Therapeutic ureas
First Claim
Patent Images
1. A compound of Formula (I):
- L1—
X—
L2
(I) wherein;
L1 is a group of formula (a);
wherein;
A is an aryl or a heteroaryl ring;
B″
is —
NRa—
wherein Ra is hydrogen, alkyl, aryl, heteroaryl, or substituted alkyl;
R1 is hydrogen or alkyl;
R2 is Het, or is selected from a group consisting of formula (i), (ii), and (iii);
wherein;
- - - is an optional double bond;
n1 is an integer of from 1 to 4;
n2 is an integer of from 1 to 3;
V is —
CH—
, —
O—
, —
S(O)n3—
(where n3 is an integer of from 0 to
2), or —
NR4—
(wherein R4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl);
“
Het”
is a heteroaryl ring which optionally attaches (a) to a linker;
R3 is hydrogen, alkyl, halo, amino, substituted amino, —
ORa (where Ra is hydrogen, alkyl, or acyl), or a covalent bond attaching (a) to a linker;
R5 is hydrogen, alkyl, halo, amino, substituted amino, —
ORb (where Rb is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching (a) to a linker;
R6, R7, and R8 are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching (a) to a linker;
K is a bond or an alkylene group;
K″
is a bond, —
C(O)—
, —
S(O)n4—
(where n4 is an integer of from 0 to
2), or an alkylene group optionally substituted with a hydroxyl group; and
B is heterocycloamino or heteroarylamino, which optionally attaches (a) to a linker;
provided that at least one of the R5, R6, R7, R8, “
Het”
, heterocycloamino or heteroarylamino groups attaches (a) to a linker;
X is a linker; and
L2 is an organic group comprising at least one primary, secondary, or tertiary amine;
or a pharmaceutically acceptable salt;
or prodrug thereof.
1 Assignment
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Accused Products
Abstract
This invention relates to urea compounds that are muscarinic receptor antagonists and agonists, pharmaceutical compositions comprising such compounds, and methods of preparing these compounds.
25 Citations
51 Claims
-
1. A compound of Formula (I):
-
L1—
X—
L2
(I)wherein;
L1 is a group of formula (a);
wherein;
A is an aryl or a heteroaryl ring;
B″
is —
NRa—
wherein Ra is hydrogen, alkyl, aryl, heteroaryl, or substituted alkyl;
R1 is hydrogen or alkyl;
R2 is Het, or is selected from a group consisting of formula (i), (ii), and (iii);
wherein;
- - - is an optional double bond;
n1 is an integer of from 1 to 4;
n2 is an integer of from 1 to 3;
V is —
CH—
, —
O—
, —
S(O)n3—
(where n3 is an integer of from 0 to
2), or —
NR4—
(wherein R4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl);
“
Het”
is a heteroaryl ring which optionally attaches (a) to a linker;
R3 is hydrogen, alkyl, halo, amino, substituted amino, —
ORa (where Ra is hydrogen, alkyl, or acyl), or a covalent bond attaching (a) to a linker;
R5 is hydrogen, alkyl, halo, amino, substituted amino, —
ORb (where Rb is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching (a) to a linker;
R6, R7, and R8 are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching (a) to a linker;
K is a bond or an alkylene group;
K″
is a bond, —
C(O)—
, —
S(O)n4—
(where n4 is an integer of from 0 to
2), or an alkylene group optionally substituted with a hydroxyl group; and
B is heterocycloamino or heteroarylamino, which optionally attaches (a) to a linker;
provided that at least one of the R5, R6, R7, R8, “
Het”
, heterocycloamino or heteroarylamino groups attaches (a) to a linker;
X is a linker; and
L2 is an organic group comprising at least one primary, secondary, or tertiary amine;
or a pharmaceutically acceptable salt;
or prodrug thereof.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 47, 48, 49, 50, 51)
-
-
19. The compound of claim 1 or 2 wherein X is alkylene optionally substituted with one, two, or three hydroxy groups, alkylene wherein one, two or three carbon atoms have been replaced by an oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fluoro groups.
-
20. The compound of claim 1 or 2 wherein X is a group of formula:
-
—
Xa—
Z—
(Ya—
Z)m—
Yb—
Z—
Xa—wherein m is an integer of from 0 to 20;
Xa at each separate occurrence is selected from the group consisting of —
O—
, —
S—
, —
NR—
, —
C(O)—
, —
C(O)O—
, —
C(O)NR—
, —
C(S)—
, —
C(S)O—
, —
C(S)NR—
or a covalent bond where R is as defined below;
Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
Ya and Yb at each separate occurrence are selected from the group consisting of —
O—
, —
C(O)—
, —
OC(O)—
, —
C(O)O—
, —
NR—
, —
S(O)n—
, —
C(O)NR′
—
, —
NR′
C(O)—
, —
NR′
C(O)NR′
—
, —
NR′
C(S)NR′
—
, —
C(═
NR′
)—
NR′
—
, —
NR′
—
C(═
NR′
)—
, —
OC(O)—
NR′
—
, —
NR′
—
C(O)—
O—
, —
N═
C(Xa)—
NR′
—
, —
NR′
—
C(Xa)═
N—
,—
P(O)(OR′
)—
O—
, —
O—
P(O)(OR′
)—
, —
S(O)nCR′
R″
—
, —
S(O)n—
NR′
—
, —
NR′
—
S(O)n—
, —
S—
S—
, and a covalent bond;
where n is 0, 1 or 2; and
R, R′ and
R″
at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
provided at least one of Xa, Ya, Yb or Z is not a covalent bond.
-
-
21. The compound of claim 1 or 2 wherein X is an alkylene group having from 3 to 20 carbon atoms;
- wherein one or more carbon atoms in the alkylene group is optionally replaced with —
O—
; and
wherein the chain is optionally substituted on carbon with one or more hydroxyl.
- wherein one or more carbon atoms in the alkylene group is optionally replaced with —
-
22. The compound of claim 1 or 2 wherein X is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.
-
23. The compound of claim 1 or 2 wherein X has the following formula:
-
24. The compound of claim 1 or 2 wherein X has one of the following the formula:
-
25. The compound of claim 2 which is a compound of Formula (Ia):
-
26. The compound of claim 25 wherein X is alkylene optionally substituted with one, two, or three hydroxy groups, alkylene wherein one, two or three carbon atoms have been replaced by an oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fluoro groups.
-
27. The compound of claim 25 wherein X is a group of formula:
-
—
Xa—
Z—
(Ya—
Z)m—
Yb—
Z—
Xa—wherein m is an integer of from 0 to 20;
Xa at each separate occurrence is selected from the group consisting of —
O—
, —
S—
, —
NR—
, —
C(O)—
, —
C(O)O—
, —
C(O)NR—
, —
C(S)—
, —
C(S)O—
, —
C(S)NR—
or a covalent bond where R is as defined below;
Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
Ya and Yb at each separate occurrence are selected from the group consisting of —
O—
, —
C(O)—
, —
OC(O)—
, —
C(O)O—
, —
NR—
, —
S(O)n—
, —
C(O)NR′
—
, —
NR′
C(O)—
, —
NR′
C(O)NR′
—
, —
NR′
C(S)NR′
—
, —
C(═
NR′
)—
NR′
—
, —
NR′
—
C(═
NR′
)—
, —
OC(O)—
NR′
—
, —
NR′
—
C(O)—
O—
, —
N═
C(Xa)—
NR′
—
, —
NR′
—
C(Xa)═
N—
,—
P(O)(OR′
)—
O—
, —
O—
P(O)(OR′
)—
, —
S(O)nCR′
R″
—
, —
S(O)n—
NR′
—
, —
NR′
—
S(O)n—
, —
S—
S—
, and a covalent bond;
where n is 0, 1 or 2; and
R, R′ and
R″
at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
provided at least one of Xa, Ya, Yb or Z is not a covalent bond.
-
-
28. The compound of claim 25 wherein X is an alkylene group having from 3 to 20 carbon atoms;
- wherein one or more carbon atoms in the alkylene group is optionally replaced with —
O—
; and
wherein the chain is optionally substituted on carbon with one or more hydroxyl.
- wherein one or more carbon atoms in the alkylene group is optionally replaced with —
-
29. The compound of claim 25 wherein X is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.
-
30. The compound of claim 25 wherein X has the following formula:
-
31. The compound of claim 25 wherein X has one of the following the formula:
-
32. The compound of claim 1 which is a compound of formula (IVa):
-
33. The compound of claim 32 wherein X is alkylene optionally substituted with one, two, or three hydroxy groups, alkylene wherein one, two or three carbon atoms have been replaced by an oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fluoro groups.
-
34. The compound of claim 32 wherein X is a group of formula:
-
—
Xa—
Z—
(Ya—
Z)m—
Yb—
Z—
Xa—wherein m is an integer of from 0 to 20;
Xa at each separate occurrence is selected from the group consisting of —
O—
, —
S—
, —
NR—
, —
C(O)—
, —
C(O)O—
, —
C(O)NR—
, —
C(S)—
, —
C(S)O—
, —
C(S)NR—
or a covalent bond where R is as defined below;
Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
Ya and Yb at each separate occurrence are selected from the group consisting of —
O—
, —
C(O)—
, —
OC(O)—
, —
C(O)O—
, —
NR—
, —
S(O)n—
, —
C(O)NR′
—
, —
NR′
C(O)—
, —
NR′
C(O)NR′
—
, —
NR′
C(S)NR′
—
, —
C(═
NR′
)—
NR′
—
, —
NR′
—
C(═
NR′
)—
, —
OC(O)—
NR′
—
, —
NR′
—
C(O)—
O—
, —
N═
C(Xa)—
NR′
—
, —
NR′
—
C(Xa)═
N—
,—
P(O)(OR′
)—
O—
, —
O—
P(O)(OR′
)—
, —
S(O)nCR′
R″
—
, —
S(O)n—
NR′
—
, —
NR′
—
S(O)n—
, —
S—
S—
, and a covalent bond;
where n is 0, 1 or 2; and
R, R′ and
R″
at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
provided at least one of Xa, Ya, Yb or Z is not a covalent bond.
-
-
35. The compound of claim 32 wherein X is an alkylene group having from 3 to 20 carbon atoms;
- wherein one or more carbon atoms in the alkylene group is optionally replaced with —
O—
; and
wherein the chain is optionally substituted on carbon with one or more hydroxyl.
- wherein one or more carbon atoms in the alkylene group is optionally replaced with —
-
36. The compound of claim 32 wherein X is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.
-
37. The compound of claim 32 wherein X has the following formula:
-
38. The compound of claim 32 wherein X has one of the following the formula:
-
39. The compound of claim 1 wherein L2 is a group of formula (d) wherein R46 and R47 together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 5 substituents independently selected from the group consisting of substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
-
40. The compound of claim 1 wherein L2 is a group of formula (d) wherein R46 is a heterocycle, optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
- and R47 is alkyl, substituted alkyl, acyl, or —
COOR50.
- and R47 is alkyl, substituted alkyl, acyl, or —
-
41. The compound of claim 1 wherein L2 is a group of formula (d) wherein R46 is alkyl that is optionally substituted with from 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, NRaRb, wherein Ra and Rb may be the same or different and and are chosen from hydrogen, alkyl, substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and heterocyclic.
-
42. The compound of claim 1 wherein L2 is a group of formula (d) wherein R46 is a heterocycle which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —
- SO-alkyl, —
SO-substituted alkyl, —
SO-aryl, —
SO-heteroaryl, —
SO2-alkyl, —
SO2-substituted alkyl, —
SO2-aryl —
SO2-heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
- SO-alkyl, —
-
43. The compound of claim 1 wherein L2 is a group of formula (d) wherein R46 is 3-piperidinyl, 4-piperidinyl, or 3-pyrrolidinyl, which R46 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
-
44. The compound of claim 1 wherein R46 and R47 together with the nitrogen atom to which they are attached form a piperidine or pyrrolidine ring which ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
-
45. The compound of claim 1 wherein R46 and R47 together with the nitrogen atom to which they are attached form a heterocycle that is an aza-crown ether (e.g. 1-aza-12-crown-4, 1-aza-15-crown-5, or 1-aza-18-crown-6).
-
47. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 or 2.
-
48. A method of treating a disease mediated by a muscarinic receptor in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of claim 1 or 2.
-
49. The method of claim 48 wherein the disease is urinary incontinence, chronic pulmonary obstructive disease, asthma, hyper-salivation, a cognitive disorder, blurred vision, or irritable bowel syndrome.
-
50. A compound of formula L1—
- H wherein L1 has the values defined in claim 1;
or a salt thereof
- H wherein L1 has the values defined in claim 1;
-
51. The compound of claim 50 which is
-
18. The compound of claim 18 wherein the piperidino nitrogen of L1 is bonded to X.
-
46. Compound number 1-643 as described in Table A, Table B, Table C, Table D, Table E, or Table F;
- or a pharmaceutically acceptable salt or prodrug thereof.
Specification