&bgr;3-adrenergic receptor agonists

Details &bgr;3-adrenergic receptor agonists &bgr;3-adrenergic receptor agonists

1999-06-08

2002-03-12

Venkat, Jyothsna (Department: 1627)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S156000, C546S255000, C546S256000, C546S261000, C546S264000, C546S265000, C546S297000, C546S300000, C546S337000, C546S342000, C548S205000, C548S306100, C548S506000, C549S467000, C560S303000, C562S024000, C564S349000

Reexamination Certificate

active

06355805

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel multibinding compounds (agents) that are 3 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 metabolic disorders such as obesity, diabetes, and the like.
References
The following publications are cited in this application as superscript numbers:
1
Hardman, J. G., et al. “The Pharmnacological 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
Kurscheid, T. et al. “The cost implications of obesity of health care and society” Intl. J. of Obesity, 22 (suppl. 1):S3, (1998).
7
Weiser, et al. “Pharmacologic approach to obesity”.
J. Clin. Pharmacol
. 37:453, (1997).
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.
2. 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, &bgr;1 is found in cardiac tissue, &bgr;2 is found in the uterus, skeletal muscle, and lungs
5
and &bgr;3 is predominantly found in adipose tissue
5
.
It has been established that obesity is the main cause of non-insulin dependent diabetes (NIDDM) and an important factor for cardiovascular disease
6.7
. It has been shown that treatment with &bgr;3-AR agonists: 1) reduces diet-induced obesity in mice; 2) leads to reduction of weight in adult dogs; and 3) regulates lipolysis in human adipocytes expressing &bgr;3-AR, in vitro
9
.
Currently, a number of &bgr;3-AR agonists such as BRL 26830A, BRL 35135, Ro 16-8174, Ro 40-2148 and CL 316,24322 are development for the treatment of obesity. Unfortunately, the half -lives of these drugs are short and their bioavailabilty is poor
7
. Furthermore, they suffer from adverse side effects including cardiovascular abnormalities, tremors, insomnia, dizziness, and elevated systolic blood pressure. Accordingly, there is a need for long acting, &bgr;3-AR selective drugs that are efficacious and lack unpleasant 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 &bgr;3 adrenergic receptor agonists and are therefore useful in the treatment and prevention of diseases related to metabolic disorders such as obesity, diabetes, and the like.
Accordingly, in one of its composition aspects, this invention provides a multibinding compound of Formula (I):
wherein:
p is an integer of from 2 to 10;
q is an integer of from 1 to 20,
each ligand, L, is independently of each other:
(i) 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
substituent optionally links the ligand to a linker via a covalent bond;
R
1
and R
2
are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, and a covalent bond that links the ligand to a linker;
R
3
is selected from the group consisting of hydrogen, alkyl, and a covalent bond that links the ligand to a linker; or
(ii) a compound of formula (b):
wherein:
Ar
2
is selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocyclyl wherein each of said Ar
2
substituent optionally links the ligand to a linker via a covalent bond;
R
4
and R
5
are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, and a covalent bond that links the ligand to a linker;
W is a covalent bond, alkyl or substituted alkyl where one or more of the carbon atoms in said alkyl or substituted alkyl group is optionally replaced by one or more heteroatom selected from —O—, S(O)
n
— (where n is an integer from 0 to 2), or —NR
4
— (where R
4
is hydrogen, or alkyl); and
Ar
3
is selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocycle wherein each of said Ar substituent optionally links the ligand to a linker via a covalent bond;
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, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, 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)
n
—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; and pharmaceutically

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