IP Library › Granted Patent US 12,291,512
Granted Patent B2
US 12,291,512 · App. 17/551,976 · Granted May 6, 2025

Oxime compounds as agonists of the muscarinic M

Inventors: Giles Albert Brown (Cambridge, GB); Benjamin Gerald Tehan (Cambridge, GB)
Assignee: Nxera Pharma UK Limited
C07D401/04A61P25/00A61P25/04A61P25/28A61P25/30A61P43/00A61P25/18
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Quick Facts
Patent No.
US 12,291,512
App. No.
17/551,976
Granted
May 6, 2025
Kind
B2
Abstract

This invention relates to compounds that are agonists of the muscarinic M 1 and/or M 4 receptor and which are useful in the treatment of diseases mediated by the muscarinic M 1 and M 4 receptors. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula (I) where p; q; X 1 ; X 2 ; Y; R 1 ; R 2 ; R 3 ; R 4 ; R 5 and R 6 are as defined herein.

Claims (56)

1. A compound of formula (1):

or a salt thereof, wherein:

p is 0;

q is 0;

Y is O;

X 1 and X 2 are saturated hydrocarbon groups which together contain a total of four to nine carbon atoms and which link together such that the moiety:

forms a mono or bicyclic ring system;

R 1 is selected from methyl, ethyl, propyl, and isopropyl

R 2 is selected from cyano, methyl, ethyl, propyl, isopropyl, butyl, and isobutyl;

R 3 is selected from hydrogen, fluorine, and methoxy;

R 4 is selected from hydrogen, methyl, ethyl, ethynyl, and 1-propynyl;

R 5 is fluorine; and

R 6 is fluorine.

2. The compound according to claim 1 , or a salt thereof, wherein the mono or bicyclic ring system formed by the moiety:

is selected from:

(a) piperidine;

(b) azepane;

(c) an azabicyclo-octane or azabicyclo-nonane ring system;

(d) a 2-aza-spiro[3.4]octane or a 6-aza-spiro[3.4]octane ring system; and

(e) a cyclopentanopyrrolidine ring system.

3. The compound according to claim 1 , or a salt thereof, wherein the mono or bicyclic ring system formed by the moiety:

is selected from ring systems below:

4. The compound according to claim 1 , having the formula (2):

or a salt thereof, wherein s is 0 or 1 and t is 0 or 1.

5. A compound, which is selected from:

Ethyl 4-{4-[N-methoxyethanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl (4S)-4-{4-[N-methoxyethanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl 4-{4-[N-methoxypropanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl (4S)-4-{4-[N-methoxypropanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl 4-{4-[N-methoxybutanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl (4S)-4-{4-[N-methoxybutanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl 4-{4-[N-methoxy-2-methylpropanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl 4-{4-[N-methoxy-4-methylpentanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl 4-{4-[N-ethoxyethanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl 4-{4-[N-propoxyethanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl 4-{4-[N-(propan-2-yloxy)ethanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl 4-{4-[N-ethoxypropanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl 4-{4-[N-propoxypropanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl 4-{4-[N-(propan-2-yloxy)propanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl 2-{4-[N-methoxyethanimidoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;

Ethyl 2-{4-[N-methoxypropanimidoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;

Ethyl 2-{4-[N-methoxybutanimidoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;

Ethyl 4-{4-[N′-methoxy-N-(2-methylpropyl)carbamimidoyl]piperidin-1-yl}azepane-1-carboxylate; and

Ethyl 4-(4-{cyano[(propan-2-yloxy)imino]methyl}piperidin-1-yl)azepane-1-carboxylate;

or a salt thereof.

6. A pharmaceutical composition comprising a compound according to claim 1 , or a salt thereof, and a pharmaceutically acceptable excipient.

7. A compound, which is selected from:

Ethyl 4-{4-[N-methoxy propanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl 4-{4-[N-methoxybutanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl 4-{4-[N-methoxy-2-methylpropanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl 4-{4-[N-(propan-2-yloxy)propanimidoyl]piperidin-1-yl}azepane-1-carboxylate;

Ethyl 2-{4-[N-methoxypropanimidoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate; and

Ethyl 2-{4-[N-methoxybutanimidoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,

or a salt thereof.

8. A method of treating a subject suffering from Alzheimer's Disease, an acute, chronic, neuropathic, or inflammatory pain, comprising administering to the subject an effective amount of a compound according to claim 1 , or a salt thereof, that exhibits selectivity for the M 1 and M 4 receptor relative to the M 2 and M 3 receptor subtypes.

9. A method of treating a subject suffering from schizophrenia, comprising administering to the subject an effective amount of a compound according to claim 1 , or a salt thereof, that exhibits selectivity for the M 4 receptor relative to the M 1 , M 2 and M 3 receptor subtypes.

Assignments (2)
CHANGE OF NAME Recorded Sep 9, 2024
From: HEPTARES THERAPEUTICS LIMITED
To: NXERA PHARMA UK LIMITED
Reel/Frame 068529/0381 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 29, 2022
From: BROWN, GILES ALBERT; TEHAN, BENJAMIN GERALD
To: HEPTARES THERAPEUTICS LIMITED
Reel/Frame 058818/0029 →
Priority Claims (1)
GB 1519352 · Nov 2, 2015 · national
Continuity (2)
Continuation 15772785
Related Publication 20220298133A1 · Sep 22, 2022
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