PHARMACEUTICAL COMPOUNDS

Abstract

This invention relates to compounds that are agonists of the muscarinic M.sub.1 and M4 receptor and which are useful in the treatment of diseases mediated by the muscarinic M.sub.1 and/or M4 receptors. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula (1): and salts thereof.

##STR00001##

Claims

1. A compound of formula (1): ##STR00043## or a salt thereof

2. The compound according to claim 1, which is a compound of formula (2): ##STR00044## or a salt thereof

3. A salt of the compound according to claim 1 or claim 2.

4. A pharmaceutically acceptable salt of the compound according to claim 1.

5. An acid addition salt of the compound according to claim 1.

6. A hydrochloride salt of the compound according to claim 1.

7. A monohydrochloride salt of the compound according to claim 1.

8. The compound according to claim which is a compound of formula (2b): ##STR00045##

9. The compound according to claim 1, which is a compound of formula (2c): ##STR00046##

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

11-12. (canceled)

13. A method of treating a disorder selected from a cognitive disorder and a psychotic disorder in a subject, comprising administering to the subject the compound of claim 1.

14. The method according to claim 13, wherein the disorder is Alzheimer's disease.

15. The method according to claim 13, wherein the disorder is dementia with Lewy bodies.

16. The method according to claim 13, wherein the disorder is schizophrenia.

17. A salt of the compound according to claim 2.

18. A pharmaceutically acceptable salt of the compound according to claim 2.

19. An acid addition salt of the compound according to claim 2.

20. A hydrochloride salt of the compound according to claim 2.

21. A monohydrochloride salt of the compound according to claim 2.

22. A method of treating or lessening the severity of acute pain, chronic pain, neuropathic pain, or inflammatory pain in a subject, comprising administering to the subject the compound of claim 1, or a salt thereof.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0280] FIG. 1: FIG. 1 shows the predicted target engagement for efficacious dose of Example 1 from allometric scaling across mouse, rat, dog and monkey species following oral administration. Data are shown as a function of the calculated % M.sub.1 receptor target engagement where 50% is equivalent to an unbound exposure equal to the recombinant human EC50 (86nM or 28ng/ml). Based on a measured equivalent unbound plasma:brain distribution profile (Kpuu=1) the exposures shown represent those in either the plasma or brain compartment.

[0281] FIG. 2: FIG. 2 shows the effect of acute treatment with Example 1 (1.0, 3.0, 10.0 & 30.0 mg/kg, p.o.) in scPCP treated rats (2 mg/kg, i.p. twice daily for seven days, followed by at least a 7-day washout period) on performance in the reversal learning task. Data are shown as mean correct responding % ±S.E.M. (n=6-9). The dashed line separates the initial phase (left) from the reversal phase of the task (right). Data were analysed by one-way ANOVA followed by LSD test. ***P<0.001; significant reduction in correct responding % in reversal phase of the task compared to the scSaline +Vehicle group. #P<0.05; ##P=0.01; ###P<0.001; significant increase in correct responding % in reversal phase of the task compared to the scPCP+Vehicle group.

EQUIVALENTS

[0282] The foregoing examples are presented for the purpose of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application.