1. A compound of formula I,
and pharmaceutically acceptable salts thereof, wherein
A is NR, O or S;
R is hydrogen, C1 to C5 alkyl, C1 to C5 acyl, C1 to C5 alkyloxycarbonyl, C2 to C5 alkenyl, C2 to C5 alkenylcarbonyl or C2 to C5 alkenyloxycarbonyl;
g is 0, 1, 2, 3, or 4; and
B is a ring forming a fused ring system with the ring containing A and is selected from;
wherein A\u2032 is as described above for A and NR\u2032 is as described above for NR,
R1, R2, R3 and R4 are independently selected from:
(i) hydrogen, C1 to C5 alkyl, OH, NH2, C1 to C5 alkylamino, di(C1 to C5
alkyl)amino, C1 to C5 alkylcarbonyl, C1 to C5 alkyloxycarbonyl, C1 to C5 alkylcarbonyloxy, carboxyl, C1 to C5 alkyl phosphonate, C1 to C5 alkenyl phosphonate, C1 to C5 alkyl phosphate, C1 to C5 alkenyl phosphate, C1 to C5 alkyl sulfonate, C1 to C5 alkenyl sulfonate, halo, halo(C1 to C5)alkyl, amino(C1 to C5)alkyl, hydroxyl(C1 to C5)alkyl, (C1 to C5)alkoxyl) C1 to C5 alkyl, NO2, C1 to C5 alkylthio, SO3H, PO4, PO3H, NH4, C2 to C5 alkenyl, C2 to C5 alkenyloxy, C2 to C4 alkenylamino, di(C2 to C5 alkenylcarbonyl), C2 to C54 alkenyloxycarbonyl, C2 to C4 alkylcarbonyloxy, halo(C2 to C5)alkynyl, amino(C2 to C5)alkenyl, hydroxy(C2 to C5)alkenyl, (C1 to C5 alkoxy) C2 to C5 alkenyl, C2 to C5 alkenylthio, C2 to C4 alkynyl, C2 to C5 alkynyloxy, C2 to C5 alkynylamino, di(C2 to C5 alkynyl)amino, C2 to C5 alkynylcarbonyl, C2 to C5 alkynyloxycarbonyl, C2 to C5 alkynylcarbonyloxy, halo(C2 to C5)alkynyl, amino(C2 to C5)alkynyl, hydroxy(C2 to C5)alkynyl, (C1 to C5 alkoxy) C2 to C5 alkynyl;
(ii) C1 to C5 alkoxy; and
(iii) aryl and arylalkyl.
2. A compound of formula I according to claim 1, wherein R1 represents a residue of the formula
wherein R5, R6 and R7 are independently selected from H, OH, NR2, NR3, and R is hydrogen, C1 to C5 alkyl, C1 to C5 acyl, C1 to C5 alkyloxycarbonyl, C2 to C5 alkenyl, C2 to C5 alkenylcarbonyl or C2 to C5 alkenyloxycarbonyl.
3. A compound according to claim 2 wherein g is 1 and R1 is
4. A compound according to claim 2 wherein g is 1 and R1 is
5. A compound according to claim 2 wherein R1 is
6. A compound of formula II
and pharmaceutically acceptable salts thereof, wherein
A, D and M are independently NR, 0 or S;
R is hydrogen, C1 to C5 alkyl, C1 to C5 acyl, C1 to C5 alkyloxycarbonyl, C2 to C5 alkenyl, C2 to C5 alkenylcarbonyl or C2 to C5 alkenyloxycarbonyl;
g is 0, 1, 2, 3 or 4; and
X and X\u2032 are independently O or S;
R1, R2 and R3 are independently selected from:
(i) hydrogen, C1 to C5 alkyl, OH, NH2, C1 to C5 alkylamino, di(C1 to C5 alkyl)amino, C1 to C5 alkylcarbonyl, C1 to C5 alkyloxycarbonyl, C1 to C5 alkylcarbonyloxy, carboxyl, C1 to C5 alkyl phosphonate, C1 to C5 alkenyl phosphonate, C1 to C5 alkyl phosphate, C1 to C5 alkenyl phosphate, C1 to C5 alkyl sulfonate, C1 to C5 alkenyl sulfonate, halo, halo(C1 to C5)alkyl, amino(C1 to C5)alkyl, hydroxyl(C1 to C5)alkyl, (C1 to C5)alkoxyl) C1 to C5 alkyl, NO2, C1 to C5 alkylthio, SO3H, PO4, PO3H, NH4, C2 to C5 alkenyl, C2 to C5 alkenyloxy, C2 to C4 alkenylamino, di(C2 to C5 alkenylcarbonyl), C2 to C54 alkenyloxycarbonyl, C2 to C4 alkylcarbonyloxy, halo(C2 to C5)alkynyl, amino(C2 to C5)alkenyl, hydroxy(C2 to C5)alkenyl, (C1 to C5 alkoxy) C2 to C5 alkenyl, C2 to C5 alkenylthio, C2 to C4 alkynyl, C2 to C5 alkynyloxy, C2 to C5 alkynylamino, di(C2 to C5 alkynyl)amino, C2 to C5 alkynylcarbonyl, C2 to C5 alkynyloxycarbonyl, C2 to C5 alkynylcarbonyloxy, halo(C2 to C5)alkynyl, amino(C2 to C5)alkynyl, hydroxy(C2 to C5)alkynyl, (C1 to C5 alkoxy) C2 to C5 alkynyl;
(ii) C1 to C5 alkoxy; and
(iii) aryl and arylalkyl.
7. A compound of formula II according to claim 6, wherein R1 represents a residue of the A compound of formula I according to claim 1, wherein R1 represents a residue of the formula
wherein R5, R6 and R7 are independently selected from H, OH, NR2, NR3, and R is hydrogen, C1 to C5 alkyl, C1 to C5 acyl, C1 to C5 alkyloxycarbonyl, C2 to C5 alkenyl, C2 to C5 alkenylcarbonyl or C2 to C5 alkenyloxycarbonyl.
8. A compound according to claim 7 wherein g is 1 and R1 is
9. A compound according to claim 7 wherein g is 1 and R1 is
10. A compound according to claim 7 wherein g is 1 and R1 is
11. A compound according to claim 1 selected from the group consisting of:
1,2-dihydro-1-oxobenzofuro2,3-cpyridine-7-carboxylic acid;
1,2-dihydro-1-oxobenzofuro2,3-cpyridine-6-carboxylic acid;
(2E)-3-(1,2-dihydro-1-oxobenzofuro2,3-cpyridin-6-yl)acrylic acid; and
1,2-dihydro-1-oxobenzofuro2,3-cpyridine-8-carboxylic acid.
12. A compound according to claim 6 selected from the group consisting of:
(Z)-5-((1H-indol-3-yl)methylene)-2-thiooxazolidin-4-one;
(Z)-5-((1H-indol-3-yl)methylene)oxazolidine-2,4-dione;
(Z)-5-((1H-indol-3-yl)methylene)thiazolidine-2,4-dione;
(Z)-5-((1H-indol-3-yl)methylene)-2-thiothiazolidin-4-one, and
pharmaceutically acceptable salts thereof.
13. A method of treating a central nervous system (CNS) disorder associated with the striatal region of the brain, the method comprising:
administering an effective dose of a pharmaceutical formulation comprising a compound of formula I to a patient in need thereof exhibiting symptoms of a CNS disorder so as to attenuate said symptoms, wherein formula I is
and pharmaceutically acceptable salts thereof, wherein
A is NR, O or S;
R is hydrogen, C1 to C5 alkyl, C1 to C5 acyl, C1 to C5 alkyloxycarbonyl, C2 to C5 alkenyl, C2 to C5 alkenylcarbonyl or C2 to C5 alkenyloxycarbonyl;
g is 0, 1, 2, 3, or 4; and
B is a ring forming a fused ring system with the ring containing A and is selected from;
wherein A\u2032 is as described above for A and NR\u2032 is as described above for NR, R1, R2, R3 and R4 are independently selected from:
(i) hydrogen, C1 to C5 alkyl, OH, NH2, C1 to C5 alkylamino, di(C1 to C5 alkyl)amino, C1 to C5 alkylcarbonyl, C1 to C5 alkyloxycarbonyl, C1 to C5 alkylcarbonyloxy, carboxyl, halo, halo(C1 to C5)alkyl, amino(C1 to C5)alkyl, hydroxyl(C1 to C5)alkyl, (C1 to C5)alkoxyl) C1 to C5 alkyl, NO2, C1 to C5 alkylthio, SO3H, PO4, PO3H, NH4, C2 to C5 alkenyl, C2 to C5 alkenyloxy, C2 to C4 alkenylamino, di(C2 to C5 alkenylcarbonyl), C2 to C54 alkenyloxycarbonyl, C2 to C4 alkylcarbonyloxy, halo(C2 to C5)alkynyl, amino(C2 to C5)alkenyl, hydroxy(C2 to C5)alkenyl, (C1 to C5 alkoxy) C2 to C5 alkenyl, C2 to C5 alkenylthio, C2 to C4 alkynyl, C2 to C5 alkynyloxy, C2 to C5 alkynylamino, di(C2 to C5 alkynyl)amino, C2 to C5 alkynylcarbonyl, C2 to C5 alkynyloxycarbonyl, C2 to C5 alkynylcarbonyloxy, halo(C2 to C5)alkynyl, amino(C2 to C5)alkynyl, hydroxy(C2 to C5)alkynyl, (C1 to C5 alkoxy) C2 to C5 alkynyl;
(ii) C1 to C5 alkoxy; and
(iii) aryl and arylalkyl.
14. A method for treating a CNS disorder according to claim 13, wherein the CNS disorder is psychosis, schizophrenia, or obsessive-compulsive disorder.
15. A method for modulating PDE10A expression in a subject, the method comprising:
administering a compound of formula I or formula II as claimed in either claim 1 or claim 6 in a pharmaceutical formulation;
measuring isolated PDE10A mRNA from a sample of blood from the patient using a quantitative replicative procedure such as QPCR; and
comparing the level of isolated mRNA from blood from the subject before and after administering the compound of formula II.
16. A method for modulating PDE10A according to claim 15, wherein the compound of formula I or formula II is selected from the group consisting of: 1,2-dihydro-1-oxobenzofuro2,3-cpyridine-7-carboxylic acid; 1,2-dihydro-1-oxobenzofuro2,3-cpyridine-6-carboxylic acid; (2E)-3-(1,2-dihydro-1-oxobenzofuro2,3-cpyridin-6-yl)acrylic acid; 1,2-dihydro-1-oxobenzofuro2,3-cpyridine-8-carboxylic acid; (Z)-5-((1H-indol-3-yl)methylene)-2-thiooxazolidin-4-one; (Z)-5-((1H-indol-3yl)methylene)oxazolidine-2,4-dione; (Z)-5-((1H-indol-3-yl)methylene)thiazolidine-2,4-dione; (Z)-5-((1H-indol-3-yl)methylene)-2-thiothiazolidin-4-one, and pharmaceutically acceptable salts thereof.
17. A method of inhibiting PDE10A according to claim 15, wherein modulating further comprises inhibiting.
18. A method for treating a central nervous system (CNS) disorder associated with the striatal region of the brain, the method comprising administering an effective dose of a pharmaceutical formulation comprising a compound of formula II to a patient in need thereof exhibiting symptoms of a CNS disorder so as to attenuate said symptoms, wherein formula II is
and pharmaceutically acceptable salts thereof, wherein
A, D and M are independently NR, O or S;
R is hydrogen, C1 to C5 alkyl, C1 to C5 acyl, C1 to C5 alkyloxycarbonyl, C2 to C5 alkenyl, C2 to C5 alkenylcarbonyl or C2 to C5 alkenyloxycarbonyl;
g is 0, 1, 2, 3 or 4; and
X and X\u2032 are independently O or S;
R1, R2 and R3 are independently selected from:
(i) hydrogen, C1 to C5 alkyl, OH, NH2, C1 to C5 alkylamino, di(C1 to C5 alkyl)amino, C1 to C5 alkylcarbonyl, C1 to C5 alkyloxycarbonyl, C1 to C5 alkylcarbonyloxy, carboxyl, halo, halo(C1 to C5)alkyl, amino(C1 to C5)alkyl, hydroxyl(C1 to C5)alkyl, (C1 to C5)alkoxyl) C1 to C5 alkyl, NO2, C1 to C5 alkylthio, SO3H, PO4, PO3H, NH4, C2 to C5 alkenyl, C2 to C5 alkenyloxy, C2 to C4 alkenylamino, di(C2 to C5 alkenylcarbonyl), C2 to C54 alkenyloxycarbonyl, C2 to C4 alkylcarbonyloxy, halo(C2 to C5)alkynyl, amino(C2 to C5)alkenyl, hydroxy(C2 to C5)alkenyl, (C1 to C5 alkoxy) C2 to C5 alkenyl, C2 to C5 alkenylthio, C2 to C4 alkynyl, C2 to C5 alkynyloxy, C2 to C5 alkynylamino, di(C2 to C5 alkynyl)amino, C2 to C5 alkynylcarbonyl, C2 to C5 alkynyloxycarbonyl, C2 to C5 alkynylcarbonyloxy, halo(C2 to C5)alkynyl, amino(C2 to C5)alkynyl, hydroxy(C2 to C5)alkynyl, (C1 to C5 alkoxy) C2 to C5 alkynyl;
(ii) C1 to C5 alkoxy; and
(iii) aryl and arylalkyl.
19. A method for treating a CNS disorder according to claim 18, wherein the CNS disorder is psychosis, schizophrenia, or obsessive-compulsive disorder.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1-78. (canceled)
79. A patch interface, comprising:
a substrate;
an adhesive coupled to the substrate formulated for attachment to the skin of a subject;
one or more interconnects embedded into the substrate for attachment of a patch to a microcircuit; and
at least one of: one or more sensors; and one or more electrodes attached to or embedded onto the surface of the substrate, and arranged, configured, and dimensioned to interface with the subject when the adhesive is attached thereto;
wherein the patch interface is configured to monitor one or more physiologic signals, physical signals, and electrophysiological signals from the subject.
80. The patch interface in accordance with claim 79, wherein the adhesive is patterned onto the substrate so as to form one or more exposed regions of the substrate, at least one of the one or more of the sensors and one or more electrodes arranged within the exposed regions; and wherein at least one of the one or more electrodes comprise one of an inherently conducting and an ionically conducting gel adhesive.
81. The patch interface in accordance with claim 79, wherein at least one of the one or more electrodes comprises an electrode feature comprising one or more microfibers, barbs, microneedles, and spikes to penetrate into a stratum corneum of the skin.
82. The patch interface in accordance with claim 81, wherein the electrode feature is configured to penetrate into the skin during engagement therewith one of less than 2 mm, less than 1 mm, less than 0.5 mm, and less than 0.2 mm.
83. The patch interface in accordance with claim 80, wherein the gel adhesive is configured to maintain an improved electrical connection to the skin for one of more than one hour, more than one day, and more than three days after one of: the electrode contacts the skin; and pressure is applied to the electrode.
84. The patch interface in accordance with claim 79, further comprising one or more stretchable electrically conducting traces attached to the substrate, arranged so as to couple one or more of the sensors and electrodes with one or more of the interconnects.
85. The patch interface in accordance with claim 84, wherein the one or more interconnects comprise a plurality of connectors, the connectors physically connected to each other through the substrate; and wherein the patch comprises an isolating region arranged so as to isolate one or more of the connectors from the skin while the patch interface is engaged therewith.
86. The patch interface in accordance with claim 79, wherein the patch interface is sufficiently physically frail such that it cannot retain a predetermined shape in a free standing state.
87. The patch interface in accordance with claim 86, further comprising a temporary stiffening member attached to the substrate, the temporary stiffening member configured to provide retention of the shape of the patch interface prior to attachment to the subject, the stiffening member being removable from the substrate after attachment to the subject.
88. The patch interface in accordance with claim 86, wherein removal of the patch interface from the skin of the subject results in a permanent loss in shape of the patch interface without tearing of the patch interface.
89. The patch interface in accordance with claim 79, wherein the adhesive has a peel tack to mammalian skin of one of greater than 0.02 Nmm, greater than 0.1 Nmm, greater than 0.25 Nmm, greater than 0.50 Nmm, and greater than 0.75 Nmm.
90. The patch interface in accordance with claim 79, wherein the substrate is formed from a soft pseudo-elastic material and the patch interface is configured to maintain operation when stretched to one of more than 25%, more than 50%, and more than 80%.
91. The patch interface in accordance with a claim 79, wherein the patch interface is configured with a moisture vapor transmission rate of one of between 200 gm224 hrs and 20,000 gm224 hrs, between 500 gm224 hrs and 12,000 gm224 hrs, and between 1,000 gm224 hrs and 8,000 gm224 hrs.
92. A module, comprising:
a housing;
a circuit board comprising one or more microcircuits; and
a module interconnect coupled to one or more of the microcircuits configured for placement and coupling of a device onto a patch interface, the patch interface comprising:
a substrate;
an adhesive coupled to the substrate formulated for attachment to the skin of a subject;
one or more interconnects embedded into the substrate for attachment of a patch to a microcircuit; and
at least one of: one or more sensors; and one or more electrodes attached to or embedded onto the surface of the substrate, and arranged, configured, and dimensioned to interface with the subject when the adhesive is attached thereto;
wherein the module is configured to monitor one or more physiologic signals, physical signals, and electrophysiological signals from the subject.
93. The module in accordance with claim 92, wherein the module interconnect is embedded into the circuit board and the circuit board constitutes at least a portion of the housing.
94. The module in accordance with claim 92, further comprising a three dimensional antenna coupled to at least one of the one or more microcircuits, the one or more microcircuits comprising a transceiver or transmitter coupled to the antenna.
95. The module in accordance with claim 92, further comprising a sensor coupled with at least one of the one or more microcircuits, the sensor configured to interface with the subject upon attachment of the module to the patch interface.
96. The module in accordance with claim 95, wherein the module comprises at least one of: one or more sensors; and one or more microelectronics, configured to interface with a sensor included on the patch interface, at least one of the one or more sensors comprising: an electrophysiologic sensor, a temperature sensor, a thermal gradient sensor, a barometer, an altimeter, an accelerometer, a gyroscope, a humidity sensor, a magnetometer, an inclinometer, an oximeter, a colorimetric monitor, a sweat analyte sensor, a galvanic skin response sensor, an interfacial pressure sensor, a flow sensor, a stretch sensor, and a microphone.
97. The module in accordance with claim 92, wherein the module is hermetically sealed.
98. The module in accordance with claim 92, further comprising a gasket coupled to the circuit board, the gasket formed so as to isolate the region formed by the module interconnect and the patch from a surrounding environment when the module is coupled with the patch.
99. A device, comprising:
a patch interface; and
a module comprising:
a housing;
a circuit board comprising one or more microcircuits; and
a module interconnect coupled to one or more of the microcircuits configured for placement and coupling of the device onto the patch interface;
wherein the module interconnect is sized and dimensioned to interface with an interconnect within the patch interface, and the patch interface is coupled to a subject to form an operable interconnection between the patch interface and the module; and
wherein the device is configured to monitor one or more physiologic signals, physical signals, and electrophysiological signals from the subject.
100. The device in accordance with claim 99, wherein the module interconnect comprises one or more electrically conducting magnetic elements, and the patch interface comprises one or more ferromagnetic regions coupled to a substrate, the one or more magnetic elements arranged so as to physically and electrically couple the module to the patch interface when the one or more magnetic elements are aligned with the ferromagnetic regions.
101. The device in accordance with claim 100, wherein the ferromagnetic regions are formed from stretchable pseudo elastic material and are printed onto the substrate.
102. The device in accordance with claim 99, wherein at least one of the module and the patch interface comprises one or more fiducial markings to visually assist with alignment of the module to the patch during coupling thereof.