Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-27
2002-06-25
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S310100, C514S394000
Reexamination Certificate
active
06410743
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel tetrahydronaphtalene derivatives, to compositions comprising these compounds and their use in therapy, e.g. in the treatment and in the prevention of type 1 and type 2 diabetes as well as cardiovascular disorders associated with diabetes.
BACKGROUND OF THE INVENTION
Insulin secretion from pancreatic &bgr;-cells is the primary physiological mechanism of blood glucose regulation. A rise in blood glucose concentration stimulates release of insulin from the pancreas, which in turn promotes glucose uptake in peripheral tissues and consequently lowers blood glucose levels, reestablishing euglycemia. Non-insulin dependent diabetes mellitus (NIDDM)(type II diabetes) is associated with impairment in glucose-induced insulin secretion in pancreatic &bgr;-cells (Vague, P. and Moulin, J. P., Metabolism 31:139-144 (1982)).
Voltage-gated Ca
2+
channels mediate a rapidly activated inward movement of Ca
2+
ions that underlies the stimulation of insulin secretion in &bgr;-cells (Boyd, A. E. III, Current Concepts, The Upjohn Company, Kalamazoo, Mich. (1991). In different tissues, four types of Ca
2+
channels have been described (L(P/Q), T, N, and E channels). The purified L-type Ca
2+
channel consists of five subunits: &agr;
1
, &agr;
2
, &bgr;, &ggr;, &dgr; (Catterall, W. A., Science 253:1499-1500 (1991)). The primary structure of the &agr;, subunit is organized in four homologous domains containing six transmembrane segments (Catterall, W. A., Science 242:50-61 (1988).
Rat and human pancreatic &bgr;-cells are equipped with L-type and T-type Ca
2+
channels (Hiriart, M. and Matteson, D. R., J Gen Physiol 91:145-159 (1988); Davalli, A. M., et al., J Endocrinology 150:195-203 (1996)). L-type Ca
2+
channels, activated at high voltages and having large unitary conductance and dihydropyridine-sensitivity, are considered the major pipe-line for Ca
2+
influx into the &bgr;-cell (Keahey, H. H., et al., Diabetes 38:188-193 (1989)). In contrast, T-type calcium channels activate at low voltages and have small unitary conductance and dihydropyridine-insensitivity.
The physiological function of T-type Ca
2+
channels in &bgr;-cell insulin-secretion has been demonstrated (Bhattacharjee, A., et al., Endocrinology 138:3735-3740 (1997). These channels facilitate exocytosis by enhancing electrical activity in these cells. L-type and T-type Ca
2+
channels, under normal conditions, work in concert promoting the rise in [Ca
2+
]
i
, during glucose-stimulated insulin secretion. In &bgr;-cells, over-expressed T-type Ca
2+
channels may be, at least in part, responsible for the hyper-responsiveness of insulin secretion to non-glucose depolarizing stimuli in GK rat and in rat with NIDDM induced by neonatal injection of streptozotocin (Kato, S., et al., Metabolism 43:1395-1400 (1994); Kato, S., et al., J Clin Invest 97:2417-2425 (1996)). However, over-expressed T-type calcium channels over time will ultimately lead to an elevation of basal Ca
2+
through it's window current properties. Therefore, there is a dual effect of T-type Ca
2+
channels in &bgr;-cells depending upon channel number and membrane potential.
Two isoforms of L-type Ca
2+
channel &agr;1 subunits have been identified in &bgr;-cells (Seino, S., et al., Proc Natl Acad Sci USA 89:584-588 (1992)). The rat neuronal T-type calcium channel has been cloned (Perez-Reyes, E., et al., Nature 391:896-900 (1998)). The &agr;1G subunit of the T-type calcium channel has been cloned from the rat insulin secreting cell line INS-1 (Zhuang et al.,
Diabetes
49: 59-64, 2000). This &agr;1G subunit is expressed in rat islets as well as in brain, neonatal heart and kidney. The &agr;1 H subunit of the T-type calcium channel has been cloned from human heart (Cribbs, L. L. Circ. Res. 83: 103-109 (1998). Other subunits of T-type Ca
2+
channel have yet to be identified.
It has recently been described that the blocker of T-type and L-type calcium channels mibefradil prevents and reverses the development of hypertension, hyperinsulinemia and hypertriglyceridemia in fructose fed rats (S. Verma et al, Cardiovascular Research 34: 121-128 (1997)).
In patients suffering from type 2 diabetes and in animal models of type 2 diabetes, an elevated intracellular level of calcium in both beta-cells and non-pancreatic tissue has been observed (J. Levy, Endocrine, 10: 1-6 (1999). It is believed that compounds able to inhibit a rise in intracellular calcium are useful to treat or prevent type 2 diabetes, and microvascular or macrovascular diseases associated with diabetes.
Blockers of T-type channels of pancreatic beta cells protect these cells from the cytotoxic effects of cytokines and reduce basal insulin release to reduce the presentations of antibodies associated with Type 1 diabetes. These effects can be used in the treatment on patients suffering from Type 1 diabetes as described by Karlsson and Bjork (
Diabetes
45:1427-30 (1996) and
Autoimmunity
26:117-122 (1997)).
U.S. Pat. No. 4,808,650 discloses mibefradil and analogues thereof as calcium antagonists which are useful in the treatment of angina pectoris, ischaemia, arrhythmias, high blood pressure and cardiac insufficiency.
The present invention provides a class of novel tetrahydronaphtalene derivatives which is able to inhibit a rise in intracellular calcium mediated by an influx through T-type calcium channels, indicating that the compounds of the present invention are useful in the treatment and in the prevention of diabetes and microvascular or macrovascular diseases associated with diabetes.
SUMMARY OF THE INVENTION
The present invention relates to novel tetrahydronaphtalene derivatives of the general formula (I) wherein R
1
, R
2
and R
3
are as defined in the detailed part of the present description.
The present compounds interfere with T-type calcium channel activity and can be used for treating and for preventing type 1 and type 2 diabetes and diabetic cardiovascular disorders.
Further, the present compounds are particularly well suited to blocking (inhibiting) the activity of T-type calcium channels but not blocking the activity of L-type calcium channels.
Further provided are pharmaceutical compositions comprising the compounds of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
The invention further provides methods of treating and methods of preventing type 1 and type 2 diabetes, as well as methods of treatment and methods of preventing microvascular or macrovascular diseases associated with diabetes, in a subject (human or animal), the method comprising administering to the subject an amount of a compound effective to modify levels of T-type calcium channels in the pancreatic beta cells and non-pancreatic tissue of the subject.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to novel tetrahydronaphtalene derivatives of the general formula (I)
wherein R
1
is H, C
1-6
-alkyl or phenyl which is optionally substituted with halogen, methoxy or C
1-6
-alkyl; and R
2
—C—R
3
together forms a C
3-6
-cycloalkyl group; or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base.
The present invention also encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other of the present compounds which, upon administration to an animal including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to prodrugs and pharmaceutically acceptable salts of the compounds of the present invention, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents.
In regard to prodrugs, the compounds of the present invention may additionally or alternatively be prepared to be delivered in a prodrug form. The term prodrug indicates a therapeutic agent that is prepared in an inactiv
Hansen John Bondo
Li Ming
Tagmose Tina Moller
Green, Esq. Reza
Higel Floyd D.
Novo Nordisk A S
Saeed Kamal
Waibel, Esq. Peter J.
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