 0.7
Hz, 2H), 5.53-5.65 (m, 2H), 7.13-7.16 and 7.26-7.37 (m,
10H); 13C NMR (CDCl3) δ 32.68, 56.98, 65.17, 69.96, 116.24,
121.15, 127.04, 128.96, 129.53, 132.68, 138.32, 163.11; HRMS-
CI calcd for C26H31N4O2 [M + H]+ 431.2447, found 431.2432.
Anal. (C26H30N4O2‚0.5H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-[H exa h yd r o-5,6-d ih yd r oxy-4,7-b is-
(p h en ylm eth yl)-1,3-d ip r op yl-2H-1,3-d ia zep in -2-ylid en e]-
cya n a m id e, Q8259 (8c). The compound 8c was obtained
from 6 by using the general procedure A in 33.1% yield as a
white solid: mp 216.6 °C; [R]D -120.2°(c 0.96, DMSO); 1H NMR
(CDCl3) δ 0.82 (t, J ) 7 Hz, 6H), 1.15-1.35 (m, 4H), 2.53-
2.65 (m, 4H), 3.04 (dd, J ) 1.5, 13.5 Hz, 2H), 3.36-3.52 (m,
4H), 3.68 (s, 4H), 3.77 (br, 2H), 7.03-7.30 (m, 10H); HRMS-
CI calcd for C26H35N4O2 [M + H]+ 435.2751, found 435.2751.
Anal. (C26H34N4O2‚H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-[1,3-Bis(cyclobu tylm eth yl)h exah ydr o-
5,6-d ih yd r oxy-4,7-bis(p h en ylm eth yl)-2H-1,3-d ia zep in -2-
ylid en e]cya n a m id e, Q8258 (8h ). The compound 8h was
obtained from 6 by using the general procedure A in 27.1%
yield as a white solid: mp 235.5 °C; [R]D -114.7°(c 0.98,
1
DMSO); H NMR (CD3OD) δ 1.55-1.95 (m, 12H), 2.35-2.70
(m, 6H), 3.02 (dd, J ) 1.8, 13.5 Hz, 2H), 3.41-3.72 (m, 6H),
7.10-7.33 (m, 10H); 13C NMR (MeOD + CDCl3) δ 18.08, 27.90,
31.73, 34.54, 60.24, 67.20, 69.58, 116.24, 126.45, 128.55,
129.00, 138.54, 162.44; HRMS-CI calcd for C30H39N4O2 [M +
H]+ 487.3073, found 487.3053. Anal. (C30H38N4O2) C, H, N.
[4R-(4r,5r,6â,7â)]-[1,3-Bis(cyclop en tylm eth yl)h exa h y-
dr o-5,6-dih ydr oxy-4,7-bis(ph en ylm eth yl)-2H-1,3-diazepin -
2-ylid en e]cya n a m id e, Q8243 (8i). The compound 8i was
obtained from 6 by using the general procedure A in 24.7%
yield as a white solid: mp 99.7 °C; [R]D -59.7°(c 0.88, DMSO);
1H NMR (CDCl3) δ 1.08-1.17 (m, 4H), 1.43-1.80 (m, 14H),
2.04-2.08 (m, 2H), 2.53 (dd, J ) 5.9, 13.9 Hz, 2H), 2.90 (dd, J
) 11, 13.9 Hz, 2H), 3.11-3.17 (m, 2H), 3.82 (dd, J ) 8.1, 13.9
Hz, 2H), 3.98 (br s, 2H), 7.18-7.21 and 7.24-7.37 (m, 10H);
13C NMR (CDCl3) δ 25.47, 25.68, 32.01, 32.53, 39.34, 61.16,
67.69, 70.42, 116.53, 126.96, 129.06, 129.44, 138.94, 162.74;
HRMS-CI calcd for C32H43N4O2 [M + H]+ 515.3386, found
515.3370. Anal. (C32H42N4O2‚0.75H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-[1,3-Dibu tylh exah ydr o-5,6-dih ydr oxy-
4,7-bis(p h en ylm eth yl)-2H-1,3-d ia zep in -2-ylid en e]cya n a -
m id e, Q8245 (8d ). The compound 8d was obtained from 6
by using the general procedure A in 41.8% yield as a white
solid: mp 58.3 °C; [R]D -80.5°(c 1.04, DMSO); 1H NMR (CDCl3)
δ 0.81 (t, J ) 7 Hz, 6H), 1.15-1.25 (m, 2H), 1.38-1.42 (m,
4H), 1.59 (br s, 2H), 2.76 (dd, J ) 10.9, 13.5 Hz, 2H), 2.78-
2.85 (m, 2H), 3.16 (dd, J ) 2.2, 13.5 Hz, 2H), 3.54-3.62 (m,
4H), 3.96 (br s, 2H), 7.16-7.19 and 7.26-7.37 (m, 10H); 13C
NMR (CDCl3) δ 13.96, 20.38, 30.64, 32.81, 54.42, 67.11, 70.14,
116.60, 126.92, 128.95, 129.55, 138.86, 163.00; HRMS-CI calcd
for C28H39N4O2 [M + H]+ 463.3073, found 463.3054. Anal.
(C28H38N4O2‚1.2H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-[1,3-Bis(cycloh exylm eth yl)h exah ydr o-
5,6-d ih yd r oxy-4,7-bis(p h en ylm eth yl)-2H-1,3-d ia zep in -2-
ylid en e]cya n a m id e, Q8257 (8j). The compound 8j was
obtained from 6 by using the general procedure A in 37.6%
yield as a white solid: mp 96.4 °C; [R]D -37.0°(c 0.95, DMSO);
1H NMR (CDCl3) δ 0.85-1.95 (m, 22H), 2.35 (dd, J ) 4, 13
Hz, 2H), 2.83 (d, J ) 11.6, 13.5 Hz, 2H), 3.12-3.40 (m, 4H),
3.62-3.70 (m, 4H), 3.95 (br s, 2H), 7.10-7.45 (m, 10H); 13C
NMR (CDCl3) δ 26.11, 26.11, 26.32, 32.33, 32.47, 32.65, 37.39,
62.72, 68.20, 70.45, 116.25, 126.98, 129.08, 129.22, 129.43,
129.81, 138.99, 162.55; HRMS-CI calcd for C34H47N4O2 [M +
H]+ 543.3699, found 543.3696. Anal. (C34H46N6O2‚H2O) C, H,
N.
[4R-(4r,5r,6â,7â)]-[Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis(3-
m eth yl-2-bu ten yl)-4,7-bis(ph en ylm eth yl)-2H-1,3-diazepin -
2-ylid en e]cya n a m id e, Q8256 (8e). The compound 8e was
obtained from 6 by using the general procedure A in 55.7%
yield as a white solid: mp 72.9 °C; [R]D -165.7°(c 0.95, DMSO);
1H NMR (CDCl3) δ 1.47 (s, 6H), 1.66 (br s, 8H), 2.73 (dd, J )
11.7, 13.5 Hz, 2H), 3.14 (dd, J ) 1.83, 13.6 Hz, 2H), 3.40 (dd,
J ) 8.4, 14.6 Hz, 2H), 3.56-3.9 (m, 2H), 3.85 (br, 2H), 4.15
(dd, J ) 6.6, 14.65 Hz, 2H), 4.99-5.04 (m, 2H), 7.15-7.38 (m,
10H); 13C NMR (CDCl3) δ 17.99, 26.18, 32.65, 51.63, 65.52,
70.34, 116.69, 118.80, 126.85, 128.91, 129.51, 138.73, 138.91,
163.07. Anal. (C30H38N4O2‚0.5H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-[H exa h yd r o-5,6-d ih yd r oxy-1,3,4,7-
tetr a k is(p h en ylm eth yl)-2H-1,3-d ia zep in -2-ylid en e]cya n -
a m id e, Q8247 (8k ). The compound 8k was obtained from 6
by using the general procedure A in 50.5% yield as a white
solid: mp 94 °C; [R]D -28.0°(c 1.03, DMSO); 1H NMR (CDCl3)
δ 1.58 (br s, 2H), 2.81 (dd, J ) 11.4, 13.9 Hz, 2H), 3.04 (dd, J
) 2.6, 13.9 Hz, 2H), 3.33 (br s, 2H), 3.56 (d, J ) 13.9 Hz, 2H),
3.68-3.72 (m, 2H), 5.02 (d, J ) 14 Hz, 2H), 7.15-7.43 (m,
20H); 13C NMR (CDCl3) δ 32.67, 58.77, 66.14, 70.15, 116.07,
127.12, 128.63, 129.10, 129.38, 130.17, 135.85, 138.64, 162.49;
HRMS-CI calcd for C34H35N4O2 [M + H]+ 531.2760, found
531.2774. Anal. (C34H34N4O2‚0.5H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-[Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis(3-
m et h ylb u t yl)-4,7-b is(p h en ylm et h yl)-2H -1,3-d ia zep in -2-
ylid en e]cya n a m id e, Q8260 (8f). The compound 8f was
obtained from 8e by using the general procedure B in 54.0%
yield as a white solid: mp 76.1 °C; [R]D -108.4°(c 0.98, DMSO);
1H NMR (CDCl3) δ 0.78-0.82 (m, 12H), 1.10-1.14 (m, 2H),
1.26-1.49 (m, 4H), 1.61 (s, 2H), 2.68-2.84 (m, 4H), 3.18 (dd,
[4R-(4r,5r,6â,7â)]-[Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis[(3-
n itr op h en yl)m eth yl]-4,7-bis(p h en ylm eth yl)-2H-1,3-d ia z-
ep in -2-ylid en e]cya n a m id e, Q8250 (8l). The compound 8l
was obtained from 6 by using the general procedure A in 71.5%
yield as a white solid: mp 114 °C; [R]D +40.0° (c 0.52, DMSO);
1H NMR (CDCl3) δ 2.39 (s, 2H), 2.60 (dd, J ) 11.5, 13.2 Hz,
2H), 3.09-3.13 (m, 2H), 3.43-3.62 (m, 4H), 3.99 (d, J ) 15