US2008108618A1PendingUtilityA1
Compounds with activity on muscarinic receptors
Est. expiryMar 31, 2018(expired)· nominal 20-yr term from priority
Inventors:Mark R. BrannTerri MessierErika CurrierKate DuggentoTracy SpaldingMikael FribergNiels Skjaerbaek
C07D 211/00A61P 25/00C07D 211/22C07D 211/26C07D 265/32C07D 211/20C07D 213/50C07D 295/108
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Claims
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
exact text as granted — not AI-modified1 . A compound of formula (I):
wherein
X 1 , X 2 , X 3 , X 4 and X 5 are selected from C, N and O;
k is 0 or 1;
t is 0, 1 or 2;
R 1 is straight or branched-chain C 1-8 alkyl, C 2-8 alkenyl, C 1-8 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 alkylthio, —O—CH 2 —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; —C(O)NR 3 R 4 , —NR 3 R 4 , —NR 3 C(O)NR 4 R 5 , —CR 3 R 4 , —OC(O)R 3 , —(O)(CH 2 ) s NR 3 R 4 or —(CH 2 ) s NR 3 R 4 ; where R 3 , R 4 and R 5 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 R 3 and R 4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and s is an integer from 0 to 8;
A is C 5-12 aryl or C 5-7 cycloalkyl, each optionally comprising 1 or more heteroatoms selected from N, S and O;
R 2 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, C 1-6 alkylthio, —CN, —CF 3 , —OR 3 , —COR 3 , NO 2 , —NHR 3 , —NHC(O)R 3 , —C(O)NR 3 R 4 , —NR 3 R 4 , —NR 3 C(O)NR 4 R 5 , —OC(O)R 3 , —C(O)R 3 R 4 , —O(CH 2 ) q NR 3 , —CNR 3 R 4 or —(CH 2 ) q NR 3 R 4 ; where q is an integer from 1 to 6;
n is 0, 1, 2, 3 or 4, the groups R 2 , when n>1, being the same or different;
p is 0 or an integer from 1 to 5;
Y is O, S, CHOH, —NHC(O)—, —C(O)NH—, —C(O)—, —OC(O)—, NR 7 or —CH═N—, and R 7 is H or C 1-4 alkyl; or absent;
Z is CR 8 R 9 wherein R 8 and R 9 are independently selected from H, and straight or branched-chain C 1-8 alkyl;
provided where —(CH 2 ) p —Y— is —(CH 2 ) 3 —C(O)— or —(CH 2 ) 3 —S—; and X 1 through X 5 are C; that -A-(R 2 ) n and R 1 are not together:
o-methyl-phenyl and n-butyl, respectively;
phenyl and n-butyl, respectively; or
p-fluoro-phenyl and —O—(CH 2 ) 2 CH 3 , respectively; or
a pharmaceutically acceptable salt, ester or prodrug thereof.
2 . The compound of claim 1 , wherein:
X 1 , X 2 , X 3 , X 4 and X 5 are C; or one of X 1 , X 2 , X 3 , X 4 or X 5 is O or N and the others are C; k is 0 or 1; t is 1; R 1 is straight or branched-chain C 1-8 alkyl, C 2-9 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, —C(O)NR 3 R 4 , —NR 3 R 4 , —NR 3 C(O)NR 4 R 5 , —OC(O)R 3 , or —(CH 2 ) s NR 3 R 4 ; where R 3 , R 4 and R 5 are the same or different, each independently being selected from H and C 1 alkyl; and s is an integer from 1 to 8; n is 1, 2 or 3; and A is phenyl or naphthyl; where R 2 is straight or branched-chain C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 aminoalkyl, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, —CN, —CF 3 , —OH, —COR 3 , —NHR 3 , —NHC(O)R 3 , —C(O)NR 3 R 4 , —NR 3 R 4 , —NR 3 C(O)NR 4 R 5 , —OC(O)R 3 , or —CH 2 ) q NR 3 R 4 ; where q is an integer from 1 to 6; or A is aryl comprising 1 or more heteroatoms selected from N, S and O; R 2 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, —CF 3 , OH, —COR 3 , —NHR 3 , —NHC(O)R 3 , —C(O)NR 3 R 4 , —NR 3 R 4 , —NR 3 C(O)NR 4 R 5 , —OC(O)R 3 or —(CH 2 ) q NR 3 R 4 ; or a pharmaceutically acceptable salt, ester or prodrug thereof.
3 . A compound of claim 1 or 2 , wherein p is 3.
4 . A compound of claim 1 or 2 , wherein k is 0.
5 . The compound of claim 1:
6 . The compound of claim 5:
7 . A compound of claim 6 , wherein t is 1 and Y is —C(O)—, —NHC(O)—, S, O or —OC(O)—.
8 . The compound of claim 7 , wherein X 3 is C.
9 . The compound of claim 8 , wherein R 1 is alkyl.
10 . The compound of claim 9 , wherein R 2 is alkyl, aminoalkyl, alkoxy or hydroxyl.
11 . A compound of claim 10 , wherein p is 3.
12 . A compound of claim 11 , wherein R 1 is C 2-8 alkyl and R 2 is methyl, hydroxyl or alkoxy.
13 . A compound of claim 12 , wherein Y is —C(O)— or O.
14 . The compound of claim 9 , wherein R 2 is halo.
15 . The compound of claim 6 , wherein t is 0.
16 . The compound of claim 8 , wherein R 1 is alkoxy.
17 . The compound of claim 8 , wherein R 1 is benzyl or phenyl.
18 . The compound of claim 7 , wherein X 3 is N.
19 . The compound of claim 18 , wherein R 1 is alkyl or alkoxy.
20 . The compound of claim 18 , wherein R 1 is benzyl or phenyl.
21 . The compound of claim 19 , wherein R 2 is alkyl or alkoxy.
22 . The compound of claim 20 , wherein R 2 is alkyl or alkoxy.
23 . The compound of claim 7 , wherein X 3 is O.
24 . The compound of claim 23 , wherein R 1 is alkyl.
25 . The compound of claim 24 , wherein R 2 is alkyl or alkoxy.
26 . The compound of claim 24 , wherein R 2 is halo.
27 . The compound of claim 5:
28 . A compound of claim 27 , wherein Y is —C(O)—, —NHC(O)—, S, O or —OC(O)—.
29 . The compound of claim 28 , wherein X 3 is C.
30 . The compound of claim 29 , wherein R 1 is alkyl.
31 . The compound of claim 30 , wherein R 2 is alkyl, aminoalkyl, alkoxy or hydroxyl.
32 . A compound of claim 31 , wherein p is 3.
33 . A compound of claim 32 , wherein R 1 is C 2-8 alkyl and R 2 is methyl, hydroxyl or alkoxy.
34 . A compound of claim 33 , wherein Y is —C(O)— or O.
35 . The compound of claim 30 , wherein R 2 is halo.
36 . The compound of claim 27 , wherein t is 0.
37 . The compound of claim 29 , wherein R 1 is alkoxy.
38 . The compound of claim 29 , wherein R 1 is benzyl or phenyl.
39 . The compound of claim 28 , wherein X 3 is N.
40 . The compound of claim 39 , wherein R 1 is alkyl or alkoxy.
41 . The compound of claim 39 , wherein R 1 is benzyl or phenyl.
42 . The compound of claim 40 , wherein R 2 is alkyl or alkoxy.
43 . The compound of claim 41 , wherein R 2 is alkyl or alkoxy.
44 . The compound of claim 28 , wherein X 3 is O.
45 . The compound of claim 44 , wherein R 1 is alkyl.
46 . The compound of claim 45 , wherein R 2 is alkyl or alkoxy.
47 . The compound of claim 45 , wherein R 2 is halo.
48 . A method of agonizing a muscarinic receptor comprising contacting said receptor with an effective amount of a compound of formula (I):
wherein
X 1 , X 2 , X 3 , X 4 and X 5 are selected from C, N and O;
k is 0 or 1;
t is 0 or 1;
R 1 is straight or branched-chain C 1-8 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 1-9 hydroxyalkyl, —SH, C is thioalkyl, —O—CH 2 —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 (89620); —C(O)NR 3 R 4 , —NR 3 R 4 , —NR 3 C(O)NR 4 R 5 , —CR 3 R 4 , —OC(O)R 3 , —C(O)(CH 2 ) s NR 3 R 4 or —(CH 2 ) s NR 3 R 4 ; where R 3 , R 4 and R 5 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 R 3 and R 4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and s is an integer from 0 to 8;
A is C 5-12 aryl or C 5-7 cycloalkyl, each optionally comprising 1 or more heteroatoms selected from N, S and O;
R 2 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, —CF 3 , —OR 3 , —COR 3 , NO 2 , —NHR 3 , —NHC(O)R 3 , —C(O)NR 3 R 4 , —NR 3 R 4 , —NR 3 C(O)NR 4 R 5 , —OC(O)R 3 , —C(O)R 3 R 4 , —O(CH 2 ) q NR 3 , —CNR 3 R 4 or —(CH 2 ) q NR 3 R 4 ; where q is an integer from 1 to 6;
n is 0, 1, 2, 3 or 4, the groups R 2 , when n>1, being the same or different;
p is 0 or an integer from 1 to 5;
Y is O, S, CHOH, —NHC(O)—, —C(O)NH—, —C(O)—, —OC(O)—, NR 7 or —CH═N—, and R 7 is H or C 1-4 alkyl; or absent; and
Z is CR 8 R 9 wherein R 5 and R 9 are independently selected from H, and straight or branched chain C 1-8 alkyl; or
a pharmaceutically acceptable salt, ester or prodrug thereof.
49 . A method of claim 48:
50 . A method of claim 49 , wherein t is 1 and Y is —C(O)—, —NHC(O)—, S, O or —OC(O)—.
51 . The method of claim 50 , wherein X 3 is C.
52 . The method of claim 51 , wherein R 1 is alkyl.
53 . The method of claim 52 , wherein R 2 is alkyl, aminoalkyl, alkoxy or hydroxyl.
54 . A method of claim 53 , wherein p is 3.
55 . A method of claim 54 , wherein R 1 is C 2-8 alkyl and R 2 is methyl, hydroxyl or alkoxy.
56 . A method of claim 55 , wherein Y is —C(O)— or 0.
57 . The method of claim 52 , wherein R 2 is halo.
58 . The method of claim 49 , wherein t is 0.
59 . The method of claim 51 , wherein R 1 is alkoxy.
60 . The method of claim 51 , wherein R 1 is benzyl or phenyl.
61 . The method of claim 52 , wherein X 3 is N.
62 . The method of claim 61 , wherein R 1 is alkyl or alkoxy.
63 . The method of claim 61 , wherein R 1 is benzyl or phenyl.
64 . The method of claim 62 , wherein R 2 is alkyl or alkoxy.
65 . The method of claim 63 , wherein R 2 is alkyl or alkoxy.
66 . The method of claim 50 , wherein X 3 is O.
67 . The method of claim 66 , wherein R 1 is alkyl.
68 . The method of claim 67 , wherein R 2 is alkyl or alkoxy.
69 . The method of claim 67 , wherein R 2 is halo.
70 . A pharmaceutical composition comprising an effective amount of a compound of formula (I):
wherein
X 1 , X 2 , X 3 , X 4 and X 5 are selected from C, N and O;
k is 0 or 1;
t is 0 or 1;
R 1 is straight or branched-chain C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkyl, 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—CH 2 —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; —C(O)NR 3 R 4 , —NR 3 R 4 , —NR 3 C(O)NR 4 R 5 , —CR 3 R 4 , —OC(O)R 3 , —C(O)(CH 2 ) s NR 3 R 4 or —(CH 2 ) s NR 3 R 4 ; where R 3 , R 4 and R 5 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 1-4 alkyl; C 3-6 cycloalkyl; or R 3 and R 4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and s is an integer from 0 to 8;
A is C 5-12 aryl or C 5-7 cycloalkyl, each optionally comprising 1 or more heteroatoms selected from N, S and O;
R 2 is H, amino, hydroxyl, halo, or straight or branched-chain C 1 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 1-6 heteroalkyl, C 1-6 aminoalkyl, C 1-6 haloalkyl, C 1-6 alkoxycarbonyl, —CN, —CF 3 , —OR 3 , —COR 3 , NO 2 , —NHR 3 , —NHC(O)R 3 , —C(O)NR 3 R 4 , —NR 3 R 4 , —NR 3 C(O)NR 4 R 5 , —OC(O)R 3 , —C(O)R 3 R 4 , —O(CH 2 ) q NR 3 , —CNR 3 R 4 or —(CH 2 ) q NR 3 R 4 ; where q is an integer from 1 to 6;
n is 0, 1, 2, 3 or 4, the groups R 2 , when n>1, being the same or different;
p is 0 or an integer from 1 to 5;
Y is O, S, CHOH, —NHC(O)—, —C(O)NH—, —C(O)—, —OC(O)—, NR 7 or —CH═N—, and R 7 is H or C 1-4 alkyl; or absent;
Z is CR 8 R 9 wherein R 8 and R 9 are independently selected from H, and straight or branched chain C 1-8 alkyl; or
a pharmaceutically acceptable salt, ester or prodrug thereof; and
a pharmaceutically acceptable carrier.
71 . A composition of claim 70 compromising:
72 . A composition of claim 71 , wherein t is 1 and Y is —C(O)—, —NHC(O)—, S, O or —OC(O)—.
73 . The composition of claim 72 , wherein X 3 is C.
74 . The composition of claim 73 , wherein R 1 is alkyl.
75 . The composition of claim 74 , wherein R 2 is alkyl, aminoalkyl, alkoxy or hydroxyl.
76 . A composition of claim 75 , wherein p is 3.
77 . A composition of claim 75 , wherein R 1 is C 2-8 alkyl and R 2 is methyl, hydroxyl or alkoxy.
78 . A composition of claim 77 , wherein Y is —C(O)— or O.
79 . The composition of claim 74 , wherein R 2 is halo.
80 . The composition of claim 71 , wherein t is 0.
81 . The composition of claim 73 , wherein R 1 is alkoxy.
82 . The composition of claim 73 , wherein R 1 is benzyl or phenyl.
83 . The composition of claim 74 , wherein X 3 is N.
84 . The composition of claim 82 , wherein R 1 is alkyl or alkoxy.
85 . The composition of claim 82 , wherein R 1 is benzyl or phenyl.
86 . The composition of claim 83 , wherein R 2 is alkyl or alkoxy.
87 . The composition of claim 84 , wherein R 2 is alkyl or alkoxy.
88 . The composition of claim 72 , wherein X 3 is O.
89 . The composition of claim 88 , wherein R 1 is alkyl.
90 . The composition of claim 89 , wherein R 2 is alkyl or alkoxy.
91 . The composition of claim 87 , wherein R 2 is halo.
92 . 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 .
93 . The method of claim 92 , wherein said disease or condition is neurogenerative disease, cognitive impairment, age-related cognitive decline or dementia.
94 . 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 70 .
95 . The method of claim 94 , wherein said disease or condition is neurogenerative disease, cognitive impairment, age-related cognitive decline or dementia.
96 . 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 muscarinic receptor agonist.
97 . The method of claim 96 , wherein said muscarinic receptor agonist comprises m1 receptor agonist activity.
98 . The method of claim 96 , wherein said muscarinic receptor agonist is m1 selective.
99 . The method of claim 98 , wherein agonist causes at least about a 10 fold greater increase in the activity of an m1 receptor subtype than of an m3 receptor subtype.
100 . The method of claim 96 , wherein said method comprises administering a therapeutically effective amount of one or more compounds of claim 1 .
101 . The method of claim 98 , wherein said method comprises administering a therapeutically effective amount of one or more compounds of claim 1 .
102 . The method of claim 96 , wherein said disease is glaucoma.
103 . 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 comprising a muscarinic receptor agonist.
104 . The method of claim 103 , wherein said muscarinic receptor agonist comprises m1 receptor agonist activity.
105 . The method of claim 103 , wherein said muscarinic receptor agonist is m1 selective.
106 . The method of claim 105 , 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.
107 . The method of claim 103 wherein said method comprises administering a therapeutically effective amount of a composition of claim 70 .
108 . The method of claim 105 , wherein said method comprises administering a therapeutically effective amount of a composition of claim 70 .
109 . The method of claim 103 , wherein said disease is glaucoma.
110 . A method of identifying agents capable of reducing intraocular pressure, said method comprising:
contacting a putative agent with an m1 muscarinic receptor subtype; contacting the putative agent with an m3 muscarinic receptor subtype; comparing the increase in activity of each receptor subtype; and identifying agents selective for the m1 muscarinic receptor subtype; thereby identifying agents capable of reducing intraocular pressure.
111 . The method of claim 110 , wherein said agent causes at least about a 10 fold greater increase in the activity of the m1 receptor subtype than of the m3 receptor subtype.Cited by (0)
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