Thio-substituted tricyclic and bicyclic aromatic methanesulfinyl 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, 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 CH 2 ;
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; or
(C 1 -C 4 alkylene) m -Z—(C 1 -C 4 alkylene) n , wherein m is 0 or 1 and n is 0 or 1;
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, 5-10 membered heteroarylene, C 3 -C 6 cycloalkylene, or 3-6 membered heterocycloalkylene; wherein said arylene, heteroarylene, cycloalkylene, and heterocycloalkylene 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 , NR 21 S(O) 2 NR 12 R 13 , and C(═O)NR 11 OR 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 R 20 groups;
R 11 at each occurrence is independently selected from H, C 1 -C 6 alkyl, and C 6 -C 10 aryl; wherein said alkyl and aryl groups 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, C 6 -C 10 aryl, and NR 23 R 24 , 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 and aryl groups and heterocyclic ring 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 alkylaryl; wherein said alkyl, aryl and alkylaryl 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 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 amino acid after the hydroxyl group of the carboxyl group is removed;
q is 0, 1, or 2; and
y is 1 or 2;
or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt form thereof;
and with the exclusion of the compounds wherein:
U is CH 2 ; Y is C 1 -C 6 alkylene optionally substituted with C 1 -C 6 alkylene; and
R 1 is CONH 2 or CO 2 R 11 where R 11 is H or C 1 -C 6 alkyl.
2. The compound according to claim 1 , wherein q is 1.
3. 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 R 13 ; C(═NR 11 )NR 12 R 13 , and NR 21 C(═O)NR 12 R 13 , C(═NR 11 )NR 12 R 13 .
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)NR 12 R 13 ; C(═NR 11 )NR 12 R 13 , and NR 21 C(═O)NR 12 R 13 .
5. The compound according to claim 1 , wherein R 1 is C(═O)NR 12 R 13 .
6. The compound according to claim 5 , wherein R 12 and R 13 are each independently selected from H, C 1 -C 6 alkyl and NR 23 R 24 .
7. The compound according to claim 5 , 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.
8. The compound according to claim 7 , wherein said heterocyclic ring is unsubstituted.
9. The compound according to claim 1 , 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 .
10. The compound according to claim 1 , having the structure of formula (III):
11. The compound according to claim 10 , wherein Y is CH 2 , or CH 2 —CH 2 .
12. 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:
Ring Ar
q
Y-R 1
Fluoren-1-yl
0
CH 2 CONHCH 2 CH 2 OH
Fluoren-1-yl
0
CH 2 CO-1-(4-acetyl)-piperazinyl
Fluoren-1-yl
0
CH 2 CO-1-(4-hydroxy)piperidinyl
Fluoren-1-yl
0
CH 2 CO-1-(4-hydroxyethyl)-piperazinyl
Fluoren-1-yl
0
CH 2 CO-1-piperazinyl-N-Boc
Fluoren-2-yl
0
CH 2 CON(CH 3 ) 2
Fluoren-2-yl
0
CH 2 CO—N-pyrrolidinyl
Fluoren-2-yl
0
CH 2 CONHCH(CH 3 ) 2
Fluoren-2-yl
0
CH 2 CONHCH 2 CH 2 OH
Fluoren-2-yl
0
CH 2 CO-1-(4-hydroxy)piperidinyl
Fluoren-2-yl
0
CH 2 CO-1-(4-acetyl)-piperazinyl
Fluoren-4-yl
0
CH 2 CON(CH 3 ) 2
Fluoren-4-yl
0
CH 2 CONHCH(CH 3 ) 2
Fluoren-4-yl
0
CH 2 CONHCH 2 CH 2 OH
Fluoren-4-yl
0
CH 2 CO-1-(4-hydroxy)piperidinyl
Fluoren-4-yl
0
CH 2 CO-1-(4-acetyl)-piperazinyl
Fluoren-4-yl
0
CH 2 CO-1-piperazinyl-N-Boc
Fluoren-4-yl
0
CH 2 CO-1-(4-hydroxyethyl)-piperazinyl
Fluoren-4-yl
0
CH 2 CO-1-(4-formyl)-piperazinyl
Fluoren-1-yl
1
CH 2 CONHCH 2 CH 2 OH
Fluoren-1-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
Fluoren-1-yl
1
CH 2 CO-1-(4-hydroxy)piperidinyl
Fluoren-1-yl
1
CH 2 CO-1-(4-hydroxyethyl)-piperazinyl
Fluoren-1-yl
1
CH 2 CO-1-piperazinyl
Fluoren-2-yl
1
CH 2 CON(CH 3 ) 2
Fluoren-2-yl
1
CH 2 CO—N-pyrrolidinyl
Fluoren-2-yl
1
CH 2 CONHCH(CH 3 ) 2
Fluoren-2-yl
1
CH 2 CONHCH 2 CH 2 OH
Fluoren-2-yl
1
CH 2 CO-1-(4-hydroxy)piperidinyl
Fluoren-2-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
Fluoren-4-yl
1
CH 2 CON(CH 3 ) 2
Fluoren-4-yl
1
CH 2 CONHCH(CH 3 ) 2
Fluoren-4-yl
1
CH 2 CONHCH 2 CH 2 OH
Fluoren-4-yl
1
CH 2 CO-1-(4-hydroxy)piperidinyl
Fluoren-4-yl
1
CH 2 CO-1-(4-acetyl)-piperazinyl
Fluoren-4-yl
1
CH 2 CO-1-piperazinyl
Fluoren-4-yl
1
CH 2 CO-1-(4-hydroxyethyl)-piperazinyl; and
Fluoren-4-yl
1
CH 2 CO-1-(4-formyl)-piperazinyl
or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt form thereof.
13. A method of treating a disease or a disorder 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, wherein the disease or disorder is sleepiness associated with narcolepsy, or obstructive sleep apnea.
14. A method according to claim 13 wherein said disease or disorder is sleepiness associated with narcolepsy.
15. A method of promoting or improving 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.
16. A pharmaceutical composition comprising a compound according to claim 1 or a stereoisomeric form, mixture of stereoisomeric forms or pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable excipient or carrier.
17. 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).
18. The method according to claim 17 , wherein the compound F is formed by reacting a compound C with thiourea and a suitable acid HA:
19. 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).
20. The method according to claim 19 , wherein the compound E is formed by reacting a compound B with the thioacetamide:
21. 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).
22. 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).
23. 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).
24. The method according to any one of claim 17 , 19 , 21 , 22 or 23 , further comprising the step of:
a5) reacting the compound (Ia) with an appropriate oxidizing agent for form a compound (Ib):
wherein Ar, Y, R 1 are as defined in claim 1 and q is 1 or 2; and optionally
b5) isolating the formed compound (Ib).