Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-07
2003-10-21
Baker, Maurie Garcia (Department: 1639)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C435S007100, C435S007200, C536S124000, C536S124000, C536S124000, C536S063000, C536S063000, C536S063000, C564S032000, C564S048000, C514S315000, C514S317000, C514S326000, C514S329000, C514S588000, C514S596000, C436S501000
Reexamination Certificate
active
06635764
ABSTRACT:
BACKGROUND OF THE INVENTION
A receptor is a biological structure with one or more binding domains that reversibly complexes with one or more ligands, where that complexation has biological consequences. Receptors can exist entirely outside the cell (extracellular receptors), within the cell membrane (but presenting sections of the receptor to the extracellular milieu and cytosol), or entirely within the cell (intracellular receptors). They may also function independently of a cell (e.g., clot formation). Receptors within the cell membrane allow a cell to communicate with the space outside of its boundaries (i.e., signaling) as well as to function in the transport of molecules and ions into and out of the cell.
A ligand is a binding partner for a specific receptor or family of receptors. A ligand may be the endogenous ligand for the receptor or alternatively may be a synthetic ligand for the receptor such as a drug, a drug candidate or a pharmacological tool.
The super family of seven transmembrane proteins (7-TMs), also called G-protein coupled receptors (GPCRs), represents one of the most significant classes of membrane bound receptors that communicate changes that occur outside of the cell's boundaries to its interior, triggering a cellular response when appropriate. The G-proteins, when activated, affect a wide range of downstream effector systems both positively and negatively (e.g., ion channels, protein kinase cascades, transcription, transmigration of adhesion proteins, and the like).
Muscarinic receptors are members of the G-protein coupled receptors that are composed of a family of five receptor sub-types (M
1
, M
2
, M
3
, M
4
and M
5
) and are activated by the neurotransmitter acetylcholine. These receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The regional distribution of these receptor subtypes in the brain and other organs has been documented (Bonner, T. I. et al.,
Science
(Washington D.C.) 1987, 237, 527-532; Goyal, R. K.,
J. Med.,
1989, 321, 1022; Hulme, E. C., et al.,
Annu. Rev. harmacol. Toxicol.
1990, 30, 633; and Eglen, R. M. and Hegde, S. S.,
Drug News Perspect.
1997, 10(8), 462-469). For example, the smooth muscle is composed largely of M
2
and M
3
receptors, cardiac muscle is composed largely of M
2
receptors, and salivary glands are largely composed of M
3
receptors.
It has been established that the muscarinic receptors are involved in diseases such as chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, and alzheimer,s disease, senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiac arrhythmia, and hyper salvation syndromes (Fisher, A.,
Invest. Drugs,
1997, 6(10), 1395-1411; Martel, A. M., et al., Drugs Future, 1997, 22(2), 135-137; Graul, A. and Castaner, J., Drugs Future, 1996, 21(11), 1105-1108; and Graul, A., et al., Drugs Future, 1997, 22(7), 733-737).
A number of compounds having muscarinic receptor antagonistic activities are being used to treat these diseases. For example, oxybutynin is being used for the treatment of urinary urge incontinence and dicyclorine is being used for the treatment of irritable bowel syndrome. However, these drugs have limited utility as they produce side effects such as dry mouth, blurred vision, and mydriasis.
There is currently a need for novel muscarinic receptor antagonists.
SUMMARY OF THE INVENTION
The invention is directed to urea derivatives that are muscarinic receptor antagonists and agonists and that are useful in the treatment and prevention of diseases mediated by muscarinic receptors (e.g. chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like).
Accordingly, the invention provides a compound of the invention which is a compound of Formula (I):
L
1
—X—L
2
wherein:
wherein:
A is an aryl or a heteroaryl ring;
B″ is —NR
a−
wherein R
a
is hydrogen, alkyl, aryl, heteroaryl, or substituted alkyl;
R
1
is hydrogen or alkyl;
R
2
is Het, or is selected from a group consisting of formula (i), (ii), and (iii):
wherein:
—— is an optional double bond;
n
1
is an integer of from 1 to 4;
n
2
is an integer of from 1 to 3;
V is —CH—, —O—, —S(O)n
3
— (where n
3
is an integer of from 0 to 2), or —NR
4
— (wherein R
4
is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl);
“Het” is a heteroaryl ring which optionally attaches (a) to a linker;
R
3
is hydrogen, alkyl, amino, substituted amino, —OR
a
(where R
a
is hydrogen, alkyl, or acyl), or a covalent bond attaching (a) to a linker;
R
5
is hydrogen, alkyl, amino, substituted amino, —OR
b
(where R
b
is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching (a) to a linker;
R
6
, R
7
, and R
8
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 n
4
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 R
5
, R
6
, R
7
, R
8
, “Het”, heterocycloamino or heteroarylamino groups attaches (a) to a linker;
X is a linker;
L
2
is a group selected from a group consisting of:
(i) a group of formula (b):
wherein:
D″ is alkylene;
D is —NR
31
R
32
, —N
+
(R
33
R
34
R
35
) or —OR
32
where R
31
, R
33
, and R
34
are, independently of each other, hydrogen, alkyl, or aralkyl; and R
32
and R
35
represent a covalent bond attaching (b) to a linker;
R
27
is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;
R
28
is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;
R
29
and R
30
are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino; or
one of R
27
, R
28
, R
29
, or R
30
together with the adjacent group forms a methylenedioxy or ethylenedioxy group;
(ii) a group of formula (c):
wherein:
n
11
is an integer of from 1 to 7;
n
12
is 0 to 7;
F is —NR
40
—, —O—, —S—, or —CHR
41
— (wherein R
40
and R
41
are, independently of each other, hydrogen, alkyl, or substituted alkyl);
F″ is a covalent bond, —OR
43
, —NR
42
R
43
, or —N
+
R
43
R
44
R
45
wherein R
42
is hydrogen or alkyl, R
44
and R
45
are alkyl, and R
43
is hydrogen, alkyl, or a covalent bond attaching (c) to a linker;
R
36
is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl
Mammen Mathai
Oare David
Baker Maurie Garcia
Boone David E.
Hagenah Jeffrey A.
Theravance Inc.
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