Calcium receptor-active compounds

Details Calcium receptor-active compounds Calcium receptor-active compounds

2002-01-17

2004-06-15

Gersh, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S655000, C564S341000, C564S353000, C564S354000

Reexamination Certificate

active

06750255

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the design, development, composition and use of novel molecules able to modulate the activity of inorganic ion receptor.
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. s282, 1994; Rogers et al., 9 Suppl. 1 J. Bone and Mineral Res. s409, 1994; Garrett et al., 9 Suppl. 1 J. Bone and Mineral Res. s409, 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 extracellular 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 Endocrinology 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, Nemeth et al., PCT/US92/07175, International Publication Number WO 93/04373, Nemeth et al., PCT/US94/12117, International Publication Number WO 95/11221 and Nemeth et al., PCT/US95/13704, International Publication Number WO 96/12697 describe various compounds which can modulate the effect of an inorganic ion on a cell having an inorganic ion receptor, preferably modulate the effects of calcium on a calcium receptor.
The object of the present invention is to provide a novel inorganic ion receptor active compound having the structure different from the compounds described above.
DISCLOSURE OF THE INVENTION
The present invention features molecules which can modulate one or more activities of an inorganic ion receptor. Preferably, the molecule can mimic or block the effect of extracellular Ca
2+
on a calcium receptor. The preferred use of such molecules is to treat diseases or disorders by altering inorganic ion receptor activity, preferably calcium receptor activity.
The present invention provides a novel calcium receptor active compound of the formula:
Ar
1
—[CR
1
R
2
]
p
—X—[CR
3
R
4
]
q
—[CR
5
R
6
]—NR
7
—[CR
8
R
9
]—Ar
2
wherein:
Ar
1
is selected from the group consisting of aryl, heteroaryl, bis(arylmethyl)amino, bis(heteroarylmethyl)amino and arylmethyl(heteroarylmethyl)amino;
X is selected from the group consisting of oxygen, sulfur, sulfinyl, sulfonyl, carbonyl and amino;
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
8
and R
9
are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, trihalomethyl, aryl, heteroaryl, heteroalicyclic, halogen, hydroxy, alkoxy, thioalkoxy, aryloxy, thioaryloxy, carbonyl, thiocarbonyl, C-carboxyl, O-carboxyl, C-amido, N-amido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, cyano, nitro, amino and NR
10
R
11
; wherein,
R
10
and R
11
are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, carbonyl, trihaloacetyl, sulfonyl, trihalomethanesulfonyl and, combined, a five- or six-member heteroalicyclic ring containing at least one nitrogen;
any two adjacent “R” groups may be combined to form five- or six-member fused cycloalkyl groups;
R
7
is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, halogen, cyano, hydroxy, alkoxy, O-carboxyl, trihaloacetyl and trihalomethanesulfonyl;
Ar
2
is selected from the group consisting of aryl and heteroaryl;
p is an integer of from 0 to 6, inclusive; and,
q is an integer of from 0 to 14, inclusive;
or a pharmaceutically acceptable salt or hydrate of said compound.
As used herein, the term “aryl” refers to an all-carbon monocyclic or fused ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups in which one or more of the rings has a completely conjugated pi-electron system. Examples, without limitation, of aryl groups, are phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, and indanyl. The aryl group may be substituted or unsubstituted. When substituted, the substituted group(s) is preferably one or more selected from halogen, trihalomethyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, S-sulfonamido, N-sulfonamido, trihalomethane-sulfonamido, amino and NR
10
R
11
wherein:
R
10
and R
11
are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, sulfonyl, trihalomethanesulfonyl, and, combined, a five- or six-member heteroalicyclic ring which heteroalicyclic ring may be unsubstituted or substituted with one or more halogens.
A “heteroaryl” group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, at least one of the rings has a completely conjugated pi-electron system. Examples, without limitation, of heteroaryl groups are pyrrole, furan, dibenzofuran, carbazole, acridine, thiophene, imidazole, benzimidazole, oxazole, thiazole, phenothiazine, triazole, thiadiazole, pyrazole, benzoxazole, benzthiazole, indole, benzofuran, indazole, pyridine, pyrimidine, quinoline, isoquinoline, quinazoline, purine, phthalazine and flavone. The heteroaryl group may be substituted or unsubstituted. When substituted, the substituted group(s) is preferably one or more selected from alkyl, cycloalkyl, halogen, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, carbonyl, thiocarbonyl, sulfonamido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, trihalomethanesulfonamido, amino and NR
10
R
11
where R
10
and R
11
are previously defined herein.
As used herein, the term “alkyl” refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to

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