Calcilytic compounds

Details Calcilytic compounds Calcilytic compounds

2000-10-05

2002-05-28

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitriles

C560S036000, C562S451000

Reexamination Certificate

active

06395919

ABSTRACT:

FIELD OF INVENTION
The present invention relates to novel calcilytic compounds, pharmaceutical compositions containing these compounds and their use as calcium receptor antagonists.
In mammals, extracellular Ca
2+
is under rigid homeostatic control and regulates various processes such as blood clotting, nerve and muscle excitability, and proper bone formation. Extracelluiar 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. Calcium receptor proteins enable certain specialized cells to respond to changes in extracellular Ca
2+
concentration.
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 H secretion. The existence of a parathyroid cell surface protein which detects changes in extracellular Ca
2+
has been confirmed. See 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+
influences various cell functions, reviewed in Nemeth et al., Cell Calcium 11:319, 1990. For example, extracellular Ca
2+
plays a role in parafollicular (C-cells) and parathyroid cells. See Nemeth, Cell Calcium 11:323, 1990. The role of extracellular Ca
2+
on bone osteoclasts has also been studied. See Zaidi, Bioscience Reports 10:493, 1990.
Various compounds are known to mimic the effects of extra-cellular Ca
2+
on a calcium receptor molecule. Calcilytics are compounds able to inhibit calcium receptor activity, thereby causing a decrease in one or more calcium receptor activities evoked by extracellular Ca
2+
. Calcilytics are useful as lead molecules in the discovery, development, design, modification and/or construction of useful calcium modulators which are active at Ca
2+
receptors. Such 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 expression and/or secretion of which is regulated or affected by activity at one or more Ca
2+
receptors. Target diseases or disorders for calcilytic compounds include diseases involving abnormal bone and mineral homeostasis.
Abnormal calcium homeostasis is characterized by one or more of the following activities: an abnormal increase or decrease in serum calcium; an abnormal increase or decrease in urinary excretion of calcium; an abnormal increase or decrease in bone calcium levels (for example, as assessed by bone mineral density measurements); an abnormal absorption of dietary calcium; an abnormal increase or decrease in the production and/or release of messengers which affect serum calcium levels such as PTH and calcitonin; and an abnormal change in the response elicited by messengers which affect serum calcium levels.
Thus, calcium receptor antagonists offer a unique approach towards the pharmacotherapy of diseases associated with abnormal bone or mineral homeostasis, such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy and fracture healing, and osteoporosis.
SUMMARY OF THE INVENTION
The present invention comprises novel calcium receptor antagonists represented by Formula (I) hereinbelow and their use as calcium receptor antagonists in the treatment of a variety of diseases associated with abnormal bone or mineral homeostasis, including but not limited to hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy and fracture healing, and osteoporosis.
The present invention further provides a method for antagonizing calcium receptors in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of Formula (I), indicated hereinbelow.
The present invention further provides a method for increasing serum parathyroid levels in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of Formula (I), indicated hereinbelow.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are selected from Formula (I) hereinbelow:
wherein:
Y
1
is a covalent bond, alkylene or alkenylene of up to 4 carbon atoms, unsubstituted or substituted by C
1-4
alkyl, or O;
Y
2
is methylene, unsubstituted or substituted by C
1-4
alkyl or haloalkyl;
Y
3
is covalent bond or O, S, N—R
IV
or C
1-4
alkylene-O, C
1-4
alkylene-S, C
1-4
alkylene-N—R
IV
;
R
3
and R
4
are, independently, methyl or ethyl, or, together, form cyclopropyl;
R
5
is aryl or fused aryl, dihydro or tetrahydro fused aryl, unsubstituted or substituted with any substituents being selected from the group consisting of OH, halogen, C
1-4
alkyl, C
1-4
alkoxy, C
3-6
cycloalkyl, OSO
2
R
IV
, CN, NO
2
, OCF
3
, CF
3
, CH
2
CF
3
, (CH
2
)
n
CO
2
R
IV
, and O—(CH
2
)
n
CO
2
R
IV
, wherein n is an integer from 0 to 3 and R
IV
is selected from the group consisting of H, C
1-4
alkyl, C
3-6
cycloalkyl;
or R
5
is heteroaryl or fused heteroaryl; wherein the hetero-ring contains N, O or S, and is aromatic, dihydro or tetrahydro, unsubstituted or substituted with any substituents being selected from the group consisting of OH, OCH
3
, CH(CH
3
)
2
, halogen, C
1-4
alkyl, C
1-4
alkoxy, C
3-6
cycloalkyl, OSO
2
R
IV
, CN, NO
2
, OCF
3
, CF
3
, CH
2
CF
3
, (CH
2
)
n
CO
2
H, (CH
2
)
n
CO
2
R
IV
, and O—(CH
2
)
n
CO
2
R
IV
;
G is a covalent bond, CHR
6
or C—R
6
wherein R
6
is H, OH or O (forming a ketone);
R
7
is H, OH, or O—C
1-4
alkyl;
R
8
is H or C
1-4
alkyl; or R
7
and R
8
together form a ketone;
A and B are, independently, selected from the group consisting of a bond, CH
2
, NH, O, S and C═O, provided that either A or B is selected from CH
2
and NH; or A and B together form a bond; or the A-B moiety is represented by CH═CH or C≡C; wherein
X
1
and X
5
are independently selected from the group consisting of H, halogen, CN, NO
2
, C
1-4
alkyl, cycloalkyl, CH
2
-aryl, and CH
2
-heteroaryl; provided that either X
1
or X
5
is H; X
2
, X
3
and X
4
are selected from the group consisting of H, halogen, O—C
1-4
alkyl, O-aryl, O-heteroaryl, CH
2
-aryl. CH
2
-heteroaryl, alkyl, C(O)aryl, C(O)heteroaryl, CH(OH)aryl, CH(OH)heteroaryl; and J—K;
J is a covalent bond, alkylene, O-alkylene or alkenylene of up to 5 carbon atoms, unsubstituted or substituted by a substituent selected from the group consisting of C
1-4
alkyl, OH, O(forming a ketone), aryl, heteroaryl, and NR′R″, wherein R′ and R″ are independently selected from the group consisting of H, alkyl, aryl, heteroaryl, C(O)alkyl, C(O)aryl, and C(O)heteroaryl;
K is selected from the group consisting of, CO
2
R
IV
, OH, and CN;
and pharmaceutically acceptable salts and complexes thereof.
Preferably, the compounds of the present invention have a structure according to Formula (II):
wherein:
R
3
and R
4
are, independently, methyl or ethyl, or, together, form cyclopropyl;
R
5
is aryl or fused aryl, or dihydro or tetrahydro fused aryl, unsubstituted or substituted with any substituents being selected from the group consisting of OH, halogen, C
1-4
alkyl, C
1-4
alkoxy, C
3-6

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