Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-19
2004-11-16
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S394000, C514S411000, C514S412000, C514S443000, C514S466000, C546S334000, C548S309700, C548S439000, C548S492000, C549S058000, C549S437000, C549S443000
Reexamination Certificate
active
06818660
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds able to inhibit calcium receptor activity and the use of such compounds. Preferably, the compounds described herein are administered to patients to achieve a therapeutic effect.
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+
). Extracellular Ca
2+
is under tight homeostatic control and regulates various processes such as blood clotting, nerve and muscle excitability, and proper bone formation.
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 (PTH) from parathyroid cells, inhibits bone resorption by osteoclasts, and stimulates secretion of calcitonin from C-cells.
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 extracellular Ca
2+
then acts as a negative feedback signal, depressing PTH secretion. The reciprocal relationship between extracellular Ca
2+
and PTH secretion forms an important 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 extracellular Ca
2+
has been confirmed. (Brown et al.,
Nature
366:574, 1993.) In parathyroid cells, this protein, the calcium receptor, acts as a receptor for extracellular Ca
2+
, detects changes in the ion concentration of extracellular Ca
2+
, and initiates a functional cellular response, PTH secretion.
Extracellular Ca
2+
can exert effects on different cell functions, reviewed in Nemeth et al.,
Cell Calcium
11:319, 1990. The role of extracellular Ca
2+
in parafollicular (C-cells) and parathyroid cells is discussed in Nemeth,
Cell Calcium
11:323, 1990. These cells were shown to express similar calcium receptors. (See, Brown et al.,
Nature
366:574, 1993; Mithal et al.,
J. Bone Miner. Res.
9, Suppl. 1, s282, 1994; Rogers et al.,
J. Bone Miner. Res.
9, Suppl, 1, s409, 1994; Garrett et al.,
Endocrinology
136:5202-5211, 1995.) The role of extracellular Ca
2+
on bone osteoclasts is discussed by Zaidi,
Bioscience Reports
10:493, 1990.
The ability of various molecules to mimic extracellular Ca
2+
, in vitro is discussed in references such as Nemeth et al., in “Calcium-Binding Proteins in Health and Disease,” 1987, Academic Press, Inc., pp. 33-35; Brown et al.,
Endocrinology
128:3047, 1991; Chen et al.,
J. Bone Miner. Res.
5:581, 1990; and Zaidi et al.,
Biochem. Biophys. Res. Commun.
167:807, 1990.
Nemeth et al., PCT/US92/07175, International Publication Number WO 93/04373, Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959, and Nemeth et al., PCT/US94/12117, International Publication Number WO 95/11211, feature calcium receptor-active molecules and refer to calcilytics as compounds able to inhibit calcium receptor activity. For example, WO 94/18959 on page 8, lines 2-13 asserts:
Applicant is also the first to describe methods by which molecules active at these Ca
2+
receptors can be identified and used as lead molecules in the discovery, development, design, modification and/or construction of useful calcimimetics or calcilytics which are active at Ca
2+
receptors.
Such calcimimetics or calcilytics are useful in the treatment of various disease states characterized by abnormal levels of one or more components, e.g., polypeptides such as hormones, enzymes or growth factors, the expresssion and/or secretion of which is regulated or affected by activity at one or more Ca
2+
receptors.
The references provided in the background are not admitted to be prior art to the pending claims.
SUMMARY OF THE INVENTION
The present invention features calcilytic compounds. “Calcilytic compounds” refer to compounds able to inhibit calcium receptor activity. The ability of a compound to “inhibit calcium receptor activity” means that the compound causes a decrease in one or more calcium receptor activities evoked by extracellular Ca
2+
.
The use of calcilytic compounds to inhibit calcium receptor activity and/or achieve a beneficial effect in a patient are described below. Also described below are techniques which can be used to obtain additional calcilytic compounds.
An example of featured calcilytic compounds are Structure I &agr;,&agr;-disubstituted arylalkylamine derivatives having the chemical formula:
where R
1
is selected from the group consisting of: aryl, longer-length alk, and cycloalk;
R
2
is selected from the group consisting of: lower alk, cycloalk, alkoxy, H, OH, ═O, C(O)OH, C(O)O-lower alk, C(O)NH-lower alk, C(O)N(lower alk)
2
, SH, S-lower alk, NH
2
, NH-lower alk, and N(lower alk)
2
;
R
3
and R
4
is each independently lower alk or together cyclopropyl;
R
5
is aryl;
R
6
if present is either hydrogen, lower alkyl or lower alkenyl, wherein R
6
is not present if R
2
is ═O;
Y
1
is either covalent bond, alkylene, or alkenylene;
Y
2
is alkylene;
Y
3
is alkylene; and
Z is selected from the group consisting of: covalent bond, O, S, NH, N-lower alk, alkylene, alkenylene, and alkynylene, provided that if Z is either O, S, NH, or N-lower alk, then Y
1
is not a covalent bond, further provided that Y
1
and Z may together be a covalent bond;
and pharmaceutically acceptable salts and complexes thereof.
The terms aryl, longer-length alk, lower alk, cycloalk, alkoxy, alkylene, alkenylene, and alkynylene, along with possible substituents are defined in Section II, infra. Section II, infra, also provides definitions for other chemical groups described in the present application.
Preferred calcilytic compounds have an IC
50
≦50 &mgr;M, more preferably an IC
50
<10 &mgr;M, and even more preferably an IC
50
<1 &mgr;M, as measured using the “Calcium Receptor Inhibitor Assay” described in Example 1, infra.
Thus, a first aspect of the present invention features a method of treating a patient by administering to the patient a therapeutically effective amount of a Structure I &agr;,&agr;-disubstituted arylalkylamine derivative. Treatment can be carried out, for example, to retard the disease in a patient having a disease or to prophylactically retard or prevent the onset of a disease.
A therapeutically effective amount is the amount of compound which achieves a therapeutic effect by retarding a disease in a patient having a disease or prophylactically retarding or preventing the onset of a disease. Preferably, it is an amount which relieves to some extent one or more symptoms of a disease or disorder in a patient; returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of the disease or disorder; and/or reduces the likelihood of the onset of the disease of disorder.
A “patient” refers to a mammal in which compounds characterized by their ability to inhibit calcium receptor activity, in vivo or in vitro, will have a beneficial effect. Preferably, the patient is a human being.
Patients benefiting from the administration of a therapeutic amount of a calcilytic compound can be identified using standard techniques known to those in the medical profession. Diseases or disorders which can be treated by inhibiting one or more calcium receptor activities include one or more of the following types: (1) those characterized by an abnormal bone and mineral homeostasis; (2) those characterized by an abnormal amount of an extracellular or intracellular messenger whose production can be affected by one or more calcium receptor activities; (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 ameliora
Barmore Robert M.
Callahan James F.
Del Mar Eric G.
Keenan Richard M.
Kotecha Nikesh R.
Foley & Lardner
NPS Pharmaceuticals Inc.
Raymond Richard L.
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