BENZIMIDAZOLIDINONE DERIVATIVES AS MUSCARINIC AGENTS
First Claim
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1. A method of treating mental disease or disorder in a mammal comprising identifying a mammal in need thereof and administering at least one compound of Formula I to said mammal:
- or a pharmaceutically acceptable salt or prodrug thereof, wherein;
X is selected from the group consisting of CH, O, N and S;
Z is selected from the group consisting of CH and N;
Y is selected from the group consisting of ═
O, ═
NH and ═
S or tautomers thereof;
-SPU- is a biradical selected from the group consisting of —
(CR6R7)n-A- and —
C3-8-cycloalkyl-, wherein n is 1, 2, 3, 4, or 5;
A is absent or an optionally substituted —
C3-8-cycloalkyl;
N together with R1 and R2 form a heterocyclic ring wherein said heterocyclic ring is 8-azabicyclo[3.2.1]octane, wherein the heterocyclic ring is substituted with one or more substituents R4 selected from the group consisting of halogen, C1-8-alkyl, C3-8-cycloalkyl, C1-8-alkoxy, C1-8-alkylcarbonyl, C1-8-alkylidene, C2-8-alkenyl, C2-8-alkynyl, C1-6-alkyloxyimino, and C1-6-alkyloxyamino each of which may be optionally substituted with a substituent R5, and wherein at least one of said substituents R4 is R4′
selected from the group consisting of C1-8-alkyl, C3-8-cycloalkyl, C1-8-alkoxy, C1-8-alkylcarbonyl, C1-8-alkylidene, each of which may be optionally substituted with a substituent R5;
R5 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-8-alkyl, C1-8-alkoxy, C3-8-cycloalkyl, C3-8-heterocyclyl, C1-8-alkylcarbonyl, C1-8-alkylidene, C2-8-alkenyl and C2-8-alkynyl;
RX may be absent or selected from the group consisting of hydrogen, optionally substituted C1-8-alkyl, optionally substituted C3-8-cycloalkyl, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, CH2—
N(R5)(R5), CH2—
OR5, CH2—
SR5, and CH2—
O—
C(═
O)R5;
R3 may be present 0-4 times and selected from the group consisting of halogen, hydroxy, optionally substituted C1-8-alkyl, C1-8-alkoxy, optionally substituted C1-8-alkylidene, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-8-cycloalkyl, optionally substituted C3-8-heterocyclyl, and optionally substituted C1-8-alkylcarbonyl; and
each R6 and each R7 is optionally and independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C1-8-alkyl, C1-8-alkoxy, optionally substituted C1-8-alkylidene, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-8-cycloalkyl, optionally substituted C3-8-heterocyclyl, and optionally substituted C1-8-alkylcarbonyl.
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Abstract
Benzimidazolidinone derivative compounds, which increase acetylcholine signaling or effect in the brain, and highly selective muscarinic agonists, particularly for the M1 and/or M4 receptor subtypes, pharmaceutical compositions comprising the same, as well as methods of treating psychosis using these compounds are disclosed.
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Citations
25 Claims
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1. A method of treating mental disease or disorder in a mammal comprising identifying a mammal in need thereof and administering at least one compound of Formula I to said mammal:
or a pharmaceutically acceptable salt or prodrug thereof, wherein;
X is selected from the group consisting of CH, O, N and S;
Z is selected from the group consisting of CH and N;
Y is selected from the group consisting of ═
O, ═
NH and ═
S or tautomers thereof;
-SPU- is a biradical selected from the group consisting of —
(CR6R7)n-A- and —
C3-8-cycloalkyl-, wherein n is 1, 2, 3, 4, or 5;
A is absent or an optionally substituted —
C3-8-cycloalkyl;
N together with R1 and R2 form a heterocyclic ring wherein said heterocyclic ring is 8-azabicyclo[3.2.1]octane, wherein the heterocyclic ring is substituted with one or more substituents R4 selected from the group consisting of halogen, C1-8-alkyl, C3-8-cycloalkyl, C1-8-alkoxy, C1-8-alkylcarbonyl, C1-8-alkylidene, C2-8-alkenyl, C2-8-alkynyl, C1-6-alkyloxyimino, and C1-6-alkyloxyamino each of which may be optionally substituted with a substituent R5, and wherein at least one of said substituents R4 is R4′
selected from the group consisting of C1-8-alkyl, C3-8-cycloalkyl, C1-8-alkoxy, C1-8-alkylcarbonyl, C1-8-alkylidene, each of which may be optionally substituted with a substituent R5;
R5 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-8-alkyl, C1-8-alkoxy, C3-8-cycloalkyl, C3-8-heterocyclyl, C1-8-alkylcarbonyl, C1-8-alkylidene, C2-8-alkenyl and C2-8-alkynyl;
RX may be absent or selected from the group consisting of hydrogen, optionally substituted C1-8-alkyl, optionally substituted C3-8-cycloalkyl, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, CH2—
N(R5)(R5), CH2—
OR5, CH2—
SR5, and CH2—
O—
C(═
O)R5;
R3 may be present 0-4 times and selected from the group consisting of halogen, hydroxy, optionally substituted C1-8-alkyl, C1-8-alkoxy, optionally substituted C1-8-alkylidene, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-8-cycloalkyl, optionally substituted C3-8-heterocyclyl, and optionally substituted C1-8-alkylcarbonyl; and
each R6 and each R7 is optionally and independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C1-8-alkyl, C1-8-alkoxy, optionally substituted C1-8-alkylidene, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-8-cycloalkyl, optionally substituted C3-8-heterocyclyl, and optionally substituted C1-8-alkylcarbonyl. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
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12. A method of treating a disease or disorder associated with increased intraocular pressure in a mammal comprising identifying a mammal in need thereof and administering at least one compound of Formula I to said mammal:
or a pharmaceutically acceptable salt or prodrug thereof, wherein;
X is selected from the group consisting of C, O, N and S;
Z is selected from the group consisting of CH and N;
Y is selected from the group consisting of ═
O, ═
N and ═
S or tautomers thereof;
-SPU- is a biradical selected from the group consisting of —
(CR6R7)n-A- and —
C3-8-cycloalkyl-, wherein n is 1, 2, 3, 4, or 5;
A is absent or an optionally substituted —
C3-8-cycloalkyl;
N together with R1 and R2 form a heterocyclic ring wherein said heterocyclic ring is 8-azabicyclo[3.2.1]octane, wherein the heterocyclic ring is substituted with one or more substituents R4 selected from the group consisting of halogen, C1-8-alkyl, C3-8-cycloalkyl, C1-8-alkoxy, C1-8-alkylcarbonyl, C1-8-alkylidene, C2-8-alkenyl, C2-8-alkynyl, C1-6-alkyloxyimino, and C1-6-alkyloxyamino each of which may be optionally substituted with a substituent R5, and wherein at least one of said substituents R4 is R4′
selected from the group consisting of C1-8-alkyl, C3-8-cycloalkyl, C1-8-alkoxy, C1-8-alkylcarbonyl, C1-8-alkylidene, each of which may be optionally substituted with a substituent R5;
R5 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-8-alkyl, C1-8-alkoxy, C3-8-cycloalkyl, C3-8-heterocyclyl, C1-8-alkylcarbonyl, C1-8-alkylidene, C2-8-alkenyl and C2-8-alkynyl;
RX may be absent or selected from the group consisting of hydrogen, optionally substituted C1-8-alkyl, optionally substituted C3-8-cycloalkyl, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, CH2—
N(R5)(R5), CH2—
OR5, CH2—
SR5, and CH2—
O—
C(═
O)R5;
R3 may be present 0-4 times and selected from the group consisting of halogen, hydroxy, optionally substituted C1-8-alkyl, C1-8-alkoxy, optionally substituted C1-8-alkylidene, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-8-cycloalkyl, optionally substituted C3-8-heterocyclyl, and optionally substituted C1-8-alkylcarbonyl; and
each R6 and each R7 is optionally and independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C1-8-alkyl, C1-8-alkoxy, optionally substituted C1-8-alkylidene, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-8-cycloalkyl, optionally substituted C3-8-heterocyclyl, and optionally substituted C1-8-alkylcarbonyl. - View Dependent Claims (13, 14)
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15. A method of increasing an activity of a cholinergic receptor comprising contacting the cholinergic receptor or a system containing the cholinergic receptor with an effective amount of at least one compound of Formula I:
or a pharmaceutically acceptable salt or prodrug thereof, wherein;
X is selected from the group consisting of C, O, N and S;
Z is selected from the group consisting of CH and N;
Y is selected from the group consisting of ═
O, ═
N and ═
S or tautomers thereof;
-SPU- is a biradical selected from the group consisting of —
(CR6R7)n-A- and —
C3-8-cycloalkyl-, wherein n is 1, 2, 3, 4, or 5;
A is absent or an optionally substituted —
C3-8-cycloalkyl;
N together with R1 and R2 form a heterocyclic ring wherein said heterocyclic ring is 8-azabicyclo[3.2.1]octane, wherein the heterocyclic ring is substituted with one or more substituents R4 selected from the group consisting of halogen, C1-8-alkyl, C3-8-cycloalkyl, C1-8-alkoxy, C1-8-alkylcarbonyl, C1-8-alkylidene, C2-8-alkenyl, C2-8-alkynyl, C1-6-alkyloxyimino, and C1-6-alkyloxyamino each of which may be optionally substituted with a substituent R5, and wherein at least one of said substituents R4 is R4′
selected from the group consisting of C1-8-alkyl, C3-8-cycloalkyl, C1-8-alkoxy, C1-8-alkylcarbonyl, C1-8-alkylidene, each of which may be optionally substituted with a substituent R5;
R5 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-8-alkyl, C1-8-alkoxy, C3-8-cycloalkyl, C3-8-heterocyclyl, C1-8-alkylcarbonyl, C1-8-alkylidene, C2-8-alkenyl and C2-8-alkynyl;
RX may be absent or selected from the group consisting of hydrogen, optionally substituted C1-8-alkyl, optionally substituted C3-8-cycloalkyl, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, CH2—
N(R5)(R5), CH2—
OR5, CH2—
SR5, and CH2—
O—
C(═
O)R5;
R3 may be present 0-4 times and selected from the group consisting of halogen, hydroxy, optionally substituted C1-8-alkyl, C1-8-alkoxy, optionally substituted C1-8-alkylidene, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-8-cycloalkyl, optionally substituted C3-8-heterocyclyl, and optionally substituted C1-8-alkylcarbonyl; and
each R6 and each R7 is optionally and independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C1-8-alkyl, C1-8-alkoxy, optionally substituted C1-8-alkylidene, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-8-cycloalkyl, optionally substituted C3-8-heterocyclyl, and optionally substituted C1-8-alkylcarbonyl. - View Dependent Claims (16, 17, 18, 19, 20)
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21. A method of treating pain in a mammal, comprising administering an effective amount of a compound of Formula I to said mammal:
or a pharmaceutically acceptable salt or prodrug thereof, wherein;
X is selected from the group consisting of C, O, N and S;
Z is selected from the group consisting of CH and N;
Y is selected from the group consisting of ═
O, ═
N and ═
S or tautomers thereof;
-SPU- is a biradical selected from the group consisting of —
(CR6R7)n-A- and —
C3-8-cycloalkyl-, wherein n is 1, 2, 3, 4, or 5;
A is absent or an optionally substituted —
C3-8-cycloalkyl;
N together with R1 and R2 form a heterocyclic ring wherein said heterocyclic ring is 8-azabicyclo[3.2.1]octane, wherein the heterocyclic ring is substituted with one or more substituents R4 selected from the group consisting of halogen, C1-8-alkyl, C3-8-cycloalkyl, C1-8-alkoxy, C1-8-alkylcarbonyl, C1-8-alkylidene, C2-8-alkenyl, C2-8-alkynyl, C1-6-alkyloxyimino, and C1-6-alkyloxyamino each of which may be optionally substituted with a substituent R5, and wherein at least one of said substituents R4 is R4′
selected from the group consisting of C1-8-alkyl, C3-8-cycloalkyl, C1-8-alkoxy, C1-8-alkylcarbonyl, C1-8-alkylidene, each of which may be optionally substituted with a substituent R5;
R5 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-8-alkyl, C1-8-alkoxy, C3-8-cycloalkyl, C3-8-heterocyclyl, C1-8-alkylcarbonyl, C1-8-alkylidene, C2-8-alkenyl and C2-8-alkynyl;
RX may be absent or selected from the group consisting of hydrogen, optionally substituted C1-8-alkyl, optionally substituted C3-8-cycloalkyl, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, CH2—
N(R5)(R5), CH2—
OR5, CH2—
SR5, and CH2—
O—
C(═
O)R5;
R3 may be present 0-4 times and selected from the group consisting of halogen, hydroxy, optionally substituted C1-8-alkyl, C1-8-alkoxy, optionally substituted C1-8-alkylidene, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-8-cycloalkyl, optionally substituted C3-8-heterocyclyl, and optionally substituted C1-8-alkylcarbonyl; and
each R6 and each R7 is optionally and independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C1-8-alkyl, C1-8-alkoxy, optionally substituted C1-8-alkylidene, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-8-cycloalkyl, optionally substituted C3-8-heterocyclyl, and optionally substituted C1-8-alkylcarbonyl. - View Dependent Claims (22, 23)
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24. A method of modulating the progression or formation of amyloid plaques in an individual susceptible to or affected by Alzheimer'"'"'s Disease, comprising administering an effective amount of a compound of Formula I, said effective amount sufficient to modulate amyloid precursor protein processing:
or a pharmaceutically acceptable salt or prodrug thereof, wherein;
X is selected from the group consisting of C, O, N and S;
Z is selected from the group consisting of CH and N;
Y is selected from the group consisting of ═
O, ═
N and ═
S or tautomers thereof;
-SPU- is a biradical selected from the group consisting of —
(CR6R7)n-A- and —
C3-8-cycloalkyl-, wherein n is 1, 2, 3, 4, or 5;
A is absent or an optionally substituted —
C3-8-cycloalkyl;
N together with R1 and R2 form a heterocyclic ring wherein said heterocyclic ring is 8-azabicyclo[3.2.1]octane, wherein the heterocyclic ring is substituted with one or more substituents R4 selected from the group consisting of halogen, C1-8-alkyl, C3-8-cycloalkyl, C1-8-alkoxy, C1-8-alkylcarbonyl, C1-8-alkylidene, C2-8-alkenyl, C2-8-alkynyl, C1-6-alkyloxyimino, and C1-6-alkyloxyamino each of which may be optionally substituted with a substituent R5, and wherein at least one of said substituents R4 is R4′
selected from the group consisting of C1-8-alkyl, C3-8-cycloalkyl, C1-8-alkoxy, C1-8-alkylcarbonyl, C1-8-alkylidene, each of which may be optionally substituted with a substituent R5;
R5 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-8-alkyl, C1-8-alkoxy, C3-8-cycloalkyl, C3-8-heterocyclyl, C1-8-alkylcarbonyl, C1-8-alkylidene, C2-8-alkenyl and C2-8-alkynyl;
RX may be absent or selected from the group consisting of hydrogen, optionally substituted C1-8-alkyl, optionally substituted C3-8-cycloalkyl, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, CH2—
N(R5)(R5), CH2—
OR5, CH2—
SR5, and CH2—
O—
C(═
O)R5;
R3 may be present 0-4 times and selected from the group consisting of halogen, hydroxy, optionally substituted C1-8-alkyl, C1-8-alkoxy, optionally substituted C1-8-alkylidene, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-8-cycloalkyl, optionally substituted C3-8-heterocyclyl, and optionally substituted C1-8-alkylcarbonyl; and
each R6 and each R7 is optionally and independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C1-8-alkyl, C1-8-alkoxy, optionally substituted C1-8-alkylidene, optionally substituted C2-8-alkenyl, optionally substituted C2-8-alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-8-cycloalkyl, optionally substituted C3-8-heterocyclyl, and optionally substituted C1-8-alkylcarbonyl. - View Dependent Claims (25)
Specification