Muscarinic receptor agonists
This invention relates to compounds that are agonists of the muscarinic M 1 receptor and which are useful in the treatment of muscarinic M 1 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula where m, p, q, W, Z, Y, X 1 , X 2 , R 1 , R 2 , R 3 and R 4 are as defined herein.
1. A compound of the formula (1a):
or a salt thereof, wherein:
m is 1;
p is 0;
q is 0;
W is C;
Z is CH 2 ;
Y is O;
X 1 and X 2 are saturated hydrocarbon groups which together contain a total of five to nine carbon atoms and which link together such that the moiety:
is selected from ring systems BA to BH below:
R 1 can be H, optionally substituted C 1-6 alkyl or CH 2 -aryl;
R 2 is H;
R 3 is H, OH, or an optionally substituted C 1-6 non-aromatic hydrocarbon group;
R 4 can be H, optionally substituted C 1-5 alkyl or optionally substituted C 2-5 alkynyl.
2. The compound according to claim 1 , wherein R 1 is selected from H, C 1-5 alkyl and benzyl.
3. The compound according to claim 1 , wherein R 3 is selected from H, OH, ethyl, n-propyl, isopropyl, isobutyl, cyclopropylmethyl and 2-methoxyethyl.
4. The compound according to claim 1 , wherein R 4 is selected from H, methyl, fluoromethyl, ethyl, ethynyl and 1-propynyl.
5. The compound according to claim 1 which is selected from the group consisting of:
ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate and prop-2-yn-1-yl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate
or a salt thereof.
6. The compound according to claim 1 which is selected from the group consisting of:
ethyl (3-endo)-3-(2-hydroxy-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate and
ethyl 5-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate or a salt thereof.
7. The compound according to claim 1 which is selected from the group consisting of:
ethyl 5-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate,
methyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, 2-fluoroethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
but-2-yn-1-yl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-(1-methyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-(1-ethyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-(3-oxo-1-propyl-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-(1-benzyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-(2-ethyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-(2-hydroxy-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-(3-oxo-2-propyl-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-[3-oxo-2-(propan-2-yl)-2,8-diazaspiro[4.5]dec-8-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-[2-(2-methylpropyl)-3-oxo-2,8-diazaspiro[4.5]dec-8-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-[2-(cyclopropylmethyl)-3-oxo-2,8-diazaspiro[4.5]dec-8-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-[2-(2-methoxyethyl)-3-oxo-2,8-diazaspiro[4.5]dec-8-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 8-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.2.1]octane-3-carboxylate,
ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate,
prop-2-yn-1-yl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate,
but-2-yn-1-yl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate,
methyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azabicyclo[3.2.1]octane-6-carboxylate,
ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azabicyclo[3.2.1]octane-6-carboxylate, and
ethyl 6-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.1.1]heptane-3-carboxylate,
or a salt thereof.
8. A pharmaceutical composition comprising the compound as defined in claim 1 and a pharmaceutically acceptable excipient.
9. A method of treating dementia in a subject, comprising administering an effective amount of the compound according to claim 1 to the subject in need thereof.
10. A method of treating Alzheimer's disease in a subject, comprising administering an effective amount of the compound according to claim 1 to the subject in need thereof.