1. A compound of formula (1) or a pharmaceutically acceptable salt thereof:
49
in which
Ar is phenyl, naphthyl, a monocyclic heteroaromatic group or a bicyclic heteroaromatic group, said Ar group being optionally substituted by 1-4 substituents, which may be the same or different, and which are selected from the group consisting of:
halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-6alkyl, trifluoromethanesulfonyloxy, pentafluoroethyl, C1-6alkoxy, arylC1-6alkoxy, C1-6alkylthio, C1-6alkoxyC1-6alkyl, C3-7cycloalkylC1-6alkoxy, C1-6alkanoyl, C1-6alkoxycarbonyl, C1-6alkylsulfonyl, C1-6alkylsulfinyl, C1-6alkylsulfonyloxy, C1-6alkylsulfonylC1-6alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC1-6alkyl, C1-6alkylsulfonamido, C1-6alkylamido, C1-6alkylsulfonamidoC1-6alkyl, C1-6alkylamidoC1-6alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC1-6alkyl, arylcarboxamidoC1-6alkyl, aroyl, aroylC1-6alkyl, arylC1-6alkanoyl, a group R3OCO(CH2)s, R3CON(R4)(CH2)), R3R4NCO(CH2), or R3R4NSO2(CH2)s where each of R3 and R4 independently represents a hydrogen atom or C1-4alkali or R3 and R4 form part of a C3-6azacyloalkane or C3-6(2-oxo)azacycloalkane ring and s represents zero or an integer from 1 to 4, and a group Ar1-Z, wherein Z represents a single bond, O, S or CH2 and Ar1 represents a phenyl or a monocyclic heteroaromatic group, said Ar1 group being optionally substituted by 1-3 substituents, which may be the same or different, and which are selected from the group consisting of: a halogen, hydroxy, cyano, trifluormethyl, C1-6alkyl. C1-6alkoxy or C1-6alkanoyl:
when Ar is a phenyl or a monocyclic heteroaromatic group, substituents positioned ortho to one another may be linked to form a 5- or 6-membered ring;
R1 is hydrogen. C1-6alkyl. C1-6alkenyl. C3-6alkynyl or arylC1-6alkyl;
R2 is halogen. C1-6alkyl, cyano, CF3, C1-6alkanoyl. C1-6alkoxy or hydroxy;
X is CH or N:
Y is a single bond, O, or CO;
p is 0, 1 or 2;
r is 0, 1, 2 or 3;
m is 2, 3 or 4;
n and q are independently 1 or 2.
2. A compound according to claim 1 in which Ar is phenyl, naphthyl, indolyl, quinolinyl, quinazolinyl, indazolyl, isoquinolinyl, cinnolinyl or benzofuranyl, said groups being optionally substituted as defined in claim 1.
3. A compound according to claim 1 or 2, in which Ar is substituted by halogen (particularly fluoro or chloro), C1-6alkyl (particularly methyl, ethyl and propyl), cyano, CF3, C1-6alkoxy (particularly methoxy, ethoxy or isopropoxy), C1-6alkanoyl or a group Ar1-Z as defined in claim 1.
4. A compound according to claim 3, in which Ar1 is a monocyclic heteroaromatic group (particularly isoxazolyl), optionally substituted as defined in claim 1 and Z is a single bond.
5. A compound according to claim 1 in which Ar is 4-indolyl 4-indolyl(2-CN), 5-quinolinyl, 5-quinolinyl(2-Me), 8-quinolinyl, 1-isoquinolinyl, naphthyl, phenyl(2-CN), phenyl(2,3-dichloro), phenyl(3-Br), phenyl(3-Me), phenyl(3-CF3), phenyl(2-propyl), phenyl(2-CN, 4-F), phenyl(2-(5-isoxazolyl), phenyl(3-ethyl-4-Cl), 2,2-dimethyl-2,3-dihydrobenzobfuran-7-yl, (5-F)-2,2,2-dimethyl-2,3-dihydrobenzobfuran-7-yl, (6-F)-3,4-dihydro-2H-benzobpyranyl. (2,2-dimethyl)3,4-dihydro-2H-benzobpyranyl, 5-oxo-5,6,7,8-tetrahydronaphthyl 7-(2,3-dihydrobenzofuranyl), 7-(2-methyl)benzobfuranyl, 7-benzobfuranyl, 5-quinolinyl(2-Me, 8-Cl), 5-quinolinyl(2Me, 8-F), 5-quinolinyl(2-Me, 7-Cl), 5-quinolinyl(2Me, 7-F) or 5-quinazolinyl(2Me).
6. A compound according to any of claims 1 to 5, wherein r is 0, 1 or 2.
7. A compound according to any of claims 1 to 6, wherein R2 is halogen, particularly fluoro.
8. A compound according to any of claims 1 to 7, in which R1 is hydrogen or methyl.
9. A compound according to any of claims 1 to 8, in which m is 2.
10. A compound according to claim 1 which is a compound selected from Example E1-E 167 or a pharmaceutically acceptable salt thereof.
11. A compound according to claim 1 which is:
6-(4-(1-(2-(4-1H-Indolyloxy)ethyl)piperidinyl)oxy)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(4-(2-Cyano)-1H-indolyloxy)ethyl)piperidinyl)oxy)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(3-(2-(5-Isoxazolyl)phenoxy)propyl)piperidinyl)oxy)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(5-Quinolinyloxy)ethyl)piperidinyl)methyl)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(3-(2-Cyanophenoxy)propyl)piperidinyl)oxy)-4H-benxo1,4oxazin-3-one;
6-(4-(1-(3-(7-(2,2-Dimethyl-2,3-dihydro)benzobfuranyloxy)propyl)piperidinyl)-oxy)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(7-(2,2-Dimethyl-2,3-dihydro)benzobfuranyloxy)ethyl)piperidinyl)oxy)-4-methyl-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(1-naphthyloxy)ethyl)piperidinyl)oxy)-4-methyl-4H-benzo1,4oxazin-3-one;
()-6-(3-(1 (3-(2-Cyanophenoxy)propyl)piperidinyl)methoxy)-4H-benzo1,4oxazin-3-10 one;
()-6-(3-(1-(3-(2-Cyanophenoxy)propyl)pyrrolidinyl)methoxy)-4H-benzo 1,4oxazin-3-one;
6-(4-(1-(3-(2-(5-Isoxazolyl)phenoxy)propyl)piperazinyl)methyl)-4H-benzo0.4oxazin-3-one;
6-(4-(1-(2-(5-(2-Methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4H-benzo1,4oxazin-1-one;
6-(4-(1-(2-(5-(3-Methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(5-quinolinyloxy)ethyl)piperidinyl)methyl)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(4-(1,2-Dihydro)benzobfuranyloxy)ethyl)piperidinyl)methyl)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(4-(1H)-Indazolyloxy)ethyl)piperidinyl)methyl)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(5-(2-Methyl)quinolinyloxy)ethyl)piperidinyl)oxy)-4H-benzo1,4oxazin-3-one;
4-Methyl-6-(4-(1-(2-(5-(2-methyl)quinolinyloxy)ethyl)piperidinyl)oxy)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(5-(2-Methyl)quinolinyloxy)ethyl)piperazinyl)methyl)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(3-(S-(2-methyl)quinolinyloxy)propyl)piperidinyl)methyl)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(5-(2-Methyl)quinolinyloxy)propyl)piperazinyl)methyl)-4-benzo1,4oxazin-3-one;
6-(4-(1-(3-(5-(2-Methyl)quinolinyloxy)propyl)piperidinyl)oxy)-4H-benzo1,4oxazin-3-one;
4-methyl-6-(4-(1-(3-(5-(2-Methyl)quinolinyloxy)propyl)piperidinyl)oxy)-4H-benzo0.4oxazin-3-one:
4-Methyl-6-(4-(1-(2-(5-(2-methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(5-(8-Chloro-2-methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4H-benzo1,4oxazin-3-one;
4-Methyl-6-(4-(1-(3-(5-(2-methyl)quinolinyloxy)propyl)piperidinyl)-methyl)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(5-(8-Chloro-2-methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4-methyl-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(5-(8-Fluoro-2-methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(5-(8-Fluoro-2-methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4-methyl-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(5-(8-Fluoro-2-methyl)quinolinyloxy)ethyl)piperidinyl)oxy)-4H-benzo1,4oxazin-3-one,
6-(4-(1-(2-(5-(8-Fluoro-2-methyl)quinolinyloxy)ethyl)piperidinyl)oxy)-4-methyl-4H-benzo1,4oxazin-3-one-
6-(4-(1-(2-(5-(7-Chloro-2-methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4H-benzo 1,4oxazin-3-one;
6-(4-(1-(2-(5-(7-Chloro-2-methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4-methyl-4H-benzo1,4oxazin-3-one;
6-(4-(1-(5-(7-Chloro-2-methyl)quinolinyloxy)ethyl)piperidinyl)oxy)-4H-benzo1,4oxazin-3-one;
6-(4-(2-(5-(7-Chloro-2-methyl)quinolinyloxy)ethyl)piperidinyl)oxyl)-4-methyl-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(5-(7-Chloro-2-methyl)quinolinyloxy)ethyl)piperazinyl)methyl)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(3-(5-(7-Chloro-2-methyl)quinolinyloxy)propyl)piperidinyl)oxy)-4H-benzo1,4oxazin-3-one;
6-(4-(1-(2-(5-(7-Chloro-2-methyl)quinolinyloxy)propyl)piperidinyl)oxy)-4-methyl-4H-benzo1,4oxazine-3-one;
6-(4-(1-(3-(5-(2-Methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4-(2-propyl)-4H-benzo1,4oxazin-3-one:
6-(4-(1-(2-(5-(2-methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4H-benzo1,4-10 oxazin-3-one:
6-(4-(1-(2)-(5-(7-Fluoro-2-methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4H-benzo1,4oxazin-3-one:
7-Fluoro-6-(4-(1-(2-(5-(2-methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4H-benzo1,4oxazin-3-one;
8-Fluoro-4-methyl-6-(4-(1-(2-(5-(2-methyl)quinolinyloxy)ethyl)piperidinyl) methyl)-4H-benzo1,4oxazin-3-one;
8-Fluoro-6-(4-(1-(2-(5-(2-methyl)quinolinyloxy)ethyl)piperidinyl)methyl)-4H-benzo1,4oxazin-3-one;
7,8-Difluoro-6-(4-(1-(2-(5-(2-methyl)quinolinyloxy)ethyl)piperazinyl)methyl)-4H-benzo1,4oxazin-3-one,
4-Ethyl-6-1-2-)-(2-methyl-quinolin-5-yloxy)-ethyl-piperidin-4-ylmethyl-4H-benzo1,4oxazin-3-one
or a pharmaceutically acceptable salt thereof.
12. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises:
(a) the coupling of a compound of formula (II):
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in which R1R2, Y, n, p, q and r are defined in formula (1),
with a compound of formula (III):
51
in which Ar and m are as defined for formula (I) and L is a leaving group: or
(b) reacting a compound of formula (11) as defined above with a compound of formula (IV)
52
in which Ar and m are defined in formula (l), in the presence of a reducing agent; or
(c) for a compound of formula (I) wherein X is N, reacting a compound of formula
(v):
53
in which p, R2, r and R1 are as defined in formula (1), with a compound of formula (VI):
54
in which Ar, m, q and n are as defined in formula (I), in the presence of a reducing agent;
and optionally thereafter for each of process (a). (b) or (c):
removing any protecting groups, andor
converting a compound of formula (I) into another compound of formula (I), andor
forming a pharmaceutically acceptable salt.
13. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier or excipient.
14. A process for preparing a pharmaceutical composition according to claim 13, the process comprising mixing a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier or excipient.
15. A compound according to any one of claims 1 to 11 or a composition according, to claim 13 for use in therapy.
16. A compound according to any one of claims 1 to 11 or a composition according to claim 13 for use in the treatment or prophylaxis of CNS and other disorders.
17. A compound according to any one of claims 1 to 11 or a composition according to claim 13 for use in the treatment or prophylaxis of depression andor anxiety.
18. A method of treating CNS and other disorders which comprises administering a safe and therapeutically effective amount to a patient in need thereof of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or a composition according to claim 13.
19. A method according to claim 18, wherein the disorder is depression andor anxiety.
20. The use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or a composition according to claim 13, in the manufacture of a medicament for the treatment or prophylaxis of CNS and other disorders.
21. The use as claimed in claim 20, wherein the medicament is for the treatment or prophylaxis of depression andor anxiety.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A cardiopulmonary resuscitator, comprising:
a panel for supporting a patient;
a first belt, disposed at a side of the panel, for wrapping around a chest of the patient;
a flexible body, disposed on one side of the panel opposite to the side for supporting the patient, functioning to tighten and loosen the first belt for compressing and releasing the chest of the patient through a inflating and deflating motion generated by a pneumatic power; and
a controlling module, connected to a pneumatic source, being capable of adjusting the airflow provided from the pneumatic source to pass in and out the flexible body.
2. The cardiopulmonary resuscitator according to claim 1, wherein the flexible body is a bladder.
3. The cardiopulmonary resuscitator according to claim 1, further comprises a second belt with two ends connecting to two ends of the first belt respectively and contacting with the flexible body.
4. The cardiopulmonary resuscitator according to claim 3, wherein there is a buckle disposed between the first belt and the second belt.
5. The cardiopulmonary resuscitator according to claim 3, further comprises a hook-and-loop fastener disposed between the second belt and the flexible body for attaching the flexible body to the second belt.
6. The cardiopulmonary resuscitator according to claim 1, wherein the pneumatic source is selected from a group consisting a high pressure bottle and a inflator, which generates air through a compression and inflation movement operated by a action force.
7. The cardiopulmonary resuscitator according to claim 1, further comprising a massage pad, made of a rubber material and disposed on side of the first belt toward the chest of the patient.
8. The cardiopulmonary resuscitator according to claim 1, wherein the panel further comprises a handle for carrying.
9. The cardiopulmonary resuscitator according to claim 1, wherein the first belt further comprises a fastener for adjusting the first belt according to size of the chest of the patient.