Compounds with activity on muscarinic receptors
First Claim
Patent Images
1. A compound of formula (I):
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whereinR1 is straight or branched-chain C2-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy, C1-8 heteroalkyl, C1-8 aminoalkyl, C1-8 haloalkyl, C1-8 alkoxycarbonyl, C1-8 hydroxyalkoxy, C1-8 hydroxyalkyl, —
SH, C1-8 thioalkyl, or —
O—
CH2—
C5-6 aryl;
A is C5-7 cycloalkyl, phenyl, naphthyl or C5-12 heteroaryl, wherein said heteroaryl contains one heteroatom selected from O, N or S;
when A is C5-7 cycloalkyl, naphthyl or C5-12 heteroaryl as defined above, R2 is H, amino, hydroxyl, halo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 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, C1-6 alkyl;
C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
C3-6 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 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, C1-6 alkyl;
C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
C3-6 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 C1-8 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.
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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.
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Citations
88 Claims
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1. A compound of formula (I):
-
wherein R1 is straight or branched-chain C2-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy, C1-8 heteroalkyl, C1-8 aminoalkyl, C1-8 haloalkyl, C1-8 alkoxycarbonyl, C1-8 hydroxyalkoxy, C1-8 hydroxyalkyl, —
SH, C1-8 thioalkyl, or —
O—
CH2—
C5-6 aryl;
A is C5-7 cycloalkyl, phenyl, naphthyl or C5-12 heteroaryl, wherein said heteroaryl contains one heteroatom selected from O, N or S;
when A is C5-7 cycloalkyl, naphthyl or C5-12 heteroaryl as defined above, R2 is H, amino, hydroxyl, halo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 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, C1-6 alkyl;
C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
C3-6 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;
orwhen A is phenyl, R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 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, C1-6 alkyl;
C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
C3-6 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 C1-8 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;
ora pharmaceutically acceptable salt, ester or prodrug thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 59, 72, 73, 76, 77, 78, 79, 80, 81)
R1 is straight or branched-chain C2-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy, C1-8 aminoalkyl, C1-8 haloalkyl, C1-8 alkoxycarbonyl; n is 1, 2 or 3, A is phenyl and R2 is chloro, bromo, straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl;
C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, —
CN, —
CF3, —
COR3, —
NHR3, —
NHC(O)R3, —
C(O)NR3R4, —
NR3R4, —
NR3C(O)NR4R5, —
OC(O)R3, or —
O(CH2)qNR3;
orA is thienyl; and
R2 is H, halo, straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl;
C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, —
CN, —
CF3, —
COR3, —
NHR3, —
NHC(O)R3, —
C(O)NR3R4, —
NR3R4, —
NR3C(O)NR4R5, —
OC(O)R3, or —
O(CH2)qNR3;
ora pharmaceutically acceptable salt, ester or prodrug thereof.
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3. The compound of claim 1 or claim 2, wherein p is 3.
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4. The compound of claim 1, wherein said compound of formula (I) is a compound represented by formula (II):
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5. The compound of claim 4, wherein said compound of formula (II) is a compound represented by formula (IIa):
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6. The compound of claim 4, wherein said compound of formula (II) is a compound represented by formula (IIb):
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7. The compound of claim 5, wherein R1 is straight or branched-chain C2-8 alkyl.
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8. The compound of claim 7, wherein wherein R2 is alkyl, aminoalkyl, alkoxy or hydroxyl.
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9. The compound of claim 8, wherein wherein p is 3.
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10. The compound of claim 9, wherein R2 is methyl, hydroxyl or alkoxy.
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11. The compound of claim 10, wherein Y is —
- C(O)—
.
- C(O)—
-
12. The compound of claim 7, wherein R2 is chloro or bromo.
-
13. The compound of claim 5, wherein R1 is alkoxy.
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14. The compound of claim 6, wherein R1 is straight or branched-chain C2-8 alkyl.
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15. The compound of claim 14, wherein R2 is alkyl, aminoalkyl, alkoxy or hydroxyl.
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16. A compound of claim 15, wherein p is 3.
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17. The compound of claim 16, wherein R2 is methyl, hydroxyl or alkoxy.
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18. The compound of claim 17, wherein Y is —
- C(O)—
.
- C(O)—
-
19. The compound of claim 14, wherein R2 is chloro or bromo.
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20. The compound of claim 6, wherein R1 is alkoxy.
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21. The compound of claim 1, wherein
Y is — - NHC(O)—
;
p is 2; and
Z is a bond.
- NHC(O)—
-
22. The compound of claim 1, wherein
Y is — - C(O)—
;
p is 3; and
Z is a bond.
- C(O)—
-
23. The compound of claim 21, wherein n is 1 or 2.
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24. The compound of claim 2, wherein A is thienyl.
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25. The compound of claim 24, wherein Y is —
- C(O)—
.
- C(O)—
-
26. The compound of any one of claims 24 or 25, wherein R2 is halo, C1-6 alkyl, or C1-6 alkoxy.
-
27. The compound of claim 24, wherein Y is —
- NHC(O)—
.
- NHC(O)—
-
28. The compound of claim 5, wherein R2 is halo, C1-6 alkyl, or C1-6 alkoxy.
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29. The compound of claim 25, wherein p is 3.
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30. The compound of claim 25, wherein Z is a bond.
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31. The compound of claim 29, wherein Z is a bond.
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32. The compound of claim 27, wherein p is 2.
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33. The compound of claim 27, wherein Z is a bond.
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34. The compound of claim 32, wherein Z is a bond.
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59. The pharmaceutical composition comprising a compound of claim 21.
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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.
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73. The method of claim 72, wherein said disease or condition is neurogenerative disease, cognitive impairment, age-related cognitive decline or dementia.
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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.
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77. The method of claim 76, wherein said compound comprises a muscarinic receptor agonist.
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78. The method of claim 77, wherein said muscarinic receptor agonist comprises m1 receptor agonist activity.
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79. The method of claim 77, wherein said muscarinic receptor agonist is m1 selective.
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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.
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81. The method of claim 76, wherein said disease is glaucoma.
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35. A compound of formula (IIa):
-
wherein R1 is alkoxy;
R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 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, C1-6 alkyl;
C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
C3-6 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)—
;
ora pharmaceutically acceptable salt, ester or prodrug thereof.
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36. A compound of formula (IIb):
-
wherein R1 is alkoxy;
R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6haloalkyl, C1-6 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, C1-6 alkyl;
C5-6aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
C3-6 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)—
;
ora pharmaceutically acceptable salt, ester or prodrug thereof.
-
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37. A compound of formula (I):
-
wherein R1 is straight or branched-chain C2-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy, C1-8 heteroalkyl, C1-8 aminoalkyl, C1-8 haloalkyl, C1-8 alkoxycarbonyl, C1-8 hydroxyalkoxy, C1-8 hydroxyalkyl, —
SH, C1-8 thioalkyl, or —
O—
CH2—
C5-6 aryl;
A is C5-7 cycloalkyl, phenyl, naphthyl or C5-12 heteroaryl, wherein said heteroaryl contains one heteroatom selected from O, N or S;
when A is C5-7 cycloalkyl, naphthyl or C5-12 heteroaryl as defined above, R2 is H, amino, hydroxyl, halo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 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, C1-6 alkyl;
C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
C3-6 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;
orwhen A is phenyl, R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 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, C1-6 alkyl;
C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
C3-6 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;
ora pharmaceutically acceptable salt, ester or prodrug thereof. - View Dependent Claims (38, 62)
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39. A compound of formula (I):
-
wherein R1 is straight or branched-chain C2-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy, C1-8 aminoalkyl, C1-8 haloalkyl, C1-8 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl;
C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 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, C1-6 alkyl;
C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
C3-6 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 C1-8 alkyl;
ora pharmaceutically acceptable salt, ester or prodrug thereof. - View Dependent Claims (40, 41, 42, 43, 44, 45, 46, 47, 48)
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49. A pharmaceutical composition comprising an effective amount of a compound of formula (I):
-
wherein R1 is straight or branched-chain C2-8alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy, C1-8 heteroalkyl, C1-8 aminoalkyl, C1-8 haloalkyl, C1-8 alkoxycarbonyl, C1-8 hydroxyalkoxy, C1-8 hydroxyalkyl, —
SH, C1-8 thioalkyl, —
O—
CH2—
C5-6 aryl, —
C(O)—
C5-6 aryl substituted with C1-3 alkyl or halo;
C5-6 aryl or C5-6 cycloalkyl optionally comprising 1 or more heteroatoms selected from N, S and O;
A is C5-7 cycloalkyl, phenyl, naphthyl or C5-12 heteroaryl, wherein said heteroaryl contains one heteroatom selected from O, N or S;
when A is C5-7 cycloalkyl, naphthyl or C5-12 heteroaryl as defined above, R2 is H, amino, hydroxyl, halo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6haloalkyl, C1-6 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, C1-6 alkyl;
C5-6 aryl optionally comprising I or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
C3-6 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 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, C1-6 alkyl;
C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
C3-6 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 C1-8 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;
ora pharmaceutically acceptable salt, ester or prodrug thereof; and
a pharmaceutically acceptable carrier. - View Dependent Claims (50, 51, 52, 53, 54, 55, 56, 57, 58, 74, 75, 82, 83, 84, 85, 86, 87)
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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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 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, C1-6 alkyl;
C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
C3-6 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. - View Dependent Claims (61)
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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 C2-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy, C1-8 heteroalkyl, C1-8 aminoalkyl, C1-8 haloalkyl, C1-8 alkoxycarbonyl, C1-8 hydroxyalkoxy, C1-8 hydroxyalkyl, —
SH, C1-8 thioalkyl, —
O—
CH2—
C5-6 aryl, —
C(O)—
C5-6 aryl substituted with C1-3 alkyl or halo;
C5-6 aryl or C5-6 cycloalkyl optionally comprising 1 or more heteroatoms selected from N, S and O;
A is C5-7 cycloalkyl, phenyl, naphthyl or C5-12 heteroaryl, wherein said heteroaryl contains one heteroatom selected from O, N or S;
when A is C5-7 cycloalkyl, naphtyl or C5-12 heteroaryl as defined above, R2 is H, amino, hydroxyl, halo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 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, C1-6 alkyl;
C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
C3-6 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;
orwhen A is phenyl, R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 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, C1-6 alkyl;
C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
C3-6 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 C1-8 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;
ora pharmaceutically acceptable salt, ester or prodrug thereof. - View Dependent Claims (64, 65, 66, 67, 68, 69, 70, 71)
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88. A method of agonizing a muscarinic receptor comprising contacting said receptor with an effective amount of a compound of formula (II):
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wherein R1 is alkoxy;
R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 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, C1-6 alkyl;
C5-6 aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl;
C3-6 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)—
;
ora pharmaceutically acceptable salt, ester or prodrug thereof.
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Specification