Leflunomide analogs for treating rheumatoid arthritis

Details Leflunomide analogs for treating rheumatoid arthritis Leflunomide analogs for treating rheumatoid arthritis

2002-07-15

2004-04-27

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S248000

Reexamination Certificate

active

06727272

ABSTRACT:

BACKGROUND
Rheumatoid arthritis (hereinafter referred to as RA) is a chronic disease that inflames joints and nearby areas. Besides the joints, other tissues can also be affected by RA. Patients with RA usually have overreactive T cells. Therefore, RA can be categorized as an autoimmune disease.
Leflunomide, N-(4-trifluoromethylphenyl)-4-carboxamidyl-5-methylisoxazole, is a drug for treating RA introduced into the market in recent years. Leflunomide and its main metabolite, malononitrilamide (MNA), were first made by Hoechst Marion Roussel.
OBJECTIVES
The objectives of this invention are as follows:
1. To synthesize a series of novel analogs of leflunomide,
2. To conduct in-vivo studies to evaluate the efficacy of the analogs, and
3. To select the leflunomide analogs that can be used for treating rheumatoid arthritis.
DETAILED DESCRIPTION OF THE INVENTION
This invention comprises the syntheses of a series of novel analogs of leflunomide for treating Rheumatoid Arthritis. To the best of our knowledge, these analogs have not been disclosed by any other parties. The in-vivo animal studies indicate that these leflunomide analogs are surpassingly more effective than leflunomide.
Representative syntheses and in-vivo animal studies are described as follows:
A. Methods of Syntheses
Wherein DCC is N,N′-dicyclohexylcarbodiimide and TEA is triethylamine.
Analog
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
R
4-H
2-Cl
3-Cl
4-Cl
3-CF
3
4-CF
3
2,4-(Cl)
2
4-OCH
3
3,4,5-(OCH
3
)
3
4-COOH
4-F
Method 1:
Weigh 1 g of 5-methylisoxazole-3-carboxylic acid; dissolve it in 10 mL of chloroform in a reactor. Place the reactor in an ice bath and add 1.2 mL of thionyl chloride. Gradually add 1 mL of triethylamine. Reduce the volume under vacuum after the reaction is complete. Add dichloromethane (10 mL) and then add the desired substituted aniline (see the table above) and mix thoroughly with cooling from an ice bath. Add triethylamine (1 mL), let it react for about 30 minutes, and monitor the reaction by thin layer chromatography. Wait till the reaction is complete and concentrate under vacuum. Use a separatory funnel to separate the organic and aqueous layers. Keep the organic layer; add anhydrous magnesium sulfate; let it sit for about 30 minutes; filter off magnesium sulfate and keep the filtered organic liquid; dry the organic liquid to obtain the crude product; re-crystallize in absolute alcohol to obtain product
5
a
and
5
b.
Aniline
Yield
Product
mL
g (%)
Appearance
5a
1.1
0.1 (4.2)
Yellow crystals
5b
1
0.1 (7.2)
Off-white crystals
Method 2:
Weigh 5-methylisoxazole-3-carboxylic acid (2 g), N-hydroxysuccinimide (2 g) and coupling agent N,N′-dicyclohexylcarbodiimide (3.6 g); add the desired substituted aniline, and crystallize in absolute alcohol to make
5
a
~
5
k
.
Anilines
Yield
Product
mL
g (%)
Appearance
5a
2
mL
1.0
(71)
Yellow crystals
5b
2
mL
0.9
(20.2)
Off-white crystals
5c
2
mL
2.4
(53.8)
White crystals
5d
2.4
g
8.7
(45)
White crystals
5e
2
mL
3.8
(89.1)
White crystals
5f
2
mL
1.6
(37)
White crystals
5g
3.4
g
4.2
(73.2)
Off-white crystals
5h
2.1
g
0.76
(18.9)
Gray crystals
5i
3.2
g
2
(39.6)
Gray crystals
5j
2.4
g
1.9
(44.6)
Light-brown crystals
5k
2
mL
0.9
(21.6)
White crystals
B. Results of Syntheses
Results of the syntheses and characteristics of the leflunomide analogs are shown as follows:
[Compound
5
a
] N-(Phenyl)-3-carboxamidyl-5-methylisoxazole
mp: 109~110° C.; UV (MeOH): &lgr;
max
nm (log &egr;)=270 (4.025); IR (KBr): &ngr;cm
−1
=3339 (N—H), 1677(C═O), 1598 (C═C); MS (EI, 70ev): 202 (M
+
, 100), 119 (65);
1
H-NMR (DMSO-d
6
, −300 MHz): &dgr;(ppm); 2.47 (3H, s, CH
3
), 6.65 (1H, s, CCH), 7.11 (1H, t, J=6.6 Hz, H
4
-phenyl), 7.34 (2H, t, J=7.5 Hz, H
3,5
-phenyl), 7.80 (2H, d, J=9 Hz, H
2,6
-phenyl), 10.64 (1H, s, NH);
13
C-NMR (DMSO-d
6
, 75 MHz): &dgr;(ppm); 12.1, 101.9, 120.9, 124.6, 129.0, 138.4, 157.8, 159.6, 171.7; CHN Analysis (Theory/Experiment) based on C
11
H
10
N
2
O
2
; % C; (65.34/65.28), % H; (4.98/4.95), % N; (13.85/13.72).
[Compound
5
b
] N-(2-Chlorophenyl)-3-carboxamidyl-5-methylisoxazole)
mp: 90~92° C.; UV (MeOH): &lgr;
max
nm (log &egr;)=250 (3.33); IR (KBr): &ngr;cm
−1
=3326 (N—H), 1626 (C═O), 1575 (C═C); MS (EI, 70ev): 236 (M
+
), 201 (100), 173 (60);
1
H-NMR (DMSO-d
6
, −300 MHz): &dgr;(ppm); 2.50 (3H, s, CH
3
), 6.69 (1H, s, CCH), 7.29 (1H, t, J=7.7 Hz, H
4
-phenyl), 7.39 (1H, t, J=7.7 Hz, H
5
-phenyl), 7.55 (1H, d, J=7.8 Hz, H
3
-phenyl), 7.71 (1H, d, J=7.9 Hz, H
6
-phenyl), 10.19 (1H, s, NH);
13
C-NMR (DMSO-d
6
, 75 MHz): &dgr;(ppm); 12.24, 101.8, 127.1, 128.0, 129.9, 134.2, 157.7, 158.9, 172.2; CHN Analysis (Theory/Experiment) based on C
11
H
9
ClN
2
O
2
. % C; (55.83/55.36), % H; (3.83/3.77), % N; (11.84/11.99).
[Compound
5
c
] N-(3-Chlorophenyl)-3-carboxamidyl-5-methylisoxazole
mp: 91~93° C.; UV (MeOH): &lgr;
max
nm (log &egr;)=260 (4.01); IR (KBr): &ngr;cm
−1
=3347 (N—H), 1689 (C═O), 1593 (C═C); MS (EI, 70ev): 236 (M
+
), 173 (100), 153 (80);
1
H-NMR (DMSO-d
6
, −300 MHz): &dgr;(ppm); 2.49 (3H, s, CH
3
), 6.66 (1H, s, CCH), 7.18 (1H, d, J=8 Hz, H
4
-phenyl), 7.37 (1H, t, J=8.1 Hz, H
5
-phenyl), 7.72 (1H, d, J=8.3 Hz, H
6
-phenyl), 7.94 (1H, s, H
2
-phenyl), 10.82 (1H, s, NH);
13
C-NMR (DMSO-
6
, 75 MHz): &dgr;(ppm); 12.2, 120.0, 119.2, 120.3, 124.3, 130.7,133.3, 139.9,.158.0, 159.3, 171.9; CHN Analysis (Theory/Experiment) based on C
11
H
9
ClN
2
O
2
; % C; (55.83/55.93), % H; (3.83/3.75), % N; (11.84/11.84).
[Compound
5
d
] N-(4-Chlorophenyl)-3carboxamidyl-5-methyisoxazole
mp: 135~140° C.; UV (MeOH): &lgr;
max
nm (log &egr;)=234 (4.55), 269 (4.74); IR (KBr): &ngr;cm
−1
=3329 (N—H), 1683 (C═O), 1528 (C═C); MS (EI, 70ev): 236 (100), 201(M
+
);
1
H-NMR (DMSO-d
6
, −300 MHz): &dgr;(ppm); 2.50 (3H, S, CH
3
), 6.68 (1H, s, CCH), 7.71 (2H, d, J=8.1 Hz, H
3,5
-phenyl), 8.02 (2H, d, J=7.8 Hz, H
2,6
-phenyl), 10.98 (1H, s, NH);
13
C-NMR (DMSO-
6
, 75 MHz): &dgr;(ppm); 12.1, 101.9, 122.4, 128.4, 128.9, 137.4, 157.9, 159.4, 171.7; CHN Analysis (Theory/Experiment) based on C
11
H
9
ClN
2
O
2
; % C; (55.83/55.93), % H; (3.83/3.98), % N; (11.84/11.17)
[Compound
5
e
] N-(3-Trifluoromethyl)-3-carboxamidyl-5-methylisoxazole
mp: 156~158° C.; UV (MeOH): &lgr;
max
nm (log &egr;)=255 (4.098); IR (KBr): 3330 (N—H), 1683 (C═O), 1557 (C═C); MS (EI, 70ev): 271 (M
+
, 90), 102 (100);
1
H-NMR (DMSO-d
6
, −300 MHz): &dgr;(ppm); 2.49 (3H, s, CH
3
), 6.68 (1H, s, CCH), 7.47 (1H, d, J=7.3 Hz, H
4
-phenyl), 7.57 (1H, t, J=7.9 Hz, H
5
-phenyl), 8.04 (1H, d, J=8.1 Hz, H
6
-phenyl), 8.26 (1H, s, H
2
-phenyl), 10.99 (1H, s,NH);
13
C-NMR (DMSO-d
6
, 75 MHz): &dgr;(ppm); 12.2, 101.9, 117.0, 117.1, 120.9, 124.5, 130.1, 130.3, 139.3, 158.2, 159.3, 171.9; CHN Analysis (Theory/Experiment) based on C
12
H
9
F
3
N
2
O
2
; % C; (53.34/53.39), % H; (3.36/3.59), % N; (10.37/10.71).
[Compound
5
f
] N-(4-Trifluoromethylphenyl)3-carboxamidyl-5-methylisoxazole
mp 179~180° C.; UV (MeOH): &lgr;
max
nm (log &egr;)=268 (3.887); IR (KBr): &ngr;cm
−1
=3334 (N—H), 1677(C═O), 1539 (C═C); MS (EI, 70ev): 270 (M
+
, 100);
1
H-NMR (DMSO-d
6
, −300 MHz): &dgr;(ppm); 2.49 (3H, s, CH
3
), 6.68 (1H, s, CCH), 7.71 (2H, d, J=8 Hz, H
2,6
-phenyl), 8.03 (2H, d, J=8.2 Hz, H
3,5
-phenyl), 10.99 (1H, s, NH);
13
C-NMR (DMSO-d
6
, 75 MHz): &dgr;(ppm); 12.1, 101.9, 122.4, 128.4, 128.9, 137.4, 157.8, 159.4, 171.7; CHN Analysis (Theory/Experiment) based on C
12
H
9
F
3
N
2
O
2
; % C; (53.34/53.01), % H; (3.36/3.46), % N; (10.37/10.38).
[Compound
5
g
] N-(2,4-Dichlorophenyl)-3carboxamidyl-5-methylisoxazole
mp: 148~156° C.; UV (MeOH): &lgr;
max
nm (log &egr;)=250 (4.89), 277 (3.88); IR (KBr): &ngr;cm
−1
=3348 (N—H), 1697 (C═O), 1589 (C═C) MS (EI, 70ev): 271 (100)

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