Compounds with activity on muscarinic receptors

• US 6,528,529 B1
• Filed: 07/16/1999
• Issued: 03/04/2003
• Est. Priority Date: 03/31/1998
• Status: Expired due to Fees

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Messier, Terri, Duggento, Kate, Brann, Mark, Currier, Erika, Spalding, Tracy, Skjaerbaek, Niels, Friberg, Mikael
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US09/356,202
• Time in Patent Office: 1,327 Days
• Field of Search: 546/237, 514/317
• US Class Current: 514/317
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 211/00 Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
• CPC Class Codes: C07D 211/20 with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
• CPC Class Codes: C07D 211/22 by oxygen atoms
• CPC Class Codes: C07D 211/26 with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 213/50 Ketonic radicals
• CPC Class Codes: C07D 265/32 with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 295/108 to an acyclic saturated chain

Abstract

Compounds and methods are provided for the alleviation or treatment of diseases or conditions in which modification of muscarinic m1 receptor activity has a beneficial effect. In the method, a therapeutically effective amount of a selective muscarinic m1 agonist compound is administered to a patient in need of such treatment.

Claims

1. A compound of formula (I):

wherein

R₁ is straight or branched-chain C_2-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_1-8 alkylidene, C_1-8 alkoxy, C_1-8 heteroalkyl, C_1-8 aminoalkyl, C_1-8 haloalkyl, C_1-8 alkoxycarbonyl, C_1-8 hydroxyalkoxy, C_1-8 hydroxyalkyl, —

SH, C_1-8 thioalkyl, or —

O—

CH₂—

C_5-6 aryl;

A is C_5-7 cycloalkyl, phenyl, naphthyl or C_5-12 heteroaryl, wherein said heteroaryl contains one heteroatom selected from O, N or S;

when A is C_5-7 cycloalkyl, naphthyl or C_5-12 heteroaryl as defined above,

R₂ is H, amino, hydroxyl, halo, or straight or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 heteroalkyl, C_1-6 aminoalkyl, C_1-6 haloalkyl, C_1-6 alkoxycarbonyl, —

CN, —

CF₃, —

OR₃, —

COR₃, NO₂, —

NHR₃, —

NHC(O)R₃, —

C(O)NR₃R₄, —

NR₃R₄, —

NR₃C(O)NR₄R₅, —

OC(O)R₃, or —

(CH₂)_qNR₃R₄;

where R₃, R₄ and R₅ are the same or different, each independently being selected from H, C_1-6 alkyl;

C_5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C_1-6 alkyl;

C_3-6 cycloalkyl;

or R₃ and R₄ together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and

q is an integer from 1 to 6;

or

when A is phenyl,

R₂ is amino, hydroxyl, chloro, bromo, or straight or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 heteroalkyl, C_1-6 aminoalkyl, C_1-6 haloalkyl, C_1-6 alkoxycarbonyl, —

CN, —

CF₃, —

OR₃, —

COR₃, NO₂, —

NHR₃, —

NHC(O)R₃, —

C(O)NR₃R₄, —

NR₃R₄, —

NR₃C(O)NR₄R₅, —

OC(O)R₃, or —

(CH₂)_qNR₃R₄;

where R₃, R₄ and R₅ are the same or different, each independently being selected from H, C_1-6 alkyl;

C_5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C_1-6 alkyl;

C_3-6 cycloalkyl;

or R₃ and R₄ together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and

q is an integer from 1 to 6;

n is 1, 2, 3 or 4, the groups R₂, when n>

1, being the same or different;

p is 0 or an integer from 1 to 5;

Y is —

NHC(O)—

or —

C(O)—

; and

Z is a bond or CR₈R₉ wherein R₈ and R₉ are independently selected from H, and straight or branched chain C_1-8 alkyl;

provided where —

(CH₂)_p—

Y—

is —

(CH₂)₃—

C(O)—

, that —

A—

(R₂)_n and R₁ are not together;

o-methyl-phenyl and n-butyl, respectively;

or

a pharmaceutically acceptable salt, ester or prodrug thereof.

2. The compound of claim 1, wherein

R₁ is straight or branched-chain C_2-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_1-8 alkylidene, C_1-8 alkoxy, C_1-8 aminoalkyl, C_1-8 haloalkyl, C_1-8 alkoxycarbonyl;

n is 1, 2 or 3,

A is phenyl and

R₂ is chloro, bromo, straight or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 heteroalkyl;

C_1-6 aminoalkyl, C_1-6 haloalkyl, C_1-6 alkoxycarbonyl, —

CN, —

CF₃, —

COR₃, —

NHR₃, —

NHC(O)R₃, —

C(O)NR₃R₄, —

NR₃R₄, —

NR₃C(O)NR₄R₅, —

OC(O)R₃, or —

O(CH₂)_qNR₃;

or

A is thienyl; and

R₂ is H, halo, straight or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 heteroalkyl;

C_1-6 aminoalkyl, C_1-6 haloalkyl, C_1-6 alkoxycarbonyl, —

CN, —

CF₃, —

COR₃, —

NHR₃, —

NHC(O)R₃, —

C(O)NR₃R₄, —

NR₃R₄, —

NR₃C(O)NR₄R₅, —

OC(O)R₃, or —

O(CH₂)_qNR₃;

or

a pharmaceutically acceptable salt, ester or prodrug thereof.

3. The compound of claim 1 or claim 2, wherein p is 3.

4. The compound of claim 1, wherein said compound of formula (I) is a compound represented by formula (II):

5. The compound of claim 4, wherein said compound of formula (II) is a compound represented by formula (IIa):

6. The compound of claim 4, wherein said compound of formula (II) is a compound represented by formula (IIb):

7. The compound of claim 5, wherein R₁ is straight or branched-chain C_2-8 alkyl.

8. The compound of claim 7, wherein wherein R₂ is alkyl, aminoalkyl, alkoxy or hydroxyl.

9. The compound of claim 8, wherein wherein p is 3.

10. The compound of claim 9, wherein R₂ is methyl, hydroxyl or alkoxy.

11. The compound of claim 10, wherein Y is —

C(O)—

.

12. The compound of claim 7, wherein R₂ is chloro or bromo.

13. The compound of claim 5, wherein R₁ is alkoxy.

14. The compound of claim 6, wherein R₁ is straight or branched-chain C_2-8 alkyl.

15. The compound of claim 14, wherein R₂ is alkyl, aminoalkyl, alkoxy or hydroxyl.

16. A compound of claim 15, wherein p is 3.

17. The compound of claim 16, wherein R₂ is methyl, hydroxyl or alkoxy.

18. The compound of claim 17, wherein Y is —

C(O)—

.

19. The compound of claim 14, wherein R₂ is chloro or bromo.

20. The compound of claim 6, wherein R₁ is alkoxy.

21. The compound of claim 1, wherein

Y is —

NHC(O)—

;

p is 2; and

Z is a bond.

22. The compound of claim 1, wherein

Y is —

C(O)—

;

p is 3; and

Z is a bond.

23. The compound of claim 21, wherein n is 1 or 2.

24. The compound of claim 2, wherein A is thienyl.

25. The compound of claim 24, wherein Y is —

C(O)—

.

26. The compound of any one of claims 24 or 25, wherein R₂ is halo, C_1-6 alkyl, or C_1-6 alkoxy.

27. The compound of claim 24, wherein Y is —

NHC(O)—

.

28. The compound of claim 5, wherein R₂ is halo, C_1-6 alkyl, or C_1-6 alkoxy.

29. The compound of claim 25, wherein p is 3.

30. The compound of claim 25, wherein Z is a bond.

31. The compound of claim 29, wherein Z is a bond.

32. The compound of claim 27, wherein p is 2.

33. The compound of claim 27, wherein Z is a bond.

34. The compound of claim 32, wherein Z is a bond.

59. The pharmaceutical composition comprising a compound of claim 21.

72. A method of treating the symptoms of a disease or condition associated with reduced levels of acetylcholine, said method comprising administering a therapeutically effective amount of one or more compounds of claim 1.

73. The method of claim 72, wherein said disease or condition is neurogenerative disease, cognitive impairment, age-related cognitive decline or dementia.

76. A method of treating the symptoms of a disease or condition associated with increased intraocular pressure, said method comprising administering a therapeutically effective amount of one or more compounds of claim 1.

77. The method of claim 76, wherein said compound comprises a muscarinic receptor agonist.

78. The method of claim 77, wherein said muscarinic receptor agonist comprises m1 receptor agonist activity.

79. The method of claim 77, wherein said muscarinic receptor agonist is m1 selective.

80. The method of claim 79, wherein said agonist causes at least about a 10 fold greater increase in the activity of an m1 receptor subtype than of an m3 receptor subtype.

81. The method of claim 76, wherein said disease is glaucoma.

35. A compound of formula (IIa):

wherein

R₁ is alkoxy;

R₂ is amino, hydroxyl, chloro, bromo, or straight or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 heteroalkyl, C_1-6 aminoalkyl, C_1-6 haloalkyl, C_1-6 alkoxycarbonyl, —

CN, —

CF₃, —

OR₃, —

COR₃, NO₂, —

NHR₃, —

NHC(O)R₃, —

C(O)NR₃R₄, —

NR₃R₄, —

NR₃C(O)NR₄R₅, —

OC(O)R₃, or —

(CH₂)_qNR₃R₄;

where R₃, R₄ and R₅ are the same or different, each independently being selected from H, C_1-6 alkyl;

C_5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C_1-6 alkyl;

C_3-6 cycloalkyl;

or R₃ and R₄ together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and

q is an integer from 1 to 6;

p is 0 or an integer from 1 to 5;

Y is —

NHC(O)—

or —

C(O)—

;

or

a pharmaceutically acceptable salt, ester or prodrug thereof.

36. A compound of formula (IIb):

wherein

R₁ is alkoxy;

R₂ is amino, hydroxyl, chloro, bromo, or straight or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 heteroalkyl, C_1-6 aminoalkyl, C_1-6haloalkyl, C_1-6 alkoxycarbonyl, —

CN, —

CF₃, —

OR₃, —

COR₃, NO₂, —

NHR₃, —

NHC(O)R₃, —

C(O)NR₃R₄, —

NR₃R₄, —

NR₃C(O)NR₄R₅, —

OC(O)R₃, or —

(CH₂)_qNR₃R₄;

where R₃, R₄ and R₅ are the same or different, each independently being selected from H, C_1-6 alkyl;

C_5-6aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C_1-6 alkyl;

C_3-6 cycloalkyl;

or R₃ and R₄ together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and

q is an integer from 1 to 6;

p is 0 or an integer from 1 to 5;

Y is —

NHC(O)—

or —

C(O)—

;

or

a pharmaceutically acceptable salt, ester or prodrug thereof.

37. A compound of formula (I):

wherein

R₁ is straight or branched-chain C_2-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_1-8 alkylidene, C_1-8 alkoxy, C_1-8 heteroalkyl, C_1-8 aminoalkyl, C_1-8 haloalkyl, C_1-8 alkoxycarbonyl, C_1-8 hydroxyalkoxy, C_1-8 hydroxyalkyl, —

SH, C_1-8 thioalkyl, or —

O—

CH₂—

C_5-6 aryl;

A is C_5-7 cycloalkyl, phenyl, naphthyl or C_5-12 heteroaryl, wherein said heteroaryl contains one heteroatom selected from O, N or S;

when A is C_5-7 cycloalkyl, naphthyl or C_5-12 heteroaryl as defined above,

R₂ is H, amino, hydroxyl, halo, or straight or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 heteroalkyl, C_1-6 aminoalkyl, C_1-6 haloalkyl, C_1-6 alkoxycarbonyl, —

CN, —

CF₃, —

OR₃, —

COR₃, NO₂, —

NHR₃, —

NHC(O)R₃, —

C(O)NR₃R₄, —

NR₃R₄, —

NR₃C(O)NR₄R₅, —

OC(O)R₃, or —

(CH₂)_qNR₃R₄;

where R₃, R₄ and R₅ are the same or different, each independently being selected from H, C_1-6 alkyl;

C_5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C_1-6 alkyl;

C_3-6 cycloalkyl;

or R₃ and R₄ together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and

q is an integer from 1 to 6;

or

when A is phenyl,

R₂ is amino, hydroxyl, chloro, bromo, or straight or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 heteroalkyl, C_1-6 aminoalkyl, C_1-6 haloalkyl, C_1-6 alkoxycarbonyl, —

CN, —

CF₃, —

OR₃, —

COR₃, NO₂, —

NHR₃, —

NHC(O)R₃, —

C(O)NR₃R₄, —

NR₃R₄, —

NR₃C(O)NR₄R₅, —

OC(O)R₃, or —

(CH₂)_qNR₃R₄;

where R₃, R₄ and R₅ are the same or different, each independently being selected from H, C_1-6 alkyl;

C_5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C_1-6 alkyl;

C_3-6 cycloalkyl;

or R₃ and R₄ together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and

q is an integer from 1 to 6;

n is 1, 2, 3 or 4, the groups R₂, when n>

1, being the same or different;

p is 2;

Y is —

NHC(O)—

; and

Z is a bond;

or

a pharmaceutically acceptable salt, ester or prodrug thereof.

38. A compound of claim 37 wherein n is 1 or 2.

62. A pharmaceutical composition comprising a compound of claim 37.

39. A compound of formula (I):

wherein

R₁ is straight or branched-chain C_2-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_1-8 alkylidene, C_1-8 alkoxy, C_1-8 aminoalkyl, C_1-8 haloalkyl, C_1-8 alkoxycarbonyl;

n is 1, 2 or 3, the groups R₂, when n>

1, being the same or different;

A is thienyl; and

R₂ is H, halo, straight or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 heteroalkyl;

C_1-6 aminoalkyl, C_1-6 haloalkyl, C_1-6 alkoxycarbonyl, —

CN, —

CF₃, —

COR₃, —

NHR₃, —

NHC(O)R₃, —

C(O)NR₃R₄, —

NR₃R₄, —

NR₃C(O)NR₅, —

OC(O)R₃, or —

O(CH₂)_qNR₃;

where R₃, R₄ and R₅ are the same or different, each independently being selected from H, C_1-6 alkyl;

C_5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C_1-6 alkyl;

C_3-6 cycloalkyl;

or R₃ and R₄ together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and

q is an integer from 1 to 6;

or R₄ together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and

q is an integer from 1 to 6;

p is 0 or an integer from 1 to 5;

Y is —

NHC(O)—

or —

C(O)—

; and

Z is a bond or CR₈R₉ wherein R₈ and R₉ are independently selected from H, and straight or branched chain C_1-8 alkyl;

or

a pharmaceutically acceptable salt, ester or prodrug thereof.

40. A compound of claim 39 wherein Y is —

C(O)—

.

41. A compound of any one of claims 39 or 40 wherein R₂ is halo, C_1-6 alkyl or C_1-6 alkoxy.

42. A compound of claim 39 wherein Y is —

NHC(O)—

.

43. A compound of claim 40 wherein p is 3.

44. A compound of claim 40 wherein Z is a bond.

45. A compound of claim 43 wherein Z is a bond.

46. A compound of claim 42 wherein p is 2.

47. A compound of claim 42 wherein Z is a bond.

48. A compound of claim 46 wherein Z is a bond.

49. A pharmaceutical composition comprising an effective amount of a compound of formula (I):

wherein

R₁ is straight or branched-chain C_2-8alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_1-8 alkylidene, C_1-8 alkoxy, C_1-8 heteroalkyl, C_1-8 aminoalkyl, C_1-8 haloalkyl, C_1-8 alkoxycarbonyl, C_1-8 hydroxyalkoxy, C_1-8 hydroxyalkyl, —

SH, C_1-8 thioalkyl, —

O—

CH₂—

C_5-6 aryl, —

C(O)—

C_5-6 aryl substituted with C_1-3 alkyl or halo;

C_5-6 aryl or C_5-6 cycloalkyl optionally comprising 1 or more heteroatoms selected from N, S and O;

A is C_5-7 cycloalkyl, phenyl, naphthyl or C_5-12 heteroaryl, wherein said heteroaryl contains one heteroatom selected from O, N or S;

when A is C_5-7 cycloalkyl, naphthyl or C_5-12 heteroaryl as defined above,

R₂ is H, amino, hydroxyl, halo, or straight or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 heteroalkyl, C_1-6 aminoalkyl, C_1-6haloalkyl, C_1-6 alkoxycarbonyl, —

CN, —

CF₃, —

OR₃, —

COR₃, NO₂, —

NHR₃, —

NHC(O)R₃, —

C(O)NR₃R₄, —

NR₃R₄, —

NR₃C(O)NR₄R₅, —

OC(O)R₃, or —

(CH₂)_qNR₃R₄;

where R₃, R₄ and R₅ are the same or different, each independently being selected from H, C_1-6 alkyl;

C_5-6 aryl optionally comprising I or more heteroatoms selected from N, O and S, and optionally substituted with halo or C_1-6 alkyl;

C_3-6 cycloalkyl;

or R₃ and R₄ together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and

q is an integer from 1 to 6;

or when A is phenyl,

R₂ is amino, hydroxyl, chloro, bromo, or straight or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 heteroalkyl, C_1-6 aminoalkyl, C_1-6 haloalkyl, C_1-6 alkoxycarbonyl, —

CN, —

CF₃, —

OR₃, —

COR₃, NO₂, —

NHR₃, —

NHC(O)R₃, —

C(O)NR₃R₄, —

NR₃R₄, —

NR₃C(O)NR₄R₅, —

OC(O)R₃, or —

(CH₂)_qNR₃R₄;

where R₃, R₄ and R₅ are the same or different, each independently being selected from H, C_1-6 alkyl;

C_5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C_1-6 alkyl;

C_3-6 cycloalkyl;

or R₃ and R₄ together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and

q is an integer from 1 to 6;

n is 1, 2, 3 or 4, the groups R₂, when n>

1, being the same or different;

p is 0 or an integer from 1 to 5;

Y is —

NHC(O)—

or —

C(O)—

; and

Z is a bond or CR₈R₉ wherein R₈ and R₉ are independently selected from H, and straight or branched chain C_1-8 alkyl;

provided where —

(CH₂)_p—

Y—

is —

(CH₂)₃—

C(O)—

, that —

A—

(R₂)_n and R₁ are not together;

o-methyl-phenyl and n-butyl, respectively;

or

a pharmaceutically acceptable salt, ester or prodrug thereof; and

a pharmaceutically acceptable carrier.

50. The composition of claim 49, wherein said compound of formula (I) is a compound represented by formula (II):

51. The composition of claim 50, wherein R₁ is straight or branched-chain C_2-8 alkyl.

52. The composition of claim 51, wherein R₂ is alkyl, aminoalkyl, alkoxy or hydroxyl.

53. The composition of claim 52, wherein p is 3.

54. The composition of claim 52, wherein R₂ is methyl, hydroxyl or alkoxy.

55. The composition of claim 54, wherein Y is —

C(O)—

.

56. The composition of claim 51, wherein R₂ is chloro or bromo.

57. The composition of claim 50, wherein R₁ is alkoxy.

58. The composition of claim 57, wherein R₂ is chloro or bromo.

74. A method of treating the symptoms of a disease or condition associated with reduced levels of acetylcholine, said method comprising administering a therapeutically effective amount of a composition of claim 49.

75. The method of claim 74, wherein said disease or condition is neurogenerative disease, cognitive impairment, age-related cognitive decline or dementia.

82. A method of treating the symptoms of a disease or condition associated with increased intraocular pressure, said method comprising administering a therapeutically effective amount of a composition of claim 49.

83. The method of claim 82, wherein said compound comprises a muscarinic receptor agonist.

84. The method of claim 83, wherein said muscarinic receptor agonist comprises m1 receptor agonist activity.

85. The method of claim 83, wherein said muscarinic receptor agonist is m1 selective.

86. The method of claim 85, wherein said agonist causes at least about a 10 fold greater increase in the activity of the m1 receptor subtype than of the m3 receptor subtype.

87. The method of claim 82, wherein said disease is glaucoma.

60. A pharmaceutical composition comprising an effective amount of a compound of formula II:

wherein

R₁ is alkoxy;

R₂ is amino, hydroxyl, chloro, bromo, or straight or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6alkoxy, C_1-6 heteroalkyl, C_1-6 aminoalkyl, C_1-6 haloalkyl, C_1-6 alkoxycarbonyl, —

CN, —

CF₃, —

OR₃, —

COR₃, NO₂, —

NHR₃, —

NHC(O)R₃, —

C(O)NR₃R₄, —

NR₃R₄, —

NR₃C(O)NR₄R₅, —

OC(O)R₃, or —

(CH₂)_qNR₃R₄;

where R₃, R₄ and R₅ are the same or different, each independently being selected from H, C_1-6 alkyl;

C_5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C_1-6 alkyl;

C_3-6 cycloalkyl;

or R₃ and R₄ together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and

q is an integer from 1 to 6;

n is 1, 2, 3 or 4, the groups R₂, when n>

1, being the same or different;

p is 0 or an integer from 1 to 5;

Y is —

NHC(O)—

or —

C(O)—

;

or.

a pharmaceutically acceptable salt, ester or prodrug thereof; and

a pharmaceutically acceptable carrier.

61. A composition of claim 60, wherein R₂ is chloro or bromo.

63. A method of agonizing a muscarinic receptor comprising contacting said receptor with an effective amount of a compound of formula (I):

wherein

R₁ is straight or branched-chain C_2-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_1-8 alkylidene, C_1-8 alkoxy, C_1-8 heteroalkyl, C_1-8 aminoalkyl, C_1-8 haloalkyl, C_1-8 alkoxycarbonyl, C_1-8 hydroxyalkoxy, C_1-8 hydroxyalkyl, —

SH, C_1-8 thioalkyl, —

O—

CH₂—

C_5-6 aryl, —

C(O)—

C_5-6 aryl substituted with C_1-3 alkyl or halo;

C_5-6 aryl or C_5-6 cycloalkyl optionally comprising 1 or more heteroatoms selected from N, S and O;

A is C_5-7 cycloalkyl, phenyl, naphthyl or C_5-12 heteroaryl, wherein said heteroaryl contains one heteroatom selected from O, N or S;

when A is C_5-7 cycloalkyl, naphtyl or C_5-12 heteroaryl as defined above,

R₂ is H, amino, hydroxyl, halo, or straight or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 heteroalkyl, C_1-6 aminoalkyl, C_1-6 haloalkyl, C_1-6 alkoxycarbonyl, —

CN, —

CF₃, —

OR₃, —

COR₃, NO₂, —

NHR₃, —

NHC(O)R₃, —

C(O)NR₃R₄, —

NR₃R₄, —

NR₃C(O)NR₄R₅, —

OC(O)R₃, or —

(CH₂)_qNR₃R₄;

where R₃, R₄ and R₅ are the same or different, each independently being selected from H, C_1-6 alkyl;

C_5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C_1-6 alkyl;

C_3-6 cycloalkyl;

or R₃ and R₄ together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and

q is an integer from 1 to 6;

or

when A is phenyl,

R₂ is amino, hydroxyl, chloro, bromo, or straight or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 heteroalkyl, C_1-6 aminoalkyl, C_1-6 haloalkyl, C_1-6 alkoxycarbonyl, —

CN, —

CF₃, —

OR₃, —

COR₃, NO₂, —

NHR₃, —

NHC(O)R₃, —

C(O)NR₃R₄, —

NR₃R₄, —

NR₃C(O)NR₄R₅, —

OC(O)R₃, —

C(O)R₃R₄, —

O(CH₂)_qNR₃, —

CNR₃R₄ or —

(CH₂)_qNR₃R₄;

where R₃, R₄ and R₅ are the same or different, each independently being selected from H, C_1-6 alkyl;

C_5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C_1-6 alkyl;

C_3-6 cycloalkyl;

or R₃ and R₄ together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and

q is an integer from 1 to 6;

n is 1, 2, 3 or 4, the groups R₂, when n>

1, being the same or different;

p is 0 or an integer from 1 to 5;

Y is —

NHC(O)—

or —

C(O)—

; and

Z is a bond or CR₈R₉ wherein R₈ and R₉ are independently selected from H, and straight or branched chain C_1-8 alkyl;

provided where —

(CH₂)_p—

Y—

is —

(CH₂)₃—

C(O)—

, that —

A—

(R₂)_n and R₁ are not together;

o-methyl-phenyl and n-butyl, respectively;

or

a pharmaceutically acceptable salt, ester or prodrug thereof.

64. The method of claim 63, wherein said compound of formula (I) is a compound represented by formula (II):

65. The method of claim 64, wherein R₁ is straight or branched-chain C_2-8 alkyl.

66. The method of claim 65, wherein R₂ is alkyl, aminoalkyl, alkoxy or hydroxyl.

67. The method of claim 66, wherein p is 3.

68. The method of claim 67, wherein R₂ is methyl, hydroxyl or alkoxy.

69. The method of claim 68, wherein Y is —

C(O)—

.

70. The method of claim 65, wherein R₂ is chloro or bromo.

71. The method of claim 64, wherein R₁ is alkoxy.

88. A method of agonizing a muscarinic receptor comprising contacting said receptor with an effective amount of a compound of formula (II):

wherein

R₁ is alkoxy;

R₂ is amino, hydroxyl, chloro, bromo, or straight or branched-chain C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, C_1-6 heteroalkyl, C_1-6 aminoalkyl, C_1-6 haloalkyl, C_1-6 alkoxycarbonyl, —

CN, —

CF₃, —

OR₃, —

COR₃, NO₂, —

NHR₃, —

NHC(O)R₃, —

C(O)NR₃R₄, —

NR₃R₄, —

NR₃C(O)NR₄R₅, —

OC(O)R₃, —

C(O)R₃R₄, —

O(CH₂)_qNR₃, —

CNR₃R₄ or —

(CH₂)_qNR₃R₄;

where R₃, R₄ and R₅ are the same or different, each independently being selected from H, C_1-6 alkyl;

C_5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C_1-6 alkyl;

C_3-6 cycloalkyl;

or R₃ and R₄ together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and

q is an integer from 1 to 6;

n is 1, 2, 3 or 4, the groups R₂, when n>

1, being the same or different;

p is 0 or an integer from 1 to 5;

Y is —

NHC(O)—

or —

C(O)—

;

or

a pharmaceutically acceptable salt, ester or prodrug thereof.