Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-26
2002-10-22
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S085000, C546S087000, C546S064000, C544S126000, C544S233000, C544S361000, C514S232800, C514S248000, C514S253030, C514S287000
Reexamination Certificate
active
06469021
ABSTRACT:
TECHNICAL FIELD AND INDUSTRIAL APPLICABILITY OF THE INVENTION
The present invention relates generally to compounds that act as antagonists to the intestinal hormone glucagon-like peptide 1 (GLP-1). More particularly, the invention relates to non-peptide GLP-1 antagonists which have advantageous physical, chemical and biological properties. The GLP-1 antagonists of the present invention inhibit binding of GLP-1 peptide to the GLP-1 receptor and/or prevent the activation of the receptor by bound GLP-1. The invention further relates to a method of inhibiting the binding of GLP-1 to the GLP-1 receptor and a method of inhibiting the activation of the GLP-1 receptor.
BACKGROUND OF THE INVENTION
GLP-1 is an intestinal hormone released within minutes of food ingestion which potentiates insulin release and aids in the regulation of glucose uptake and metabolism. GLP-1 is derived by post-translational processing of proglucagon and is secreted by the intestinal endocrine L-cells (Fehman et al., 1995,
Endocr. Rev.
16:390-410; Thorens et al., 1995,
Diabetes Metab.
(Paris) 21:311-318). The insulin-trophic effects of GLP-1 make it a useful target in the management of diabetes and other glucose intolerance management problems during critical illness.
Results of recent studies conducted in non-diabetic women aged 59 years suggest that GLP-1 reduces plasma glucose levels primarily by reducing hepatic glucose production and increasing the metabolic clearance rate of glucose through indirectly increasing the insulin-to-glucagon ratio in healthy individuals (Larsson et al., 1997,
Acta Physiol. Scand.
160:413-422). Glucose intolerance is a common feature of the aging process; aging has been identified as an etiologic factor for Type II diabetes mellitus.
In a study designed to characterize the abnormalities in beta cells that occur in the aging process, insulin responses were found to be similar in both age groups studied. GLP-1 in conjunction with IVGTT was found to restore the acute insulin response to glucose while increasing the clearance of glucose in the older animals. The conclusion drawn is that an impaired glucose-mediated insulin response is present in the older animals although the animals maintained their insulin responsivity to GLP-1 (Ore et al., 1997,
Journal of Gerontology: Biological Sciences
52A(5):B245-B249).
A GLP-1 agonist refers to a compound or agent that mimics the physiological and pharmacological properties of endogenous GLP-1. A GLP-1 antagonist refers to a compound or agent that attenuates the effects of GLP-1 through the ability of these compounds or agents to inhibit GLP-1 peptide binding to the GLP-1 receptor and/or prevent the activation of the receptor by bound GLP-1.
The glucagon-like peptides GLP-1-(7-36)-amide and exendin-4-(1-39) have been identified as GLP-1 agonists. The glucagon-secretin-vasoactive intestinal peptide exendin-(9-39) has been identified as a GLP-1 antagonist (Montrose-Rafizadeh et al., 1997,
J. Biol. Chem.
272(34):21201-21206).
Peptide antagonists of peptide hormones are often quite potent. However, the use of peptide antagonists is typically associated with problems due to susceptibility to enzymatic degradation and poor biodistribution, i.e., the inability to be readily transported from the digestive system into the blood stream. Thus, such antagonists have limited effectiveness as drugs since it is difficult to achieve the desired blood levels of peptide antagonists in low dosages. Consequently, there is a need for GLP-1 antagonists, and particularly for non-peptide GLP-1 antagonists.
GLP-1 antagonists have potential to be used therapeutically to increase eating in disorders characterized by cachexia. For example, work by Larsen et al. has shown that the central administration of GLP-1 activates the central CRH-containing neurons of the hypothalamo-pituitary-adrenocortical axis, which may be responsible for feeding behaviors (Larsen et al., 1997,
Endocrinology
138(10):4445-4455). Much evidence shows that GLP-1 agonists inhibit food and water intake in rat, and these effects are blocked by the GLP-1 receptor antagonist exendin-(9-39) amide (Navarro et al., 1996,
J. Neurochem.
67(5):1982-1991; Tang-Christensen, 1996,
Amer. J. Physiol.
271(4 Part 2):R848-856). Exendin-(9-39) alone increases feeding in other rat models (Turton et al., 1996,
Nature
379(6560):69-72). In addition, GLP-1 receptor antagonists may be useful in post-prandial hypoglycemia and the dumping syndrome, where there is an exaggerated GLP-1 release (Vecht, 1997,
Scand. J. Gastroenterol. Suppl.
223:21-27).
Thus, there is a need for effective non-peptide GLP-1 antagonists useful for the therapeutic regulation of GLP-1 that avoid the in vivo degradation and biodistribution problems exhibited by peptide GLP-1 antagonists.
SUMMARY OF THE INVENTION
An object of the present invention is to provide non-peptide GLP-1 antagonists useful as pharmaceuticals. A further object of the invention is to provide methods of synthesizing the compounds and intermediate compounds useful in such syntheses. The compounds of the invention are pharmaceutically superior to peptide compounds since they provide better biodistribution and tolerance to degradation by physiological enzymes.
The invention is directed to GLP-1-antagonizing compounds of the general formula:
wherein:
R
1
is a phenyl or pyridyl group optionally substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, trifluoromethyl, cyano, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, and C
1
-C
6
alkoxy groups;
R
2
is:
where R′ is: hydrogen; a hydroxy group; —OR
5
, where R
5
is a C
1
-C
6
alkyl or C
2
-C
6
alkenyl group optionally substituted with a hydroxy group or an amino, C
1
-C
6
alkoxy, cycloalkyl, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from alkyl, hydroxyalkyl, carboxyl, C
1
-C
6
alkoxycarbonyl, oxygen, halogen, and trifluoromethyl groups; or —NR
6
R
7
, where R
6
and R
7
are each independently hydrogen or a C
1
-C
6
alkyl, C
2
-C
6
alkenyl, amino, or imino group optionally substituted with a hydroxy group, a C
1
-C
6
alkoxy group, or an amino, thioether, heterocycloalkyl, aryl, or heteroaryl group optionally substituted with one or more substituents independently selected from oxygen, halogen, trifluoromethyl, and carboxyl groups, or where —NR
6
R
7
forms a 5- or 6-membered heterocyclic ring optionally containing, in addition to the nitrogen heteroatom, a heteroatom selected from O, N, and S;
—(CH
2
)
n
—O—R″, where n is 1 or 2, and R″ is hydrogen, a C
5
-C
7
heteroaryl group, or
where R
8
is hydrogen, a C
1
-C
6
alkyl group, a C
3
-C
6
cycloalkyl group, or a 5- or 6-membered heteroaryl group optionally substituted with one or more substituents independently selected from halogens, methyl, and trifluoromethyl;
—(CH
2
)
p
—N(R″)(R′″), where p is 1 or 2, R″ is as defined above, and R′″ is hydrogen or an alkyl or alkoxy group optionally substituted with a C
3
-C
6
cycloalkyl group optionally substituted with cyano;
—CH═N—R″″, where R″″ is hydrogen, hydroxy, or —OR
9
, where R
9
is an alkyl, cycloalkyl, aryl, or heteroaryl group; or
a 5- or 6-membered heterocyclic ring containing one to three heteroatoms independently selected from O, N, and S, the ring being optionally substituted with one or two substituents independently selected from methyl, methoxymethyl, oxygen, and C
1
-C
6
alkoxy groups;
R
3
is hydrogen or a C
1
-C
6
alkyl, C
2
-C
6
alkenyl, or (C
1
-C
3
alkoxy)C
1
-C
3
alkyl group;
or R
2
and R
3
together with the atoms to which they are bound form a 5- or 6-membered ring containing one or two heteroatoms selected from O, N, and S, the ring being optionally substituted with oxygen, hydroxyl, or a C
1
-C
6
alkyl group optionally substituted with a 5- or 6-membered heterocycloalkyl containing one or two heteroatoms independently selected from O, N, and S; and
R
4
is hydr
Bychowski Richard A.
Chou Tso-sheng
Dhanoa Daljit S.
Gonzalez Javier
Gregor Vlad Edward
Agouron Pharmaceuticals , Inc.
Aulakh Charanjit S.
Shanks & Herbert
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