Calcilytic compounds

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C514S237500, C514S239500, C514S255030, C514S330000, C514S331000, C514S423000, C514S424000, C514S603000, C514S619000, C544S059000, C544S159000, C544S162000, C544S165000, C544S383000, C544S386000, C546S226000, C546S232000, C548S539000, C548S542000, C558S390000, C564S086000

Reexamination Certificate

active

06294531

ABSTRACT:

The present invention relates to novel arylalkylamine 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. 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. 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+
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. 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 effect of extra-cellular Ca
2+
on a calcium receptor. 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 arylalkylamine derivatives represented by Formula (I) and their use as calcium receptor antagonists which are useful 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 compounds maintain calcium receptor activity and selectivity while having minimal affinity for the beta adrenergic receptor.
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).
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are represented by structural Formula (I):
wherein:
Y
1
is a covalent bond, alkylene or alkenylene of up to 4 carbon atoms, unsubstituted or substituted by C
1-4
alkyl;
Y
2
is methylene, unsubstituted or substituted by C
1-4
alkyl or CF
3
;
Z is selected from the group consisting of a covalent bond, O, S, NH, N—C
1-4
alkyl, O(CH
2
)
n
, (CH
2
)
n
O, NR′″ C═O and C═ONR′″, where R′″ is C
1-4
alkyl and n is an integer from 1 to 3, R
3
and R
4
are, independently, methyl or ethyl, or, together, form cyclopropyl;
R
5
is phenyl or naphthyl, unsubstituted or substituted with one or more substituents selected from the group consisting of OH, C
1-4
alkyl, halo, CH(CH
3
)
2
, halo C
1-4
alkyl, C
1-4
alkoxy, C
3-6
cycloalkyl, OSO
2
R
IV
, CN, NO
2
, OCF
3
, CF
3
, and CH
2
CF
3
, wherein R
IV
represents C
1-4
alkyl or C
3-6
cycloalkyl;
G is a covalent bond or C—R
6
wherein R
6
is H, OH or O (forming a carbonyl moiety);
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 carbonyl moiety; the —A—B— moiety is represented by CH
2
CH
2
, a covalent bond, —CH═CH— or —C≡C—; and
X is selected from the group consisting of sub-formulae (Ia), (Ib), (Ic) (Id) and (Ie) hereinbelow:
 wherein:
in sub-formula (Ia):
W is selected from the group consisting of R
1
, SO
2
R
1
, C(O)R
1
, SO
2
NR
1
R
1
′, C(O)NR
1
R
1
′, C(O)OR
1
SO
3
R
1
′, wherein R
1
and R
1
′ are independently selected from the group consisting of hydrogen, C
1-4
alkyl, C
3-6
cycloalkyl, C
2-5
alkenyl, C
2-5
alkynyl, heterocycloalkyl aryl and aryl C
1-4
alkyl; or R
1
and R
1
′ together form a 3 to 7 membered optionally substituted heterocyclic ring; wherein any substituents are selected from the group consisting of CN, aryl, CO
2
R, CO
2
NHR, OH, OR, NH
2
, halo, CF
3
, OCF
3
and NO
2
; wherein R represents C
1-4
alkyl, or C
3-6
cycloalkyl;
X
1
is selected from the group consisting of CN, NO
2
, Cl, F, Br, I, H, R′, OR′, CF
3
, OCF
3
and OSO
2
R′, wherein R′ represents C
1-4
alkyl, or C
3-6
cycloalkyl;
X
2
, X
3
and X
4
are, independently, selected from the group consisting of CN, NO
2
, Cl, F, Br, I, H, R″, OR″, CF
3
, OCF
3
and OSO
2
R″, wherein R′ is C
1-4
alkyl or haloalkyl; or X
1
and X
2
together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected from N, S and O; and any substituents are selected from the group consisting of halo, C
1-4
alkyl, OCF
3
, CF
3
, OMe, CN, OSO
2
R′ and NO
2
; or X
3
and X
4
independently represent C(O)R
1
; provided that when there are multiple halo substitutions in the haloalkyl, halo represents F; also provided that either X
1
or X
3
is hydrogen; and
R
2
is selected from the group consisting of hydrogen, C
1-4
alkyl, C
3-6
cycloalkyl, C
2-5
alkenyl, C
2-5
alkynyl, heterocycloalkyl aryl and aryl-C
1-4
alkyl;
in sub-formula (Ib):
X
1
′ is selected from the group consisting of CN, NO
2
, Cl, F, Br, I, H, R, OR, CF
3
, OCF
3
and OSO
2
R, wherein R represents C
1-4
alkyl, or C
3-6
cycloalkyl;
X
2
″, X
3
″ and X
4
″ are, in

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