Thio-substituted arylmethanesulfinyl derivatives
View Patent ↗The present invention is related to chemical compositions, processes for the preparation thereof and uses of the composition. Particularly, the present invention relates to compositions of compounds of Formula (A): wherein Ar, X, Y, R 1 , R 2 , R 3 , and q are as defined herein; and their use in the treatment of diseases, including treatment of sleepiness, promotion of wakefulness, treatment of Parkinson's disease, cerebral ischemia, stroke, sleep apneas, eating disorders, stimulation of appetite and weight gain, treatment of attention deficit hyperactivity disorder (“ADHD”), enhancing function in disorders associated with hypofunctionality of the cerebral cortex, including, but not limited to, depression, schizophrenia, fatigue, in particular, fatigue associated with neurologic disease, such as multiple sclerosis, chronic fatigue syndrome, and improvement of cognitive dysfunction.
1. A compound of formula (A):
wherein:
Ar is C 6 -C 10 aryl wherein:
C 6 -C 10 aryl is optionally substituted with one to three groups selected from F, Cl, Br, I, OR 22 , OR 25 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, phenyl, arylalkyl, C(═O)R 22 , CO 2 R 22 , OC(═O)R 22 , C(═O)NR 23 R 24 , NR 21 C(═O)R 22 , NR 21 CO 2 R 22 , OC(═O)NR 23 R 24 , NR 21 C(═S)R 22 , and S(O) y R 22 ;
X is O, S(O) y , N(R 10 ), OC(R 22 ) 2 , (R 22 ) 2 CO, C(R 22 ) 2 NR 21 , NR 21 C(R 22 ) 2 , C(═O)N(R 21 ), NR 21 C(═O), S(O) 2 —NR 22 , NR 22 S(O) 2 , C(R 22 C(R 22 ) 2 , CR 21 ═CR 21 , C≡C;
Y is C 1 -C 6 alkylene; or (C 1 -C 4 alkylene) m - Z -(C 1 -C 4 alkylene) n ; wherein said alkylene groups are optionally substituted with one to three R 20 groups;
Z is O, NR 10A , S(O) y , CR 21 ═CR 21 , C≡C, C 6 -C 10 arylene, or C 3 -C 6 cycloalkylene, wherein said arylene, and cycloalkylene groups are optionally substituted with one to three R 20 groups;
R 1 is selected from NR 12 R 13 , NR 21 C(═O)R 14 , C(═O)R 14 , CO 2 R 11 , OC(═O)R 11 , C(═O)NR 12 R 13 , C(═NR 11 )NR 12 R 13 , OC(═O)NR 12 R 13 , NR 21 S(O) 2 R 11 , NR 21 C(═O)NR 12 R 13 , and NR 21 S(O) 2 NR 12 R 13 ;
wherein said aryl groups are optionally substituted with one to three R 20 groups;
R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OR 22 , OR 25 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, phenyl, arylalkyl, C(═O)R 22 , CO 2 R 22 , OC(═O)R 22 , C(═O)NR 23 R 24 , NR 21 C(═O)R 22 , NR 21 CO 2 R 22 , OC(═O)NR 23 R 24 , NR 21 C(═S)R 22 , and S(O) y R 22 ;
R 10 and R 10A are each independently selected from H, C 1 -C 6 alkyl, C 6 -C 10 aryl, C(═O)R 14 , and S(O) y R 14 ; wherein said alkyl and aryl groups are optionally substituted with one to three groups;
R 11 at each occurrence is independently selected from H, C 3 -C 7 alkyl and C 6 -C 10 aryl; wherein said alkyl and aryl group are optionally substituted with one to three R 20 groups;
R 12 and R 13 at each occurrence are each independently selected from H, C 1 -C 6 alkyl;
wherein said alkyl group is optionally substituted with one to three R 20 groups;
R 14 at each occurrence is independently selected from C 1 -C 6 alkyl, C 6 -C 10 aryl, and arylalkyl;
wherein said alkyl, aryl and arylalkyl groups are optionally substituted with one to three R 20 groups;
R 20 at each occurrence is independently selected from F, Cl, Br, I, OR 22 , OR 25 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6 alkyl optionally substituted by one to three OH, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, phenyl, 5 membered arylalkyl, C(═O)R 22 , CO 2 R 22 , OC(═O)R 22 , C(═O)NR 23 R 24 , NR 21 C(═O)R 22 , NR 21 CO 2 R 22 , OC(═O)NR 23 R 24 , NR 21 C(═S)R 22 , and S(O) y R 22 ;
R 21 at each occurrence is independently selected from H and C 1 -C 6 alkyl;
R 22 at each occurrence is independently selected from H, C 1 -C 6 alkyl, and C 6 -C 10 aryl;
R 23 and R 24 at each occurrence are each independently selected from H, C 1 -C 6 alkyl, and C 6 -C 10 aryl;
R 25 at each occurrence is independently the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;
m is 0 or 1;
n is 0 or 1;
q is 1 or 2;
y is 0, 1, or 2;
Ar—X is positioned ortho or para to —CH 2 —S(O) n —Y—R 1 ;
with the exclusion of the compounds wherein:
Y is C 2 alkylene substituted with one to three C 1 -C 6 alkylene and/or NR 23 R 24
and/or NR 21 CO 2 R 22 ; and
R 1 is C(═O)NR 12 R 13
and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts forms thereof.
2. The compound according to claim 1 , wherein:
Y is C 1 -C 6 alkylene;
(C 1 -C 4 alkylene) m -Z 1 -(C 1 -C 4 alkylene) n ;
C 1 -C 4 alkylene-Z 2 -C 1 -C 4 alkylene;
wherein said alkylene groups are optionally substituted with one to three R 20 groups;
Z 1 is CR 21 ═CR 21 , C≡C, C 6 -C 10 arylene, or
C 3 -C 6 cycloalkylene; wherein said arylene, and cycloalkylene groups are optionally substituted with one to three R 22 groups;
Z 2 is O, NR 10A , or S(O) y .
3. The compound according to claim 1 wherein q is 1.
4. The compound according to claim 1 wherein R 1 is selected from NR 12 R 13 , NR 21 C(═O)R 14 , C(O═)R 14 , CO 2 R 11 , OC(═O)R 11 , C(═O)NR 12 R 13 , C(═NR 11 )NR 12 R 13 , OC(═O)NR 12 R 13 , NR 21 S(O) 2 R 11 , NR 21 C(═O)NR 12 R 13 ; and NR 21 S(O) 2 NR 12 R 13 .
5. The compound according to claim 1 wherein R 1 is selected from NR 12 R 13 ; NR 21 C(═O)R 14 ; C(═O)NR 12 R 13 ; C(═NR 11 )NR 12 R 13 ; and NR 21 C(═O)NR 12 R 13 .
6. The compound according to claim 5 wherein R 1 is C(═O)NR 12 R 13 .
7. The compound according to claim 6 wherein R 12 and R 13 are each independently selected from H and C 1 -C 6 alkyl.
8. The compound according to claim 4 wherein R 1 is selected from C(═O)R 14 , CO 2 R 11 , OC(═O)R 11 , C(═O)NR 12 R 13 , OC(═O)NR 12 R 13 , NR 21 S(O) 2 R 11 , and NR 21 S(O) 2 NR 12 R 13 .
9. The compound according to claim 1 wherein X is O, S(O) y , N(R 10 ).
10. The compound according to claim 1 wherein X is OC(R 22 ) 2 , C(R 22 ) 2 O, C(R 22 ) 2 NR 21 , NR 21 C(R 22 ) 2 , C(═O)N(R 21 ), NR 21 C(═O), S(O) 2 NR 22 , NR 22 S(O) 2 , C(R 22 ) 2 C(R 22 ) 2 .
11. The compound according to claim 10 wherein X is OC(r 22 ) 2 , C(R 22 ) 2 NR 21 , C(═O)N(R 21 ), S(O) 2 —NR 22 .
12. The compound according to claim 1 wherein Y is C 1 -C 6 alkylene.
13. The compound according to claim 12 wherein Y is CH 2 .
14. The compound according to claim 2 wherein Y is (C 1 -C 4 alkylene) m -Z 1 -(C 1 -C 4 alkylene) n .
15. The compound according to claim 14 wherein Z 1 is C 6 -C 10 arylene or C 3 -C 6 cycloalkylene.
16. The compound according to claim 15 wherein Z 1 is phenylene.
17. The compound according to claim 14 wherein Z 1 is CR 21 ═CR 21 or C≡C.
18. The compound according to claim 2 wherein Y is C 1 -C 4 alkylene-Z 2 -C 1 -C 4 alkylene.
19. The compound according to claim 18 wherein Z 2 is O.
20. The compound according to claim 1 with the structure:
wherein:
Ar is optionally substituted with one to three groups selected from F, Cl, Br, I, OR 22 , OR 25 , NR 23 R 24 , NHOH, NO 2 , CN, C 1 -C 6 alkyl, phenyl, arylalkyl, and C(═O)R 22 ;
X is O, S(O) y , N(R 10 ), OC(R 22 ) 2 , C(R 22 ) 2 O, C(R 22 ) 2 NR 21 , NR 21 C(R 22 ) 2 , C(═O)N(R 21 ), NR 21 C(O), S(O) 2 NR 22 , NR 22 S(O) 2 ;
Y is C 1 -C 6 alkylene;
C 1 -C 4 alkylene-Z 1 —(C 1 -C 4 alkylene) m , or
C 1 -C 4 alkylene-Z 2 —C 1 -C 4 alkylene;
wherein said alkylene groups are optionally substituted with one to three R 20 groups;
Z 1 is CR 21 ═CR 21 , C≡C, C 6 -C 10 arylene, or
C 3 -C 6 cycloalkylene
Z 2 is O, NR 10A , or S(O) y ;
R 1 is selected from NR 21 C(═O)R 14 , C(═O)R 14 , CO 2 R 11 , OC(═O)R 11 , C(═O)NR 12 R 13 , C(═NR 11 )NR 12 R 13 , OC(═O)NR 12 R 13 , NR 21 S(O) 2 R 11 , NR 21 C(═O)NR 12 R 13 , and NR 21 S(O) 2 NR 12 R 13 ;
R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OR 22 , OR 25 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, phenyl, arylalkyl, C(═O)R 22 ;
R 10 and R 10A are each independently selected from H, C 1 -C 6 alkyl, C(═O)R 14 , and S(O) y R 14 ; wherein said alkyl groups are optionally substituted with one to three R 20 groups;
R 11 at each occurrence is independently selected from H or C 3 -C 7 alkyl, wherein said alkyl group is optionally substituted with one to three R 20 groups;
R 12 and R 13 at each occurrence are each independently selected from H, and C 1 -C 6 alkyl; wherein said alkyl group is are optionally substituted with one to three R 20 groups;
R 14 at each occurrence is independently selected from C 1 -C 6 alkyl, C 6 -C 10 aryl, and arylalkyl; wherein said alkyl, aryl and arylalkyl groups are optionally substituted with one to three R 20 groups;
R 20 at each occurrence is independently selected from F, Cl, Br, I, OR 22 , OR 25 , NR 22 R 24 , NHOH, NO 2 , CN, CF 3 , phenyl, benzyl, C(═O)R 22 , CO 2 R 22 , OC(═O)R 22 , C(═O)NR 23 R 24 , NR 21 C(═O)R 22 , NR 21 CO 2 R 22 , OC(═O) NR 23 R 24 , NR 21 C(═S)R 22 , and S(O) y R 22 ;
R 21 at each occurrence is independently selected from H and C 1 -C 6 alkyl; and R 22 at each occurrence is independently selected from H, C 1 -C 6 alkyl, and C 6 -C 10 aryl;
R 23 and R 24 at each occurrence are each independently selected from H, and C 1 -C 6 alkyl;
R 25 at each occurrence is independently the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;
n is 0 or 1;
y is 0, 1, or 2;
and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts forms thereof.
21. The compound according to claim 20 wherein: Y is C 1 -C 6 alkylene, C 1 -C 4 alkylene-Z 1 —C 1 -C 4 alkylene, or C 1 -C 4 alkylene-Z 2 —C 1 -C 4 alkylene, wherein said alkylene groups are optionally substituted with one to three C 1 -C 6 alkyl groups;
Z 1 is CR 21 ═CR 21 , C≡C, or phenyl;
Z 2 is O, NR 10A , or S(O) y ;
X is O, S(O) y , N(R 10 ), OC(R 22 ) 2 , C(R 22 ) 2 O, C(R 22 ) 2 NR 21 , NR 21 C(R 22 ) 2 , C(═O)N(R 21 ), NR 21 C(═O), S(O) 2 NR 22 , NR 22 S(O) 2 ; and
R 1 is selected from NR 21 C(═O)R 14 , C(═O)R 14 , CO 2 R 11 , OC(═O)R 11 , and C(═)NR 12 R 13 .
22. The compound according to claim 21 wherein R 1 is C(═O)NR 12 R 13 .
23. The compound according to claim 22 having the structure of formula (Ib):
24. The compound according to claim 23 wherein X is O, S(O) y , N(R 10 ), OC(R 22 ) 2 , C(R 22 ) 2 O, C(R 22 ) 2 NR 21 , NR 21 C(R 22 ) 2 , C(═O)N(R 21 ), NR 21 C(═O), S(O) 2 —NR 22 , NR 22 S(O) 2 .
25. The compound according to claim 24 wherein X is O, S(O) y , NH.
26. The compound according to claim 24 wherein X is OCH 2 , CH 2 O, CH 2 NH, NHCH 2 , C(═O)NH, NHC(═O), S(O) 2 NH, NHS(O) 2 .
27. The compound according to claim 24 wherein X is NH, O—CH 2 , CH 2 NH, C(═O)NH, or S(O) 2 —NH.
28. The compound according to any of claims 1 , 20 , or 23 wherein R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OR 22 , OR 25 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, phenyl, arylalkyl, C(═O)R 22 .
29. The compound according to claim 23 wherein Y is C 1 -C 6 alkylene.
30. The compound according to claim 29 wherein Y is CH 2 .
31. The compound according to claim 23 wherein Y is (C 1 -C 4 alkylene) n -Z 1 —C 1 -C 4 alkylene and Z 1 is phenyl, CR 21 ═CR 21 , or C≡C.
32. A compound selected in accordance with the following table, wherein:
TABLE 1
Ex.
No.
Ar
X
Position*
R 2
R 3
q
Y—R 1
29
Ph
O
para
H
H
1
CH 2 CONHCHMe 2
Ph
O
meta
H
H
0
CH 2 CONH 2
32
Ph
O
meta
H
H
1
CH 2 CONH 2
Ph
O
meta
H
H
0
CH 2 CONMe 2
33
Ph
O
meta
H
H
1
CH 2 CONMe 2
Ph
O
meta
H
H
0
CH 2 CONHCHMe 2
34
Ph
O
meta
H
H
1
CH 2 CONHCHMe 2
4-OCH 3 Ph
O
para
H
H
0
CH 2 CONH 2
36
4-OCH 3 Ph
O
para
H
H
1
CH 2 CONH 2
3,4-DiClPh
O
para
H
H
0
CH 2 CONH 2
39
3,4-DiClPh
O
para
H
H
1
CH 2 CONH 2
30
3,4-DiClPh
O
para
H
H
1
CH 2 COOH
15
3,4-DiClPh
O
ortho
H
H
0
CH 2 CONH 2
20
3,4-DiClPh
O
ortho
H
H
1
CH 2 CONH 2
4-OCH 3 Ph
O
ortho
H
H
0
CH 2 CONH 2
42
4-OCH 3 Ph
O
ortho
H
H
1
CH 2 CONH 2
2-ClPh
O
para
H
H
0
CH 2 CONH 2
43
2-ClPh
O
para
H
H
1
CH 2 CONH 2
4-OHPh
O
ortho
H
H
0
CH 2 CONH 2
44
4-OHPh
O
ortho
H
H
1
CH 2 CONH 2
2-ClPh
O
ortho
H
H
0
CH 2 CONH 2
45
2-ClPh
O
ortho
H
H
1
CH 2 CONH 2
96
4-FPh
O
para
H
H
1
CH 2 COOH
4-FPh
O
para
H
H
0
CH 2 CONH 2
50
4-FPh
O
para
H
H
1
CH 2 CONH 2
4-FPh
O
ortho
H
H
0
CH 2 CONH 2
51
4-FPh
O
ortho
H
H
1
CH 2 CONH 2
2-Naphthyl
O
ortho
H
H
0
CH 2 CONH 2
52
2-Naphthyl
O
ortho
H
H
1
CH 2 CONH 2
2-Naphthyl
O
para
H
H
0
CH 2 CONH 2
54
2-Naphthyl
O
para
H
H
1
CH 2 CONH 2
2-BiPh
O
para
H
H
0
CH 2 CONH 2
55
2-BiPh
O
para
H
H
1
CH 2 CONH 2
2-BiPh
O
ortho
H
H
0
CH 2 CONH 2
56
2-BiPh
O
ortho
H
H
1
CH 2 CONH 2
4-ClPh
O
para
H
H
0
CH 2 CONH 2
67
4-ClPh
O
para
H
H
1
CH 2 CONH 2
Ph
O
ortho
H
H
0
CH 2 CONH 2
97
Ph
O
ortho
H
H
1
CH 2 CONH 2
Ph
O
ortho
H
H
0
CH 2 CONMe 2
99
Ph
O
ortho
H
H
1
CH 2 CONMe 2
Ph
O
para
H
H
0
CH 2 CONMe 2
100
Ph
O
para
H
H
1
CH 2 CONMe 2
Ph
O
para
H
H
0
CH 2 CONH 2
102
Ph
O
para
H
H
1
CH 2 CONH 2
Ph
O
ortho
H
H
0
CH 2 CONHCH 2 CN
103
Ph
O
ortho
H
H
1
CH 2 CONHCH 2 CN
Ph
O
ortho
H
H
0
CH 2 CONHCHMe 2
104
Ph
O
ortho
H
H
1
CH 2 CONHCHMe 2
Ph
O
ortho
H
H
0
CH 2 CONHCMe 3
105
Ph
O
ortho
H
H
1
CH 2 CONHCMe 3
12
Ph
O
ortho
H
H
0
CH 2 CONH(CH 2 ) 2 OH
21
Ph
O
ortho
H
H
1
CH 2 CONH(CH 2 ) 2 OH
Ph
O
meta
H
H
0
CH 2 CONH(CH 2 ) 2 OH
108
Ph
O
meta
H
H
1
CH 2 CONH(CH 2 ) 2 OH
111
Ph
O
para
H
H
1
CH 2 CONH(CH 2 ) 2 OH
113
4-ClPh
CONH
ortho
H
H
1
CH 2 CONH 2
114
3,4-DiOCH 3 Ph
CONH
ortho
H
H
1
CH 2 CONH 2
115
2-Naphthyl
CONH
ortho
H
H
1
CH 2 CONH 2
117
3,4-DiFPh
CONH
ortho
H
H
1
CH 2 CONH 2
118
2,4-DiOCH 3 Ph
CONH
ortho
H
H
1
CH 2 CONH 2
119
3,4,5-
CONH
ortho
H
H
1
CH 2 CONH 2
TriOCH 3 Ph
120
3,4-DiOCH 3 Ph
CONH
meta
H
H
1
CH 2 CONH 2
125
2,4-DiOCH 3 Ph
CONH
meta
H
H
1
CH 2 CONH 2
126
4-FPh
CONH
meta
H
H
1
CH 2 CONH 2
127
3,4-DiClPh
CONH
meta
H
H
1
CH 2 CONH 2
2,5-DiClPh
O
ortho
H
H
0
CH 2 CONH 2
76
2,5-DiClPh
O
ortho
H
H
1
CH 2 CONH 2
2,3-DiClPh
O
ortho
H
H
0
CH 2 CONH 2
77
2,3-DiClPh
O
ortho
H
H
1
CH 2 CONH 2
2,4-DiClPh
O
para
H
H
0
CH 2 CONH 2
80
2,4-DiClPh
O
para
H
H
1
CH 2 CONH 2
2,4-DiClPh
O
ortho
H
H
0
CH 2 CONH 2
81
2,4-DiClPh
O
ortho
H
H
1
CH 2 CONH 2
3,5-DiCiPh
O
para
H
H
0
CH 2 CONH 2
84
3,5-DiClPh
O
para
H
H
1
CH 2 CONH 2
3,5-DiClPh
O
ortho
H
H
0
CH 2 CONH 2
85
3,5-DiClPh
O
ortho
H
H
1
CH 2 CONH 2
2,5-DiClPh
S
para
H
H
0
CH 2 CONH 2
88
2,5-DiClPh
S
para
H
H
1
CH 2 CONH 2
3,4-DiClPh
S
para
H
H
0
CH 2 CONH 2
89
3,4-DiClPh
S
para
H
H
1
CH 2 CONH 2
2,6-DiClPh
O
para
H
H
0
CH 2 CONH 2
92
2,6-DiClPh
O
para
H
H
1
CH 2 CONH 2
2,3-DiClPh
O
para
H
H
0
CH 2 CONH 2
93
2,3-DiClPh
O
para
H
H
1
CH 2 CONH 2
94
2,3-DiClPh
O
para
H
H
2
CH 2 CONH 2
152
Ph
OCH 2
ortho
H
H
0
CH 2 CONH 2
153
Ph
OCH 2
ortho
H
H
1
CH 2 CONH 2
18
4-ClPh
O
para
2′-Cl
H
0
CH 2 CONH2
26
4-ClPh
O
para
2′-Cl
H
1
CH 2 CONH 2
149a
3,4-DiClPh
CONH
para
H
H
1
CH 2 CONH 2
109a
4-ClPh
O
ortho
H
H
1
CH 2 CONH 2
109b
3-Cl-4-FPh
O
ortho
H
H
1
CH 2 CONH 2
109c
4-Cl-3-FPh
O
ortho
H
H
1
CH 2 CONH 2
109d
3-Cl-4-FPh
O
ortho
H
H
2
CH 2 CONH 2
10a
4-ClPh
O
ortho
4′-Cl
H
0
CH 2 COOH
18a
4-ClPh
O
ortho
4′-Cl
H
0
CH 2 CONH 2
27a
4-ClPh
O
ortho
4′-Cl
H
1
CH 2 CONH 2
27b
4-ClPh
O
ortho
4′-Cl
H
2
CH 2 CONH 2
109e
3,4-DiFPh
O
ortho
4′-Cl
H
1
CH 2 CONH 2
109f
3,4-DiClPh
O
ortho
H
H
2
CH 2 CONH 2
30a
3,4-DiClPh
O
ortho
H
H
1
CH 2 COOH
30d
3,4-DiClPh
O
ortho
H
H
0
CH 2 COOMenthyl (1R,2S,5R)
30e
3,4-DiClPh
O
ortho
H
H
1
CH 2 COOH
(−)
30f
3,4-DiClPh
O
ortho
H
H
1
CH 2 COOH
(+)
20a
3,4-DiClPh
O
ortho
H
H
1
CH 2 CONH 2
(−)
20b
3,4-DiClPh
O
ortho
H
H
1
CH 2 CONH 2
(+)
30b
3,4-DiClPh
O
ortho
H
H
2
CH 2 COOH
112a
3,4-DiClPh
O
ortho
H
H
1
CH 2 CONHCH3
112b
3,4-DiClPh
O
ortho
H
H
1
CH 2 CON(C 2 H 5 ) 2
30f
3,4-DiClPh
O
ortho
H
H
0
CH 2 CON(CH 3 ) 2
30g
3,4-DiClPh
O
ortho
H
H
1
CH 2 CON(CH 3 ) 2
Ph = phenyl, ClPh = chlorophenyl, DiClPh = di-chlorophenyl, FPh = Fluorophenyl;
*Position: the position refers to the position of the ArX lateral side chain as compared to —CH 2 —S(O) q —Y—R 1 group on the central benzyl ring;
Ortho is position 2′, meta is position 3′ and para is position 4′
and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts forms thereof.
33. A method of treating a disease or a disorder selected from the group consisting of sleepiness associated with narcolepsy; obstructive sleep apnea; shift work disorder, attention deficit disorder; attention deficit; hyperactivity disorder; depression; and fatigue, comprising administering to a patient in need thereof a compound of claim 1 or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salts form thereof.
34. The method according to claim 33 wherein the disease or disorder is sleepiness associated with narcolepsy.
35. A method for the treatment of a sleep-affecting disease, or disorder in order to promote wakefulness comprising administering to a patient in need thereof a compound according to claim 1 or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt form thereof.
36. A pharmaceutical composition comprising a compound of claim 1 and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts forms thereof, in admixture with one or more pharmaceutically acceptable excipients.
37. A method for preparing a compound of claim 1 , comprising the steps of:
i.) reacting a thiouronium compound (E) with a reactant of structure LG-YR 1 to form a compound of formula (I):
wherein Ar, X, R 2 , R 3 , Y, R 1 are as defined in claim 1 , q=0 and LG represents a leaving group; and optionally
ii) isolating the formed compound of formula (I).
38. The method of claim 37 , wherein step i) comprises:
a) converting the compound of formula (E) into the corresponding thiol compound; and
b) reacting the obtained thiol compound with the reactant LG-Y-R 1 .
39. The method of claim 38 , wherein the compound (E) is formed by reacting the compound (D) with thiourea and a suitable acid HA:
wherein Ar, X, R 2 , R 3 are as defined in claim 1 .
40. The method of claim 39 , wherein the compound (D) is formed by reacting a compound (C) with a suitable reducing agent:
wherein Ar, X, R 2 , R 3 are as defined in claim 1 and W is C(═O)H or COOH.
41. The method according to claim 40 , wherein compound (C) is formed by reacting a compound (A) with a compound (B):
42. The method according to claim 41 , wherein the compound formed at step i) is a compound of formula (I) wherein q is 0, R 1 is COOR, and R represents H or (C 1 -C 6 ) alkyl
43. The method according to claim 42 further comprising:
a1) reacting the carboxylic acid or ester of formula (I) with an appropriate amine of general structure NHR 12 R 13 , wherein R 12 and R 13 are as defined in claim 1 ; and optionally b1) isolating the obtained compound of formula (I) wherein R 1 is C(═O)NR 12 R 13 .
44. The method of claim 42 or 43 further comprising:
a2) oxidizing the compound of formula (I) wherein q is 0; and optionally b2) isolating the obtained compound of formula (I) wherein q is 1 or 2.
45. A compound according to claim 1 ,
wherein:
Ar is C 6 -C 10 aryl wherein:
C 6 -C 10 aryl is optionally substituted with one to three groups selected from Cl, Br, I, OR 22 , OR 25 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, phenyl, arylalkyl, C(═O)R 22 , CO 2 R 22 , OC(═O)R 22 , C(═O)NR 23 R 24 , NR 21 C(═O)R 22 , NR 21 CO 2 R 22 , OC(═O)NR 23 R 24 , NR 21 C(═S)R 22 , and S(O) y R 22 .
46. The compound according to claim 32 selected in accordance with the following table, wherein:
TABLE 1
Ex.
No.
Ar
X
Position*
R 2
R 3
q
Y—R 1
29
Ph
O
para
H
H
1
CH 2 CONHCHMe 2
Ph
O
meta
H
H
0
CH 2 CONH 2
32
Ph
O
meta
H
H
1
CH 2 CONH 2
Ph
O
meta
H
H
0
CH 2 CONMe 2
33
Ph
O
meta
H
H
0
CH 2 CONMe 2
Ph
O
meta
H
H
1
CH 2 CONHCHMe 2
34
Ph
O
meta
H
H
1
CH 2 CONHCHMe 2
4-OCH 3 Ph
O
para
H
H
0
CH 2 CONH 2
36
4-OCH 3 Ph
O
para
H
H
1
CH 2 CONH 2
3,4-DiClPh
O
para
H
H
0
CH 2 CONH 2
39
3,4-DiClPh
O
para
H
H
1
CH 2 CONH 2
30
3,4-DiCiPh
O
para
H
H
1
CH 2 COOH
15
3,4-DiClPh
O
ortho
H
H
0
CH 2 CONH 2
20
3,4-DiClPh
O
ortho
H
H
1
CH 2 CONH 2
4-OCH 3 Ph
O
ortho
H
H
0
CH 2 CONH 2
42
4-OCH 3 Ph
O
ortho
H
H
1
CH 2 CONH 2
2-ClPh
O
para
H
H
0
CH 2 CONH 2
43
2-ClPh
O
para
H
H
1
CH 2 CONH 2
4-OHPh
O
ortho
H
H
0
CH 2 CONH 2
44
4-OHPh
O
ortho
H
H
1
CH 2 CONH 2
2-ClPh
O
ortho
H
H
0
CH 2 CONH 2
45
2-ClPh
O
ortho
H
H
1
CH 2 CONH 2
2-Naphthyl
O
ortho
H
H
0
CH 2 CONH 2
52
2-Naphthyl
O
ortho
H
H
1
CH 2 CONH 2
2-Naphthyl
O
para
H
H
0
CH 2 CONH 2
54
2-Naphthyl
O
para
H
H
1
CH 2 CONH 2
2-BiPh
O
para
H
H
0
CH 2 CONH 2
55
2-BiPh
O
para
H
H
1
CH 2 CONH 2
2-BiPh
O
ortho
H
H
0
CH 2 CONH 2
56
2-BiPh
O
ortho
H
H
1
CH 2 CONH 2
4-ClPh
O
para
H
H
0
CH 2 CONH 2
67
4-ClPh
O
para
H
H
1
CH 2 CONH 2
Ph
O
ortho
H
H
0
CH 2 CONH 2
97
Ph
O
ortho
H
H
1
CH 2 CONH 2
Ph
O
ortho
H
H
0
CH 2 CONMe 2
99
Ph
O
ortho
H
H
1
CH 2 CONMe 2
Ph
O
para
H
H
0
CH 2 CONMe 2
100
Ph
O
para
H
H
1
CH 2 CONMe 2
Ph
O
para
H
H
0
CH 2 CONH 2
102
Ph
O
para
H
H
1
CH 2 CONH 2
Ph
O
ortho
H
H
0
CH 2 CONHCH 2 CN
103
Ph
O
ortho
H
H
1
CH 2 CONHCH 2 CN
Ph
O
ortho
H
H
0
CH 2 CONHCHMe 2
104
Ph
O
ortho
H
H
1
CH 2 CONHCHMe 2
Ph
O
ortho
H
H
0
CH 2 CONHCMe 3
105
Ph
O
ortho
H
H
1
CH 2 CONHCMe 3
12
Ph
O
ortho
H
H
0
CH 2 CONH(CH 2 ) 2 OH
21
Ph
O
ortho
H
H
1
CH 2 CONH(CH 2 ) 2 OH
Ph
O
meta
H
H
0
CH 2 CONH(CH 2 ) 2 OH
108
Ph
O
meta
H
H
1
CH 2 CONH(CH 2 ) 2 OH
111
Ph
O
para
H
H
1
CH 2 CONH(CH 2 ) 2 OH
113
4-ClPh
CONH
ortho
H
H
1
CH 2 CONH 2
114
3,4-DiOCH 3 Ph
CONH
ortho
H
H
1
CH 2 CONH 2
115
2-Naphthyl
CONH
ortho
H
H
1
CH 2 CONH 2
118
2,4-DiOCH 3 Ph
CONH
ortho
H
H
1
CH 2 CONH 2
119
3,4,5-
CONH
ortho
H
H
1
CH 2 CONH 2
TriOCH 3 Ph
120
3,4-DiOCH 3 Ph
CONH
meta
H
H
1
CH 2 CONH 2
125
2,4-DiOCH 3 Ph
CONH
meta
H
H
1
CH 2 CONH 2
127
3,4-DiClPh
CONH
meta
H
H
1
CH 2 CONH 2
2,5-DiClPh
O
ortho
H
H
0
CH 2 CONH 2
76
2,5-DiClPh
O
ortho
H
H
1
CH 2 CONH 2
2,3-DiClPh
O
ortho
H
H
0
CH 2 CONH 2
77
2,3-DiClPh
O
ortho
H
H
1
CH 2 CONH 2
2,4-DiClPh
O
para
H
H
0
CH 2 CONH 2
80
2,4-DiClPh
O
para
H
H
1
CH 2 CONH 2
2,4-DiClPh
O
ortho
H
H
0
CH 2 CONH 2
81
2,4-DiClPh
O
ortho
H
H
1
CH 2 CONH 2
3,5-DiClPh
O
para
H
H
0
CH 2 CONH 2
84
3,5-DiClPh
O
para
H
H
1
CH 2 CONH 2
3,5-DiClPh
O
ortho
H
H
0
CH 2 CONH 2
85
3,5-DiClPh
O
ortho
H
H
1
CH 2 CONH 2
2,5-DiClPh
S
para
H
H
0
CH 2 CONH 2
88
2,5-DiClPh
S
para
H
H
1
CH 2 CONH 2
3,4-DiClPh
S
para
H
H
0
CH 2 CONH 2
89
3,4-DiClPh
S
para
H
H
1
CH 2 CONH 2
2,6-DiClPh
O
para
H
H
0
CH 2 CONH 2
92
2,6-DiClPh
O
para
H
H
1
CH 2 CONH 2
2,3-DiClPh
O
para
H
H
0
CH 2 CONH 2
93
2,3-DiClPh
O
para
H
H
1
CH 2 CONH 2
94
2,3-DiClPh
O
para
H
H
2
CH 2 CONH 2
152
Ph
OCH 2
ortho
H
H
0
CH 2 CONH 2
153
Ph
OCH 2
ortho
H
H
1
CH 2 CONH 2
18
4-ClPh
O
para
2′-Cl
H
0
CH 2 CONH 2
26
4-ClPh
O
para
2′-Cl
H
1
CH 2 CONH 2
149a
3,4-DiClPh
CONH
para
H
H
1
CH 2 CONH 2
109a
4-ClPh
O
ortho
H
H
1
CH 2 CONH 2
10a
4-ClPh
O
ortho
4′-Cl
H
0
CH 2 COOH
18a
4-ClPh
O
ortho
4′-Cl
H
0
CH 2 CONH 2
27a
4-ClPh
O
ortho
4′-Cl
H
1
CH 2 CONH 2
27b
4-ClPh
O
ortho
4′-Cl
H
2
CH 2 CONH 2
109f
3,4-DiClPh
O
ortho
H
H
2
CH 2 CONH 2
30a
3,4-DiClPh
O
ortho
H
H
1
CH 2 COOH
30d
3,4-DiClPh
O
ortho
H
H
0
CH 2 COOMenthyl (1R,2S,5R)
30e
3,4-DiClPh
O
ortho
H
H
1
CH 2 COOH
(−)
30f
3,4-DiClPh
O
ortho
H
H
1
CH 2 COOH
(+)
20a
3,4-DiClPh
O
ortho
H
H
1
CH 2 CONH 2
(−)
20b
3,4-DiClPh
O
ortho
H
H
1
CH 2 CONH 2
(+)
30b
3,4-DiClPh
O
ortho
H
H
2
CH 2 COOH
112a
3,4-DiClPh
O
ortho
H
H
1
CH 2 CONHCH 3
112b
3,4-DiClPh
O
ortho
H
H
1
CH 2 CON(C 2 H 5 ) 2
30f
3,4-DiClPh
O
ortho
H
H
0
CH 2 CON(CH 3 ) 2
30g
3,4-DiClPh
O
ortho
H
H
1
CH 2 CON(CH 3 ) 2
Ph = phenyl, ClPh = chlorophenyl, DiClPh = di-chlorophenyl;
*Position: the position refers to the position of the ArX lateral side chain as compared to —CH 2 —S(O) q —Y—R 1 group on the central benzyl ring;
Ortho is position 2′, meta is position 3′ and para is position 4′;
and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts forms thereof.