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BY (11) 8909
(13) C1
(46) 2007.02.28
(19)
(12)
7
(51) C 07D 231/06,
A 61K 31/415,
A 61P 29/00
,
(54)
(21)
: a 20001186
(22) 1999.05.27
(31) P 9801129 (32) 1998.05.29 (33) ES
(85) 2000.12.29
(86) PCT/ES99/00156, 1999.05.27
(87) WO 99/62884, 1999.12.09
(43) 2001.09.30
(71)
:
.
,
. (ES)
(72)
:
,
;
-
,
;
;
(ES)
,
(73)
:
.
,
(56) US 4425179, 1984.
WO 88/06583 A1.
(57)
1.
. (ES)
I:
R1
R3
R2
R4
N
N
R8
, (I)
5
R
R7
R6
BY 8909 C1 2007.02.28
R1
1
,
,
,
,
4
R2
R3, R4, R7
,
,
,
;
;
R8
,
,
,
,
-
;
R5
,
R6
R5
,
,
R6
,
,
,
-
,
-
,
R1
,
,
2
R
R3
;
R4
R5
R6
;
R8
,
,
,
,
,
,
,
,
,
-
;
,
,
,
,
,
,
,
,
;
-
BY 8909 C1 2007.02.28
R5 R6
,
,
,
7
R
2.
;
,
,
.
,
. 1,
,
,
-
,
1-(41-(4-
)-4,5)-4,5-
-5-(4-5-
)-3-
-1
-5-(4-
;
)-3-
-
;
1-(4;
4,5;
1-(44,54,5;
1-(44,54,51-(4;
5-(2,4;
1-(4;
1-(4;
1-(41-(41-(44,51-(4;
1-(4;
1-(4-
)-5-(2,4-1-(4-
)-4,5-
)-5-(4-5-
-1-(4-
-1
-1
-5-(4-
-5-(2-
-4-
)-4,5-
;
;
-1 -1
-3-1 -
)-3)-3)-3)-3-
-1
-1
-1
-1
)-3-
)-4,5-
-3-
-1 -
)-3-
-5-(4-
)-5-(3-
;
-3-
)-4,5-
-5-(3-5-(2-5-(3-
-
-1
-1
-1
)-3-
)-4,5-
-5-(3-
)-3)-3)-3-
-1-(4-
)-4,5)-4,5)-4,5)-1-(4)-4,5-
-1
)-4,5-
)-5-(2,4-
;
;
)-3-
)-4,5)-1-(4)-5-(4)-5-(3,4)-4,5-
-1
-3)-3-
)-1-(4-
-5-(4-1-(4-
-1 -
)-3-
)-4,5-5-5-(4-
-3-
;
;
;
-1
-3-
;
-1 -
-5-(4-
)-
;
1-(4;
1-(4;
5-(3,4;
1-(44,51-(44,51-(41-(44,54,5-
)-5-(2,3-
)-4,5-
)-4,5)-4,5-
-3-
-1-(4)-4,5)-3)-4,5-
-5-(4-5-(4-
)-4,5)-4,5-5-3-
-1-(4-1-(4-
-5-(2,4-
-5-(4-1-(4-3-5-(4)-1-(4-3-5-(4-5-1
)-1
)-5-(42
)-3-
-3-
-1 -
)-3-
-1 -
)-3-
-1 -
-1
)-1
)-1
)-1
;
;
;
;
)-1
;
)-1
;
;
;
BY 8909 C1 2007.02.28
1-(4;
1-(44,5;
-5-(4-
)-4,5-
-5-(4-
)-4,5)-1-(4-
-5-
)-1
-1
-3-3-
;
)-1
-1-(4-
)-4,5-
-5-(4-
-1-(4-4,5-
)-4,5)-1-(4-
-5-
-3)-1
-3-
-
-3-
;
-
;
-5-(4-
-1
-3)-1
;
1-(41-(44,531-(4;
1-(4-
)-4,5)-4,5)-1-(4-
-5-(4;
-4,5-
-5-(4-
-5-5-(4-
-1
-3-
)-1-(4-5-(3,4-
)-4,5-
;
)-1
)-1
-3-3)-1
)-3-
;
;
-1 -
)-4,5-
-5-(3-
-4-
)-3-
-
)-4,5-
-5-(3-
-4-
)-3-
-
)-4,5-
-5-(2-
-4-
)-3-
-
)-4,5-
-5-(2,4-
)-4,5-
-5-(4-
;
1-(4;
1-(4;
1-(4;
1-(4-
)-3-2-
-1 -
)-3-
-
;
1-(4;
1-(4;
1-(4-
)-3-
-4,5-
)-4,5-
-5-(2,4-
-5-(2,3,4-
)-5-(2-
-4-
)-1 -
)-3)-4,5-
-1 -
-3-
-
;
1-(4-1
1-(4-1
1-(4-
)-4,5-
-5-(2-
-4-
)-3-
-
-3-
-
;
)-5-[2,4-(
]-4,5-
;
)-4,5-
-5-(2-
-3-
)-3-
-
;
1-(4-
)-4,5-
-5-(2-
)-5-(2,4)-4,5-
-5-(4-
-4-
)-3-
-
;
1-(41-(4-1
1-(2,4;
1-(41-(4;
1-(4;
)-3-
-4,5-2-
-1
)-3-
;
-
;
)-4,5-
-5-(4)-5-(2)-5-(4)-4,5-
)-3)-4,5-
-2-5-(4-
3
-3)-4,5-2-
-1 -1
-3)-3-
;
-1 -1 -
BY 8909 C1 2007.02.28
1-(4;
1-(4-
)-4,5-
-5-(2-
-4-
)-5-(2,4-
)-4,5-
;
1-(4)-4,5-5-(44,5-1-5-(44,5-1-(2)-5-(41-(4-2)-4,5-5-(4;
4,5-1-(3)-5-(44,5-1-(3)-5-(44,5-1-(2,4)-5-(4;
1-(2)-4,5-5-(44,5-1-(2)-5-(41-(2,4)-4,5-5-(4;
( + )-1-(4)-5-(2,4;
(-)-1-(4)-5-(2,4;
( + )-4,5-1-(4)-5-(4;
(-)-4,5-1-(4)-5-(44,5-
-5-(4-
)-3-
-1 -
-3-
-
)-3-
-1
)-3-
-1
;
;
)-3-
-1
;
-1 -
-1
-1
;
;
-1 -
-1
-1
;
;
-1 -
)-3)-3)-3)-3)-3)-3)-3)-4,5-
-3-
)-4,5-
-
-3-
-1 -
)-3-
-1 -
)-3-
)-3-
-1
-1-(2-
)-
,
.
3.
I
. 1,
-
II:
O
R2
R
R1
3
, (II)
R4
5
R
1
R
R , R3, R4
,
2
R
5
,
,
,
,
,
. 1,
III
:
NH2
HN
8
R
, (III)
7
R
6
R ,R
4.
1
7
8
R
R6
,
. 1.
I
4
2
3
4
5
6
7
,R,R,R,R,R,R
8
R
,
I,
4
. 1,
R1
R1
. 1,
,
BY 8909 C1 2007.02.28
R2, R3, R4, R5, R6, R7
R8
,
. 1,
,
,
1
-
4
,
.
5.
I
1
2
3
2
3
4
5
5
7
8
,R,R,R,R,R,R
4
4
5
6
7
8
R,R,R,R,R,R
R
,
6.
, R2, R3, R4, R5, R6, R7
4
6
6
R,R ,R ,R
7
8
R
R
,
I
8
R
,
R1
I,
,
,
,
4
5
6
7
R
8
I,
. 1,
R8
I
. 1,
R1
,
. 1,
R6
I,
,
. 1,
R8
,
6
R
,
9.
R , R4, R6, R7
3
. 1,
R5
I,
,
5
. 1,
R
,
10.
I
. 1,
I
11.
I
. 1,
12.
I
R1
2
3
4
5
, R,R,R,R,
,
.
I
. 1,
R1, R2,
,
R1, R2, R3, R4, R5, R7 R8
,
.
I
. 1,
R1, R2,
,
R1, R2, R3, R4, R6, R7 R8
,
.
.
.
,
,
8.
R , R4, R5, R7
R2, R3,
-
.
R8
3
R1
. 1,
,
-
.
.1
,R,R,R,R,R,R
R6, R7
. 1,
. 1,
R1
I,
. 1,
,
3
R1
,
7.
2
. 1,
. 1,
. 1,
I
-
.
13.
,
-2,
I
.1
-
2
.
14.
I
,
.1
2
-
,
-2,
,
-2,
.
15.
,
-
. 13
,
,
5
.
BY 8909 C1 2007.02.28
16.
. 13
,
,
-
,
.
(I)
,
-
,
.
R1
R3
R2
R
4
N
N
R8
. (I)
R5
R7
R6
.
(NSAIDS)
-
,
,
.
,
-
,
,
,
.
NSAIDS
,
,
.
NSAIDS
) (J.R. Vane, Nature, 1971, 231, 232)
(
,
(Flower R.J., Vane J.R. Biochem. Pharm., 1974, 23, 1439; Vane J.R., Botting R.M. Postgrad. Med. J., 1990, 66 (Suppl. 4),
S2).
NSAIDS,
.
(
,
,
.)
,
-
NSAIDS,
,
-2),
-1 (
-2
.
,
,
-1) (Sirois J., Richards J.R., Biol J. Chem., 1992, 267, 6382),
.
,
.
6
-2
-
BY 8909 C1 2007.02.28
.
-1
,
.
,
-2
,
-2
(Vane J.R., Botting R.M. Inflamm. Res., 1995, 44, 1).
-2
,
,
.
,
,
,
,
,
-
,
-2
,
.
-1
(Picot D., Loll P.J., Garavito R.M. Nature, 1994, 367, 243).
,
.
-
,
NSAIDS
.
-2,
,
-1
(Service R.S. Science, 1996, 273, 1660)
,
,
-1
,
-2
-2.
,
,
,
.
,
,
-1,
-2.
,
.
NSAIDS,
-
-1
,
,
-2
,
,
-1.
,
-2.
-
-2.
(W.W. Wilkerson et al, J. Med. Chem., 1994, 37, 988;
Wilkerson W.W. et al, J. Med. Chem., 1995, 38, 3895; Khanna I.K. et al, J. Med. Chem., 1997,
40, 1619),
(T.D. Penning et al, J. Med. Chem., 1997, 40, 1347; Tsuji K. et al,
Chem. Pharm. Bull., 1997, 45, 987; Tsuji K. et al, Chem. Pharm. Bull., 1997, 45, 1475)
(Khanna et al, J. Med. Chem., 1997, 40, 1634).
,
,
(I),
,
.
,
,
,
-2,
,
NSAIDS.
,
-2,
,
-2,
.
,
.
,
2
,
,
7
BY 8909 C1 2007.02.28
4,5-
-1
.
,
.
,
,
.
,
R
(I):
R1
3
R2
R
4
N
N
R8
, (I)
5
R
R7
R6
R1
,
,
R2
R3, R4, R7 R8,
,
R5 R6
,
,
,
,
1-4
,
-
,
;
;
,
,
,
,
,
R5
,
,
-
R6
.
1
R
;
R3
,
2
,
R8,
R
,
,
,
-
;
R4
,
,
;
R5
,
,
,
;
R6
,
,
,
,
,
,
R5
,
,
,
,
R6
R7
,
,
,
-
.
(I)
.
-
(I)
,
,
,
,
,
(I)
-
.
.
(I),
,
,
,
,
.,
,
8
,
,
,
,
BY 8909 C1 2007.02.28
,
, n-
,
,
-
.
(I)
,
,
,
,
.
(I)
,
,
,
,
,
,
.
(I)
,
,
,
,
,
,
-
,
,
,
.
(I)
,
,
,
-
,
.
(I)
.
,
.
(I)
-
(II):
O
R2
R1
R3
,
(II)
R4
R5
R1
,
,
,
,
-
;
R2, R3, R4
R5
,
(I),
(III)
-
:
NH2
HN
R8
, (III)
R7
R6
R6, R7
R8
,
,
,
,
,
9
,
(I).
,
,
,
-
BY 8909 C1 2007.02.28
.
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
-
.
.
.
.
(I),
R1
6
7
R,R,R,R,R,R
R8
2
1-4
3
4
-
5
,
,
(I),
1
R
(
,
2
)
3
4
5
6
7
R,R,R,R,R,R
8
R
,
,
,
,
-
,
,
1-4
,
,
,
,
.
,
,
,
,
-
,
,
,
,
-
,
.
0°
,
10
24 .
.
R1
(I),
2
3
4
5
6
R,R,R,R,R,R
7
R
8
,
,
(I),
(
)
R2, R3, R4, R5, R6, R7
R
1
R8
,
,
,
,
,
.
,
,
,
,
,
,
.
0°
,
1-24 .
.
R1
(I),
5
6
7
R, R, R
8
R
R2, R3, R4,
,
,
R1
(I),
R2, R3, R4, R5, R6, R7
,
R8
,
,
,
-
,
.
,
,
.
0°
,
15
,
-
24 .
.
(II),
-
(I),
,
.
10
BY 8909 C1 2007.02.28
-1.
(II),
R1
, a R3, R4 R5
, R2
-,
,
-
(I),
-
(IV):
CHO
R3
, (IV)
R4
R5
R3, R4
R5
-,
N,
LDA (
,
(I),
-
,
,
),
-,
,
-
,
,
.
,
,
,
,
,
,
,
.
-70 °
,
15
-2.
-
20 .
R1
R3, R4
(II),
2
,R
R5
,
(I),
(V):
R2
CH2
R3
,
(V)
R4
R5
R2
R3, R4 R5
-, -
(I),
,
.
,
,
,
,
,
,
,
,
,
.
-70 °
,
20
20 .
11
-
BY 8909 C1 2007.02.28
-3.
R1
R3, R4
(II),
, R2
R5
,
-
(I),
,
(IV)
1,1,1,
;
,
(IV)
,
2,
α,α
,
,
(IV)
,
-
;
),
,
-
(VI):
O
Cl
, (VI)
R3
R4
R5
R3, R4
R5
,
(I),
.
,
,
,
,
;
;
,
,
,
,
,
;
.
,
-60 °
-
,
2
.
-4.
(II),
R3, R4
,
R5
R1
R2
,
,
,
,
(I),
-
(IV)
α,β
,
(IV)
, (IV)
-
(Dibal);
),
α,α
,
.
.
(I),
5
,
R
6
R
,
,
12
R1, R2, R3, R4, R7
,
,
R8
,
,
,
R5
R6
BY 8909 C1 2007.02.28
R1, R2, R3, R4, R7
,
,
(I),
6
R
R8
,
R6
R5
,
,
,
,
R5
,
,
,
,
.
,
,
,
-
.
0°
,
15
,
14 .
,
,
,
-
,
(I)
.
(I)
,
.
-
.
,
,
.
,
-
,
,
.
,
1-(4)-4,5-
-5-(4-
)-3-
-
-1HCF3
N
N
H3C
SO2NH2
(E)-1,1,1-
(5
),
, 10
-4-(4-
)-315
-70 ° .
(0,75 , 5
30
.
(1,04 , 5
)(
kami H., et al. J. Org. Chem., 1993, 58, 32-35),
1 .
n(0,6 , 5
-2-
-1)
(
2 LDA
),
)
(
-
5
,
Nc Tamura ., Mizu-
),
,
16 .
10
2 .
l
4 .
(3 × 20 ),
,
5 %-
-
~6.
.
, 1:9),
75 %)
( )-1,1,1.
(
13
(
-4-(4)-3-2- (0,8 ,
, -1): 1715, 1601, 1201, 1183, 1145,
BY 8909 C1 2007.02.28
1056, 811, 703. 1
(CDCl3, δ): 2.4 ( , 3 ), 6.97 (d, J = 18 , 1 ), 7.25 (d, J = 9 , 2 ),
7.54 (d, J = 9 , 2 ), 7.95 (d, J = 18 , 1 ).
(
,
): Rf 0.16.
1-(4)-4,5-5-(4)3-1H(
)
4-(
(0,82 , 3,69
) (E)-1,1,1-4-(4)-3-2(0,79 , 3,69
) 15
3
.
,
.
,
.
,
1-(4)-4,5-5-(4)-3-1H-1
(0,65 ,
45 %). . . 140-143 ° .
(
,
): 3356, 3268, 1594, 1326, 1170, 1139,
1
1120, 1097.
(CDCl3, δ):2.34 ( , 3 ), 2.99-3.06 (dd, J = 6.9 14 , 1 ), 3.66-3.73 (dd,
J = 12.6 14 , 1 ), 4.69 ( . , 2 ), 5.38-5.45 (dd, J = 6.9 12.6 , 1 ), 7.04-7.11 (dd,
J = 8.1 9.3 , 4 ), 7.17 (d, J = 8.1 , 2 ), 7.70 (d, J = 9.3 , 2 ). 13
(CDCl3): 20.9,
41.2, 64.5, 113.4, 120.5 ( , J = 268 ), 125.3, 127.6, 130.1, 133.2, 136.7, 138.3, 138.8 ( ,
J = 38 ), 146,0.
(
): Rf 0.89.
2(
2
).
1-(4)-4,5-5-5-3-1H- CF3
H3C
N
N
SO2NH2
(E)-1,1,1,
(6,3 , 30
-4-
-4-
-3-
-2(
(3,9 , 30
-2)
75
-
-60 ° ,
).
(3,54 , 30
10
)
15
,
-50 °
15
)
,
0°
30
.
50
.
50
,
.
,
.
,
-3-21204, 1142, 1072. 1
-60 ° .
10 %-
(
,
.
2,0 (51 %)
α
,
2,35 (E)-1,1,1-4-475 %)
.
(
, -1): 1709, 1596,
(CDCl3, δ): 2.71 ( , 3 ), 6.8 ( , 1 ), 7.45 (m, 3 ), 7.6 (m, 2 ).
14
BY 8909 C1 2007.02.28
1-(43)-3(2 , 9
-2)
)-4,5-1H-
(1,75 , 8,2
),
(0,85 , 10
5,5 .
(
(E)-1,1,14-(
),
-5)
-5-
-
-4-
-4-(4-
100
-
,
,
-
,
.
,
.
,
,
(4 : 6)
1-(4)-4,5-5-5-3-1
(1,46 ,
47 %), . . 60-66 ° .
(
, -1):
3384, 3266, 1593, 1498, 1327, 1151, 1099, 703. 1
(CDCl3, δ): 1.6 ( , 3 ), 2.8 (m, 1 ),
3.1 (m, 1 ), 4.5 ( . , 2 ), 7.2 (m, 3 ), 7.4-7.55 (m, 4 ), 7.7 (d, 2H). 13
(CDCl3): 27.6,
54.2, 63.1, 114.6, 124.0 ( , J = 268 ), 125.6, 127.4, 127.8, 129.1, 131.0, 142.0 ( , J = 38 ),
142.6, 147.5.
3(
3
).
1-(4)-5-(2,4)-4,5-3-1
CF3
F
N
N
F
SO2NH2
(E)-1,1,12,4(12,2 , 0,2
)
5-10 °
,
1,5
(5 , 0,045
),
35 (0.31
,
.
(2,4)-31146, 1059, 706. 1
J = 16 , 1 ).
-4-(2,4-
)-3-2(
(20 , 0,14
),
(12,2 , 0,14
)
(300 ).
(CF3COCH3) (8 , 0,07
-3)
).
.
1,5
1,5 .
)
5 ,
.
,
.
),
.
50
,
.
, 5%
,
.
,
18,1 (E)-1,1,1-4-2- , . . 50-51 ° .
( r, -1): 1717, 1602, 1583, 1277,
(CDCl3,δ): 6.9 (m, 2 ), 7.05 (d, J = 16 , 1 ), 7.6 (m, 1 ), 8.0 (d,
15
20 %
(50
BY 8909 C1 2007.02.28
1-(4-
)-5-(2,4-1
)-4,5(
-3-
-
)
4-(
(47,8 , 0,21
) ( )1,1,1-4-(2,4)-3-2(53,1 95 %, 0,21
) 315
24
.
,
.
,
,
46,2 .
,
12,6
.
1-(4)-5-(2,4)-4,5-3-1
58,8 (68 %), . . 160-162 ° .
:
(0,53 , 7,72
),
45
, 1,1,1- -4-(2,4)-3-2- (
-1) (0,913 , 3,86
)
4-(
(0,87 , 3,87
),
16 .
,
,
,
,
.
,
,
.
(50:50),
1-(4)-5-(2,4)-4,5-31H(1,02 ,
65 %)
, . . 160-162 ° .
( r, -1):
3315, 3232, 1617, 1593, 1506, 1326, 1179, 1099, 1067. 1
(CDCl3, δ): 3.0 (dd, J = 6.3
11.4 , 1 ), 3.80 (dd, J = 11.4 12.6 , 1 ), 4.79 ( . , 2 ), 5.70 (dd, J = 6.3 12.6 ,
), 6.8-6.95 (m, 2 ), 7.01-7.09 (m, 3 ), 7.74 (d, J = 8.7 , 2 ).
4(
4
).
4,5-1-(4)-5-(4)-1-(4)3- -1H(
)
CF3
N
N
CH3O2S
CH3
)-3-
-2-
(
4-
(1,04 , 6,58
)
,
.
(E)-1,1,1-1) (1,83 , 6,58
50
.
-4-(4)
4
,
)-5-(4-
,
.
.
4,5-1-(4)-3-1H(0.8 ,
32 %)
-1
, . . 140-143 ° .
( r,
): 1516, 1310, 1148, 1131, 1060, 774. 1
(CDCl3, δ): 2.2 ( , 3 ), 2.9 (dd, J = 7.8 17.1 , 1 ), 3.05 ( , 3 ), 3.7 (dd, J = 12.9 17.1 ,
), 5.45 (dd, J = 7.8 12.9 , 1 ), 6.8 (d, J = 8.4 , 2 ), 7.0 (d, J = 8.4 , 2 ), 7.45 (d,
J = 8.4 , 2 ), 7.9 (d, J = 8.4 , 2 ).
16
BY 8909 C1 2007.02.28
5(
-4,5-
39
-5-(4-
(
).
)-1-(4-
)-1H-
-3-
-
)
CO2CH3
N
N
H3C
SO2CH3
4,5-
-5-(4(6,9 , 19,3
)-1-(4)
(3,5
)-1H) 50
16 .
, 48
,
-3-
,
8
(58
2 .
.
150
,
)
,
,
,
(5,8 ,
82 %)
, . . 155-160 ° .
( r, -1): 1741, 1561, 1260,
(CDCl3, δ): 2.3 ( , 3 ), 3.0 ( , 3 ), 3.1 (dd, J = 6 18.3 , 1 ),
18.3
, 1 ), 5.4 (dd, J = 6
12.6
, 1 ), 7-7,25 (m, 6 ), 7.7 (d,
1226, 1135, 1089. 1
3.75 (dd, J = 12.6
J = 8.7 , 2 ).
6(
41
1-(4(
)
).
)-4,5-
-5-(4-
)-1
-3-
CONH2
N
N
H3C
SO2NH2
1-(4(3,7 , 10,3
)-4,5-
-5-(4(3 , 25,8
)
16
)-1
) 70
.
-3-
,
30
,
17
0° .
20
9
.
-
BY 8909 C1 2007.02.28
16 ,
.
,
-
,
,
.
,
2,6 (
72 %)
, .
1
210-215 ° .
( r,
): 3450, 3337, 1656, 1596, 1345, 1141.
(CD3OD, δ): 2.4 (
), 3.05 (dd, J = 6 17.7 , 1 ), 3.8 (dd, J = 12.9 17.7 , 1 ), 5.6 (dd, 1 = 6 12.9
), 7.2-7.3 (m, 6 ), 7.75 (d, J = 8.7 , 2 ).
7(
43
).
3-4,5-5-(4)-1-(4)-1H(
)
-1
.
,
,
-
CN
N
N
H3C
SO2CH3
6,3
0°
,
)-1-(4-
.
4,5-5-(4)-1
-3(3,8 , 10,6
) 30
,
5
0° ,
16
.
,
.
3.35 (
93 %)
,
-1
,
, . . 162-164 .
( r,
): 2220,
1
1593, 1500, 1389, 1296, 1143.
(CDCl3, δ): 2.3 ( , 3 ), 3-3.1 (c + dd, 4 ), 3.75 (dd,
J = 12.6 18 , 1 ), 5.5 (dd, J = 6.3 12.6 , 1 ), 7-7.2 (m, 6H), 7.7 (d, J = 8.7 , 2 ).
8(
64
).
1-(4)-5-(2,4)-4,5-31H(
)
2
2,1
.
CF3
F
N
N
F
SO2NHCOCH3
18
BY 8909 C1 2007.02.28
,
0,58
)-4,5-
-32 .
(1,43
-1H-
) 1-(4-
)-5-(2,4,
2
,
-
,
,
,
.
0,49
(76 %) 1-(4)-5-(2,4)-4,5-3-1
, . . 172-174 ° .
( r, -1): 3302, 1723, 1593, 1506,
1
1337, 1165.
(CDCl3, δ): 2.0 ( , 3 ), 3.0 (dd, J = 6.6 18.0 , 1 ), 3.8 (dd, J = 12.9
18.0 , 1 ), 5.7 (dd, J = 6.6 12.9 , 1 ), 6.9 (m, 2 ), 7.05 (m + d, 3 ), 7.85 (d, J = 8.7 ,
), 8.1 ( , 1 ).
9 10 (
75 76
).
(+)-1-(4)-5-(2,4)-4,5-3-1 (-)-1-(4)-5-(2,4)-4,5-31HCF3
F
H
N
N
F
SO2NH2
(±)-1-(4-3-
-1
,
(Daicel),
10
,
(4[α]D + 189,3 (
1,
[α]D = -189,4 ( 1,
.1
65-74
,
)-5-(2,4-
64 -
)-4,5-
-
CHIRALPAK AS
25 × 2
0,1 %
8
.
7,4
(+)-1)-5-(2,4)-4,5-3-1H, .
. 173-174 ° ,
99.9 %,
).
9,2
(-)-1-(4)-5-(2,4)-4,5-3-1
, .
. 173-174 ° ,
>99,9 %,
).
,
77 78
.
,
(I),
.2
.
1-36, 44-63
,
37-39 ,
40-42 ,
75-78
.
19
BY 8909 C1 2007.02.28
1
1
R
R3
R2
R
4
N
N
R8
5
R
7
R
R6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
R1
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CH3
CH3
CH3
CH3
CH3
H
H
3
2
R2
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
R3
H
H
F
H
H
H
H
H
H
H
H
Cl
Cl
CH3
H
F
F
H
H
H
H
H
F
CH3
H
H
H
H
H
H
H
H
H
H
R4
H
H
H
H
H
H
H
H
H
H
F
H
H
H
CH3
H
H
F
F
H
Cl
H
F
H
F
H
H
H
H
H
H
H
H
H
20
R5
3
H
F
SO2CH3
H
H
3
F
F
SO2CH3
F
Cl
Cl
H
H
H
H
H
H
OCH3
F
OCF3
H
CH3
F
F
F
CH3
CH3
CF3
H
H
CF3
CH3
R6
SO2NH2
SO2NH2
SO2NH2
CH3
SO2NH2
SO2CH3
SO2CH3
SO2NH2
SO2CH3
F
SO2NH2
SO2CH3
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2CH3
SO2NH2
SO2CH3
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2CH3
SO2NH2
SO2CH3
SO2NH2
SO2CH3
SO2NH2
SO2NH2
SO2CH3
SO2CH3
SO2NH2
R7
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
R8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
BY 8909 C1 2007.02.28
.1
1
2
R
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
2
2
2
3
2
3
2
3
CONH2
CONH2
CONH2
CN
CF3
CF3
CF3
CF3
CF3
CF3
CHF2
CF3
CF3
CF3
CF3
CF3
CF3
CHF2
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
R
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3
R
H
H
H
H
H
H
H
H
H
H
H
H
F
OCH3
OCH3
CH3
F
Cl
F
CF3
CH3
CH3
F
CF3
H
Cl
F
CH3
F
F
H
H
H
H
H
H
H
H
H
H
4
R
H
H
H
H
H
H
H
H
H
CH3
CH3
F
H
H
H
H
F
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
21
5
R
H
CH3
CH3
H
CH3
CH3
CH3
CH3
CH3
OCH3
OCH3
OCH3
OCH3
F
CH3
F
F
CF3
CF3
OCH3
F
F
SO2CH3
Cl
F
CH3
F
SO2CH3
SO2CH3
SO2CH3
SO2CH3
SO2CH3
SO2CH3
SO2CH3
SO2CH3
SO2CH3
SO2CH3
6
R
SO2NH2
SO2CH3
SO2NH2
SO2NH2
SO2CH3
SO2NH2
SO2NH2
SO2CH3
SO2CH3
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
F
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NHAC
Cl
H
H
Cl
H
H
CH3
H
H
Cl
7
R
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
CH3
H
H
H
H
8
R
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
F
CH3
H
H
CH3
Cl
CH3
Cl
BY 8909 C1 2007.02.28
1(
R
R
3
R
R
)
1
2
4
N
N
R
R
8
5
R7
6
R
R1
R2
R3
R4
R5
75
CF3
H
F
H
76
CF3
H
F
77
CF3
H
78
CF3
78
CF3
R6
-
R7
R8
F
SO2NH2 H
H
>99
H
F
SO2NH2 H
H
>99
H
H
SO2CH3
F
H
H
>99
H
H
H
SO2CH3
F
H
H
>99
H
H
H
SO2CH3
H
H
CF3
,%
[α]D
+183.9 (c = 1;
CH3OH)
-189.4 (c = 1;
CH3OH)
+181.2 (c = 1;
CH3OH)
-183.4 ( = 1;
)
3
2
.
1
., °
140-3
(
r)
-1
3356, 3268, 1594,
1326, 1170, 1139,
1120, 1097
3384, 3266, 1593,
1498,1327,1151,
1099, 703
3315, 3232, 1617,
1593, 1506, 1326,
1179, 1099, 1067
2
60-6
3
160-2
4
140-3
1516, 1310, 1148,
1131, 1060, 774
5
156-7
3350, 3269, 1596,
1315 1188, 1142,
1101
6
137-40
1595, 1333, 1297,
1282, 1148, 771
l3) δ,
.
2.34(s, 3H); 3(dd, J = 6.9,14Hz,1H); 3.7(dd, J = 12.6,
14Hz, 1H); 4.7(broad s, 2H); 5.4(dd, J = 6.9, 12.6Hz,
1H); 7.1 (2d, J = 8.1, 9.3Hz, 4H); 7.2(d,J = 8.1 Hz,
2H); 7.7(d, J = 9.3Hz, 2H)
1.6(s, 3H); 2.8(m, 1H); 3.1(m, 1H); 4.5(broad s, 2H);
72(m, 3H); 7.4-7.55(m. 4H); 7.7(d, 2H)
1
3(dd, J = 6.3, 11.4Hz, 1H); 3.8(dd, J = 11.4, 12.6Hz,
1H); 4.8(broad s, 2H); 5.7(dd, J = 6.3, 12.6Hz, 1H);
6.8-6.95(m, 2H); 7-7.1(m, 3H); 7.7(d, J = 8.7Hz, 2H)
2.2(s, 3H): 2.9(dd, J = 7.8, 17.1Hz, 1H); 3(s, 3H);
3.7(dd, J = 12.9, 17.1Hz, 1H); 5.45(dd. J = 7.8,
12.9Hz, 1H); 6.8(d, J = 8.4Hz. 2H); 7(d, J = 8.4Hz,
2H); 7.45(d, J = 8.4Hz, 2H); 7.9(d, J = 8.4Hz, 2H)
3.04(dd, J = 6.6, 18Hz, 1H); 3.7(dd, J = 12.9, 18Hz,
1H); 4.8(s, 2H); 5.45(dd, J = 6.6, 12.9Hz, 1H); 7.0(d,
J = 9Hz, 2H);7.2(d, J = 6.6Hz, 2H); 7.3(m, 3H);
7.7(d, J = 9Hz, 2H)
3.0(s, 3H); 3.06(dd, J = 6.6, 18Hz, 1H); 3.75(dd,
J = 12.8, 18.1H); 5.45(dd, J = 6.6, 12.6Hz, 1H);
7.05(d, J = 9Hz, 2H);7.2(d, J = 7.8Hz, 2H); 7.4(m,
3H); 7.7(d, J = 9Hz, 2H)
22
BY 8909 C1 2007.02.28
.2
.
., °
(
r)
-1
115-19
1592, 1332, 1148,
1133, 825, 775
8
154-6
3337, 3254, 1594,
1510, 1324, 1158,
740
9
121-22
1592, 1509, 1148,
1120, 774
10
103-5
1514, 1313, 1155,
1133, 1061, 827
11
153-5
3318, 3250, 1596,
1323, 1135, 1066
12
198-200
1596, 1320, 1303,
1138, 775
13
143-5
3425, 3275, 1594,
1332, 1158, 1111,
825
14
124-6
3370, 3240, 1595,
1331, 1154, 1103
15
125-8
3370, 3265, 1595,
1329, 1158, 1066
16
166-8
3330, 3239, 1597,
1334, 1122, 769
17
117-121
1594, 1304, 1150,
1119, 776
18
132-3
3323, 3249, 1596,
1323, 1179, 1131,
741
19
149-151
1593, 1296, 1144,
965, 789
20
125-8
3336, 3254, 1593,
1329, 1156, 1112,
834
7
l3) δ,
.
2.3(s, 3H); 3.0(s, 3H); 3.05(dd, J = 6.6, 19Hz, 1H)
3.7(dd, J = 12.6, 19.1H); 5.4(dd, J = 6.6, 12.6Hz,
1H); 7.1(2d, J = 8.1, 8.7Hz, 4H); 7.2(d,J = 8.1
Hz,2H); 7.7(d,J = 8.7Hz, 2H)
3.0(dd, J = 6.6, 18Hz, 1H); 3.7(dd, J = 12.6, 18Hz,
1H); 4.8(s,2H); 5.4(dd, J = 6.6, 12.6Hz, 1H); 7.1(m,
4H); 7.2(m, 2H); 7.7(d, J = 9Hz, 2H)
3.0(s, 3H); 3.05(dd, J = 6.6, 17.4Hz, 1H); 3.7(dd,
J = 12.6, 17.4Hz, 1H); 5.4(dd, J = 6.6 12.6Hz, 1H);
7.0(m, 4H); 7.2(m, 2H); 7.7(d, J = 9Hz, 2H)
2.9(dd, J = 8.4, 17.4Hz, 1H); 3(s, 3H); 3.7(dd,
J = 12.6,17.4Hz, 1H); 5.4(dd, J = 8.4, 12.6Hz, 1H);
6.9(m, 4H); 7.45(d, J = 8.4Hz, 2H); 7.95(d, J = 8.4
Hz, 2H)
3(dd, J = 6.9 18Hz, 1H); 3.7(dd, J = 12.6.18Hz,
1H); 4.7(broad s, 2H); 5.4(dd, J = 6.9, 12.6Hz, 1H);
7.0(m, 4H); 7.2(m, 1H); 7.7(d, J = 9Hz, 2H)
2.9-3.0(dd + s, 4H); 3.85(dd ,J = 12.6, 18.3Hz, 1H)
5.8(dd, J = 6.6, 12.6Hz, 1H); 7.0(2d, J = 9Hz, 3H);
7.2(d,J = 9Hz, 1H); 7.5(s, 1H); 7.8(d, J = 9Hz, 2H)
2.95(dd, J = 6.3, 18.3Hz, 1H); 3.8(dd, J = 12.3,
18.3Hz, 1H); 4.8(s, 2H); 5.8(dd, J = 6.3, 12.3Hz,
1H); 7.0(2d, 3H); 7.2(d, J = 8.7Hz, 1H); 7.5(s, 1H);
7.7(d, J = 8.1Hz, 2H)
(d6-DMSO), 2.4(s, 3H);2.9(dd, J = 6.3, 18Hz, 1H)
3.9(dd, J = 13.2, 18Hz, 1H); 5.9(dd, J = 6.3, 13.2Hz,
1H); 6.8(broad s, 1H); 7.0(d, J = 9Hz, 2H); 7.1(m,
3H); 7.2(t, 1H); 7.25(d, 1H); 7.6(d, J = 9Hz, 2H)
(d6-DMSO), 2.3(s, 3H); 3(dd, J = 6.3, 18.3Hz, 1H)
3.9(dd, J = 12.6, 18.3Hz, 1H); 5.7(dd, J = 6.3,
12.6Hz, 1H); 7-7.15(m, 5H); 7.25(t, 1H); 7.6(d,
J = 9Hz, 2H)
3.05(dd. J = 6.3, 17.7Hz, 1H); 3.7(dd, J = 12.6,
17.7Hz, 1H); 5.7(dd, J = 6.3, 12.6Hz, 1H); 7-7.2(m,
5H); 7.3(m, 1H); 7.7(d, J = 9Hz, 2H)
3(s, 3H); 3.05(dd, J = 6.6, 17.1Hz, 1H); 3.8(dd,
J = 12.9, 17.1Hz, 1H); 5.75(dd, J = 6.6, 12.9Hz, 1H);
7-7.2(m, 5H); 7.3(m, 1H); 7.75(d, J = 9Hz, 2H)
3(dd, J = 7.2, 16.8Hz, 1H); 3.75(dd, J = 12.9, 16.8Hz,
1H); 4.8(broad s, 2H); 5.4(dd, J = 7.2, 12.9Hz, 1H);
6.9(d, J = 9Hz, 1H); 7.05(m, 4H); 7.4(m, 1H); 7.7(d,
J = 9Hz, 2H)
3(s + dd, 4H); 3.75(dd, J = 12.6, 13.8Hz, 1H); 5.4(dd,
J = 6.9, 12.6Hz, 1H); 6.9-7.1(m, 5H); 7.4(m, 1H);
7.7(d, J = 9Hz, 2H)
3(dd, J = 6.6, 18Hz, 1H); 3.7(s + dd, 4H); 4.75(broad
s, 2H); 5.4(dd, J = 6.6, 12.9Hz, 1H); 6.9(d, J = 8.4Hz,
2H);7.05(d, J = 8.4Hz, 2H); 7.1(d,J = 8.4Hz, 2H);
7.7(d, J = 8.4Hz, 2H)
1
23
BY 8909 C1 2007.02.28
.2
.
., °
(
r)
-1
21
171-3
3376, 3239, 1593,
1500, 1328, 1153
22
134-7
3386, 3265, 1595,
1259, 1159
23
152-4
3334, 3237, 1595,
1331, 1128, 831
24
158-160
3361, 3270, 1593,
1325, 1168, 1140,
821
25
132-5
1595, 1325, 1281,
1135, 774
26
206-8
3329, 3215, 1593,
1509, 1333, 1155,
817
27
120-3
1590, 1508, 1293,
1141
28
195-7
3300, 3210, 1594,
1509, 1330, 1157
29
113-7
1592, 1509, 1298,
1142, 771
30
190-4
3344, 3263, 1596,
1329, 1155, 616
31
206-8
1595, 1290, 1144,
774
32
197-202
3320, 3250, 1594,
1325, 1165
33
136-8
1595, 1512, 1325,
1141, 771
l3) δ,
.
3(dd, J = 6.9.18, 3Hz, 1H); 3.75(dd, J = 12.6, 18.3Hz,
1H); 4.7(broad s, 2H); 5.4(dd, J = 6.9, 12.6Hz, 1H);
7-7.2(m, 4H); 7.3(m, 1H); 7.7(d, J = 8.7Hz, 2H)
(d6-DMSO): 3(dd, J = 6, 18.3Hz, 1H); 3.9(dd,
J = 12.9, 18.3Hz, 1H); 5.9(dd, J = 6, 12.9Hz, 1H);
7.05(d, J = 8.7Hz, 2H); 7.1(broad s, 2H); 7.4(s, 4H);
7.6(d, J = 8.7Hz, 2H)
3.05(dd, J = 6.6, 18.6Hz, 1H); 3.8(dd, J = 12.9,
18.6Hz, 1H); 4.7(broad s, 2H); 5.7(dd, J = 6.6,
12.9Hz, 1H); 6.8(m, 1H); 7-7.2(m, 4H); 7.7(d,
J = 7.8Hz, 2H)
2.3(s, 3H); 2.4(s, 3H); 2.9(dd, J = 6.9, 17.7Hz, 1H);
3.8(dd, J = 12.9, 17.7Hz, 1H); 4.7(broad s, 2H);
5.6(dd, J = 6.9, 12.9Hz, 1H); 6.8-7.0(m, 4H); 7.1(s,
1H);7.7(d, J = 8.4Hz, 2H)
3(s + dd, 4H); 3.8(dd, J = 6.6, 18Hz, 1H); 5.45(dd,
J = 12.6, 18Hz, 1H); 6.9-7.05(m, 4H); 7.2(m, 1H);
7.75(d, J = 9Hz, 2H)
(d6-DMSO): 2(s, 3H); 2.65(dd, J = 5.6, 20Hz, 1H);
3.55(dd, J = 12.6, 20Hz, 1H); 5.35(dd, J = 5.6.
12.6Hz, 1H); 6.8(d, J = 8.4Hz, 2H); 6.95(s, 2H); 7.17.25(m, 4H); 7.5(d, J = 8.4Hz, 2H)
2.1(s, 3H); 2.7(dd, J = 6, 18.3Hz, 1H); 2.95(s, 3H);
3.5(dd, J = 12, 18.3Hz, 1H); 5.1(dd, J = 6, 12Hz, 1H);
6.9(d, J = 9Hz, 2H); 7(m, 2H); 7.2(m, 2H); 7.6(d,
J = 9Hz, 2H)
(d4-CH3OH): 2(s, 3H); 2.2(s, 3H); 2.6(dd, J = 5.4;
17.7Hz, 1H); 3.5(dd, J = 11.7, 17.7Hz, 1H); 5.3(dd,
J = 5.4, 11.7Hz, 1H); 6.8(d, J = 8.7Hz, 2H) 6.9(s,
2H); 7.1(m, 4H); 7.5(d, J = 8.7Hz, 2H)
2.1(s, 3H); 2.3(s, 3H); 2.7(dd, J = 6.3, 20Hz, 1H)
2.95(s, 3H); 3.5(dd, J = 13, 20Hz, 1H); 5.1(dd,
J = 6.3, 13Hz. 1H); 6.9(d, J = 9Hz, 2H); 7.1(m,
4H);7.6(d, J = 9Hz, 2H)
(d4-CH3OH): 2.9(dd, J = 6.18, 3Hz, 1H); 3.7(dd,
J = 12, 18.3Hz, 1H); 5.3(dd, J = 6, 12Hz, 1H); 7.1(m,
3H); 7.4(m, 5H); 7.7(d, J = 8.7Hz, 2H)
2.9(s + dd, 4H); 3.6(dd, J = 12.3, 18.3Hz, 1H);
5.1(dd, J = 6.3, 12.3Hz, 1H); 6.9(s, 1H); 7(d, J = 9Hz,
2H); 7.3(m, 5H); 7.7(d, J = 9Hz, 2H)
(d6-DMSO): 2(s, 3H); 2.7(dd, J = 5.4, 18Hz, 1H);
3.6(dd, J = 12, 18Hz, 1H); 5.5(dd, J = 5.4, 12Hz, 1H);
6.85(d, J = 8.1Hz, 2H); 7(s, 2H); 7.4(d, J = 8.1Hz,
2H); 7.5(d, J = 8.1Hz, 2H); 7.7(d, J = 8.1Hz, 2H)
2.1(s, 3H); 2.7(dd, J = 6.3, 19Hz, 1H); 3(s, 3H);
3.5(dd, J = 12.6.19Hz, 1H); 5.2(dd, J = 6.3, 12.6Hz,
1H); 6.9(d, J = 8.4Hz, 2H); 7.35(d, J = 8.4Hz, 2H);
7.6(2d, 4H)
1
24
BY 8909 C1 2007.02.28
.2
.
., °
(
r)
-1
34
172-6
3304, 3237, 1706,
1326, 1138,
35
157-164
3247, 1700, 1595,
1333, 1150, 1098
36
202-5
1730, 1582, 1275,
1206, 1134, 1087
37
192-7
3306, 3231, 1706,
1324, 1158
38
84-90
3308, 3224, 1700,
1317, 1147, 1094
39
155-160
1741, 1561, 1260,
1226, 1135, 1089
40
200-5
3431, 3285, 1647,
1592, 1328, 1142
41
210-5
3450, 3337, 1656,
1596, 1345, 1141
42
128-132
3440, 3200, 1680,
1590, 1135
43
162-4
2220, 1593, 1500,
1389, 1296, 1143
152-5
3316, 3240, 1594,
1323, 1178, 1121,
1065, 549
170-5
3360, 3267, 1595,
1507, 1329, 1255,
1159, 619
46
108-114
3383, 2270, 1595,
1519, 1329, 1277,
1160, 1066
47
157-9
3357, 3267, 1630
1595, 1508, 1330,
1264, 1158, 1066
44
45
l3) δ,
.
(d4-CH3OH): 2.35(s, 3H); 3.05(dd, J = 6.6, 18.6Hz,
1H); 3.8(dd, J = 12.6, 18.6Hz, 1H); 5.5(dd, J = 6.6,
12.6Hz, 1H); 7.2(m, 6H), 7.7(d, J = 9Hz, 2H)
(d4-CH3OH): 3.1(dd, J = 6, 18.3Hz, 1H); 3.9(dd,
J = 12.6, 18.3Hz, 1H); 5.7(dd, J = 6, 12.6Hz, 1H);
7.2-7.5(m, 7H); 7.7(d, J = 8.7Hz, 2H)
(d6-DMSO): 2.2(s, 3H); 2.8(dd, J = 6.3, 18Hz, 1H);
3.05(s, 3H); 3.8(dd, J = 12.6, 18Hz, 1H); 5.7(dd,
J = 6.3, 12.6Hz, 1H); 7.2(m, 6H); 7.7(d, J = 9Hz,
2H); 13.2(broad s, 1H)
2.2(s, 3H); 3(dd, J = 6.3, 18Hz, 1H); 3.2(broad s,
2H); 3.65(dd, J = 12.6, 18Hz, 1H); 3.8(s, 3H); 5.4(dd,
J = 6.3, 12.6Hz, 1H); 7-7.1(m, 6H); 7.6(d, J = 8.7Hz,
2H)
(d4-CH3OH): 3.1(dd, J = 6, 18.3Hz, 1H); 3.9(s + dd,
4H); 5.7(dd, J = 6, 12.9Hz, 1H); 7.2-7.4(m, 7H);
7.75(d, J = 8.7Hz, 2H)
2.3(s, 3H); 3(s, 3H); 3.1(dd, J = 6, 18.3Hz, 1H);
3.75(dd, J = 12.6, 18.3Hz, 1H); 5.4(dd, J = 6, 12.6Hz,
1H); 7-7.25(m, 6H); 7.7(d, J = 8.7Hz, 2H)
(d4-CH3OH): 3.1(dd, J = 6, 18.3Hz, 1H); 3.9 (dd,
J = 12.9, 18.3Hz, 1H); 5.7(dd, J = 6.12.9Hz, 1H); 7.27.5(m, 7H); 7.75(d, J = 8.7Hz, 2H)
(d4-CH3OH): 2.4(s, 3H); 3.05(dd, J = 6, 17.7Hz, 1H);
3.8(dd, J = 12.9, 17.7Hz, 1H); 5.6(dd, J = 6, 12.9Hz,
1H); 7.2-7.3(m, 6H); 7.75(d, J = 8.7Hz, 2H)
2.3(s, 3H); 3(s, 3H); 3.1(dd, J = 6.3, 18.6Hz, 1H);
3.8(dd, J = 12.6, 18.6Hz, 1H); 5.4(dd, J = 6.3,
12.6Hz, 1H); 5.6(broad s, 1H); 6.7(broad s, 1H); 77.2(m, 6H); 7.7(d, J = 8.7Hz, 2H)
2.3(s, 3H); 3-3.1(s + dd, 4H); 3.75(dd, J = 12.6,
18Hz, 1H); 5.5(dd, J = 6.3, 12.6Hz, 1H); 7-7.2(m,
); 7.7 (d, J = 8.7Hz, 2H)
2.2(s, 6H); 3(dd, J = 6.3, 18.3Hz, 1H); 3.7(dd,
J = 12.6, 18.3Hz, 1H); 4.7(broad s, 2H); 5.4(dd,
J = 6.3, 12.6Hz, 1H); 6.95(s + d, J = 7.8Hz, 2H);
7.1(2d, J = 7.8, 8.7Hz, 3H); 7.7(d, J = 8.7Hz, 2H)
2.2(s, 3H); 3(dd, J = 7.2, 18Hz, 1H); 3.6-3.8(s + dd
,4H); 4.6(broad s, 2H); 5.35(dd, J = 7.2, 12.9Hz, 1H);
6.75(d, J = 7.8Hz, 1H); 7(s + d, 2H); 7.1(d,
J = 8.7Hz, 2H); 7.7(d, J = 8.7Hz, 2H)
3(dd, J = 6.6, 18.3Hz, 1H); 3.75(dd, J = 12.3, 18.3Hz,
1H); 3.9(s, 3H); 5.4(dd, J = 6.6, 12.3Hz, 1H); 6.95(m,
3H); 7.05(d, J = 8.7Hz, 2H); 7.7(d, J = 8.7Hz, 2H)
3.05(dd, J = 6.3, 18Hz, 1H); 3.7-3.8(s + dd, 4H);
4.8(broad s, 2H); 5.7(dd, J = 6.3, 12.9Hz, 1H); 6.66.7(m, 2H);6.95(t, J = 8.7Hz, 1H); 7.05(d, J = 9Hz,
2H); 7.7(d, J = 9Hz, 2H)
1
25
BY 8909 C1 2007.02.28
.2
.
., °
(
r)
-1
48
121-6
3376, 3268, 1593,
1507, 1329, 1160
49
179-82
3317, 3231, 1593,
1507, 1326, 1178
50
181-3
3348, 3268, 1593,
1321, 1165
51
159-61
3382, 3285, 1595,
1514, 1328, 1161
52
167-9
3318, 3239, 1593,
1503, 1492, 1321,
1068
53
170-3
3425, 3284, 1595,
1330, 1138
54
212-4
3376, 3277, 1597,
1332, 1274, 1132
55
193-5
3353,3270, 1593,
1509, 1321, 1141
56
148-50
3384, 3266, 1593,
1324, 1252, 1166
57
157-60
3384, 3346, 3277,
3255, 1596, 1503,
1341, 1158
58
174-7
3384, 3261, 1596,
1329, 1117
59
105-6
1596, 1510, 1314,
1264, 1150, 845
60
157-9
3354, 3268, 1594,
1325, 1122, 753
l3) δ,
.
2.9(dd, J = 6, 18Hz, 1H); 3.65(dd, J = 12.6, 18Hz,
1H); 3.75(s, 3H); 3.85(s, 3H); 4.9(s, 2H); 5.65(dd,
J = 6, 12.6Hz, 1H); 6.35(d, J = 8.7Hz, 1H) 6.5(s, 1H);
6.9(d, J = 8.7Hz, 1H); 7(d, J = 8.7Hz, 2H);7.7(d,
J = 8.7Hz, 2H)
(d6-DMSO): 2.95(dd, J = 5.4, 18Hz, 1H); 3.7-3.8(m,
4H); 5.8(dd, J = 5.4, 12.6Hz, 1H); 6,7(dd, J = 8.1,
10.5Hz, 1H); 6.9-7.1 (m, 6H); 7.6(d, J = 8.7Hz, 2H)
2.25(s, 3H); 2.35(s, 3H); 2.85(dd, J = 6.9, 18Hz, 1H);
3.7(dd, J = 12.6, 18Hz, 1H); 5.45(dd, J = 6.9, 12.6Hz,
1H); 6.5(t, J = 54Hz, 1H); 6.8-6.9(m, 4H); 7(s, 1H);
7.65(d, J = 9Hz, 2H)
3(dd, J = 6.3, 17.7Hz, 1H); 3.8(dd, J = 12.6, 17.7Hz,
1H); 4.7(s, 2H); 5.7(dd, J = 6.3, 12.6Hz, 1H); 6.8(m,
1H); 6.9(m, 1H); 7(d, J = 9Hz, 2H); 7.75(d, J = 9Hz, 2H)
(d6-DMSO): 3(dd, J = 6.3, 18.3Hz, 1H); 3.95(dd,
12.9, 18.3Hz, 1H); 5.95(dd, J = 6.3, 12.9Hz, 1H);
7(d, J = 8.7Hz, 2H); 7.1-7.2(m, 4H); 7.55(d,
J = 8.4Hz, 1H);7.65(d, J = 8.7Hz, 2H)
(d6-DMSO): 3.2(dd, J = 5.7, 18Hz, 1H); 3.9(dd,
J = 12.9, 18Hz, 1H); 6(dd, J = 5.7, 12.9Hz, 1H);
7.1(m,4H); 7.4-7.7(m, 4H); 7.8(d, J = 10.8Hz, 1H)
2.8(dd, J = 6.3, 18.5Hz, 1H); 3.7(dd, J = 13, 18.5Hz,
1H); 5.75(dd, J = 6.3, 13Hz, 1H); 6.1(s, 2H); 6.8(d,
J = 8.5Hz, 2H); 7.2(d, J = 8.3Hz, 1H); 7.6(d,
J = 8.5Hz, 2H); 7.65(d, J = 8.3Hz, 1H); 7.9(s, 1H)
(d6-DMSO): 2.3(s, 3H); 2.9(dd, J = 6.1, 12.2Hz,
1H); 3.95(dd, J = 12.2, 12.9Hz, 1H); 5.95(dd, J = 6.1,
12.9Hz, 1H); 6.65(broad s, 1H); 7(d, J = 8.8Hz, 2H);
7.1-7.2(m, 4H); 7.65(d, J = 8.8Hz, 2H)
2.35(s, 3H); 2.9(dd, J = 5.6, 18Hz, 1H); 3.7-3.8(m,
4H); 4.9(broad peak, 2H); 5.5(dd, J = 5.6, 12.6Hz,
1H); 6.6(dd, J = 2.2, 8.5Hz, 1H); 6.8(s, 1H); 6.856.95(2d, 3H); 7.7(d, J = 9Hz, 2H)
3(dd, J = 6.1, 17.8Hz, 1H); 3.7(dd, J = 12.4, 17.8Hz,
1H); 4.75(s, 2H); 5.6(dd, J = 6.1, 12.4Hz, 1H); 6.5(t,
J = 54Hz, 1H); 6.8-7(m, 5H); 7.7(d, J = 8.8Hz, 2H)
2.95(dd, J = 5.6, 17.3Hz, 1H); 3.75(dd, J = 12.4,
17.3Hz, 1H); 4.7(broad s, 2H); 5.8(dd, J = 5.6,
12.4Hz, 1H); 6.95(d, J = 8.3Hz, 2H); 7.2(m, 2H);
7.5(d, J = 7.5Hz, 1H); 7.75(d, J = 8.3Hz, 2H)
3(s + dd, 4H); 3.6(dd, J = 12.2, 17.6Hz, 1H); 5.6(dd,
J = 6.2, 12.2Hz, 1H); 6.65(t, J = 9Hz, 1H); 6.75(t,
J = 8Hz, 1H); 7.35(m, 3H); 7.8(d, J = 8.3Hz, 2H)
2.95(dd, J = 6.6, 18.5Hz, 1H); 3.85(dd, J = 12.7,
18.5Hz, 1H); 4.8(s, 2H); 5.8(dd, J = 6.6, 12.7Hz,
1H); 6.9-7(m, 3H); 7.1-7.3(m, 2H); 7.45(d,
J = 7.8Hz, 1H); 7.7(d, J = 8.6Hz, 2H)
1
26
BY 8909 C1 2007.02.28
.2
.
., °
(
r)
-1
61
180-5
3407, 3295, 1593,
1334, 1161
62
154-60
3406, 3262, 1593,
1330, 1155
63
166-7
3430, 3298, 1593,
1508, 1334, 1161,
1123
64
172-4
3302, 1722, 1593,
1506, 1337, 1165
65
117-21
1594, 1492, 1310,
1257, 1154, 1063
66
114-5
1598, 1503, 1275,
1156, 1079, 749
67
98-9
1606, 1503, 1317,
1148, 1123, 762
68
104-8
1617, 1496, 1310,
1253, 1154, 1113,
809
69
116-7
1616, 1587, 1498,
1310, 1155, 828
70
114-6
1597, 1315, 1149,
1072, 959, 789
71
132-3
1601, 1509, 1314,
1154, 1113, 809
72
l3) δ,
.
(d4-CH3OH): 3.2(dd, J = 6.3, 18.1Hz, 1H); 3.95(dd,
J = 12.9, 18.1Hz, 1H); 6(dd, J = 6.3, 12.9Hz, 1H);
7.2(d, J = 8.8Hz, 2H); 7.3(m, 2H); 7.4(d, J = 10.3Hz,
1H); 7.8(d, J = 8..8Hz, 2H)
2.4(s, 3H); 2.9(dd, J = 6.6, 17.8Hz, 1H); 3.75(dd,
J = 12.7, 17.8Hz, 1H); 4.8(s, 2H); 5.5(dd, J = 6.6,
12.7Hz, 1H); 6.8-7(m, 5H); 7.7(d, J = 8.8Hz, 2H)
2.3(s, 3H); 3(dd, J = 6.3, 18.3Hz, 1H); 3.75(dd,
J = 12.7, 18.3Hz, 1H); 4.65(s, 2H); 5.7(dd, J = 6.3,
12.7Hz, 1H); 6.85-7(m, 3H); 7.05(d, J = 8.8Hz, 2H);
7.7(d, J = 8.8Hz, 2H)
2(s, 3H); 3(dd, J = 6.6, 18Hz, 1H); 3.8(dd, J = 12.9,
18Hz, 1H); 5.7(dd, J = 6.6, 12.9Hz, 1H); 6.8-6.95(m,
2H); 7-7.1(m, 3H); 7.85(d, J = 8.7Hz, 2H);8.1(s, 1H)
2.95(dd, J = 7.3, 17.8Hz, 1H); 3(s, 3H); 3.7 (dd,
J = 12.7, 17.8Hz, 1H); 5.45(dd, J = 7.3, 12.7Hz, 1H);
6.8(d, J = 8.8Hz, 2H); 7.1(d, J = 8.8Hz, 2H); 7.4(d,
J = 8.3Hz, 2H); 7.9(d, J = 8.3Hz, 2H)
2.95(dd, J = 7.6, 17.8Hz, 1H); 3(s, 3H); 3.7 (dd,
J = 12.7, 17.8Hz, 1H); 5.45(dd, J = 7.6, 12.7Hz, 1H);
6.9(m, 3H); 7.15(t, J = 7.8Hz, 2H); 7.4(d, J = 8.1Hz,
2H); 7.9(d, J = 8.1Hz, 2H)
3(s + dd, 4H); 3.65(dd, J = 13.1, 17.1 Hz, 1H);
5,8(dd, J = 7.6, 13.1Hz, 1H); 6.9(m, 2H); 7(t,
J = 8.1Hz, 1H); 7.3(d, J = 8.1Hz, 2H); 7.45(t,
J = 8.3Hz, 1H); 7.8(d, J = 8.1Hz, 2H)
2.3(s, 3H); 3(m, 4H); 3.5(dd, J = 11.7, 17.1Hz, 1H);
5.45(t, J = 11.7Hz, 1H); 6.75(d, J = 8.5Hz, 1H); 7 (d,
J = 8.5Hz, 1H); 7.1(s, 1H); 7.45(d, J = 8Hz, 2H);
7.9(d, J = 8Hz, 2H)
2.9(dd, J = 7.5, 16.8Hz, 1H); 3(s, 3H); 3.7(dd,
J = 12.7, 16.8Hz, 1H); 5.4(dd, J = 7.5, 12.7Hz, 1H);
6.6(m, 2H); 6.7(d, J = 11Hz, 1H); 7.1(dd, J = 7.6,
14.9Hz, 1H); 7.4(d, J = 8Hz, 2H); 7.9(d, J = 8Hz, 2H)
2.25(s, 3H); 2.9(dd, J = 7.6, 17.8Hz, 1H); 3(s, 3H);
3.7(dd, J = 12.9, 17.8Hz, 1H); 5.45(dd, J = 7.6,
12.9Hz, 1H); 6.6(d, J = 7.8Hz, 1H); 6.7(d, J = 7.8Hz,
1H); 6.9(s, 1H); 7(t, J = 7.8Hz, 1H); 7.45(d, J = 8Hz,
2H); 7.9(d, J = 8Hz, 2H)
2.2(s, 3H); 2.3(s, 3H); 3(m, 4H); 3.5(dd, J = 11.7,
16.6Hz, 1H); 5.4(t, J = 11.7Hz, 1H); 6.8(m,2H);
6.9(s, 1H); 7.5(d, J = 8Hz, 2H); 7.85(d, J = 8Hz, 2H)
2.95(s, 3H); 3.15(dd, J = 6.5, 17.8Hz, 1H); 3.65(dd,
J = 12.7, 17.8Hz, 1H); 5.95(dd, J = 6.5, 12.7Hz, 1H);
6.95(d, J = 7.8Hz, 1H); 7.1(t, J = 7.3Hz, 1H); 7.2(m,
2H); 7.35(d, J = 8.3Hz, 2H); 7.8(d, J = 8.3Hz, 2H)
1
27
BY 8909 C1 2007.02.28
.2
.
., °
(
r)
-1
73
1625, 1483, 1312,
1150, 1130, 819
74
103-6
75
173-4
76
173-4
77
113-5
1508, 1315, 1155,
1133, 1067, 831
78
113-4
1508, 1315, 1155,
1133, 1067, 827
3330, 3250, 1617,
1593, 1506, 1329,
1121, 1099, 855
3330, 3250, 1617,
1593, 1506, 1329,
1121, 1099, 855
1603, 1318, 1148,
1060, 955, 760
79
1
. 2
, broad s ,J,
st-
l3) δ,
.
2.3(s, 3H); 3(s + dd, 4H); 3.5(dd, J = 11.7, 17.8Hz,
1H); 5.5(t, J = 11.7Hz, 1H); 6.85(d, J = 7.8Hz, 1H);
7(m, 2H); 7.1(d, J = 6.1Hz, 1H); 7.5(d, J = 8.3Hz,
2H); 7.85(d, J = 8.3Hz, 2H)
3(s, 3H); 3.15(dd, J = 5.9, 17.8Hz, 1H); 3.7(dd,
J = 11.7, 17.8Hz, 1H); 5.95(dd, J = 5.9, 11.7Hz, 1H);
7.05(d, J = 8.8Hz, 1H); 7.2(m, 2H); 7.3(d, J = 8.1Hz,
2H); 7.8(d, J = 8.1Hz, 2H)
3(dd, J = 6.3, 11.4Hz, 1H); 3.8(dd, J = 11.4. 12.6Hz,
1H); 4.8(broad s, 2H); 5.7(dd, J = 6.3, 12.6Hz, 1H);
6.8-6.95(m, 2H); 7-7.1(m, 3H); 7.7(d, J = 8.7Hz, 2H)
3(dd, J = 6.3, 11.4Hz, 1H); 3.8(dd, J = 11.4, 12.6Hz,
1H); 4.8(broad s, 2H); 5.7(dd, J = 6.3, 12.6Hz, 1H);
6.8-6.95(m, 2H); 7-7.1(m, 3H); 7.7(d, J = 8.7Hz, 2H)
2.9(dd, J = 8.4, 17.4Hz, 1H); 3(s, 3H); 3.7(dd,
J = 12.6, 17.4Hz, 1H); 5.4(dd, J = 8.4, 12.6Hz, 1H);
6.9(m, 4H); 7.45(d, J = 8.4Hz, 2H); 7.95(d,
J = 8.4Hz, 2H)
2.9(dd, J = 8.4, 17.4Hz, 1H); 3(s, 3H); 3.7(dd,
J = 12.6, 17.4Hz, 1H); 5.4(dd, J = 8.4, 12.6Hz, 1H);
6.9(m, 4H); 7.45(d, J = 8.4Hz, 2H); 7.95(d,
J = 8.4Hz, 2H)
3(s, 3H); 3.1(dd, J = 8.8, 16.4Hz, 1H); 3.6(dd,
J = 12.7, 16.4Hz, 1H); 5.6(dd, J = 8.8, 12.7Hz, 1H);
7(d, J = 7.8Hz, 1H); 7.15(t, J = 8.1Hz, 1H); 7.3(t,
J = 8.1Hz, 1H); 7.4(d, J = 8.3Hz, 2H); 7.6(d,
J = 7.8Hz, 1H); 7.8(d, J = 8.3Hz, 2H)
1
,d-
, dd -
:
,
,m, Hz -
(
).
,
-2
,
,
.
-
.
,
-2,
.
. TofanetLi et al. (Med. Sci. Res. 1989, 17, 745-746).
40
.
,
,
.
.
,
PGE2
.
,
28
-
PGE2
-
BY 8909 C1 2007.02.28
-2,
-1,
,
PGEn
,
-1.
.3
,
ED50 (50 %-
3,
.
),
.4
-
,
.
3
-2/
40
3
,
-1 in vivo
PGE2, %
)
92
91
93
0
65
0
4
ED50
-2/
PGE2, ED50 (
3
-1 in vivo
,
3,6
11,0
>40
>40
"
,
)
",
. Hargreaves et al. Pain, 1988, 32, 77-78.
.
40
,
.
,
-
.
.
,
,
,
.5
3,
,
.
,
.6
,
-
ED50,
,
-2,
.
5
,
(
40
,
)
,%
3
100
97
95
29
BY 8909 C1 2007.02.28
6
ED50
,
ED50 (
,
0,2
1,0
2,1
3
(GI):
)
,
-
.
Rainsford K.D. (Agents and Actions, 1975, 5, 553-55S).
.
-15 °
1 .
1
.
,
.
15
.
-
Project C.S.V. vs 1.2.
,
,
.
,
3,
. 7.
-
,
,
,
-2.
-1,
,
,
-
.
7
,
,
3
)
>80
1,2
1,7
3
.
Jaffee B.J. et al. Agents and Actions, 1989, 27,
(
Mycobacterium butiricum
.
14
,
,
-
,
344-346.
)
,
.
10
11
3
.
-
.
,
3,
5
.
,
3
,
10
71 %.
30
-
BY 8909 C1 2007.02.28
,
,
,
,
,
.
.
100
,
400
.
,
,
,
,
.
3
50
16
1
1
3
4
25
200
-90 (Povidone K-90)
3
100
20
2
4
200
.
220034, .
,
.
-
.
, 20.
31
-
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