Thio-substituted tricyclic and bicyclic aromatic methanesulfinyl derivatives
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, Y, R 1 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:
wherein:
U is O or S;
rings A and B are optionally substituted with one to three groups selected from F, cl, Br, I, OR 22 , OR 27 , 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, 3–7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, 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 ;
Y is C 1 –C 6 alkylene;
wherein said alkylene groups are optionally substituted with one to three R 20 groups;
R 1 is C(═O)NR 12 R 13 ,
R 12 and R 13 at each occurrence are each independently selected from H, C 1 –C 6 alkyl, or R 12 and R 13 , together with the nitrogen to which they are attached, form a 3–7 membered heterocyclic ring;
wherein said alkyl groups and heterocyclic ring 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 27 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 –C 6 alkyl optionally substituted with OH, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 7 cycloalkyl, 3–7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl, ═O, 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 C(═O)OR 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 optionally substituted with OH, arylalkyl 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, or R 23 and R 24 , together with the nitrogen to which they are attached, form a 3–7 membered heterocyclic ring optionally substituted with ═O;
R 27 at each occurrence is independently the residue of an naturally occurred amino acid after the hydroxyl group of the carboxyl group is removed;
q is 1, or 2;
y is 0, 1, or 2;
and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts forms thereof.
2. The compound according to claims 1 , wherein q is 1.
3. The compound according to claim 1 , wherein R 12 and R 13 are each independently selected from H and C 1 –C 6 alkyl.
4. The compound according to claim 1 , wherein R 12 and R 13 together with the nitrogen to which they are attached, form a 3–7 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one R 20 group.
5. The compound according to claim 4 , wherein said heterocyclic ring is unsubstituted.
6. The compound according to claim 1 , wherein Y is C 1 to C 6 alkylene.
7. The compound according to claim 1 , wherein Y is CH 2 .
8. The compound according to claim 1 ,
wherein
rings A, B, and C are optionally substituted with one to three groups selected from F, Cl, Br, I, OR 22 , OR 27 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 –C 6 alkyl, phenyl, arylalkyl, and C(═O)R 22 ;
R 20 at each occurrence is independently selected from F, Cl, Br, I, OR 22 , OR 27 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 –C 6 alkyl optionally substituted with OH, phenyl, ═O, 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 ;
and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts forms thereof.
9. The compound according to claim 8 , wherein Y is CH 2 , or CH 2 —CH 2 .
10. The compound according to claim 1 , selected in accordance with the following table:
wherein Ar, q, Y—R 1 are defined in the table below;
Ex. No.
Ring Ar
q
Y-R 1
36
Dibenzofuran-2-yl
1
CH 2 CONH 2
54
Dibenzofuran-2-yl
1
CH 2 CON(CH 3 ) 2
55
Dibenzofuran-2-yl
1
CH 2 CO-N-pyrrolidinyl
56
Dibenzofuran-2-yl
1
CH 2 CONHCH(CH 3 ) 2
57
Dibenzofuran-2-yl
1
CH 2 CO-1-piperazinyl
58
Dibenzofuran-2-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
59
Dibenzofuran-2-yl
1
CH 2 CONHCH 2 CH 2 OH
60
Dibenzofuran-2-yl
1
CH 2 CO-1-(4-hydroxy)piperidinyl
61
Dibenzofuran-2-yl
1
CH 2 CONHCH 2 CH 2 OCH 2 CH 2 OH
34
Dibenzofuran-2-yl
1
CH 2 CO-1-[4-(2-hydroxyethyl)-piperazinyl]
62
Dibenzofuran-2-yl
1
CH 2 CO-1-(4-formyl)-piperazinyl
63
Dibenzofuran-2-yl
1
CH 2 CO-1-(4-tert-butoxycarbonyl)-piperazinyl
35
Dibenzofuran-2-yl
1
CH 2 CO-1-(4-ethoxycarbonyl)-piperazinyl
64
Dibenzofuran-2-yl
1
CH 2 CO-1-(4-methyl)-piperazinyl
65
Dibenzofuran-2-yl
1
CH 2 CO-1-(4-ethyl)-piperazinyl
66
Dibenzofuran-2-yl
1
CH 2 CO-1-(4-propyl)-piperazinyl
67
Dibenzofuran-2-yl
1
CH 2 CON-morpholinyl
69
Dibenzofuran-2-yl
1
CH 2 CONHN-morpholinyl
70
Dibenzofuran-2-yl
1
CH 2 CO-4-(2-oxo-piperazinyl)
71
Dibenzofuran-2-yl
1
CH 2 CO-1-(4-isopropylaminocarbonyl)-
piperazinyl
72
Dibenzofuran-2-yl
1
CH 2 CO-1-(4-aminocarbonyl)-piperazinyl
73
Dibenzofuran-2-yl
1
CH 2 CO-1-(4-pyrrolidinylcarbonyl)-piperazinyl
74
Dibenzofuran-2-yl
1
CH 2 CO-1-(4-dimethylaminocarbonyl)-
piperazinyl
75
Dibenzofuran-2-yl
1
CH 2 CO-1-(4-benzyloxycarbonyl)-piperazinyl
76
Dibenzofuran-2-yl
1
CH 2 CH 2 CONH 2
77
Dibenzofuran-2-yl
1
CH 2 CH 2 CO-1-piperazinyl
78
Dibenzofuran-2-yl
1
CH 2 CH 2 CO-1-(4-acetyl)-piperazinyl
79
Dibenzofuran-2-yl
1
CH 2 CON-[3-(2-oxo-pyrrolidin-1-yl)-propyl]
80
Dibenzofuran-2-yl
1
CH 2 CON-(2-pyrrolidin-1-yl-ethyl)
81
Dibenzofuran-2-yl
1
CH 2 CON-(2-piperidin-1-yl-ethyl)
82
Dibenzofuran-2-yl
1
CH 2 CON-(2-morpholin-4-yl-ethyl
84
6-Chloro-dibenzofuran-2-yl
1
CH 2 CO-1-piperazinyl
85
6-Chloro-dibenzofuran-2-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
41
8-Chloro-dibenzofuran-2-yl
1
CH 2 CO-1-piperazinyl
86
8-Chloro-dibenzofuran-2-yl
1
CH 2 CONH 2
42
8-Chloro-dibenzofuran-2-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
146
8-Chloro-dibenzofuran-2-yl
2
CH 2 CO-1-(4-acetyl)-piperazinyl
40
8-Chloro-dibenzofuran-2-yl
1
CH 2 CO-1-(4-hydroxyethyl)-piperazinyl
37
8-Methoxy-dibenzofuran-2-yl
1
CH 2 CONH 2
87
8-Methoxy-dibenzofuran-2-yl
1
CH 2 CO-1-piperazinyl
88
8-Methoxy-dibenzofuran-2-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
45
8-Fluoro-dibenzofuran-2-yl
1
CH 2 CO-1-piperazinyl
89
8-Fluoro-dibenzofuran-2-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
38
8-Fluoro-dibenzofuran-2-yl
1
CH 2 CONH 2
90
4-Chloro-dibenzofuran-2-yl
1
CH 2 CONH 2
91
4-Fluoro-dibenzofuran-2-yl
1
CH 2 CONH 2
92
4-Chloro-dibenzofuran-2-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
93
4-Fluoro-dibenzofuran-2-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
94
4-Fluoro-8-chloro-dibenzofuran-
1
CH 2 CONH 2
2-yl
95
Dibenzofuran-4-yl
1
CH 2 CONHCH 2 CH 2 OH
96
Dibenzofuran-4-yl
1
CH 2 CONH 2
97
Dibenzofuran-4-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
98
Dibenzofuran-4-yl
1
CH 2 CO-1-(4-hydroxy)piperidinyl
99
Dibenzofuran-4-yl
1
CH 2 CO-1-piperazinyl
100
Dibenzofuran-4-yl
1
CH 2 CON-(2-pyrrolidin-1-yl-ethyl)
101
Dibenzofuran-4-yl
1
CH 2 CON-[3-(2-oxo-pyrrolidin-1-yl)-propyl]
102
Dibenzofuran-4-yl
1
CH 2 CON-(2-piperidin-1-yl-ethyl)
103
Dibenzofuran-4-yl
1
CH 2 CON-(2-morpholin-4-yl-ethyl)
104
Dibenzofuran-4-yl
1
CH 2 CO-1-(4-hydroxyethyl)-piperazinyl
105
Dibenzofuran-3-yl
1
CH 2 CO-1-piperazinyl
106
Dibenzofuran-1-yl
1
CH 2 CO-1-piperazinyl
107
Dibenzofuran-3-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
44
Dibenzothiophen-2-yl
1
CH 2 CO-1-piperazinyl
108
Dibenzothiophen-2-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
109
Dibenzothiophen-2-yl
1
CH 2 CO-1-(4-ethoxycarbonyl)-piperazinyl
39
Dibenzothiophen-2-yl
1
CH 2 CONH 2
110
Dibenzothiophen-4-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
111
Fluoren-1-yl
1
CH 2 CONHCH 2 CH 2 OH
112
Fluoren-1-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
113
Fluoren-1-yl
1
CH 2 CO-1-(4-hydroxy)piperidinyl
115
Fluoren-1-yl
1
CH 2 CO-1-(4-hydroxyethyl)-piperazinyl
116
Fluoren-1-yl
1
CH 2 CO-1-piperazinyl
118
Fluoren-2-yl
1
CH 2 CON(CH 3 ) 2
119
Fluoren-2-yl
1
CH 2 CO-N-pyrrolidinyl
120
Fluoren-2-yl
1
CH 2 CONHCH(CH 3 ) 2
121
Fluoren-2-yl
1
CH 2 CONHCH 2 CH 2 OH
122
Fluoren-2-yl
1
CH 2 CO-1-(4-hydroxy)piperidinyl
123
Fluoren-2-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
125
Fluoren-4-yl
1
CH 2 CON(CH 3 ) 2
126
Fluoren-4-yl
1
CH 2 CONHCH(CH 3 ) 2
127
Fluoren-4-yl
1
CH 2 CONHCH 2 CH 2 OH
128
Fluoren-4-yl
1
CH 2 CO-1-(4-hydroxy)piperidinyl
129
Fluoren-4-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
130
Fluoren-4-yl
1
CH 2 CO-1-piperazinyl
43
Fluoren-4-yl
1
CH 2 CO-1-(4-hydroxyethyl)-piperazinyl
131
Fluoren-4-yl
1
CH 2 CO-1-(4-formyl)-piperazinyl
151
7-chlorodibenzofuran-1-yl
1
CH2CONH2
152
8-chlorodibenzofuran-1-yl
1
CH2CONH2
153
7,8-dichlorodibenzofuran-1-yl
1
CH2CONH2.
11. A method of treating sleepiness associated with narcolepsy 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 salt form thereof.
12. A pharmaceutical composition comprising a compound of claim 1 , or the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts forms thereof, in admixture with one or more pharmaceutically acceptable excipients.
13. A method for preparing a compound of claim 1 , comprising the steps of:
a1) reacting a compound F with a compound G to form a compound of formula (Ia):
wherein Ar, Y, R 1 are as defined in claim 1 , q=0 and LG is a leaving group; and optionally
b1) isolating the formed compound (Ia); and reacting the compound (Ia) with an appropriate oxidizing agent to form a compound (Ib):
wherein Ar, Y, R 1 are as defined in claim 1 and q is 1 or 2; and optionally isolating the formed compound (Ib).
14. The method according to claim 13 , wherein the compound F is formed by reacting a compound C with thiourea and a suitable acid HA:
15. A method for preparing a compound of claim 1 , comprising the steps of:
a2) reacting a compound E with a compound G to form a compound of formula (Ia):
wherein Ar, Y, R 1 are as defined in claim 1 , q=0 and LG is a leaving group; and optionally
b2) isolating the formed compound (Ia); and reacting the compound (Ia) with an appropriate oxidizing agent to form a compound (Ib):
wherein Ar, Y, R 1 are as defined in claim 1 and q is 1 or 2; and optionally isolating the formed compound (Ib).
16. The method according to claim 15 , wherein the compound E is formed by reacting a compound B with the thioacetamide:
17. A method for preparing a compound of claim 1 , comprising the steps of:
a3) reacting a compound A with a compound D to form a compound of formula (Ia):
wherein Ar, Y, R 1 are as defined in claim 1 and q=0; and optionally
b3) isolating the formed compound of formula (Ia); and reacting the compound (Ia) with an appropriate oxidizing agent to form a compound (Ib):
wherein Ar, Y, R 1 are as defined in claim 1 and q is 1 or 2; and optionally isolating the formed compound (Ib).
18. A method for preparing a compound of claim 1 comprising the steps of:
a4) reacting a compound C with a compound H to form a compound (Ia):
wherein Ar, Y, R 1 are as defined in claim 1 and q=0; and optionally
b4) isolating the formed compound (Ia); and reacting the compound (Ia) with an appropriate oxidizing agent to form a compound (Ib):
wherein Ar, Y, R 1 are as defined in claim 1 and q is 1 or 2; and optionally isolating the formed compound (Ib).
19. A method for preparing a compound of claim 1 comprising the steps of:
a4) reacting a compound B with a compound H to form a compound (Ia):
wherein Ar, Y, R 1 are as defined in claim 1 and q=0; and optionally
b4) isolating the formed compound (Ia); and reacting the compound (Ia) with an appropriate oxidizing agent to form a compound (Ib):
wherein Ar, Y, R 1 are as defined in claim 1 and q is 1 or 2; and optionally isolating the formed compound (Ib).