Muscarinic receptor agonists

Details Muscarinic receptor agonists Muscarinic receptor agonists

2001-01-29

2002-04-23

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S342000

Reexamination Certificate

active

06376675

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to muscarinic receptor ligands with agonist activity. More particularly, this invention relates to compounds based on the tetrahydropyridyl moiety that have unusually high affinity for muscarinic receptors, and exhibit agonist activity useful in the treatment of neurological and other disorders, in which stimulating cholinergic activity is desirable.
BACKGROUND OF THE INVENTION
Recent advances have been made in the understanding of the cholinergic nervous system and the receptors therein. Cholinergic receptors are proteins embedded in the cell membrane that respond to the chemical acetylcholine. Cholinergic receptors are subdivided into the nicotinic and muscarinic receptor families, and muscarinic receptors represent a family of five subtypes.
Muscarinic receptors mediate a variety of physiological responses to the neurotransmitter acetylcholine in the central and peripheral nervous systems. M
1
muscarinic receptors play a role in learning and memory function in the brain and regulate gastric acid secretion in the stomach. M
2
receptors regulate acetylcholine release in the central nervous system and control cardiac muscle contraction. Acetylcholine stimulates smooth muscle contraction in a variety of tissues and promotes secretion from exocrine glands. These effects are mediated by M
3
receptors. Though less well characterized pharmacologically, M
4
receptors appear to play a role in the perception of pain, and M
5
receptors may regulate dopaminergic activity in the brain.
It has been suggested that compounds capable of mimicking the action of acetylcholine at these receptors would be useful in treating pathological conditions involving imbalances in these cholinergic pathways. Despite the wealth of knowledge about muscarinic receptor subtypes, relatively few selective ligands are available to characterize muscarinic receptor subtypes. Consequently, the tendency for ligands to bind indiscriminately to muscarinic receptor subtypes has made difficult the development of drugs that are muscarinic receptor subtype selective.
In view of the foregoing, it would be desirable to provide such compounds, particularly so side effects are minimized during treatment of the conditions noted above. It is an object of the present invention to provide compounds having muscarinic receptor affinity and activity. It is another object of the present invention to provide compounds having improved muscarinic receptor selectivity profiles. It is another object of the present invention to provide pharmaceutical composition comprising compounds of the present invention, as active ingredients.
SUMMARY OF THE INVENTION
According to one aspect of the present invention, there is provided a compound of Formula I:
wherein R is a linkage independently selected from (CH
2
)
12
or (CH
2
CH
2
)
4
O
3
, i.e., CH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
—; and acid addition salts, solvates and hydrates thereof.
According to another aspect of the present invention, there is provided a compound of the Formula III:
wherein X and R are
IIIa=CDD-0297-A: X=(CH
2
)
12
, R
1
=R
2
=R
3
=H
IIIb=CDD-0299-A: X=(CH
2
)
12
, R
1
=R
2
=H, R
3
=COCH
3
IIIc=CDD-0300-A: X=(CH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
), R
1
=R
2
=R
3
=H
IIId=CDD-0301-A: X=(CH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
), R
1
=R
2
=R
3
=CH
2
CH
3
IIIe=CDD-0303-A: X=(CH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
), R
1
=R
2
=H, R
3
=COCH
3
IIIf=CDD-0304-A: X=(CH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
), R
1
=H, R
2
=R
3
=
and acid addition salts, solvates and hydrates thereof.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising compounds of Formula (I) or (III) and a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
One aspect of the invention relates to bis-alkyloxy-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine that bind to and activate muscarinic receptors. The compounds incorporate two functional muscarinic agonists into the same molecule with an alkyloxy linkage. More particularly, the present invention is directed to compounds of Formula (I):
wherein R is a linkage independently selected from (CH
2
)
12
or (CH
2
CH
2
)
4
O
3
, and acid addition salts, solvates and hydrates thereof.
According to another aspect of the present invention, there is provided a compound of the Formula III:
wherein X and R are
IIIa=CDD-0297-A: X=(CH
2
)
12
, R
1
=R
2
=R
3
=H
IIIb=CDD-0299-A: X=(CH
2
)
12
, R
1
=R
2
=H, R
3
=COCH
3
IIIc=CDD-0300-A: X=(CH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
), R
1
=R
2
=R
3
=H
IIId=CDD-0301-A: X=(CH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
), R
1
=R
2
=R
3
=CH
2
CH
3
IIIe =CDD-0303-A: X=(CH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
), R
1
=R
2
=H, R
3
=COCH
3
IIIf=CDD-0304-A: X=(CH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
OCH
2
CH
2
), R
1
=H, R
2
=R
3
=
and acid addition salts, solvates and hydrates thereof.
The compounds of Formula (I), 2,2′-bis-{[3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yloxy]ethyloxy}-diethyl ether and 1,12-bis-[3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yloxy]-dodecane, exhibit very high affinity for muscarinic receptors as compared to the parent compound xanomeline. In addition, the compounds appear to interact with multiple M
2
receptors expressed in A9 L cells. It is believed that compounds of Formula (I) may act as agonists at muscarinic receptors coupled to the inhibition of adenylyl cyclase activity.
TABLE 1
M1
M2
Ligand/
Receptors
% High
Receptors
Linkage
K
1
(nM)
affinity
K
h
(pM)
K
1
(nM)
Xanomeline
 82 ± 6.7 
26 ± 8.5
23 ± 16
32 ± 12 
(CH
2
)
6
0.61 ± 0.18 
18 ± 4.5
0.0086 ±
0.28 ± 0.020
0.0069
(CH
2
)
8
0.19 ± 0.040
40 ± 11 
58 ± 56
0.38 ± 0.15 
(CH
2
)
10
0.23 ± 0.10 
26 ± 3.1
3.1 ± 2.4
0.23 ± 0.040
(CH
2
CH
2
)
4
O
3
0.12 ± 0.057
—
—
—
It was heretofore believed that as the length of the alkoxy chain increases agonist activity decreases. As reported in the Journal of Medicinal Chemistry, 1993, Vol. 36, No. 7, pages 843-844, increasing the length of the 3-alkyl chain on the 1,2,4-oxadiazole ring of 1,4,5,6-tetrahydropyrimidine dramatically decreased activity in the phosphoinositide metabolism assay. Again these data are consistent with similar observations in 1,2,4-oxadiazole derivatives of 1,2,5,6-tetrahydro-1-methylpyridine and quinuclidine where increasing the length of the 3-alkyl substituent led to compounds with higher affinity yet lower agonist activity. As shown in Tables 1 and 2, it has been surprisingly found that compounds of Formula I with increasing alkoxy chains displayed M
1
agonist efficacy comparable to xanomeline, yet with higher potency and higher affinity for M
1
receptors.
The receptor binding properties and agonist activity of bis-thiadiazole derivatives, (Formula (II)), at M
1
muscarinic receptors expressed in A9 L cells is provided below in Table 2. PI metabolism represents the percentage stimulation above basal levels at 100 &mgr;M expressed relative to the carbachol response (100%). Full dose-response curves were obtained for a few compounds. The data represents the mean (±s.e.m.) from two to five assays for each compound.
wherein R is a linkage independently selected from (CH
2
)
2
, (CH
2
)
3
, (CH
2
)
4
, (CH
2
)
5
, (CH
2
)
6
, (CH
2
)
7
, (CH
2
)
8
, (CH
2
)
9
, (CH
2
)
10
, (CH
2
)
12
and (CH
2
CH
2
)
4
O
3
.
TABLE 2
Compound/
PI
Linkage
metabolism
EC
50
(&mgr;M)
S

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