Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-25
2004-02-17
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, C436S501000, C436S518000, C514S079000, C514S252120, C514S315000, C514S317000, C514S361000, C514S419000, C514S482000, C514S506000, C514S588000, C540S450000, C544S358000, C546S190000, C546S191000, C546S192000, C546S244000, C548S400000, C548S469000, C548S473000, C548S477000, C548S486000, C548S530000, C548S517000, C548S518000, C548S519000, C548S520000, C548S521000, C562S400000
Reexamination Certificate
active
06693202
ABSTRACT:
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
This invention relates to novel multibinding compounds (agents) that are muscarinic receptor antagonists, pharmaceutical compositions comprising such compounds, and methods of preparing these compounds. Accordingly, the multibinding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of diseases mediated by these receptors such as chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like.
REFERENCES
The following publications are cited in this application as superscript numbers:
1
Bonner, T. I. et al.,
Science
(Washington D.C.) 1987, 237, 527-532.
2
Goyal, R. K.,
J. Med,
1989, 321, 1022.
3
Hulme, E. C., et al.,
Annu. Rev. Pharmacol. Toxicol.
1990, 30, 633.
4
Eglen, R. M. and Hegde, S. S.,
Drug News Perspect.
1997, 10(8), 462-469.
5
Fisher, A.,
Invest. Drugs,
1997, 6(10), 1395-1411.
6
Martel, A. M., et al., Drugs Future, 1997, 22(2), 135-137.
7
Graul, A. and Castaner, J., Drugs Future, 1996, 21(11), 1105-1108.
8
Graul, A., et al., Drugs Future, 1997, 22(7), 733-737.
All of the above publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.
STATE OF THE ART
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
1
. 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
1-4
. 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
5-6
, asthma, irritable bowel syndrome
7
, urinary incontinence
7-8
, rhinitis, spasmodic colitis, chronic cystitis, and alzheimer,s disease, senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiac arrhythmia, and hyper salvation syndromes. Currently, 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 dicyclomine 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. Therefore, there is a need for muscarinic receptor antagonists that will help in the treatment of the above diseases without the adverse side effects.
The multibinding compounds of the present invention fulfill this need.
SUMMARY OF THE INVENTION
This invention is directed to novel multibinding compounds (agents) that are muscarinic receptor antagonists and are therefore useful in the treatment and prevention of diseases such as chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like.
Accordingly, in one of its composition aspects, this invention provides a multibinding compound comprising of from 2 to 10 ligands covalently attached to one or more linkers, wherein each of said ligands comprises, independently of each other, a muscarinic receptor antagonist or an allosteric modulator of a muscarinic receptor, and pharmaceutically acceptable salts thereof provided that at least one of said ligands is a muscarinic receptor antagonist and further provided that when the multibinding compound comprises 2 or 3 ligands, then only one of the ligands is 11-acetyl-5,11-dihydro-6H-pyrido[2,3b][1,4]benzodiazepin-6-one, N-methylquinuclidine, or a compound of formula:
wherein:
n
a
is 0 or 1;
R
c
is hydrogen or alkyl;
R
d
is hydrogen; and
R
e
is —CO
2
CR
f
(phenyl)
2
wherein R
f
is hydrogen or hydroxy.
In a second aspect, this invention provides a multibinding compound of Formula (I):
(L)
p
(X)
q
(I)
wherein:
each L is, independently of each other, a muscarinic receptor antagonist or an allosteric modulator of a muscarinic receptor;
each X is independently a linker;
p is an integer of from 2 to 10; and
q is an integer of from 1 to 20, and pharmaceutically acceptable salts thereof, provided that at least one of said ligands is a muscarinic receptor antagonist, and further provided that when the multibinding compound comprises of 2 or 3 ligands, then only one of the ligands is 11-acetyl-5,11-dihydro-6H-pyrido[2,3][1,4]benzodiazepin-6-one, N-methylquinuclidine, or a compound of formula:
wherein:
n
a
is 0 or 1;
R
c
is hydrogen or alkyl;
R
d
is hydrogen; and
R
e
is —CO
2
CR
f
(phenyl)
2
wherein R
f
is hydrogen or hydroxy.
Preferably, q is less than p in the multibinding compounds of this invention.
Preferably, each ligand, L, that is a muscarinic receptor antagonist in the multibinding compound of Formula (I) is independently selected from the group consisting of:
(1) A Compound of Formula (a):
wherein:
A is an aryl or a heteroaryl ring;
B″ is —CH
2
—, —O— or —NR
a
— where R
a
is hydrogen, alkyl, or substituted alkyl;
R
1
is hydrogen or alkyl;
R
2
is selected from a group consisting of formula (i), (ii), (iii), or “Het”:
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 the ligand to a linker;
R
3
is hydrogen, alkyl, amino, substituted amino, —OR
3
(where R
a
is hydrogen, alkyl, or acyl), or a covalent bond attaching the ligand 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 the ligand 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
Aggen James
Griffin John H.
Mammen Mathai
Marquess Daniel
Moran Edmund J.
Baker Maurie Garcia
Cohen Joyce G.
Hagenah Jeffrey A.
Theravance Inc.
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