U.S. patent application number 10/181338 was filed with the patent office on 2003-01-23 for calcilytic compounds.
Invention is credited to Bhatnagar, Pradip Kumar, Bryan, William M., Burgess, Joelle L., Callahan, James Francis, Del Mar, Eric G., Largo, Maria Amparo.
Application Number | 20030018203 10/181338 |
Document ID | / |
Family ID | 22663860 |
Filed Date | 2003-01-23 |
United States Patent
Application |
20030018203 |
Kind Code |
A1 |
Largo, Maria Amparo ; et
al. |
January 23, 2003 |
Calcilytic compounds
Abstract
Novel calcilytic compounds and methods of using them are
provided.
Inventors: |
Largo, Maria Amparo;
(Audubon, PA) ; Callahan, James Francis;
(Philadelphia, PA) ; Bhatnagar, Pradip Kumar;
(Exton, PA) ; Del Mar, Eric G.; (Salt Lake City,
UT) ; Bryan, William M.; (Phoenixville, PA) ;
Burgess, Joelle L.; (Trappe, PA) |
Correspondence
Address: |
SMITHKLINE BEECHAM CORPORATION
CORPORATE INTELLECTUAL PROPERTY-US, UW2220
P. O. BOX 1539
KING OF PRUSSIA
PA
19406-0939
US
|
Family ID: |
22663860 |
Appl. No.: |
10/181338 |
Filed: |
July 17, 2002 |
PCT Filed: |
January 24, 2001 |
PCT NO: |
PCT/US01/02402 |
Current U.S.
Class: |
548/561 ;
558/418; 558/420; 560/37; 564/165; 564/348 |
Current CPC
Class: |
C07C 211/26 20130101;
C07D 303/22 20130101; C07C 33/34 20130101; C07C 255/57 20130101;
C07C 255/58 20130101; C07C 2602/08 20170501; C07C 229/36 20130101;
C07C 233/05 20130101; C07C 69/738 20130101; C07C 251/48 20130101;
C07C 211/30 20130101; C07C 69/616 20130101 |
Class at
Publication: |
548/561 ;
558/418; 558/420; 560/37; 564/165; 564/348 |
International
Class: |
C07C 255/56; C07C
255/53; C07D 207/30 |
Claims
What is claimed is:
1. A compound according to Formula (I) herein below: 7wherein: A is
an aryl or fused aryl, dihydro or tetrahydro fused aryl, heteroaryl
or fused heteroaryl, dihydro or tetrahydro fused heteroaryl,
unsubstituted or substituted with any substituent being selected
from the group consisting of OH, halogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, CF.sub.3, OCF.sub.3, CN,
and NO.sub.2; X.sub.1 and X.sub.5 are independently selected from
the group consisting of H, halogen, CN, and NO.sub.2, provided that
either X.sub.1 or X.sub.5 is H; X.sub.2, X.sub.3 and X.sub.4 are
selected from the group consisting of H, halogen, O--C.sub.1-4
alkyl, and J-K, wherein: J is a covalent bond, alkylene, O-alkylene
or alkenylene; and K is selected from the group consisting of,
CO.sub.2R.sub.5, CONR.sub.4R'.sub.4, OH, NR.sub.4R'.sub.4 and CN;
R.sub.4 and R'.sub.4 are independently H, alkyl, aryl or
heteroaryl; R.sub.5 is H, alkyl, or alkyl-(O-alkyl).sub.m-O-alkyl;
n is an integer from 0 to 4; and m is an integer from 1-3; or a
pharmaceutically acceptable salt thereof of.
2. A compound according to claim 1 with a structure according to
Formula (II) herein below: 8wherein: A is an aryl or fused aryl,
dihydro or tetrahydro fused aryl, heteroaryl or fused heteroaryl,
dihydro or tetrahydro fused heteroaryl, unsubstituted or
substituted with any substituent being selected from the group
consisting of halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3,
and OCF.sub.3; X.sub.1 and X.sub.5 are independently selected from
the group consisting of H, halogen, CN, and NO.sub.2, provided that
either X.sub.1 or X.sub.5 is H; X.sub.2, X.sub.3 and X.sub.4 are
selected from the group consisting of H, halogen, O--C.sub.1-4
alkyl, and J-K, wherein: J is a covalent bond, alkylene, O-alkylene
or alkenylene; and K is selected from the group consisting of,
CO.sub.2R.sub.5, CONR.sub.4R'.sub.4, and NR.sub.4R'.sub.4; R.sub.4
and R'.sub.4 are independently H, alkyl, aryl or heteroaryl;
R.sub.5 is H, alkyl, or alkyl-(O-alkyl).sub.m-O-alkyl; n is an
integer from 0 to 4; and m is an integer from 1-3.
3. A compound according to claim 2 having a structure according to
Formula (III) herein below: 9wherein: A is an aryl or fused aryl,
dihydro or tetrahydro fused aryl, heteroaryl or fused heteroaryl,
dihydro or tetrahydro fused heteroaryl, unsubstituted or
substituted with any substituent being selected from the group
consisting of halogen, C.sub.1-4 alkoxy, CF.sub.3, and OCF.sub.3;
X.sub.1 and X.sub.5 are independently selected from the group
consisting of H, halogen and CN, provided that either X.sub.1 or
X.sub.5 is H; X.sub.2, X.sub.3 and X.sub.4 are selected from the
group consisting of H, halogen, O--C.sub.1-4 alkyl, and J-K,
wherein: J is a covalent bond, alkylene, O-alkylene or alkenylene;
and K is CO.sub.2R.sub.5; R.sub.5 is H, or alkyl; and n is an
integer from 0 to 4.
4. A compound according to claim 1 selected from the group
consisting of:
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-prop-
oxy]-phenyl}-propionic ethyl ester;
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-
-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid;
3-{4-Cyano-3-[(S)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-prop-
oxy]-phenyl}-propionic ethyl ester;
3-{4-Cyano-3-[(S)-2-hydroxy-3-(2-indan-
-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid;
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-prop-
oxy]-phenyl}-propionic acid octyl ester;
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2--
indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid
2-methoxy-ethyl ester;
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-di-
methyl-ethylamino)-propoxy]-phenyl}-propionic acid butyl ester;
3-{4-Cyano-3-[(R)-2-hydoxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propo-
xyl]-phenyl}-propionic acid isopropyl ester;
3-{4-Cyano-3-[(R)-2-hydroxy-3-
-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic
acid pentyl ester;
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-et-
hylamino)-propoxy]-phenyl}-propionic acid 2-ethoxy ethyl ester;
3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethylamino)-propoxy]-
-phenyl}-propionic acid 3-methyl-butyl ester;
3-{4-cyano-3-[(R)-2-hydroxy--
3-(2-indan-2-yl-dimethyl-ethylamino)-propoxy]-phenyl}-propionic
acid 1-ethyl-propyl ester;
3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethy-
l-ethylamino)-propoxy]-phenyl}-propionic acid sec-butyl ester;
3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethylamino)-propoxy]-
-phenyl}-propionic acid 2-methoxy-1-methyl-ethyl ester;
2,2-Dimethyl-propionic acid
3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1-
,1-dimethyl-ethylamino)-propoxy]-phenyl}-propanoyloxymethyl ester;
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-prop-
oxy]-phenyl}-propionic acid (S)-2-amino-3-methyl-butyl ester;
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-prop-
oxy]-phenyl}-propionic acid 5-amino-pentyl ester;
3-{4-Cyano-3-[(R)-2-hydr-
oxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic
acid methyl ester;
3-(4-Cyano-3-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydr-
o-naphthalen-2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic
acid;
3-(4-Cyano-3-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)--
ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid ethyl ester;
3-(3-Cyano-4-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)--
ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid;
3-(3-Cyano-4-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)--
ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid ethyl ester;
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-5-yl-1,1-dimethyl-ethylamino)-prop-
oxy]-phenyl}-propionic acid;
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-5-yl-1-
,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionate ethyl ester;
3-{2-Chloro-4-cyano-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylam-
ino)-propoxy]-phenyl}-propionic ethyl ester;
3-{2-Chloro-4-cyano-5-[(R)-2--
hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propioni-
c acid;
3-{2-Fluoro-4-cyano-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl--
ethylamino)-propoxy]-phenyl}-propionic ethyl ester;
3-{2-Fluoro-4-cyano-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylam-
ino)-propoxy]-phenyl}-propionic acid;
3-{2-Cyano-3-[(R)-3-(1,1-dimethyl-2--
naphthalen-2-yl-ethylamino)-2-hydroxy-propoxy]-phenyl}-propionic
acid ethyl ester;
4-{2-Cyano-3-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylami-
no)-2-hydroxy-propoxy]-phenyl}-butyric acid ethyl ester;
3-{2-Cyano-3-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-hydroxy-
-propoxy]-phenyl}-propionic acid;
4-{2-Cyano-3-[(R)-3-(1,1-dimethyl-2-naph-
thalen-2-yl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid;
4-{4-Cyano-3-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-hydroxy-
-propoxy]-phenyl}-butyric acid ethyl ester;
4-{4-Cyano-3-[(R)-3-(1,1-dimet-
hyl-2-naphthalen-2-yl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric
acid;
4-{3-Cyano-4-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-hydroxy-
-propoxy]-phenyl}-butyric acid ethyl ester;
4-{3-Cyano-4-[(R)-3-(1,1-dimet-
hyl-2-naphthalen-2-yl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric
acid;
3-{2-Cyano-3-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydroxy-prop-
oxy]-phenyl}-propionic acid ethyl ester;
4-{2-Cyano-3-[(R)-3-(2-indan-2-yl-
-1,1-dimethyl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid
ethyl ester;
3-{2-Cyano-3-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydro-
xy-propoxy]-phenyl}-propionic acid;
4-{2-Cyano-3-[(R)-3-(2-indan-2-yl-1,1--
dimethyl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid;
4-{4-Cyano-3-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydroxy-prop-
oxy]-phenyl}-butyric acid ethyl ester;
4-{4-Cyano-3-[(R)-3-(2-indan-2-yl-1-
,1-dimethyl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid;
4-{3-Cyano-4-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydroxy-prop-
oxy]-phenyl}-butyric acid ethyl ester;
4-{3-Cyano-4-[(R)-3-(2-indan-2-yl-1-
,1-dimethyl-ethylamino)-2-hydroxy-propoxy]-phenyl}-butyric acid;
(S)-2-Amino-3-{4-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-hyd-
roxy-propoxy]-3-nitro-phenyl}-propionic acid ethyl ester;
(S)-2-Amino-3-{4-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-hyd-
roxy-propoxy]-3-nitro-phenyl}-propionic acid;
(R)-2-Amino-5-{4-cyano-3-[(R-
)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pent-
anoic acid ethyl ester;
(R)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-
-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoic acid;
5-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-prop-
oxy]-phenyl}-pentanoic acid ethyl ester;
5-{4-Cyano-3-[(R)-2-hydroxy-3-(2--
indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-pentanoic
acid;
(R)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethy-
lamino)-propoxy]-phenyl}-propionic acid ethyl ester;
(R)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethy-
lamino)-propoxy]-phenyl}-propionic acid;
(S)-2-Amino-5-{4-cyano-3-[(R)-2-h-
ydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic
acid ethyl ester; and
(S)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan--
2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid; and
pharmaceutically acceptable salts thereof.
5. A compound according to claim 4 selected from the group
consisting of:
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-prop-
oxy]-phenyl}-propionic ethyl ester;
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-
-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid;
3-{4-Cyano-3-[(R)-2-hydoxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propo-
xyl]-phenyl}-propionic acid isopropyl ester;
3-{4-Cyano-3-[(R)-2-hydroxy-3-
-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic
acid 2-ethoxy ethyl ester;
3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethy-
l-ethylamino)-propoxy]-phenyl}-propionic acid
2-methoxy-1-methyl-ethyl ester;
3-(4-Cyano-3-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen-
-2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid;
3-(4-Cyano-3-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)--
ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid ethyl ester;
3-(3-Cyano-4-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)--
ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid;
3-(3-Cyano-4-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)--
ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid ethyl ester;
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-5-yl-1,1-dimethyl-ethylamino)-prop-
oxy]-phenyl}-propionic acid; and
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-5--
yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionate ethyl
ester; and pharmaceutically acceptable salts and complexes
thereof.
6. A compound according to claim 5 selected from the group
consisting of:
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-prop-
oxy]-phenyl}-propionic ethyl ester; and
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-i-
ndan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propionic acid;
and pharmaceutically acceptable salts and complexes thereof.
7. A method of antagonizing a calcium receptor, which comprises
administering to a subject in need thereof, an effective amount of
a compound according to claim 1.
8. A method of treating a disease or disorder characterized by an
abnormal bone or mineral homeostasis, which comprises administering
to a subject in need of treatment thereof an effective amount of a
compound of claim 1.
9. A method according to claim 8 wherein the bone or mineral
disease or disorder is selected from the group consisting of
osteosarcoma, periodontal disease, fracture healing,
osteoarthritis, rheumatoid arthritis, Paget's disease, humoral
hypercalcemia, malignancy and osteoporosis.
10. A method according to claim 8 wherein the bone or mineral
disease or disorder is osteoporosis.
11. A method of increasing serum parathyroid levels which comprises
administering to a subject in need of treatment an effective amount
of a compound of claim 1.
12. A method according to claim 7 wherein the calcilytic compound
is co-administered with an anti-resorptive agent.
13. A method according to claim 12 wherein the anti-resorptive
agent is selected from the group consisting of estrogen, 1, 25
(OH).sub.2 vitamin D3, calcitonin, selective estrogen receptor
modulators, vitronectin receptor antagonists, V-H+-ATPase
inhibitors, src SH.sub.2 antagonists, bisphosphonates and cathepsin
K inhibitors.
14. A compound selected from the group consisting of:
2-Indan-2-yl-1,1-dimethyl-ethylamine; Indan-2-yl-acetic acid methyl
ester; 1-Indan-2-yl-2-methyl-propan-2-ol;
N-(2-Indan-2-yl-1,1-dimethyl-et- hyl)-acetamide; Ethyl
(R)-4-cyano-3-(oxiranylmethoxy)benzenepropionate; Ethyl
4-formyl-3-hydroxybenzenepropionate; Ethyl
3-hydroxy-4-[(hydroxyimi- no)methyl]benzenepropionate; Ethyl
3-acetoxy-4-cyanobenzenepropionate; and Ethyl
4-cyano-3-hydroxybenzenepropionate.
Description
FIELD OF INVENTION
[0001] The present invention relates to novel calcilytic compounds,
pharmaceutical compositions containing these compounds and their
use as calcium receptor antagonists.
[0002] In mammals, extracellular Ca.sup.2+ is under rigid
homeostatic control and regulates various processes such as blood
clotting, nerve and muscle excitability, and proper bone formation.
Extracellular Ca.sup.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.sup.2+ concentration.
[0003] PTH is the principal endocrine factor regulating Ca.sup.2+
homeostasis in the blood and extracellular fluids. PTH, by acting
on bone and kidney cells, increases the level of Ca.sup.2+ in the
blood. This increase in extracellular Ca.sup.2+ then acts as a
negative feedback signal, depressing PTH secretion. The reciprocal
relationship between extracellular Ca.sup.2+ and PTH secretion
forms an important mechanism maintaining bodily Ca.sup.2+
homeostasis.
[0004] Extracellular Ca.sup.2+ acts directly on parathyroid cells
to regulate PTH secretion. The existence of a parathyroid cell
surface protein which detects changes in extracellular Ca.sup.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.sup.2+ detects changes in the ion
concentration of extracellular Ca.sup.2+, and initiates a
functional cellular response, PTH secretion.
[0005] Extracellular Ca.sup.2+ influences various cell functions,
reviewed in Nemeth et al., Cell Calcium 11:319, 1990. For example,
extracellular Ca.sup.2+ plays a role in parafollicular (C-cells)
and parathyroid cells. See Nemeth, Cell Calcium 11:323, 1990. The
role of extracellular Ca.sup.2+ on bone osteoclasts has also been
studied. See Zaidi, Bioscience Reports 10:493, 1990.
[0006] Various compounds are known to mimic the effects of
extra-cellular Ca.sup.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.sup.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.sup.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.sup.2+ receptors. Target diseases or disorders for
calcilytic compounds include diseases involving abnormal bone and
mineral homeostasis.
[0007] 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.
[0008] 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
[0009] 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.
[0010] 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.
[0011] 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 herein
below.
DETAILED DESCRIPTION OF THE INVENTION
[0012] The compounds of the present invention are selected from
Formula (I) herein below: 1
[0013] wherein:
[0014] A is an aryl or fused aryl, dihydro or tetrahydro fused
aryl, heteroaryl or fused heteroaryl, dihydro or tetrahydro fused
heteroaryl, unsubstituted or substituted with any substituent being
selected from the group consisting of OH, halogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, CF.sub.3, OCF.sub.3, CN,
and NO.sub.2;
[0015] X.sub.1 and X.sub.5 are independently selected from the
group consisting of H, halogen, CN, and NO.sub.2, provided that
either X.sub.1 or X.sub.5 is H;
[0016] X.sub.2, X.sub.3 and X.sub.4 are selected from the group
consisting of H, halogen, O--C.sub.1-4 alkyl, and J-K, wherein:
[0017] J is a covalent bond, alkylene, O-alkylene or alkenylene;
and
[0018] K is selected from the group consisting of, CO.sub.2R.sub.5,
CONR.sub.4R'.sub.4, OH, NR.sub.4R'.sub.4 and CN;
[0019] R.sub.4 and R'.sub.4 are independently H, alkyl, aryl or
heteroaryl;
[0020] R.sub.5 is H, alkyl, alkyl-(O-alkyl).sub.m-O-alkyl; n is an
integer from 0 to 4; and m is an integer from 1-3.
[0021] Preferred compounds of the present invention have a
structure according to Formula (II) hereinbelow: 2
[0022] wherein:
[0023] A is an aryl or fused aryl, dihydro or tetrahydro fused
aryl, heteroaryl or fused heteroaryl, dihydro or tetrahydro fused
heteroaryl, unsubstituted or substituted with any substituent being
selected from the group consisting of halogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CF.sub.3, and OCF.sub.3;
[0024] X.sub.1 and X.sub.5 are independently selected from the
group consisting of H, halogen, CN, and NO.sub.2, provided that
either X.sub.1 or X.sub.5 is H;
[0025] X.sub.2, X.sub.3 and X.sub.4 are selected from the group
consisting of H, halogen, O--C.sub.1-4 alkyl, and J-K, wherein:
[0026] J is a covalent bond, alkylene, O-alkylene or
alkenylene;
[0027] K is selected from the group consisting of, CO.sub.2R.sub.5,
CONR.sub.4R'.sub.4, and NR.sub.4R'.sub.4;
[0028] R.sub.4 and R'.sub.4 are independently H, alkyl, aryl or
heteroaryl;
[0029] R.sub.5 is H, alkyl, or alkyl-(O-alkyl).sub.m-O-alkyl;
[0030] n is an integer from 0 to 4; and
[0031] m is an integer from 1-3.
[0032] More preferred compounds of the present invention have a
structure according to Formula (III) hereinbelow: 3
[0033] wherein:
[0034] A is an aryl or fused aryl, dihydro or tetrahydro fused
aryl, heteroaryl or fused heteroaryl, dihydro or tetrahydro fused
heteroaryl, unsubstituted or substituted with any substituent being
selected from the group consisting of halogen, C.sub.1-4 alkoxy,
CF.sub.3, and OCF.sub.3;
[0035] X.sub.1 and X.sub.5 are independently selected from the
group consisting of H, halogen and CN, provided that either X.sub.1
or X.sub.5 is H;
[0036] X.sub.2, X.sub.3 and X.sub.4 are selected from the group
consisting of H, halogen, O--C.sub.1-4 alkyl, and J-K, wherein:
[0037] J is a covalent bond, alkylene, O-alkylene or alkenylene;
and
[0038] K is CO.sub.2R.sub.5;
[0039] R.sub.5 is H, or alkyl; and
[0040] n is an integer from 0 to 4.
[0041] As used herein, "alkyl" refers to an optionally substituted
hydrocarbon group joined by single carbon-carbon bonds and having
1-20 carbon atoms joined together. The alkyl hydrocarbon group may
be linear, branched or cyclic, saturated or unsaturated.
Preferably, substituents on optionally substituted alkyl are
selected from the group consisting of aryl, heteroaryl,
CO.sub.2R.sub.1, CO.sub.2NR.sub.1R.sub.1', OH, OR.sub.1, COR.sub.1,
NR.sub.1R.sub.1', halogen, CF.sub.3, OCF.sub.3 and NO.sub.2,
wherein R.sub.1 represents H, C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, heterocycloalkyl,
aryl or heteroaryl, C.sub.1-4 alkyl; additional substituents are
selected from F, Cl, Br, I, N, S and O. Preferably, no more than
three substituents are present. More preferably, the alkyl has 1-12
carbon atoms and is unsubstituted. Preferably, the alkyl group is
linear.
[0042] As used herein "cycloalkyl" refers to optionally substituted
3-7 membered carbocyclic rings wherein any substituents are
selected from the group consisting of, F, Cl, Br, I,
N(R.sub.1).sub.2, SR.sub.1 and OR.sub.1, unless otherwise
indicated.
[0043] As used herein "alkylene" is a linker of up to 5 carbon
atoms, unsubstituted or substituted by a substituent selected from
the group consisting of C.sub.1-4 alkyl, NR.sub.4R'.sub.4, OH, O
(forming a ketone), aryl, heteroaryl.
[0044] As used herein "alkenylene" is a linker of up to 5 carbon
atoms containing one unsaturation, unsubstituted or substituted by
a substituent selected from the group consisting of C.sub.1-4
alkyl, NR.sub.4R'.sub.4, OH, O (forming a ketone), aryl,
heteroaryl.
[0045] As used herein, "aryl" refers to an optionally substituted
aromatic group with at least one ring having a conjugated
pi-electron system, containing up to two conjugated or fused ring
systems. Aryl includes carbocyclic aryl, and biaryl groups, all of
which may be optionally substituted. Preferred aryl include phenyl
and naphthyl. More preferred aryl include phenyl. Preferred
substituents are selected from the group consisting of halogen,
C.sub.1-4 alkyl, OCF.sub.3, CF.sub.3, OMe, CN, OSO.sub.2R.sub.2 and
NO.sub.2, wherein R.sub.2 represents C.sub.1-4 alkyl or C.sub.3-6
cycloalkyl.
[0046] As used herein, "heteroaryl" refers to an optionally
substituted aromatic group with at least one ring having a
conjugated pi-electron system, containing up to two conjugated or
fused ring systems and 1-3 heteroatoms selected from O, S and N.
Heteroaryl includes carbocyclic heteroarylaryl, aryl-heteroaryl and
biheteroarylaryl groups, all of which may be optionally
substituted. Preferred aryl include phenyl and naphthyl. More
preferred aryl include phenyl. Preferred substituents are selected
from the group consisting of halogen, C.sub.1-4 alkyl, OCF.sub.3,
CF.sub.3, OMe, CN, OSO.sub.2R.sub.2 and NO.sub.2, wherein R.sub.2
represents C.sub.1-4 alkyl or C.sub.3-6 cycloalkyl.
[0047] As used herein, "alkenyl" refers to an optionally
substituted hydrocarbon group containing at least one carbon-carbon
double bond and containing up to 5 carbon atoms joined together.
The alkenyl hydrocarbon chain may be straight, branched or cyclic.
Any substituents are selected from the group consisting of halogen,
C.sub.1-4 alkyl, OCF.sub.3, CF.sub.3, OMe, CN, OSO.sub.2R.sub.3 and
NO.sub.2, wherein R.sub.3 represents C.sub.1-4 alkyl or C.sub.3-6
cycloalkyl.
[0048] As used herein, "alkynyl" refers to an optionally
substituted hydrocarbon group containing at least one carbon-carbon
triple bond between the carbon atoms and containing up to 5 carbon
atoms joined together. The alkynyl hydrocarbon group may be
straight-chained, branched or cyclic. Any substituents are selected
from the group consisting of halogen, C.sub.1-4 alkyl, OCF.sub.3,
CF.sub.3, OMe, CN, OSO.sub.2R.sub.3 and NO.sub.2, wherein R.sub.3
represents C.sub.1-4 alkyl or C.sub.3-6 cycloalkyl.
[0049] The compounds of the present invention may contain one or
more asymmetric carbon atoms and may exist in racemic and optically
active forms. All of these compounds and diastereomers are
contemplated to be within the scope of the present invention.
[0050] Preferred compounds of the present inventions include:
[0051]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic ethyl ester;
[0052]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic acid;
[0053]
3-{4-Cyano-3-[(S)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic ethyl ester;
[0054]
3-{4-Cyano-3-[(S)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic acid;
[0055]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic acid octyl ester;
[0056]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic acid 2-methoxy-ethyl ester;
[0057]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic acid butyl ester;
[0058]
3-{4-Cyano-3-[(R)-2-hydoxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-
-propoxyl]-phenyl}-propionic acid isopropyl ester;
[0059]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic acid pentyl ester;
[0060]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic acid 2-ethoxy ethyl ester;
[0061]
3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethylamino)-pr-
opoxy]-phenyl}-propionic acid 3-methyl-butyl ester;
[0062]
3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethylamino)-pr-
opoxy]-phenyl}-propionic acid 1-ethyl-propyl ester;
[0063]
3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethylamino)-pr-
opoxy]-phenyl}-propionic acid sec-butyl ester;
[0064]
3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethylamino)-pr-
opoxy]-phenyl}-propionic acid 2-methoxy-1-methyl-ethyl ester;
[0065] 2,2-Dimethyl-propionic acid
3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan--
2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propanoyloxymethyl
ester;
[0066]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic acid (S)-2-amino-3-methyl-butyl
ester;
[0067]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic acid 5-amino-pentyl ester;
[0068]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic acid methyl ester;
[0069]
3-(4-Cyano-3-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen--
2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid;
[0070]
3-(4-Cyano-3-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen--
2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid ethyl
ester;
[0071]
3-(3-Cyano-4-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen--
2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid;
[0072]
3-(3-Cyano-4-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen--
2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid ethyl
ester;
[0073]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-5-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic acid;
[0074]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-5-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionate ethyl ester;
[0075]
3-{2-Chloro-4-cyano-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-e-
thylamino)-propoxy]-phenyl}-propionic ethyl ester;
[0076]
3-{2-Chloro-4-cyano-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-e-
thylamino)-propoxy]-phenyl}-propionic acid;
[0077]
3-{2-Fluoro-4-cyano-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-e-
thylamino)-propoxy]-phenyl}-propionic ethyl ester;
[0078]
3-{2-Fluoro-4-cyano-5-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-e-
thylamino)-propoxy]-phenyl}-propionic acid;
[0079]
3-{2-Cyano-3-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-h-
ydroxy-propoxy]-phenyl}-propionic acid ethyl ester;
[0080]
4-{2-Cyano-3-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-h-
ydroxy-propoxy]-phenyl}-butyric acid ethyl ester;
[0081]
3-{2-Cyano-3-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-h-
ydroxy-propoxy]-phenyl}-propionic acid;
[0082]
4-{2-Cyano-3-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-h-
ydroxy-propoxy]-phenyl}-butyric acid;
[0083]
4-{4-Cyano-3-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-h-
ydroxy-propoxy]-phenyl}-butyric acid ethyl ester;
[0084]
4-{4-Cyano-3-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-h-
ydroxy-propoxy]-phenyl}-butyric acid;
[0085]
4-{3-Cyano-4-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-h-
ydroxy-propoxy]-phenyl}-butyric acid ethyl ester;
[0086]
4-{3-Cyano-4-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-2-h-
ydroxy-propoxy]-phenyl}-butyric acid;
[0087]
3-{2-Cyano-3-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydrox-
y-propoxy]-phenyl}-propionic acid ethyl ester;
[0088]
4-{2-Cyano-3-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydrox-
y-propoxy]-phenyl}-butyric acid ethyl ester;
[0089]
3-{2-Cyano-3-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydrox-
y-propoxy]-phenyl}-propionic acid;
[0090]
4-{2-Cyano-3-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydrox-
y-propoxy]-phenyl}-butyric acid;
[0091]
4-{4-Cyano-3-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydrox-
y-propoxy]-phenyl}-butyric acid ethyl ester;
[0092]
4-{4-Cyano-3-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydrox-
y-propoxy]-phenyl}-butyric acid;
[0093]
4-{3-Cyano-4-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydrox-
y-propoxy]-phenyl}-butyric acid ethyl ester;
[0094]
4-{3-Cyano-4-[(R)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-2-hydrox-
y-propoxy]-phenyl}-butyric acid;
[0095]
(S)-2-Amino-3-{4-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-
-2-hydroxy-propoxy]-3-nitro-phenyl}-propionic acid ethyl ester;
[0096]
(S)-2-Amino-3-{4-[(R)-3-(1,1-dimethyl-2-naphthalen-2-yl-ethylamino)-
-2-hydroxy-propoxy]-3-nitro-phenyl}-propionic acid;
[0097]
(R)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethy-
l-ethylamino)-propoxy]-phenyl}-pentanoic acid ethyl ester;
[0098]
(R)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethy-
l-ethylamino)-propoxy]-phenyl}-pentanoic acid;
[0099]
5-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-pentanoic acid ethyl ester;
[0100]
5-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-pentanoic acid;
[0101]
(R)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethy-
l-ethylamino)-propoxy]-phenyl}-propionic acid ethyl ester;
[0102]
(R)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethy-
l-ethylamino)-propoxy]-phenyl}-propionic acid;
[0103]
(S)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethy-
l-ethylamino)-propoxy]-phenyl}-propionic acid ethyl ester; and
[0104]
(S)-2-Amino-5-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethy-
l-ethylamino)-propoxy]-phenyl}-propionic acid;
[0105] and pharmaceutically acceptable salts thereof.
[0106] More preferred compounds of the present invention
include:
[0107]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic ethyl ester;
[0108]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic acid;
[0109]
3-{4-Cyano-3-[(R)-2-hydoxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-
-propoxyl]-phenyl}-propionic acid isopropyl ester;
[0110]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic acid 2-ethoxy ethyl ester;
[0111]
3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethylamino)-pr-
opoxy]-phenyl}-propionic acid 2-methoxy-1-methyl-ethyl ester;
[0112]
3-(4-Cyano-3-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen--
2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid;
[0113]
3-(4-Cyano-3-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen--
2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid ethyl
ester;
[0114]
3-(3-Cyano-4-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen--
2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid;
[0115]
3-(3-Cyano-4-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthalen--
2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid ethyl
ester;
[0116]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-5-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic acid; and
[0117]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-5-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionate ethyl ester
[0118] and pharmaceutically acceptable salts and complexes
thereof.
[0119] Most preferred compounds of the present invention
include:
[0120]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic ethyl ester; and
[0121]
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylamino-
)-propoxy]-phenyl}-propionic acid;
[0122] and pharmaceutically acceptable salts and complexes
thereof.
[0123] Pharmaceutically acceptable salts are non-toxic salts in the
amounts and concentrations at which they are administered.
[0124] Pharmaceutically acceptable salts include acid addition
salts such as those containing sulfate, hydrochloride, fumarate,
maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate, cyclohexylsulfamate and quinate. A preferred
salt is a hydrochloride. Pharmaceutically acceptable salts can be
obtained from acids such as hydrochloric acid, maleic acid,
sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric
acid, lactic acid, tartaric acid, malonic acid, methanesulfonic
acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic
acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
[0125] Pharmaceutically acceptable salts also include basic
addition salts such as those containing benzathine, chloroprocaine,
choline, diethanolamine, ethylenediamine, meglumine, procaine,
aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium,
alkylamine, and zinc, when acidic functional groups, such as
carboxylic acid or phenol are present.
[0126] The present invention provides compounds of Formula (I)
above, which can be prepared using standard techniques. An overall
strategy for preparing preferred compounds described herein can be
carried out as described in this section. The examples that follow
illustrate the synthesis of specific compounds. Using the protocols
described herein as a model, one of ordinary skill in the art can
readily produce other compounds of the present invention.
[0127] All reagents and solvents were obtained from commercial
vendors. Starting materials (e.g., amines and epoxides) were
synthesized using standard techniques and procedures.
[0128] Compounds of Formula (I) are prepared by the general methods
described in Schemes 1-3. In general, a solution of a glycidyl
ether (e.g., 7 of Scheme 1) and a primary amine (e.g.,
2-indan-2-yl-1,1-dimethy- l-ethylamine of Scheme 1) in a solvent
such as absolute ethanol, acetonitrile, toluene, THF or any other
similar solvent optionally in the presence of a suitable catalyst
such as LiClO.sub.4 (0.1-2 equiv.) is stirred overnight or longer
at reflux. The product (e.g., 8-Scheme 1) is purified by
chromatography and/or recrystallization. An acid salt e.g.,
hydrochloride salt is prepared by treatment of the corresponding
free base with the acid (e.g., HCl either in gas phase or 4M
dioxane solution), or by any other standard method. Hydrolysis of
the ester under either basic or acidic conditions yields the
corresponding acid (e.g., 9-Scheme 1).
[0129] A general synthesis of the epoxide with compound 7 as an
example is outlined in Scheme 2.
[0130] The syntheses of some of the required amines are outlined in
Scheme 3. 4 5 6
[0131] In order to use a compound of Formula (I) or a
pharmaceutically acceptable salt thereof for the treatment of
humans and other mammals, it is normally formulated in accordance
with standard pharmaceutical practice as a pharmaceutical
composition.
[0132] The calcilytic compounds can be administered by different
routes including intravenous, intraperitoneal, subcutaneous,
intramuscular, oral, topical (transdermal), or transmucosal
administration. For systemic administration, oral administration is
preferred. For oral administration, for example, the compounds can
be formulated into conventional oral dosage forms such as capsules,
tablets, and liquid preparations such as syrups, elixirs, and
concentrated drops.
[0133] Alternatively, injection (parenteral administration) may be
used, e.g., intramuscular, intravenous, intraperitoneal, and
subcutaneous. For injection, the compounds of the invention are
formulated in liquid solutions, preferably, in physiologically
compatible buffers or solutions, such as saline solution, Hank's
solution, or Ringer's solution. In addition, the compounds may be
formulated in solid form and redissolved or suspended immediately
prior to use. Lyophilized forms can also be produced.
[0134] Systemic administration can also be by transmucosal or
transdermal means. For transmucosal or transdermal administration,
penetrants appropriate to the barrier to be permeated are used in
the formulation. Such penetrants are generally known in the art,
and include, for example, for transmucosal administration, bile
salts and fusidic acid derivatives. In addition, detergents may be
used to facilitate permeation. Transmucosal administration, for
example, may be through nasal sprays, rectal suppositories, or
vaginal suppositories.
[0135] For topical administration, the compounds of the invention
can be formulated into ointments, salves, gels, or creams, as is
generally known in the art.
[0136] The amounts of various calcilytic compounds to be
administered can be determined by standard procedures taking into
account factors such as the compound IC.sub.50, EC.sub.50, the
biological half-life of the compound, the age, size and weight of
the patient, and the disease or disorder associated with the
patient. The importance of these and other factors to be considered
are known to those of ordinary skill in the art.
[0137] Amounts administered also depend on the routes of
administration and the degree of oral bioavailability. For example,
for compounds with low oral bioavailability, relatively higher
doses will have to be administered.
[0138] Preferably, the composition is in unit dosage form. For oral
application, for example, a tablet, or capsule may be administered,
for nasal application, a metered aerosol dose may be administered,
for transdermal application, a topical formulation or patch may be
administered and for transmucosal delivery, a buccal patch may be
administered. In each case, dosing is such that the patient may
administer a single dose.
[0139] Each dosage unit for oral administration contains suitably
from 0.01 to 500 mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a
compound of Formula (I) or a pharmaceutically acceptable salt
thereof, calculated as the free base. The daily dosage for
parenteral, nasal, oral inhalation, transmucosal or transdermal
routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound
of Formula(I). A topical formulation contains suitably 0.01 to 5.0%
of a compound of Formula (I). The active ingredient may be
administered, for example, from 1 to 6 times per day, preferably
once, sufficient to exhibit the desired activity, as is readily
apparent to one skilled in the art.
[0140] As used herein, "treatment" of a disease includes, but is
not limited to prevention, retardation and prophylaxis of the
disease.
[0141] Diseases and disorders which might be treated or prevented,
based upon the affected cells, include bone and mineral-related
diseases or disorders; hypoparathyroidism; those of the central
nervous system such as seizures, stroke, head trauma, spinal cord
injury, hypoxia-induced nerve cell damage, such as occurs in
cardiac arrest or neonatal distress, epilepsy, neurodegenerative
diseases such as Alzheimer's disease, Huntington's disease and
Parkinson's disease, dementia, muscle tension, depression, anxiety,
panic disorder, obsessive-compulsive disorder, post-traumatic
stress disorder, schizophrenia, neuroleptic malignant syndrome, and
Tourette's syndrome; diseases involving excess water reabsorption
by the kidney, such as syndrome of inappropriate ADH secretion
(SIADH), cirrhosis, congestive heart failure, and nephrosis;
hypertension; preventing and/or decreasing renal toxicity from
cationic antibiotics (e.g., aminoglycoside antibiotics); gut
motility disorders such as diarrhea and spastic colon; GI ulcer
diseases; GI diseases with excessive calcium absorption such as
sarcoidosis; autoimmune diseases and organ transplant rejection;
squamous cell carcinoma; and pancreatitis.
[0142] In a preferred embodiment of the present invention, the
present compounds are used to increase serum parathyroid hormone
("PTH") levels. Increasing serum PTH levels can be helpful in
treating diseases such as hypoparathyroidism, osteosarcoma,
periodontal disease, fracture, osteoarthritis, rheumatoid
arthritis, Paget's disease, humoral hypercalcemia malignancy and
osteoporosis.
[0143] Another aspect of the present invention describes a method
of treating a patient comprising administering to the patient an
amount of a present compound sufficient to increase the serum PTH
level. Preferably, the method is carried out by administering an
amount of the compound effective to cause an increase in duration
and/or quantity of serum PTH level sufficient to have a therapeutic
effect.
[0144] In various embodiments, the compound administered to a
patient causes an increase in serum PTH having a duration of up to
one hour, about one to about twenty-four hours, about one to about
twelve hours, about one to about six hours, about one to about five
hours, about one to about four hours, about two to about five
hours, about two to about four hours, or about three to about six
hours.
[0145] In an alternative embodiment of the present invention, the
compound administered to a patient causes an increase in serum PTH
having a duration of more than about twenty-four hours provided
that it is co-administered with an anti resorptive agent.
[0146] In additional different embodiments, the compound
administered to a patient causes an increase in serum PTH of up to
two fold, two to five fold, five to ten fold, and at least 10 fold,
greater than peak serum PTH in the patient. The peak serum level is
measured with respect to a patient not undergoing treatment.
[0147] In a preferred embodiment of the present invention, the
present compound is co-administered with an anti-resorptive agent.
Suitable anti-resorptive agents for co-administration include, but
are not limited to estrogen, 1, 25 (OH).sub.2 vitamin D3,
calcitonin, selective estrogen receptor modulators, vitronectin
receptor antagonists, V-H+-ATPase inhibitors, src SH.sub.2
antagonists, bisphosphonates and cathepsin K inhibitors.
[0148] Composition of Formula (I) and their pharmaceutically
acceptable salts, which are active when given orally, can be
formulated as syrups, tablets, capsules and lozenges. A syrup
formulation will generally consist of a suspension or solution of
the compound or salt in a liquid carrier for example, ethanol,
peanut oil, olive oil, glycerine or water with a flavoring or
coloring agent. Where the composition is in the form of a tablet,
any pharmaceutical carrier routinely used for preparing solid
formulations may be used. Examples of such carriers include
magnesium stearate, terra alba, talc, gelatin, acacia, stearic
acid, starch, lactose and sucrose. Where the composition is in the
form of a capsule, any routine encapsulation is suitable, for
example using the aforementioned carriers in a hard gelatin capsule
shell. Where the composition is in the form of a soft gelatin shell
capsule any pharmaceutical carrier routinely used for preparing
dispersions or suspensions may be considered, for example aqueous
gums, celluloses, silicates or oils, and are incorporated in a soft
gelatin capsule shell.
[0149] Typical parenteral compositions consist of a solution or
suspension of a compound or salt in a sterile aqueous or
non-aqueous carrier optionally containing a parenterally acceptable
oil, for example polyethylene glycol, polyvinylpyrrolidone,
lecithin, arachis oil or sesame oil.
[0150] Typical compositions for inhalation are in the form of a
solution, suspension or emulsion that may be administered as a dry
powder or in the form of an aerosol using a conventional propellant
such as dichlorodifluoromethane or trichlorofluoromethane.
[0151] A typical suppository formulation comprises a compound of
Formula (I) or a pharmaceutically acceptable salt thereof which is
active when administered in this way, with a binding and/or
lubricating agent, for example polymeric glycols, gelatins,
cocoa-butter or other low melting vegetable waxes or fats or their
synthetic analogs.
[0152] Typical dermal and transdermal formulations comprise a
conventional aqueous or non-aqueous vehicle, for example a cream,
ointment, lotion or paste or are in the form of a medicated
plaster, patch or membrane.
[0153] Preferably the composition is in unit dosage form, for
example a tablet, capsule or metered aerosol dose, so that the
patient may administer a single dose.
[0154] No unacceptable toxological effects are expected when
compounds of the present invention are administered in accordance
with the present invention.
[0155] The biological activity of the compounds of Formula (I) are
demonstrated by the following tests:
[0156] (I) Calcium Receptor Inhibitor Assay
[0157] Calcilytic activity was measured by determining the
IC.sub.50 of the test compound for blocking increases of
intracellular Ca.sup.2+ elicited by extracellular Ca.sup.2+ in HEK
293 4.0-7 cells stably expressing the human calcium receptor. HEK
293 4.0-7 cells were constructed as described by Rogers et al., J.
Bone Miner. Res. 10 Suppl. 1:S483, 1995 (hereby incorporated by
reference herein). Intracellular Ca.sup.2+ increases were elicited
by increasing extracellular Ca.sup.2+ from 1 to 1.75 mM.
Intracellular Ca.sup.2+ was measured using fluo-3, a fluorescent
calcium indicator.
[0158] The procedure was as follows:
[0159] 1. Cells were maintained in T-150 flasks in selection media
(DMEM supplemented with 10% fetal bovine serum and 200 ug/mL
hygromycin B), under 5% CO.sub.2: 95% air at 37.degree. C. and were
grown up to 90% confluency.
[0160] 2. The medium was decanted and the cell monolayer was washed
twice with phosphate-buffered saline (PBS) kept at 37.degree. C.
After the second wash, 6 mL of 0.0.sub.2% EDTA in PBS was added and
incubated for 4 minutes at 37.degree. C. Following the incubation,
cells were dispersed by gentle agitation.
[0161] 3. Cells from 2 or 3 flasks were pooled and pelleted
(100.times.g). The cellular pellet was resuspended in 10-15 mL of
SPF-PCB+ and pelleted again by centrifugation. This washing was
done twice.
[0162] Sulfate- and phosphate-free parathyroid cell buffer
(SPF-PCB) contains 20 mM Na-Hepes, pH 7.4, 126 mM NaCl, 5 mM KCl,
and 1 mM MgCl.sub.2. SPF-PCB was made up and stored at 4.degree. C.
On the day of use, SPF-PCB was supplemented with 1 mg/mL of
D-glucose and 1 mM CaCl.sub.2 and then split into two fractions. To
one fraction, bovine serum albumin (BSA; fraction V, ICN) was added
at 5 mg/mL (SPF-PCB+). This buffer was used for washing, loading
and maintaining the cells. The BSA-free fraction was used for
diluting the cells in the cuvette for measurements of
fluorescence.
[0163] 4. The pellet was resuspended in 10 mL of SPF-PCB+
containing 2.2 uM fluo-3 (Molecular Probes) and incubated at room
temperature for 35 minutes.
[0164] 5. Following the incubation period, the cells were pelleted
by centrifugation. The resulting pellet was washed with SPF-PCB+.
After this washing, cells were resuspended in SPF-PCB+ at a density
of 1-2.times.106 cells/mL.
[0165] 6. For recording fluorescent signals, 300 uL of cell
suspension were diluted in 1.2 mL of SPF buffer containing 1 mM
CaCl.sub.2 and 1 mg/mL of D-glucose. Measurements of fluorescence
were performed at 37.degree. C. with constant stirring using a
spectrofluorimeter. Excitation and emission wavelengths were
measured at 485 and 535 nm, respectively. To calibrate fluorescence
signals, digitonin (5 mg/mL in ethanol) was added to obtain Fmax,
and the apparent Fmin was determined by adding Tris-EGTA (2.5 M
Tris-Base, 0.3 M EGTA). The concentration of intracellular calcium
was calculated using the following equation:
Intracellular calcium=(F-F.sub.min/F.sub.max).times.K.sub.d;
[0166] where K.sub.d=400 nM.
[0167] 7. To determine the potential calcilytic activity of test
compounds, cells were incubated with test compound (or vehicle as a
control) for 90 seconds before increasing the concentration of
extracellular Ca.sup.2+ from 1 to 2 mM. Calcilytic compounds were
detected by their ability to block, in a concentration-dependent
manner, increases in the concentration of intracellular Ca.sup.2+
elicited by extracellular Ca.sup.2+.
[0168] In general, those compounds having lower IC.sub.50 values in
the Calcium Receptor Inhibitor Assay are more preferred compounds.
Compounds having an IC.sub.50 greater than 50 uM were considered to
be inactive. Preferred compounds are those having an IC.sub.50 Of
10 uM or lower, more preferred compounds have an IC.sub.50 of 1 uM,
and most preferred compounds have an IC.sub.50 of 0.1 uM or
lower.
[0169] (II) Calcium Receptor Binding Assay
[0170] HEK 293 4.0-7 cells stably transfected with the Human
Parathyroid Calcium Receptor ("HuPCaR") were scaled up in T180
tissue culture flasks. Plasma membrane is obtained by polytron
homogenization or glass douncing in buffer (50 mM Tris-HCl pH 7.4,
1 mM EDTA, 3 mM MgCl.sub.2) in the presence of a protease inhibitor
cocktail containing 1 uM Leupeptin, 0.04 uM Pepstatin, and 1 mM
PMSF. Aliquoted membrane was snap frozen and stored at -80.degree.
C. .sup.3H labeled compound was radiolabeled to a radiospecific
activity of 44 Ci/mmole and was aliquoted and stored in liquid
nitrogen for radiochemical stability.
[0171] A typical reaction mixture contains 2 nM .sup.3H compound
((R,R)-N-4'-Methoxy-t-3-3'-methyl-1'-ethylphenyl-1-(1-naphthyl)ethylamine-
), or .sup.3H compound
(R)-N-[2-Hydroxy-3-(3-chloro-2-cyanophenoxy)propyl]-
-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine 4-10 ug membrane in
homogenization buffer containing 0.1% gelatin and 10% EtOH in a
reaction volume of 0.5 mL. Incubation is performed in 12.times.75
polyethylene tubes in an ice water bath. To each tube 25 uL of test
sample in 100% EtOH is added, followed by 400 uL of cold incubation
buffer, and 25 uL of 40 nM .sup.3H-compound in 100% EtOH for a
final concentration of 2 nM. The binding reaction is initiated by
the addition of 50 uL of 80-200 ug/mL HEK 293 4.0-7 membrane
diluted in incubation buffer, and allowed to incubate at 4.degree.
C. for 30 min. Wash buffer is 50 mM Tris-HCl containing 0.1% PEI.
Nonspecific binding is determined by the addition of 100-fold
excess of unlabeled homologous ligand, and is generally 20% of
total binding. The binding reaction is terminated by rapid
filtration onto 1% PEI pretreated GF/C filters using a Brandel
Harvestor. Filters are placed in scintillation fluid and
radioactivity assessed by liquid scintillation counting.
EXAMPLES
[0172] Nuclear magnetic resonance spectra were recorded at either
300 or 400 MHz using, respectively, a Bruker ARX 300 or Bruker
AVANCE 400 spectrometer. CDCl.sub.3 is deuteriochloroform,
DMSO-d.sub.6 is hexadeuteriodimethylsulfoxide, and CD.sub.3OD is
tetradeuteriomethanol. Chemical shifts are reported in parts per
million (.alpha.) downfield from the internal standard
tetramethylsilane. Abbreviations for NMR data are as follows:
s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet
of doublets, dt=doublet of triplets, app=apparent, br=broad. J
indicates the NMR coupling constant measured in Hertz. Fourier
transform infrared (FTIR) spectra were recorded on a Nicolet 510
infrared spectrometer. FTIR spectra were recorded in transmission
mode, and band positions are reported in inverse wavenumbers
(cm.sup.-1). Mass spectra were taken on either a SCIEX5 or
Micromass instruments, using electrospray (ES) ionization
techniques. Elemental analyses were obtained using a Perkin-Elmer
240C elemental analyzer. Melting points were taken on a
Thomas-Hoover melting point apparatus and are uncorrected. All
temperatures are reported in degrees Celsius.
[0173] Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin
layer plates were used for thin layer chromatography. Both flash
and gravity chromatography were carried out on E. Merck Kieselgel
60 (230-400 mesh) silica gel. Analytical and preparative HPLC were
carried out on Rainin or Beckman chromatographs. ODS refers to an
octadecylsilyl derivatized silica gel chromatographic support.
5.mu. Apex-ODS indicates an octadecylsilyl derivatized silica gel
chromatographic support having a nominal particle size of 5.mu.,
made by Jones Chromatography, Littleton, Colo. YMC ODS-AQ.RTM. is
an ODS chromatographic support and is a registered trademark of YMC
Co. Ltd., Kyoto, Japan. PRP-1.RTM. is a polymeric
(styrene-divinylbenzene) chromatographic support, and is a
registered trademark of Hamilton Co., Reno, Nev.) Celite.RTM. is a
filter aid composed of acid-washed diatomaceous silica, and is a
registered trademark of Manville Corp., Denver, Colo. Following the
general procedure described above the following compounds have been
synthesized:
Example 1
Preparation of 2-Indan-2-yl-1,1-dimethyl-ethylamine
[0174] a) Indan-2-yl-acetic acid methyl ester
[0175] A solution of indan-2-yl-acetic acid (Lancaster, 20 g, 0.11
mol) in methanol (200 mL) was stirred and cooled to 0-10.degree. C.
in an ice bath and treated drop-wise with thionyl chloride (14.8 g,
0.125 mol). The mixture was stirred at RT for 16 h, concentrated in
vacuo, and the oily residue was dissolved in ethyl acetate, washed
with 2.5 N sodium hydroxide, water, and brine, dried (MgSO.sub.4),
and concentrated in vacuo to give the title compound (21 g, 97%)
which solidified.
[0176] b) 1-Indan-2-yl-2-methyl-propan-2-ol
[0177] A solution of the compound from Example 1(a) (6.3 g, 33
mmol) in ether (150 mL) was added drop-wise to 1.4 M methyllithium
in ether (100 mL, 4.25 eq) stirred in an ice bath. The mixture was
allowed to warm to RT, stirred for 2 h, and very carefully quenched
by drop-wise addition of saturated aqueous ammonium chloride (150
mL). The aqueous phase was separated and extracted with ether, and
the combined ether phase was washed with brine, dried (MgSO.sub.4),
and concentrated in vacuo to afford the title compound as an oil
which crystallized on standing (.about.89%).
[0178] c) N-(2-Indan-2-yl-1,1-dimethyl-ethyl)-acetamide
[0179] To a mixture of concentrated sulfuric acid (1.7 mL) in
acetonitrile (6 mL) stirred in an ice bath for 45 min. a drop-wise
solution of the compound from Example 1(b) (3.3 g, 17.3 mmol) in
glacial acetic acid (5 mL) was added. The mixture was allowed to
warm to RT, stirred for 16 h, poured into ice water, and extracted
with ethyl acetate. The combined organic extract was washed with
2.5 N sodium hydroxide, water, and brine, dried (MgSO.sub.4), and
concentrated in vacuo to give an oily residue that was triturated
with hexane and a few drops of ethyl acetate, seeded, and cooled to
afford a solid which was isolated by filtration to afford the title
compound as tan solid (1.9 g, 47%). MS(ES) m/e 231.9 [M+H].sup.+.
The filtrate was concentrated in vacuo to afford additional title
compound as an oil (1.5 g, 37%).
[0180] d) 2-Indan-2-yl-1,1-dimethyl-ethylamine
[0181] A mixture of the compound from Example 1(c) (6.5 g, 28 mmol)
in ethylene glycol (170 mL) was treated with crushed potassium
hydroxide pellets (13 g), stirred, and heated to 190.degree. C. for
24 h. The mixture was poured into water and extracted with ethyl
acetate. The combined organic phase was washed with brine and
extracted with 1 N hydrochloric acid. The combined acidic extract
was washed with ethyl acetate, basified with 2.5 N sodium
hydroxide, and extracted with ethyl acetate. The combined organic
extract was washed with brine, dried (MgSO.sub.4), and concentrated
in vacuo to afford the title compound (3.2 g, 60%). MS(ES) m/e
190.6 [M+H].sup.+.
Example 2
Preparation of ethyl
(R)-4-cyano-3-(oxiranylmethoxy)benzenepropionate
[0182] a) Ethyl 3-hydroxybenzenepropionate
[0183] A solution of 3-(3-hydroxyphenyl)propionic acid (Lancaster,
66.4 g, 0.4 mol) in ethanol (700 mL) was treated with concentrated
sulfuric acid (6 mL), heated to reflux for 2 h, and allowed to cool
to RT. The mixture was cooled in ice, neutralized with 10% aqueous
sodium carbonate and concentrated in vacuo to about 50 mL. Water
(.about.200 mL) was added and the mixture was extracted three-times
with ethyl acetate. The combined ethyl acetate extract was washed
with water and brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to yield the title compound as an oil (70 g,
90%).
[0184] b) Ethyl 4-formyl-3-hydroxybenzenepropionate
[0185] To a solution of the compound from Example 2(a) (77.2 g, 0.4
mol) in dry acetonitrile (1 L) stirred under argon was added
triethylamine (152 g, 1.5 mol) followed by magnesium chloride (57.1
g, 0.6 mol). After stirring for 5 min, paraformaldehyde (81 g) was
added and the reaction was refluxed under argon for 1.5 h. The
reaction was cooled, 6 N hydrochloric acid (400 mL) was added and
the resulting mixture was extracted with ethyl acetate. The
combined ethyl acetate extract was washed with water, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residual oil
was purified by flash column chromatography (silica gel, 10% ethyl
acetate/hexane) to give the title compound (66.6 g, 75%).
[0186] c) Ethyl
3-hydroxy-4-[(hydroxyimino)methyl]benzenepropionate
[0187] A solution of the compound from Example 2(b) (66.6 g, 0.3
mol) in absolute ethanol (500 mL) was treated with triethylamine
(40.4 g, 0.4 mol) followed by hydroxylamine hydrochloride (23 g,
0.33 mol). The reaction was stirred under argon at reflux for 18 h,
concentrated in vacuo, and the residual oil was dissolved in ethyl
acetate and washed with 1N hydrochloric acid. The ethyl acetate
phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo
to give the title compound as an oil which was used in the next
step.
[0188] d) Ethyl 3-acetoxy-4-cyanobenzenepropionate
[0189] The compound from Example 2(c) was treated with acetic
anhydride (500 ML) and refluxed under argon for 90 min. The
reaction was concentrated in vacuo and the resulting oil was
dissolved in ethyl acetate and washed with water. The ethyl acetate
layer was dried (MgSO.sub.4), filtered, and concentrated in vacuo
to give the title compound as an oil which was used in the next
step.
[0190] e) Ethyl 4-cyano-3-hydroxybenzenepropionate
[0191] A solution of the compound from Example 2(d) was dissolved
in ethanol (200 mL) and treated with a solution of sodium carbonate
(64 g, 0.6 mol) in water (1.5 L). After stirring at RT for 5 h, the
mixture was neutralized with 6 N hydrochloric acid to pH 5 and
concentrated in vacuo. The resulting mixture was extracted with
ethyl acetate. The ethyl acetate solution was dried (MgSO.sub.4),
filtered, and concentrated in vacuo to give the title compound as
an oil [61.9 g, 94.2% overall yield from the compound of
Preparation 2(c)].
[0192] f) Ethyl
(R)-4-cyano-3-(oxiranylmethoxy)benzenepropionate
[0193] A solution of the compound from Example 2(e) (28.3 g, 0.13
mol) and (2R)-glycidyl 3-nitrobenzenesulfonate (33.7 g, 0.13 mol)
in dry acetone (500 mL) was treated with potassium carbonate (36 g,
0.26 mol) and refluxed under argon for 18 h. The reaction was
cooled, filtered, and the filtrate was concentrated in vacuo and
the residue was purified by flash column chromatography (silica,
30% ethyl acetate/hexane) to yield the title compound (29.5 g,
82.4%).
Example 3
Preparation of Ethyl
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimet-
hyl-ethylamino)-propoxy]-phenyl}-propionate
[0194] A mixture the compounds from Example 2(f) (6 g, 31.7 mmol)
and Example 1(d) (8.6 g, 31.7 mmol) in absolute ethanol (200 mL)
was stirred and heated to reflux for 56 h, cooled, concentrated in
vacuo. The residue was dissolved in dichloromethane (30 mL) and
acidified with 1.0 N hydrogen chloride in ether. The white solid
which formed was isolated by filtration and recrystallized to
afford the title compound (10 g, 63%). mp (dichloromethane/ether)
155-157.degree. C.; MS(ES) m/e 465.4 [M+H].sup.+.
Example 4
Preparation of
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-et-
hylamino)-propoxy]-phenyl}-propionic acid
[0195] A solution of the compound from Example 3 (1.5 g, 3 mmol) in
ethanol (120 mL) and water (40 mL) was treated with 2.5 N sodium
hydroxide (5 mL) and stirred for RT under argon overnight. The
ethanol was removed in vacuo, and the pH was adjusted to pH 5 with
1 N hydrochloric acid while stirring. The precipitated white solid
was collected by filtration, washed with water and dried in vacuo
to afford the title compound (1.3 g, quant). MS(ES) m/e 437.4
[M+H].sup.+.
Example 5
Preparation of
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-et-
hylamino)-propoxy]-phenyl}-propionic acid hydrochloride
[0196] The compound from Example 4 (80 mg, 0.18 mmol) was suspended
in acetonitrile (8 mL) and treated with 1 N hydrogen chloride in
ether dropwise with stirring until the solid dissolved. The mixture
was quickly filtered and cooled in an ice bath. The white
crystalline solid which formed was isolated by filtration, washed
with ether, and dried in vacuo to afford the title compound (80 mg,
94%). Mp 180-181.degree. C.; MS(ES) m/e 437.2 [M+H].sup.+.
Example 6
Preparation of
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-et-
hylamino)-propoxy]-phenyl}-propionic acid octyl ester hyrochloride
salt
[0197] A solution of the compound from Example 5 (100 mg, 0.2 mmol)
in dry DMF (15 ml) was treated with cesium carbonate (141 mg, 0.4
mmol) and 18-crown-6 (100 mg, 0.41 mmol) followed by 1-iodooctane
(144 mg, 0.6 mmol). The resulting mixture was heated at 70.degree.
C. under argon for 20 h. The reaction was cooled, concentrated and
the residue partitioned between water and ethyl acetate. The
organic layer was washed with 10% Na.sub.2CO.sub.3 (aqueous),
brine, dried over MgSO.sub.4 and evaporated. Purification by flash
chromatography (4% MeOH in CH.sub.2Cl.sub.2) gave the ester as a
yellow oil. The oil in ether was treated with HCl and filtered to
give the above titled compound (50 mg, 46%). LC-MS m/e 549.4
[M+H].sup.+.
Example 7
Preparation of
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-et-
hylamino)-propoxy]-phenyl}-propionic acid 2-methoxy-ethyl ester
hyrochloride salt
[0198] Using the procedure of Example 6 but substituting
1-bromo-2-methoxy-ethane for 1-iodooctane gave the above titled
compound. LC-MS m/e 495.4 [M+H].sup.+.
Example 8
Preparation of
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-et-
hylamino)-propoxy]-phenyl}-propionic acid butyl ester hyrochloride
salt
[0199] Using the procedure of Example 6 but substituting
1-iodobutane for 1-iodooctane gave the above titled compound. LC-MS
m/e 493.4 [M+H].sup.+.
Example 9
Preparation of
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-et-
hylamino)-propoxyl]-phenyl}-propionic acid isopropyl ester
trifluoroacetate salt
[0200] a) 3-(4-Cyano-3-hydroxy-phenyl)-propionic acid
[0201] A solution of 3-(4-Cyano-3-hydroxy-phenyl)-propionic acid
ethyl ester (2.2 g, 10 mmol) in ethanol (10 mL) and water (40 mL)
was treated with aqueous sodium hydroxide solution (2.5 M, 44 mL)
at room temperature overnight. The solvent was removed under vacuum
and the residue was dissolved in water (150 mL). The pH of the
aqueous solution was adjusted to 2-4 by the addition of 3N HCl
(aqueous) and the precipitate was then filtered and washed with
water to give the title compound as white solid (1.88 g, 0.98 mmol,
98.4% yield). ESMS m/z: 192 [M+H].sup.+.
[0202] b) 3-(4-cyano-3-hydroxy-phenyl)-propionic acid isopropyl
ester
[0203] A solution of compound from Example 9 (a) (0.25 g, 1.3 mmol)
and propan 2-ol (0.4 g, 0.67 mmol) in CH.sub.2Cl.sub.2 (10 ml) was
treated dropwise with a solution of 4-pyrrolidinopyridine (0.2 g,
1.3 mmol) in CH.sub.2Cl.sub.2 (1 mL). The reaction mixture under
N.sub.2 was cooled to 0.degree. C. and then treated with EDC
(1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride
(Aldirch, 0.27 g, 1.4 mmol). The subsequent mixture was stirred at
0.degree. C. for 30 min and slowly brought to room temperature and
stirred overnight. The reaction mixture was washed with 3 N HCl
(3.times.25 mL), brine (1.times.25 mL) and H.sub.2O (1.times.25
mL). The organic layer was dried over anhydrous sodium sulfate and
concentrated under vacuum to give the above titled compound.
[0204] c) 3-(4-Cyano-3-oxiranylmethoxy-phenyl)-propionic acid
isopropyl ester
[0205] A solution of compound from Example 9 (b),
R-glycidylnosylate (0.33 g; 1.4 mmol) and K.sub.2CO.sub.3 (0.36 g,
2.6 mmol) in acetone (10 mL) was refluxed under N.sub.2 overnight.
The reaction mixture was then cooled to room temperature and
filtered. The filtrate was concentrated under vacuum to give the
above titled compound as a light brown oil.
[0206] d)
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylam-
ino)-propoxyl]-phenyl}-propionic acid isopropyl ester
trifluoroacetate salt
[0207] The compound from Example 9 (c) and the compound from
Example 1 (d) was dissolved in toluene (12.5 mL) and the mixture
was stirred at 120.degree. C. overnight. The solvent was removed
under vacuum and the residue was purified by preparative HPLC
(Gilson) to give the above titled compound as a light yellow oil.
ESMS m/z: 479 [M+H].sup.+.
Example 10
Preparation of
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-et-
hylamino)-propoxy]-phenyl}-propionic acid pentyl ester
trifluoroacetate salt
[0208] The title compound was prepared by the same procedure as
Example 9 except that propan-2-ol was replaced with pentan-1-ol to
give the above titled compound as oil. ESMS m/z: 507
[M+H].sup.+.
Example 11
Preparation of
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-et-
hylamino)-propoxy]-phenyl}-propionic acid 2-ethoxy ethyl ester
trifluoroacetate salt
[0209] The title compound was prepared by the same procedure as
Example 9 except that propan-2-ol was replaced with
2-ethoxy-ethanol to give the above titled compound as an oil. ESMS
m/z: 509 [M+H].sup.+.
Example 12
Preparation of
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-et-
hylamino)-propoxy]-phenyl}-propionic acid 2-methoxy ethyl ester
trifluoroacetate salt
[0210] The title compound was prepared by the same procedure as
Example 9 except that propan-2-ol was replaced with
2-methoxy-ethanol to give the above titled compound as an oil. ESMS
m/z: 495 [M+H].sup.+.
Example 13
Preparation of
3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethyla-
mino)-propoxy]-phenyl}-propionic acid methyl-butyl ester
trifluoroacetate salt
[0211] The title compound was prepared by the same procedure as
Example 9 except that propan-2-ol was replaced with
3-methyl-butan-1-ol to give the above titled compound as an oil.
ESMS m/z: 507 [M+H].sup.+.
Example 14
Preparation of
3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethyla-
mino)-propoxy]-phenyl}-propionic acid 1-ethyl-propyl ester
trifluoroacetate salt
[0212] The title compound was prepared by the same procedure as
Example 9 except that propan-2-ol was replaced with pentan-3-ol to
give the above titled compound as an oil. ESMS m/z: 507
[M+H].sup.+.
Example 15
Preparation of
3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethyla-
mino)-propoxy]-phenyl}-propionic acid sec-butyl ester
trifluoroacetate salt
[0213] The title compound was prepared by the same procedure as
Example 9 except that propan-2-ol was replaced with butan-2-ol to
give the above titled compound as an oil. ESMS m/z: 493
[M+H].sup.+.
Example 16
Preparation of
3-{4-cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-dimethyl-ethyla-
mino)-propoxy]-phenyl}-propionic acid 2-methoxy-1-methyl-ethyl
ester
[0214] The title compound was prepared by the same procedure as
Example 9 except that propan-2-ol was replaced with
1-methoxy-propan-2-ol to give the above titled compound as an oil.
ESMS m/z: 509 [M+H].sup.+.
Example 17
Preparation of 2,2-Dimethyl-propionic acid
3-{4-cyano-3-[(R)-2-hydroxy-3-(-
2-indan-2-yl-1,1-dimethyl-ethylamino)-propoxy]-phenyl}-propanoyloxymethyl
ester hydrochloride salt
[0215] To a suspension of 200 mg (0.44 mmole) of the sodium salt of
the compound from Example 4 in 10 mL of DMF was added 17 mg (0.011
mmole) of sodium iodide, 290 mg (1.1 mmole) of 18-crown-6 and 100 g
(0.66 mmole) of chloromethylpivalate. The reaction was stirred at
70.degree. C. for 24 h and concentrated to a gum which was purified
by flash chromatography on silica gel eluting with 4% MeOH in
CH.sub.2Cl.sub.2 to yield 100 mg of an oil which was treated with
1N HCl/ether to yield the above titled compound (90 mg) as a white
solid. ES-MS m/z: 551 [M+H].sup.+.
Example 18
Preparation of
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-et-
hylamino)-propoxy]-phenyl}-propionic acid
(S)-2-amino-3-methyl-butyl ester
[0216] a) 3-(4-Cyano-3-hydroxy-phenyl)-propionic acid
(S)-2-tert-butoxycarbonylamino-3-methyl-butyl ester
[0217] To 0.95 g (5 mmol) of 4-cyano-3-hydroxybenzenepropionic
acid, 0.74 g (5 mmol) of 4-pyrrolinopyridine, 1.06 g (5.5 mmol) of
EDC-HCl in 25 mL of THF was added 1.02 g (4.5 mmol) of
t-butyloxycarbonyl-S-valinol. The reaction was stirred 18 h. The
reaction was concentrated, diluted with EtOAc and washed with 3N
HCl and 5% NaCO.sub.3. The EtOAc extracts were concentrated and the
residue was purified by flash chromatography on silica gel eluting
with 10% EtOH in CH.sub.2Cl.sub.2to yield 1.73 g of the above
titled compound as a yellow oil ESMS m/z: 377 [M+H].sup.+.
[0218] b) 3-[4-Cyano-3-((R)-1-oxiranylmethoxy)-phenyl]-propionic
acid (S)-2-tert-butoxycarbonylamino-3-methyl-butyl ester.
[0219] To 1.73 gm (0.0046 mole) of the compound from Example 18 (a)
in 25 mL of acetone was added 1.19 g (4.6 mmol) of (2R)-glycidyl
3-nitrobenzenesulfonate and 1.38 g (10 mmol) of K.sub.2CO.sub.3.
The mixture was heated at reflux for 18 h, filtered and
concentrated to give the above titled compound as a gum which was
used without purification.
[0220] c)
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-ethylam-
ino)-propoxy]-phenyl}-propionic acid (S)-2-amino-3-methyl-butyl
ester
[0221] To 0.43 g (1 mmol) of the compound from Example 18 (b) in 25
mL of MeCN was added 0.19 g (1 mmol) of
2-indan-2-yl-1,1-dimethyl-ethylamine and the reaction heated at
reflux for 18 h. The mixture was concentrated and treated for 30
min with 10 mL of a solution of 1:1 TFA-CH.sub.2Cl.sub.2. The
reaction was concentrated and the resulting oil was purified by
preparative HPLC on a 50.times.20 mm ID YMC Combiprep ODS column
eluting at 20 mL/min with a linear gradient of 30% MeCN(0.1%
TFA)/30% water(0.1% TFA) to 70% MeCN(0.1% TFA) over 15 min to give
the above titled compound (25 mg). ESMS m/z: 522 [M+H].sup.+.
Example 19
Preparation of
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-et-
hylamino)-propoxy]-phenyl}-propionic acid 5-amino-pentyl ester
[0222] The title compound was prepared by the same procedure as
Example 18 except that t-butyloxycarbonylpentanol was used in place
of t-butyloxycarbonyl-S-valinol to give the above titled compound
(22 mg). ESMS m/z: 522 [M+H].sup.+.
Example 20
Preparation of
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-2-yl-1,1-dimethyl-et-
hylamino)-propoxy]-phenyl}-propionic acid methyl ester
hydrochloride
[0223] To 100 mg of the compound from Example 3 in 100 mL of
methanol was added 1 mL of 12M HCl. The reaction was heated at
reflux for 72 h and then concentrated to yield the above titled
compound (77 mg) as a white powder. ESMS m/z: 451[M+H].sup.+.
Example 21
Preparation of
3-(4-Cyano-3-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-nap-
hthalen-2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic
acid
[0224] a)
6-(1,1-Dimethyl-1-aminoethyl)-1,2,3,4-tetrahydronaphthalene
hydrochloride
[0225] A solution of 1.0 g (4.2 mmol) of
6-(1,1-dimethyl-1-aminoethyl)naph- thalene hydrochloride in glacial
acetic acid (100 mL) was treated under Argon atmosphere with
PtO.sub.2 (350 mg). The mixture was hydrogenated in a Parr shaker
at 50 psi for 1 h. and filtered through a plug of celite. The
filtrate was concentrated in vacuo and concentrated from ether. The
residue was triturated with ether and the white crystalline solid
(850 mg, 85% yield) was collected, washed with ether and dried.
MS(ES) m/z 204.2 (M+H).sup.+; Elemental analysis: theoretical for
C.sub.14H.sub.21N.HCl.1/2H.sub.2O: C, 67.58; H, 9.31; N, 5.63.
Found: C, 67.51; H, 9.31; N, 5.63.
[0226] b)
3-(4-Cyano-3-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthal-
en-2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid
ethyl ester.
[0227] Following the procedure described in Example 3 except using
amine from Example 21 (a), the above titled compound was obtained.
MS(ES) m/z 479.6 (M+H).sup.+; Elemental analysis: theoretical for
C.sub.29H.sub.38N.sub.2O.sub.4.HCl.1/2H.sub.2O: C, 66.46; H, 7.60;
N, 5.34. Found: C, 66.11; H, 7.66; N, 5.24.
[0228] c)
3-(4-Cyano-3-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-naphthal-
en-2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic acid.
[0229] Following the procedure described in Experiment 4 for the
ester hydrolysis of compound in experiment 21(b) the above titled
compound was obtained. MS(ES) m/z 451.7 (M+H).sup.+.
Example 22
Preparation of
3-(3-Cyano-4-{(R)-3-[1,1-dimethyl-2-(5,6,7,8-tetrahydro-nap-
hthalen-2-yl)-ethylamino]-2-hydroxy-propoxy}-phenyl)-propionic
acid
[0230] Following the procedure described in Example 3 using ethyl
(R)-2-cyano-4-(oxiranylmethoxy)benzenepropionate and the amine from
example 21(a) the above titled compound was obtained. MS(ES) m/z
451.4 (M+H).sup.+.
Example 23
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-5-yl-1,1-dimethyl-ethylamino)-propo-
xy]-phenyl}-propionic acid
[0231] a) 5-(2-Methyl-propenyl)-indan
[0232] In a flamed dried flask under argon
isopropyltriphenylphosphonium iodide (6.48 g, 15 mmol) in 30 mL of
dry THF was cooled to 0.degree. C. Then n-BuLi (2.5 M) in hexanes
(6.0 mL) was added via syringe. The reaction mixture was stirred
0.degree. C. for 45 min. Then a solution of the
2,3-dihydro-1H-indene-5-carboxaldehyde (J. Med. Chem. 1993, 36,
3700-3706) was added (1.7, 12.0 mmol) in THF (20 mL) was added
drop-wise and the reaction was stirred under Argon at RT overnight.
The reaction was filtered, the filtrate was concentrated in vacuo
and the residue purified by flash colum chromatography (ethyl
acetate/hexane, 1:99) to yield the above titled compound as a pale
yellow oil (1.7 g, 67%).
[0233] b) N-(2-Indan-5-yl-1,1-dimethyl-ethyl)-acetamide
[0234] Following the procedure described in Example 1 (c) the above
titled compound was obtained as a crystalline solid. Melting point
130-131.degree. C. (ethyl acetate); MS(ES) m/z 463.7 (2M+H).sup.+,
322.7 (M+H).sup.+; Elemental Analysis: theoretical for
C.sub.15H.sub.21NO: C, 77.85; H, 915; N, 6.05. Found: C, 77.54; H,
9.09; N, 6.03.
[0235] c) 2-Inda-5-yl-1,1-dimethyl-ethylamine
[0236] Following the procedure described in experiment 1(d), the
above titled compound was obtained. MS(ES) m/z 190.6
(M+H).sup.+.
[0237] d) Ethyl
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-5-yl-1,1-dimethyl-e-
thylamino)-propoxy]-phenyl}-propionate hydrochloride salt.
[0238] Following the procedure described in Example 3 using the
amine from Example 23 (c) the above titled compound was obtained.
MS(ES) m/z 465.8 (M+H).sup.+; Elemental analysis: theoretical for
C.sub.28H.sub.36N.sub.2O- .sub.4.HCl.{fraction (3/4)}H.sub.2O: C,
65.34; H, 7.44; N, 5.44. Found: C, 65.11; H, 7.66; N, 5.25.
[0239] e)
3-{4-Cyano-3-[(R)-2-hydroxy-3-(2-indan-5-yl-1,1-dimethyl-ethylam-
ino)-propoxy]-phenyl}-propionic acid
[0240] Following the procedure described in Example 4 the title
compound was obtained. MS(ES) m/z 437.8 (M+H).sup.+.
Example 24
Parenteral Formulation
[0241] A pharmaceutical composition for parenteral administration
is prepared by dissolving an appropriate amount of a compound of
Formula (I) in polyethylene glycol with heating. This solution is
then diluted with water for injections (to 100 mL). The solution is
then rendered sterile by filtration through a 0.22 micron membrane
filter and sealed in sterile containers.
[0242] All publications, including but not limited to patents and
patent applications cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference as though fully set forth.
* * * * *