&bgr;2-adrenergic receptor agonists

Details &bgr;2-adrenergic receptor agonists &bgr;2-adrenergic receptor agonists

2000-02-14

2003-07-15

Baker, Maurie (Department: 1639)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C435S007100, C435S007200, C436S501000, C436S518000, C564S347000, C544S062000, C544S360000, C544S363000, C544S370000, C544S372000, C544S373000, C544S380000, C544S382000, C546S156000, C549S404000, C548S325500, C548S346100, C548S440000, C548S486000, C548S490000, C514S649000, C514S651000, C514S653000

Reexamination Certificate

active

06593497

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel multibinding compounds (agents) that are &bgr;2 adrenergic receptor agonists and pharmaceutical compositions comprising such compounds. Accordingly, the multibinding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of respiratory diseases such as asthma and chronic bronchitis. They are also useful in the treatment of nervous system injury and premature labor.
2. References
The following publications are cited in this application as superscript numbers:
1
Hardman, J. G., et al. “The Pharmacological Basis of Therapeutics”, McGraw-Hill, New York, (1996)
2
Strosberg, A. D. “Structure, Function, and Regulation of Adrenergic Receptors”
Protein Sci
. 2, 1198-1209 (1993).
3
Beck-Sickinger, A. G. “Structure Characterization and Binding Sites of G-Protein-coupled Receptors”
DDT
, 1, 502-513, (1996).
4
Hein, L. & Kobilka, B. K. “Adrenergic Receptor Signal Transduction and Regulation”
Neuropharmacol
, 34, 357-366, (1995).
5
Strosberg, A. D. & Pietri-Rouxel, F. “Function, and Regulation of &bgr;3 Adrenoceptor”
TiPS
, 17, 373-381, (1996).
6
Barnes, P. J. “Current Therapies for Asthma”
CHEST
, 111:17S-26S, (1997).
7
Jack, D. A. “A way of Looking at Agonism and Antagonism: Lessons from Salbutamol, Salmeterol and other &bgr;-Adrenoceptor Agonists”
Br. J. Clin. Pharmac
. 31, 501-514, (1991).
8
Kissei Pharmaceutical Co. Ltd. “2-Amino-1-(4-hydroxy-2-methyl-phenyl)propanol derivatives” JP-10152460 (Publication date Jun. 9, 1998).
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.
3. 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).
Adrenergic receptors (AR) are members of the G-protein coupled receptors that are composed of a family of three receptor sub-types: &agr;1 (
A,B,D
) &agr;2 (
A,B,C
) and &bgr;(
1,2,3
).
1-5
These receptors are expressed in tissues of various systems and organs of mammals and the proportions of the &agr; and the &bgr; receptors are tissue dependant. For example, tissues of bronchial smooth muscle express largely &bgr;2-AR while those of cutaneous blood vessels contain exclusively &agr;-AR subtypes.
It has been established that the &bgr;2-AR sub-type is involved in respiratory diseases such as such as asthma
6
and chronic bronchitis, nervous system injury, and premature labor
8
. Currently, a number of drugs e.g., albuterol, formoterol, isoprenolol, or salmeterol having &bgr;2-AR agonist activities are being used to treat asthma. However, these drugs have limited utility as they are either non-selective thereby causing adverse side effects such as muscle tremor, tachycardia, palpitations, and restlesness
6
, or have short duration of action and/or slow onset time of action.
7
Accordingly, there is a need for &bgr;2-selective AR agonists that are fast acting and have increased potency and/or longer duration of action.
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 agonists of &bgr;2 adrenergic receptor and are therefore useful in the treatment and prevention of respiratory diseases such as asthma and chronic bronchitis. They are also useful in the treatment of nervous system injury and premature labor.
Accordingly, in one of its composition aspects, this invention provides a multibinding compound of Formula (I):
(L)
p
(X)
q
  (I)
wherein:
p is an integer of from 2 to 10;
q is an integer of from 1 to 20,
L is a ligand wherein:
one of the ligands, L, is a compound of formula (a):
 wherein:
Ar
1
is selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocyclyl wherein each of said Ar
1
and Ar
2
substituent optionally links the ligand to a linker;
R
1
is selected from the group consisting of hydrogen, alkyl, and substituted alkyl, or R
1
is a covalent bond linking the ligand to a linker;
R
2
and R
3
are independently selected from the group consisting of hydrogen, alkyl, acyl, and substituted alkyl, or R
2
and R
3
are a covalent bond linking the ligand to a linker; and
the other ligands are independently selected from a compound of formula (b):
—Q—Ar
2
  (b)
 wherein:
Ar
2
is selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocyclyl;
Q is a covalent bond, or a substituted alkylene group wherein one or more of the carbon atoms in said substituted alkylene group is optionally replaced by a substituent selected from —NR
a
— (where R
a
is hydrogen, alkyl, acyl, or a covalent bond linking the ligand to a linker), —O—, —S(O)
n
(where n is an integer of from 0 to 2), —CO—, —PR
b
— (where R
b
is alkyl), —P(O)
2
—, and —O—P(O)O— and links the ligand to a linker;
each linker, X, in the multibinding compound of Formula (I) independently has the formula:
—X
a
—Z—(Y
a
—Z)
m
—X
a
—
 wherein:
m is an integer of from 0 to 20;
X
a
at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NR—, —NRC(O)—, C(S), —C(S)O—, —C(S)NR—, —NRC(S)—, 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, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, or a covalent bond;
each Y
a
at each separate occurrence is 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(X
a
)—NR′—, —NR′—C(X
a
)═N—,—P(O)(OR′)—O—, —O—P(O)(OR′)—, —S(O)
n
CR′ R″—, —S(O), —NR′—, —NR′—S(O)
n
—, 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 that X
a
, X
b
, and Z are not covalent bonds at the same time; and
pharmaceutically acceptable salts thereof provided that:
(i) when Q is a 2-hydroxyethylamino group then the linker is not alkylene or —C(O)-alk

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