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BY (11) 8203
(13) C1
(46) 2006.06.30
(19)
(12)
7
(51) C 07D 409/06,
A 61K 31/38,
A 61P 29/02
,
(54)
(21)
: a 20001019
(22) 1999.04.15
(31) P 9800793 (32) 1998.04.15 (33) ES
(85) 2000.11.15
(86) PCT/ES99/00098, 1999.04.15
(87) WO 99/52525, 1999.10.21
(43) 2001.06.30
(71)
:
.
,
. (ES)
(72)
:
,
:
(73)
.
,
(56) EP 0289380 A1, 1988.
RU 96117979 , 1998.
(57)
1.
;
-
. (ES)
I:
R
2
R1
Az
,
O
S
R3
N
(I)
R4
R4
1
BY 8203 C1 2006.06.30
,
;
(ES)
,
R
R2, R3
Az
,
,
1
R4
,
4
1
4
N,
Z1
III:
Z2
Z3
,
N
Z1, Z2
,
(III)
CH3
Z3
,
2.
.
,
. 1,
,
.
3.
. 1,
,
,
,
5-{α-[2-(
5-{α-[2-(
5-{α-[2-(
2-{α-[2-(
]-2]-2]-3]-2-
}-1}-1}-1}-1-
-1
-1
-1
-1
,
,
,
,
-
BY 8203 C1 2006.06.30
5-{α-[2-(
5-{α-[2-(
5-{α-[2-(
5-{α-[2-(
5-{1-[2-(
(+)- 5-{α-[2-(
(-)-5-{α-[2-(
(+)-5-{α-[2-(
(-)-5-{α-[2-(
(+)-5-{α-[2-(
]-3]-5]-5]-4]-1-(2]-2]-2]-2]-2]-2-
(-)-5-{α-[2-(
.
4.
. 1,
-2-2-2-2-
}-1}-1}-1}-1}-1-1
}-1-1
}-1-1
}-1-1
}-1-1
}-1-1
]-2-
}-1-
-1
-1
-1
-1
,
,
,
,
,
,
,
,
,
-1
-D-
-
-D-
I
IV:
R2
R1
1
R ,R
Az
Az
.1
V:
R3
R R
5.
. 1,
(V)
R4
N
4
,
,
X
3
(IV)
OH
S
2
,
R4
.1
.
I
VI:
R2
R1
Az
Az
(VI)
Y
S
R1, R2
,
.1
,Y
,
,
VII:
R4
HO
N
R3
3
4
R R
6.
.1
.1
,
(VII)
R4
.
I
-
,
I
,
.
7.
I
. 1,
I
-
.
8.
,
,
,
,
,
2
,
-
BY 8203 C1 2006.06.30
I
-
. 1-3
.
9.
I
. 1-3
,
,
,
.
10.
IV:
R2
R1
R1
.1
, Az
I
11.
5-{α
5-{α
5-{α
5-{α
5-{α
5-[112.
,
,
}-1-
-1
}-1}-1}-1}-1-1
-2-2-2-2]-1-
,
,
,
,
.
IV
Az
,
R2
. 10,
VIII:
-
(VIII)
O
S
.1
Az
N-
. 12,
.
,
,
,
-
.
14.
IV
IX:
R
1
R2
,
. 10,
-
(IX)
O
S
R2
-
,
-1
-1
-1
-1
,
R1
-
,
R1
R1
13.
VIII
N-
. 1.
. 10,
,
-2-3-5-5-4-1-(2-
(IV)
OH
S
R2
,
Az
.1
,
:
Az - M,
Az
N-
,
MgX
,
.
15.
IV
X:
-
R2
Az
,
R2
. 10,
(X)
O
.1
Az
N-
,
XI:
R1
M
S
3
,
(XI)
-
BY 8203 C1 2006.06.30
R1
MgX
.1
,
.
,
I,
,
,
.
2
R
R1
Az
(I)
O
S
R3
N
R4
R4
,
,
-
.
IV,
I.
289380
II:
R1
Het
,
(II)
O
R2
1
; R2
R
Het
-
.
,
I,
.
.
,
,
.
.
,
,
I:
R2
R1
Az
S
,,
O
R3
N
R4
4
R4
(I)
BY 8203 C1 2006.06.30
R1
R , R R4
Az
,
2
,
C1-C4
3
C1-C4
;
;
N,
Z1
,
N
2
Z,Z
(III)
CH3
3
Z
,
III:
Z2
Z3
1
-
CH
Z1, Z2
,
Z3
CH.
.
,
I
(
)
.
,
,
.
I
-
,
,
-
I
.
,
-
.
I,
,
,
,
,
,
,
,
,
,
,
-
,
,
,
.
,
[1] 5-{α-[2-(
[2] 5-{α-[2-(
[3] 5-{α-[2-(
[4] 2-{α-[2-(
[5] 5-{α-[2-(
[6] 5-{α-[2-(
[7] 5-{α-[2-(
[8] 5-{α-[2-(
[9] 5-{1-[2-(
[10] (+)-5-{α-[2-(
[11] (-)-5-{α-[2-(
[12] (+)-5-{α-[2-(
[13] (-)-5-{α-[2-(
[14] (+)-5-{α-[2-(
;
[15] (-)-5-{α-[2-(
.
,
:
]-2]-2]-3]-2]-3-2]-5-2]-5-2]-4-2]-1-(2]-2]-2]-2]-2]-2]-2-
IV:
5
I,
}-1}-1}-1}-1-
-1
;
-1
-1
;
-1
;
}-1-1
}-1-1
}-1-1
}-1-1
}-1-1
;
}-1-1
;
}-1-1
;
}-1-1
}-1-1
}-1-1
}-1-
-1
;
-D-
;
;
;
;
;
;
-D- -
BY 8203 C1 2006.06.30
R2
R1
,
R
Az
C1-C4
N-
(IV)
OH
S
R1
2
,
Az
C1-C4
;
;
,
I.
,
IV,
[16] 5-(α
[17] 5-(α
[18] 5-(α
[19] 5-(α
[20] 5-(α
[21] 5-[1-
-
,
:
-2-3-2-5-2-5-2-4-2-1-(-2-
)-1-
-1
)-1)-1)-1)-1]-1-1
;
-1
-1
-1
-1
;
;
;
;
.
I,
,
:
IV:
R2
R1
(IV)
Az
S
OH
V:
R4
X
N
3
R
1
4
R -R
,
(V)
4
R
, Az
,
N,
III
X
-
,
,
,
.
IV
V,
,
,
,
,
-
,
,
,
,
-
,
,
.
,
,
,
-
,
.
,
,
,
.
VI:
6
-
BY 8203 C1 2006.06.30
R2
R1
(VI)
Az
Y
S
VII:
R4
HO
N
R
1
3
,
(VII)
4
R
4
R -R
, Az
,
N,
III
-
,
-
Y
,
,
,
.
VI
VII,
,
,
,
,
,
,
,
,
-
,
,
,
.
,
,
,
,
,
-
.
,
,
,
.
Y
-
,
,
,
,
-
,
.
VIII:
R1
Az
,
(VIII)
O
S
R1
Az
NIV,
,
R2
-
.
VIII
,
,
,
.
,
,
,
,
,
,
,
,
,
-
,
,
,
,
,
-
,
.
1,01
7
BY 8203 C1 2006.06.30
20,2
(
1
20
20 °
),
1-24
100 °
.
IV
,
-
,
IX:
R1
R2
(IX)
O
S
:
R1
Az-M,
, Az
MgX
R2
N-
M
,
X
,
.
X:
R2
Az
(X)
O
XI:
R1
M
,
(XI)
S
R1, R2
, Az
N-
M
MgX
,
X
,
.
I
I
,
,
,
,
,
,
,
,
,
,
,
,
,
,
-
,
.,
,
,
-
,
,
.
E
I
,
,
-
,
-
,
I
,
,
,
,
,
,
.
,
,
,
,
,
,
0,5 % - 50 %.
,
(-)-
8
BY 8203 C1 2006.06.30
-L-
(+)-
-D-
,
,
,
,
.
,
,
,
,
,
,
,
,
,
,
,
,
,
, 1,2-
,
, 1,4-
,
,
,
.
-20 °
.
,
,
I(
1:1)
,
I (
,
.
-
,
,
-
),
.
,
,
,
,
-
,
,
-
I
.
-
I
,
,
.
,
.
-
.
,
,
,
.
.
5-{α-[2-(
18 5-(α
-2, 150
1.
]-2)-150 %-
}-1-
-1
-1
, 26,7 N-(2NaOH, 300
24-
.
.
5-{α-[2-(
]-2-
}-1-
21,4
-1
,
,
. 1.
(87 %)
,
,
1
.
3-9,
-
1,
5-{α-[2-(
8,7 5-(α
0,5
8
1.
]-2-2-
)-1-
}-1-1
-1
, 6,23 2-(
80
.
9
,
BY 8203 C1 2006.06.30
,
.
1-
-1
4,7
(40 %) 5-{α-[2-(
}-
]-2-
.
,
3-9,
,
. 1.
-
1,
5-(α
16.
)-1-
-2-
-1
3,2
)-1-
-1
.
3,2
100
5-(α
-21
-
.
2,9
)-1-1
17-20,
(90 %)
.
,
.
,
,
5-(α
-2-
,
,
. 3.
-
16,
5-(α
1,6 M
-5 °
100
-78 °
100
16.
)-1-
-2-
-1
11,6
N-
.
15,9
2-
.
4-20 °
100
.
.
,
1-
-1
23,5 (85 %)
.
,
,
. 3.
-
.
,
5-(α
-2-
17-21,
.
)-
16,
5-{α-[2-(
16,2
20,5 5-{α-[2-(
]-2.
31 (88 %) 5-{α-[2-(
2.
]-2-
}-140
}-1-
-1
]-2-
116 ° .
,
,
-1H-
12
2,
50
}-1-
-1 115-
. 1.
13,
-
. 2.
10
BY 8203 C1 2006.06.30
11.
]-2-
(-)-5-{α-[2-(
(-)'-L16,6 (±)-5-{α-2-[2-(
.
.
.
9,4
,
]-2-
}-112,09
}-1-1
-1
63
5,95
L1
,
,
(
AGP (α
),
0,16
(94:6). 9,2
)
.
30
(0,06
44
(95,4:4,6).
91,3
(0,046
5,55
(97,7:2,3).
(0,023
)
)]-215)
)
}-1-
-1
98,5 % (97 %AGP (α
(-)-5-{α-[2-(
).
-1
-L)-
]-2-
-
158
}-1-
-1
)
6,8
L-
-
38,1
4,34 (-)-5-{α-[2-L(
130-131 ° ; )
); [α]D = -85,4° ( = 2,0;
)]-2}-1(-)-5-{α-[2; [α]D = -31,8° ( = 2,0,
-
).
,
10
,
11
14,
15,
. 2.
1
:
s
;d
; Hz
;t
;m
.
11
; dd
1
R2
Tfn
Az
O
R3
N
R
-
Tfn
N
R2
H
N
R3
H
R4
CH3
S
CH3
2
N
H
N
H
CH3
S
12
CH3
3
N
H
N
H
CH3
S
CH3
N
4
H
N
S
CH3
H
CH3
T.
. (° )
1
(
)(
)δ
(300
) (CDCl3) 2,24 (s, 6H), 2,54
(t, J = 6 Hz, 2H), 3,58 (m, 2H), 3,79
(s, 3H), 5,76 (s, 1H), 6,17 (d, J = 1,8 Hz,
1H), 6,83 (m, 1H) 6,93 (m, 1H), 7,28
(m, 1H), 7,38 (d, J = 1,8 Hz, 1H)
(300
) ( MCO-d6) 2,51 (AB
, J = 15 Hz, 2H), 2,71 (AB
, J = 15 Hz, 2H), 2,66 (s, 6H),
115-116 3,18 (m, 2H), 3,70-3,80 ( , 5H,
(δ = 3,74, s)), 6,07 (s, 1H), 6,16
(s, 1H), 7,01 (m, 1H), 7,10 (m, 1H),
7,34 (s, 1H) 7,57 (m, 1H)
(300
) (CDCl3) 2,24 (s, 6H), 2,54
(t, J = 6 Hz, 2H), 3,56 (m, 2H), 3,77
(s, 3H), 5,59 (s, 1H), 6,08 (d, J = 1,8 Hz,
1H), 6,99 (dd, J = 5 Hz, J' = 1,2 Hz,
1H), 7,19 (m, 1H), 7,30 (dd, J = 5 Hz,
J' = 3 Hz, 1H), 7,37 (d, J = 1,8 Hz, 1H)
(300
) (CDCl3) 2,24 (s, 6H), 2,56
(m, 2H), 3,54 (m, 1H), 3,56 (s, 3H),
3,67 (m, 1H), 5,90 (s, 1H), 6,77 (m, 1H),
6,85 (d, J = 1,2 Hz, 1H), 6,93 (m, 1H),
6,98 (d, J = 1,2 Hz, 1H), 7,27 (m, 1H)
-1
) 2944, 2863,
2821, 2771, 1457,
1100, 1092, 1066,
1056, 1042, 705, 651
(KBr) 3300-2300
.), 1732, 1589,
1475, 1398, 1380,
1356, 1220, 1203,
1183
) 2942, 2819,
2769, 1456, 1103,
783, 753
) 2943, 2864,
2820, 2770, 1496,
1456, 1278, 1103,
1056, 772, 702
BY 8203 C1 2006.06.30
1
Az
R4
4
CH3
5
N
H
N
CH3
S
CH3
N
N
H3C
H
H
CH3
H
H
CH3
S
CH3
7
N
N
13
Br
S
CH3
Br
8
N
H
N
N
CH3
N
S
CH3
CH3
S
CH3
9
H
H
CH3
) 2944, 2865,
2821, 2772, 1455,
1100, 1092, 1067,
1055, 1042, 782, 715
) 2944, 2863,
2820, 2772, 1456,
1286, 1101, 1092,
1067, 1055, 1042,
798, 783, 762, 652
) 2943, 2864,
2821, 2772, 1441,
1101, 1093, 1066,
1055, 1042, 968, 793,
761,651
) 2994, 2864,
2821, 2772, 1456,
1344, 1101, 1093,
1056, 1042, 780
) 2940, 2819,
2770, 1456, 1369,
1235, 1108, 1041,
930, 699.
BY 8203 C1 2006.06.30
6
H
(300
) (CDCl3) 2,14 (s, 3H), 2,23
(s, 6H), 2,54 (t, J = 6 Hz, 2H), 3,59
(m, 2H), 3,84 (s, 3H), 5,74 (S, 1H),
6,04 (s, 1H), 6,80 (d, J = 5,0 Hz, 1H),
7,18 (d, J = 5,0 Hz, 1H), 7,33 (s, 1H)
(300
) (CDCl3) 2,24 (s, 6H), 2,43
(s, 3H), 2,53 (t, J = 6 Hz, 2H), 3,56
(m, 2H), 3,80 (s, 3H), 5,65 (s, 1H), 6,17
(d, J = 1,5 Hz, 1H), 6,62 (d, J = 2,4 Hz,
1H), 7,37 (d, J = 1,5 Hz, 1H)
(300
) (CDCl3) 2,25 (s, 6H), 2,55
(t, J = 6 Hz, 2H), 3,57 (m, 2H), 3,80
(s, 3H), 5,68 (s, 1H), 6,20 (d, J = 2,1 Hz,
1H), 6,56 (d, J = 4 Hz, 1H), 6,90 (d,
J = 4 Hz, 1H), 7,40 (d, J = 2,1 Hz, 1H)
(300
) (CDCl3) 2,23 (s, 6H), 2,53
(t, J = 5,7 Hz, 2H), 3,57 (m, 2H), 3,78
(s, 3H), 5,72 (s, 1H), 6,18 (d, J = 2,1 Hz,
1H), 6,74 (d, J = 1,5 Hz, 1H), 7,19
(d, J = 1,5 Hz, 1H), 7,39 (d, J = 2,1 Hz,
1H)
(300
) (CDCl3) 1,91 (s, 3H), 2,26
(s, 6H), 2,52 (m, 2H), 3,17 (m, 1H),
3,59 (m, 1H), 3,63 (s, 3H), 6,31
(d, J = 1,5 Hz, 1H), 6,58 (m, 1H), 6,88
(m, 1H), 7,21 (m, 1H), 7,41 (d, J = 1,5
Hz, 1H)
2
2
R
Az
Tfn
O
N
CH3
H3C
10
Tfn
N
N
R2
T.
,%
H
(+)
99
+31,8 ( = 2,0 CH2Cl2)
H
(+)
98,5
-31,8 ( = 2,0 CH2Cl2)
H
(+)
99
+2,8 ( = 2,0 CH2Cl2)
. (° )
S
CH3
11
14
N
N
S
CH3
12
N
N
S
CH3
121-122
BY 8203 C1 2006.06.30
Az
121-122
13
N
H
N
(-)
98,5
-2,3 ( = 2,0 CH2Cl2)
(+)
99
+87,5 ( = 2,0 CH2Cl2)
130-131
(-)
98,5
-85,4 ( = 2,0 CH2Cl2)
130-131
S
CH3
14
(D)-
N
H
N
S
15
(L)-
N
H
N
S
CH3
3
2
15
R
Tfn
Az
OH
Az
16
Tfn
N
H
N
S
CH3
R2
T.
. (° )
1
(
)(
)δ
-1
(300
) (CDCl3) 3,67 (s, 3H), 5,00
) 3210
(d, J = 4,5 Hz, 1H), 6,06 (d, J = 4,5 Hz,
.), 1433, 1400,
1H), 6,16 (s, 1H), 6,84 (m, 1H), 6,94 1284, 1201, 1055,
(m, 1H), 7,23 (s, 1H), 7,27 (d, J = 5,1 1037, 1003,781, 760,
Hz, 1H)
706
BY 8203 C1 2006.06.30
CH3
CH3
17
N
N
N
H
131-132
N
H3C
S
CH3
19
N
16
H
N
Br
107-109
S
CH3
Br
20
N
H
N
S
CH3
21
N
CH3
N
S
CH3
95-6
130-131
(KBr) 3199 (
.),
1400, 1282, 1200,
1060, 998, 940, 796,
776, 732
(KBr) 3163 (
.),
3100, 1282, 1206,
1025, 1010, 801, 788
(KBr) 3170 (
.),
3104, 1440, 1395,
1205, 1181, 1025,
1011, 966, 800, 791
(KBr) 3112 (
.),
1397, 1343, 1205,
1182, 1132, 1052,
823, 795, 768
(300
) (CDCl3) 2,00 (s, 3H), 3,27
(KBr) 3264 (
.),
, 1H), 3,68 (S, 3H), 6,26 (d, J = 2,0
1384, 1221, 1159,
Hz, 1H), 6,68 (m, 1H), 6,91 (m, 1H),
1114, 802, 779, 707
7,23 (m, 1H), 7,32 (d, J = 2,0 Hz, 1H)
BY 8203 C1 2006.06.30
109-111
S
CH3
18
H
(300
) (CDCl3) 2,19 (s, 3H), 2,63
(d, J = 4,5 Hz, 1H), 3,82 (s, 3H), 6,13
(d, J = 4,5 Hz, 1H), 6,16 (d, J = 1,5 Hz,
1H), 6,83 (d, J = 5,1 Hz, 1H), 7,20 (d,
J = 5,1 Hz, 1H), 7,37 (d, J = 1,5 Hz,
1H)
(300
) (CDCl3) 2,46 (s, 3H), 2,79
(d, J = 4,6 Hz, 1H), 3,80 (s, 3H), 6,04
(d, J = 4,6 Hz, 1H), 6,25 (d, J = 1,8 Hz,
1H), 6,62 (d, J = 3,3 Hz, 1H), 6,70 (d,
J = 3,3 Hz, 1H), 7,39 (d, J = 1,8Hz,
1H)
(300
) (CDCl3) 3,76 (s, 3H), 3,86
, 1H), 6,02 (s, 1H), 6,20 (d, J = 1,8
Hz), 6,61 (d, J = 4,0 Hz, 1H), 6,91 (d,
J = 4,0 Hz, 1H), 7,32 (d, J = 1,8 Hz,
1H)
(300
) (CDCl3) 3,60 ( , 1H),
3,78 (S, 3H), 6,08 (S, 1H), 6,20 (d,
J = 1,8 Hz, 1H), 6,80(s, 1H), 7,21 (S,
1H), 7,35 (d, J = 1,8Hz, 1H)
BY 8203 C1 2006.06.30
:
,
:
Siegmund (E. Siegmund, et. al,
Swiss
17-22
,
1957 95, 729).
.
. Biol. Med.,
,
.
(25
0,02 %
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160
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(
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BY 8203 C1 2006.06.30
:
2
30
46
1,15
1,15
4,60
4,60
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230
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, 20.
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