Anthranilic Acid Sulfonamide MetAP2 Inhibitors
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 13 3841
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using method B. MS (DCI) m/e 452 (M + H)+; H NMR (400
MHz, DMSO-d6) δ 8.51 (ddd, 1H), 7.70 (td, 1H), 7.54 (dd, 1H),
7.33 (d, 1H), 7.29 (ddd, 1H), 7.22 (ddd, 1H), 6.90 (d, 1H), 6.80 (d,
1H), 6.76 (d, 1H), 6.58 (m, 1H), 6.14 (br s, 1H), 3.47 (t, 2H), 3.02
(t, 2H), 2.90 (m, 2H), 2.59 (m, 2H), 1.60 (m, 4H). Anal.
(C24H25N3O4S‚1 TFA) C, H, N.
(d, 1H), 6.78 (d, 1H), 6.67 (m, 1H), 3.24 (m, 4H), 3.09 (m, 4H),
2.66 (m, 4H), 1.85 (m, 2H), 1.67 (m, 4H), 1.13 (t, 6H). Anal.
(C25H35N3O4S‚TFA) C, H, N.
2-[4-Chloro-2-(3-diethylaminopropylamino)benzenesulfo-
nylamino]-5,6,7,8-tetrahydronaphthalene-1-carboxylic Acid (10al).
The title compound was prepared from 9h and N,N-diethyl-1,3-
propanediamine using method B. MS [ESI] m/z 494 [M + H]+;
1H NMR (300 MHz, DMSO-d6) δ 7.47 (d, 1H), 6.97 (d, 1H), 6.87
(s, 1H), 6.65 (m, 1H), 3.34 (m, 4H), 3.11 (m, 4H), 2.66 (m, 4H),
1.84 (m, 2H), 1.66 (m, 4H), 1.15 (t, 6H). Anal. (C24H32ClN3O4S‚
TFA) C, H, N.
2-{[(2-{[2-(4-Pyridinyl)ethyl]amino}phenyl)sulfonyl]amino}-
5,6,7,8-tetrahydro-1-naphthalenecarboxylic Acid (10ad). The title
compound was prepared from 9a and 4-(2-aminoethyl)pyridine
using method B. MS (ESI(+)) m/e 452 (M + H)+; MS (ESI(-))
m/e 450 (M - H)-; H NMR (300 MHz, DMSO-d6) δ 9.48 (s,
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1H), 8.63 (d, 2H), 7.66 (d, 2H), 7.49 (dd, 1H), 7.40 (t, 1H), 6.95
(d, 1H), 6.89 (d, 1H), 6.65 (d, 1H), 6.59 (d, 1H), 5.97 (bd s, 1H),
3.01 (t, 2H), 2.66 (m, 4H), 2.55 (m, 2H), 1.66 (m, 4H). Anal.
(C24H25N3O4S‚1 TFA) C, H, N.
2-{[(2-{[3-(2-Oxo-1-pyrrolidinyl)propyl]amino}phenyl)sulfonyl]-
amino}-5,6,7,8-tetrahydro-1-naphthalenecarboxylic Acid (10ae).
The title compound was prepared from 9a and 1-(3-aminopropyl)-
2-pyrrolidinone using method B. MS (DCI) m/e 472 (M + H)+;
1H NMR (500 MHz, DMSO-d6) δ 13.11 (br s, 1H), 9.50 (br s,
1H), 7.48 (dd, 1H), 7.37 (m, 1H), 6.94 (d, 1H), 6.76 (d, 1H), 6.60
(m, 2H), 5.91 (m, 1H), 3.32 (t, 2H), 3.22 (t, 2H), 3.11 (m, 2H),
2.65 (m, 4H), 2.23 (t, 2H), 1.92 (m, 2H), 1.71 (m, 2H), 1.66 (br s,
4H). Anal. (C24H29N3O5S‚0.67 H2O) C, H, N.
2-[2-(3-Diethylaminopropylamino)-6-fluorobenzenesulfonyl-
amino]-5,6,7,8-tetrahydronaphthalene-1-carboxylic Acid (10af).
The title compound was prepared from 9b and N,N-diethyl-1,3-
propanediamine using method B. MS [ESI] m/z 478 [M + H]+;
1H NMR (300 MHz, DMSO-d6) δ 7.26-7.21 (m, 2H), 6.87 (d,
1H), 6.52 (d, 1H), 6.28 (dd, 1H), 3.30 (m, 4H), 3.10 (m, 4H), 2.83
(m, 2H), 2.60 (m, 2H), 1.79 (m, 2H), 1.59 (m, 4H), 1.17 (t, 6H).
Anal. (C24H32FN3O4S‚0.75 H2O) C, H, N.
2-[2-(3-Diethylaminopropylamino)-5-fluorobenzenesulfonyl-
amino]-5,6,7,8-tetrahydronaphthalene-1-carboxylic Acid (10ag).
The title compound was prepared from 9c and N,N-diethyl-1,3-
propanediamine using method B. MS [ESI] m/z 478 [M + H]+;
1H NMR (300 MHz, DMSO-d6) δ 7.50 (m, 1H), 7.40-7.30 (m,
2H), 7.08 (d, 1H), 6.86 (d, 1H), 3.50 (q, 4H), 3.42 (m, 2H), 3.07
(m, 2H), 2.98 (m, 4H), 2.59 (m, 2H), 1.59 (m, 4H), 1.16 (t, 6H).
Anal. (C24H32FN3O4S‚TFA) C, H, N.
2-[3-Chloro-2-(3-diethylaminopropylamino)-benzenesulfonyl-
amino]-5,6,7,8-tetrahydronaphthalene-1-carboxylic Acid (10ah).
The title compound was prepared from 9d and N,N-diethyl-1,3-
propanediamine using method B. MS [(-)-ESI] m/z 492.1 [M -
H]-; 1H NMR (300 MHz, DMSO-d6) δ 7.74 (dd, J ) 7.8, 1.4 Hz,
1 H), 7.51 (dd, J ) 8.0, 1.2 Hz, 1 H), 7.15 (d, J ) 8.5 Hz, 1 H),
6.94 (t, J ) 8.0 Hz, 1 H), 6.87 (d, J ) 8.5 Hz, 1 H), 3.42-3.24
(m, 4 H), 3.18-3.06 (m, 6 H), 2.93-2.85 (m, 2 H), 2.63-2.54
(m, 2 H), 2.07-1.94 (m, 2 H), 1.63-1.55 (m, 4 H), 1.21 (t, J )
7.1 Hz, 6 H). Anal. (C24H32ClN3O4S‚0.67 H2O) C, H, N.
2-[5-Chloro-2-(3-diethylaminopropylamino)-benzenesulfonyl-
amino]-5,6,7,8-tetrahydronaphthalene-1-carboxylic Acid (10ai).
The title compound was prepared from 9e and N,N-diethyl-1,3-
propanediamine using method B. MS [ESI] m/z 494 [M + H]+;
1H NMR (300 MHz, DMSO-d6) δ 7.35 (d, 1H), 7.32 (dd, 1H),
7.26 (d, 1H), 6.93 (d, 1H), 6.76 (d, 1H), 3.26 (m, 4H), 3.07 (m,
4H), 2.79 (m, 2H), 2.61 (m, 2H), 1.75 (m, 2H), 1.59 (m, 4H), 1.17
(t, 6H). Anal. (C24H32ClN3O4S‚2 H2O) C, H, N.
2-[2-(3-Diethylaminopropylamino)-4-methylbenzenesulfonyl-
amino]-5,6,7,8-tetrahydronaphthalene-1-carboxylic Acid (10am).
The title compound was prepared from 9i and N,N-diethyl-1,3-
propanediamine using method B. MS [ESI] m/z 474 [M + H]+;
1H NMR (300 MHz, DMSO-d6) δ 7.41 (d, 1H), 6.96 (d, 1H), 6.65
(s, 1H), 6.65 (m, 1H), 6.47 (d, 1H), 3.27 (m, 4H), 3.10 (m, 4H),
2.65 (m, 4H), 1.87 (m, 2H), 1.66 (m, 4H), 1.14 (t, 6H). Anal.
(C25H35N3O4S‚1.4 TFA) C, H, N.
2-[2-(3-Diethylaminopropylamino)-5-(trifluoromethyl)benzene-
sulfonylamino]-5,6,7,8-tetrahydronaphthalene-1-carboxylic Acid
(10an). The title compound was prepared from 9j and N,N-diethyl-
1,3-propanediamine using method B. MS [ESI] m/z 528[M + H]+;
1H NMR (300 MHz, DMSO-d6) δ 7.71 (m, 2H), 7.02 (d, 1H), 6.98
(d, 1H), 6.53 (m, 1H), 3.37 (m, 4H), 3.11 (m, 4H), 2.66 (m, 4H),
1.88 (m, 2H), 1.67 (m, 4H), 1.15 (t, 6H). Anal. (C25H32F3N3O4S‚
1.1 TFA) C, H, N.
2-{[(2-{[4-(N,N-Dimethylamino)butyl]amino}phenyl)sulfonyl]-
amino}-5,6,7,8-tetrahydro-1-naphthalenecarboxylic Acid (10ao).
The title compound was prepared from 9a and 4-(N,N-dimethyl-
amino)butylamine using method B. MS (DCI) m/e 446 (M + H)+;
1H NMR (500 MHz, DMSO-d6) δ 13.09 (br s, 1H), 9.52 (br s,
1H), 7.51 (d, 1H), 7.38 (m, 1H), 6.95 (d, 1H), 6.79 (d, 1H), 6.68
(br s, 1H), 6.62 (t, 1H), 5.90 (br s, 1H), 3.18 (m, 2H), 3.06 (m,
2H), 2.74 (s, 6H), 2.68-2.65 (m, 4H), 1.69-1.66 (m, 6H), 1.57
(m, 2H). Anal. (C23H31N3O4S‚1.9 TFA) C, H, N.
2-{[(2-{[4-(Diethylamino)-1-methylbutyl]amino}phenyl)-
sulfonyl]amino}-5,6,7,8-tetrahydro-1-naphthalenecarboxylic Acid
(10ap). The title compound was prepared from 9d and 4-(N,N-
diethylamino)-1-methylbutylamine using method B. MS (DCI) m/e
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488 (M + H)+; H NMR (500 MHz, DMSO-d6) δ 13.10 (br s,
1H), 9.66 (br s, 1H), 7.54 (d, 1H), 7.35 (t, 1H), 6.93 (d, 1H), 6.80
(d, 1H), 6.59 (t, 1H), 5.65 (d, 1H), 3.63 (m, 1H), 3.07-2.97 (br m,
6H), 2.63 (br s, 4H), 1.76-1.47 (br m, 8H), 1.16 (t, 6H), 1.10 (d,
3H). Anal. (C26H37N3O4S‚TFA) C, H, N.
2-{[(2-Aminophenyl)sulfonyl]amino}-5,6,7,8-tetrahydro-1-
naphthalenecarboxylic Acid (11a). Methyl 2-{[(2-nitrophenyl)-
sulfonyl]amino}-5,6,7,8-tetrahydro-1-naphthalenecarboxylate was
prepared from 8 and 2-nitrobenzenesulfonyl chloride using method
A, followed by saponification with aqueous LiOH at 160 °C for
30 min in a microwave reactor to give 2-{[(2-nitrophenyl)sulfonyl]-
amino}-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid. A solution
thereof (1.4192 g, 3.77 mmol) in methanol (20 mL) was treated
with Raney nickel (14.1 g), pressurized to 60 psi with H2 and shaken
for 5 h. The reaction was then filtered, and the filtrate was
concentrated to yield 11a (1.18 g, 90%). MS (ESI(+)) m/e 332 (M
+ H)+, 364 (M + NH4)+, 369 (M + Na)+; MS (ESI(-)) m/e 345
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(M - H)-; H NMR (300 MHz, DMSO-d6) δ 7.48 (d, 1H), 7.17
2-[4-Chloro-2-(3-diethylaminopropylamino)-5-fluorobenzene-
sulfonylamino]-5,6,7,8-tetrahydronaphthalene-1-carboxylic Acid
(10aj). The title compound was prepared from 9f and N,N-diethyl-
1,3-propanediamine using method B. MS [ESI] m/z 512 [M + H]+;
1H NMR (300 MHz, DMSO-d6) δ 7.36 (d, 1H), 7.26 (d, 1H), 6.92
(d, 1H), 6.88 (d, 1H), 3.22 (m, 4H), 3.09 (m, 4H), 2.82 (m, 2H),
2.61 (m, 2H), 1.75 (m, 2H), 1.59 (m, 4H), 1.17 (t, 6H). Anal.
(C24H31ClFN3O4S‚0.5 H2O) C, H, N.
2-[2-(3-Diethylaminopropylamino)-5-methylbenzenesulfonyl-
amino]-5,6,7,8-tetrahydronaphthalene-1-carboxylic Acid (10ak).
The title compound was prepared from 9g and N,N-diethyl-1,3-
propanediamine using method B. MS [ESI] m/z 474 [M + H]+;
1H NMR (300 MHz, DMSO-d6) δ 7.36 (m, 1H), 7.25 (d, 1H), 6.96
(t, 1H), 6.92 (d, 1H), 6.80 (d, 1H), 6.71 (d, 3H), 6.52 (t, 1H), 2.92
(m, 2H), 2.58 (m, 2H), 1.60 (m, 4H). Anal. (C17H18N2O4S) C, H,
N.
Methyl 2-{[(2-Aminophenyl)sulfonyl]amino}-5,6,7,8-tetrahy-
dro-1-naphthalenecarboxylate (11b). Methyl 2-{[(2-nitrophenyl)-
sulfonyl]amino}-5,6,7,8-tetrahydro-1-naphthalenecarboxylate was
prepared from 8 and 2-nitrobenzenesulfonyl chloride using method
A. A solution thereof (2.0873 g, 5.35 mmol) in 4:1 methanol/ethyl
acetate (120 mL) was treated with Raney nickel (4.00 g), pressurized
to 60 psi with H2 and shaken for 2 h. The reaction was then filtered,
and the filtrate was concentrated to yield 11b (1.8750 g, 97%).
MS (ESI(+)) m/e 361 (M + H)+, 383 (M + Na)+; MS (ESI(-))
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m/e 359 (M - H)-; H NMR (300 MHz, DMSO-d6) δ 7.32 (dd,