Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1995-10-23
2001-04-03
Geist, Gary (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C564S182000, C564S271000, C564S374000, C536S023500
Reexamination Certificate
active
06211244
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the design, development, composition and use of compounds able to modulate one or more inorganic ion receptor activities.
BACKGROUND OF THE INVENTION
Certain cells in the body respond not only to chemical signals, but also to ions such as extracellular calcium ions (Ca
2+
). Changes in the concentration of extracellular Ca
2+
(referred to herein as “[Ca
2+
]”) alter the functional responses of these cells. One such specialized cell is the parathyroid cell which secretes parathyroid hormone (PTH). PTH is the principal endocrine factor regulating Ca
2+
homeostasis in the blood and extracellular fluids.
PTH, by acting on bone and kidney cells, increases the level of Ca
2+
in the blood. This increase in [Ca
2+
] then acts as a negative feedback signal, depressing PTH secretion. The reciprocal relationship between [Ca
2+
] and PTH secretion forms the essential mechanism maintaining bodily Ca
2+
homeostasis.
Extracellular Ca
2+
acts directly on parathyroid cells to regulate PTH secretion. The existence of a parathyroid cell surface protein which detects changes in [Ca
2+
] has been confirmed. Brown et al., 366
Nature
574, 1993. In parathyroid cells, this protein acts as a receptor for extracellular Ca
2+
(“the calcium receptor”), and detects changes in [Ca
2+
] and to initiate a functional cellular response, PTH secretion.
Extracellular Ca
2+
can exert effects on different cell functions, reviewed in Nemeth et al., 11
Cell Calcium
319, 1990. The role of extracellular Ca
2+
in parafollicular (C-cells) and parathyroid cells is discussed in Nemeth, 11
Cell Calcium
323, 1990. These cells have been shown to express similar Ca
2+
receptor. Brown et al., 366
Nature
574, 1993; Mithal et al., 9 Suppl. 1
J. Bone and Mineral Res. s
282, 1994; Rogers et al., 9 Suppl. 1
J. Bone and Mineral Res. s
409, 1994; Garrett et al., 9 Suppl. 1
J. Bone and Mineral Res. s
409, 1994. The role of extracellular Ca
2+
on bone osteoclasts is discussed by Zaidi, 10
Bioscience Reports
493, 1990. In addition keratinocytes, juxtaglomerular cells, trophoblasts, pancreatic beta cells and fat/adipose cells all respond to increases in extracellular calcium which likely reflects activation of calcium receptors of these cells.
The ability of various compounds to mimic extra-cellular Ca
2+
in vitro is discussed by Nemeth et al., (spermine and spermidine) in “Calcium-Binding Proteins in Health and Disease,” 1987, Academic Press, Inc., pp. 33-35; Brown et al., (e.g., neomycin) 128
Endocrinolocy
3047, 1991; Chen et al., (diltiazem and its analog, TA-3090) 5
J. Bone and Mineral Res.
581, 1990; and Zaidi et al., (verapamil) 167
Biochem. Biophys. Res. Commun.
807, 1990. Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959, and Nemeth et al., PCT/US92/07175, International Publication Number WO 93/04373, describe various compounds which can modulate the effect of an inorganic ion on a cell having an inorganic ion receptor.
The references provided in the background are not admitted to be prior art.
SUMMARY OF THE INVENTION
The present invention features compounds able to modulate one or more activities of an inorganic ion receptor and methods for treating diseases or disorders by modulating inorganic ion receptor activity. Preferred compounds can mimic or block the effect of extracellular calcium on a cell surface calcium receptor.
Diseases or disorders which can be treated by modulating inorganic ion receptor activity include one or more of the following types: (1) those characterized by abnormal inorganic ion homeostasis, preferably calcium homeostasis; (2) those characterized by an abnormal amount of an extracellular or intracellular messenger whose production can be affected by inorganic ion receptor activity, preferably calcium receptor activity; (3) those characterized by an abnormal effect (e.g., a different effect in kind or magnitude) of an intracellular or extracellular messenger which can itself be ameliorated by inorganic ion receptor activity, preferably calcium receptor activity; and (4) other diseases or disorders in which modulation of inorganic ion receptor activity, preferably calcium receptor activity will exert a beneficial effect, for example, in diseases or disorders where the production of an intracellular or extracellular messenger stimulated by receptor activity compensates for an abnormal amount of a different messenger. Examples of extracellular messengers whose secretion and/or effect can be affected by modulating inorganic ion receptor activity include inorganic ions, hormones, neurotransmitters, growth factors, and chemokines. Examples of intracellular messengers include cAMP, cGMP, IP3, and diacylglycerol.
Thus, a compound of this invention preferably modulates calcium receptor activity and is used in the treatment of diseases or disorders which can be affected by modulating one or more activities of a calcium receptor. Calcium receptor proteins enable certain specialized cells to respond to changes in extracellular Ca
2+
concentration. For example, extracellular Ca
2+
inhibits the secretion of parathyroid hormone from parathyroid cells, inhibits bone resorption by osteoclasts, and stimulates secretion of calcitonin from C-cells.
In a preferred embodiment, the compound is used to treat a disease or disorder characterized by abnormal bone and mineral homeostasis, more preferably calcium homeostasis. Extracellular Ca
2+
is under tight homeostatic control and controls various processes such as blood clotting, nerve and muscle excitability, and proper bone formation. Abnormal calcium homeostasis is characterized by one or more of the following activities: (1) an abnormal increase or decrease in serum calcium; (2) an abnormal increase or decrease in urinary excretion of calcium; (3) an abnormal increase or decrease in bone calcium levels, for example, as assessed by bone mineral density measurements; (4) an abnormal absorption of dietary calcium; (5) an abnormal increase or decrease in the production and/or release of messengers which affect serum calcium levels such as parathyroid hormone and calcitonin; and (6) an abnormal change in the response elicited by messengers which affect serum calcium levels. The abnormal increase or decrease in these different aspects of calcium homeostasis is relative to that occurring in the general population and is generally associated with a disease or disorder.
Diseases and disorders characterized by abnormal calcium homeostasis can be due to different cellular defects such as a defective calcium receptor activity, a defective number of calcium receptors, or a defective intracellular protein acted on by a calcium receptor. For example, in parathyroid cells, the calcium receptor is coupled to the G
i
protein which in turn inhibits cyclic AMP production. Defects in G
i
protein can affect its ability to inhibit cyclic AMP production.
Thus, a first aspect the invention features an inorganic ion receptor modulating compound having the formula:
STRUCTURE I
where Ar
1
is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH
2
OH, CONH
2
, CN, acetoxy, N(CH
3
)
2
, phenyl, phenoxy, benzyl, benzyloxy, &agr;,&agr;-dimethylbenzyl, NO
2
, CHO, CH
3
CH(OH), acetyl, ethylene dioxy;
Ar
2
is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH
2
OH, CONH
2
, CN, and acetoxy;
q is 0, 1, 2, or 3; and
R is either H, or lower alkyl;
and pharmaceutically salts and complexes thereof.
Compounds of this invention have preferred stereochemistry. The CH
3
shown in S
Balandrin Manuel F.
DelMar Eric G.
Moe Scott T.
Nemeth Edward F.
Van Wagenen Bradford C.
Geist Gary
NPS Pharmaceuticals Inc.
Padmanabhan Sreeni
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