Note: Descriptions are shown in the official language in which they were submitted.
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AMINOALKYLENEPHOSPHONATES FOR TREATMENT OF BONE
DISORDERS
This invention relates to the use of
aminoalkylenephosphonates for treatment of bone disorders
such as osteoporosis.
This invention involves the use of
l0 aminoalkylenephosphonates, such as, for example, 1,4,7,10-
tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic
acid (DOTMP) and 3,6,9,15-tetraazabicyclo[9.3.1]tetradeca-
1(15),11,13-triene-3,6,9-trimethylenephosphonic acid
(PCTMP) for use in the inhibition of bone resorption.
This application is directed toward use in the prevention
and/or treatment of bone diseases such as osteoporosis.
Bone is a dynamic tissue, continually undergoing
remodeling. Hydroxyapatite, the main inorganic
constituent of bone, is constantly being deposited and
resorbed. In pathological states such as osteoporosis a
shift in the balance of these two processes occurs,
resulting in a net loss of mineralized tissue. This loss
results in impaired skeletal function and clinical
fractures. Osteoporosis is an enormous public health
problem affecting as many as 25 million people in the
United States alone. It is a pervasive disease that has
staggering costs to society in terms of morbidity,
mortality, and economics. As the population becomes more
aged, the magnitude of this problem will certainly become
3o greater.
Currently only three drugs - estrogen, calcitonin,
and alendronate are approved by the FDA for use in the
treatment of osteoporosis. Both estrogen and calcitonin
have some drawbacks (for example, estrogen - risk of
endometrial carcinoma, calcitonin - allergic reaction) and
are not always successful. The recently approved
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bisphosphonate alendronate (4-amino-1-
hydroxybutylidenebisphosphonate) is a member of a class of
compounds that has received much attention for their
potential in treating bone-related illnesses.
Bisphosphonates all contain the basic P-C-P
structure. Examples such as etidronate (1-hydroxy-
ethylidenebisphosphonate), risedronate [1-hydroxy-2-(3-
pyridinyl)ethylenebisphosphonate], pamidronate (3-amino-1-
l0 hydroxypropylidenebisphosphonate), tiludronate (4-
chlorophenylthiomethylenebisphosphonate) have already been
approved for the treatment of a rare bone condition called
Paget's disease.
Aminoalkylenephosphonates have not been investigated
for these applications. It is known that these compounds
have a strong affinity for bone (for example, EDTMP and
DOTMP radiopharmaceutical bone agents) and have low soft
tissue localization. They have unique properties such as
the ability to inhibit calcium phosphate scale formation
at very low concentrations.
It has now been discovered that aminoalkylene
phosphonates can inhibit bone mineral density loss. In
fact, a screening study of various aminomethylene-
phosphonates in an ovarectomized rat osteoporosis model
has now shown that PCTMP is as good as, and may even be
superior to, alendronate in its ability to inhibit bone
mineral loss.
The present invention relates to a method for
preventing or minimizing loss of bone mineral in mammals
which method comprises administering to a mammal an amount
of an aminoalkylenephosphonate which is effective to
prevent or minimize loss of bone mineral density.
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In another aspect, the present invention relates to
the use of an aminoalkylenephophonate or a
pharmaceutically acceptable salt thereof in the
manufacture of a pharmaceutical formulation for preventing
or minimizing loss of bone mineral in mammals.
The term "aminoalkylenephosphonate" as used herein
refers to those phosphonates and phosphonic acids which
incorporate an amine moiety, whether aliphatic or cyclic,
l0 attached via the amine nitrogen through an alkylene group
to the phosphonate or phosphonic acid moiety. The
aminoalkylenephosphonates of the present invention should
have at least one R-N(Alk-P03Hz)2 group or at least two
RR'N-Alk-P03Hz groups wherein R and R' can be, same or
different, aliphatic or cyclic moiety, and Alk is an
alkylene group having from 1 to 4 carbon atoms.
The amine moiety of the aminoalkylenephosphonates of
the present invention represented by the R-N= and RR'N- in
the aforementioned R-N (Alk-P03H2) 2 and RR' N-Alk-P03Hz groups
is derived from either an aliphatic or a cyclic polyamine
in which hydrogen atoms bonded to the nitrogen atoms) in
the amine moiety are partially or completely substituted
by an alkylphoshonate group. Non-limiting examples of the
amines suitable as amine moieties in the practice of the
present invention are ethylenediamine (EDA),
diethylenetriamine (DETA), triethylenetetraamine (TETA),
1,4,7,10-tetraazacyclododecane, 3,6,9,15-tetraaza-
bicyclo[9.3.1]tetradeca-1(15),11,13-triene, 2,11-
diaza[3.3](2,6)pyridinophane, 2-(aminomethyl)pyridine,
2,6-bis(aminomethyl)pyridine.
The alkylene group having from 1 to 4 carbon atoms
contemplated by Alk in the aforementioned formulas can be
straight or branched chain alkylene group. Non-limiting
examples of such alkylene groups are methylene, ethylene,
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propylene, isopropylene, and butylene. The preferred
alkylene group is methylene (-CHI-) group.
Preferred aminoalkylenephosphonates are
aminomethylenephosphonates. Particularly preferred
aminoalkylenephosphonates are 1,4,7,10-tetraaza-
cyclododecane-1,4,7,10-tetramethylenephosphonic acid
(DOTMP), 3,6,9,15-tetraazabicyclo[9.3.1]tetradeca-
1(15),11,13-triene-3,6,9-trimethylenephosphonic acid
l0 (PCTMP), N,N'-bis(methylenephosphonic acid)-2,11-
diaza[3.3](2,6)pyridinophane (BP2MP) and N,N-bis(methylene
.phosphonic acid)-2-(aminomethyl)pyridine (AMPDMP).
The aminoalkylenephosphonates contemplated by the
present invention are well known in the art and numerous
methods for their preparation have been disclosed. See,
for example, U.S. Patent No. 3,288,846 (Irani et al) and
U.S. Patent No. 4,898,724 (Simon et al), both incorporated
herein by reference.
The aminoalkylenephosphonates of the present
invention are used in an amount effective to prevent or
minimize loss of bone mineral. The effective amount will
vary depending on the mammal, aminoalkylenephosphonate
used and the method of its administration (for example,
oral or parenteral). A person of ordinary skill in the
art will know how to determine the effective amount of
aminoalkylene-phosphonate.
The aminoalkylenephosphonates of the present
invention can be administered to a mammal on a daily or
weekly regiment basis. Typically, for average 50 kg
mammal, the effective weekly parenteral dose is in the
range of from about 0.01 mg to about 500 mg, preferably
from about 0.1 mg to about 250 mg, most preferably from
about 0.1 to about 70 mg. Typically, for average 50 kg
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mammal, the effective daily oral dose is in the range of
from about 0.1 mg to about 40 g, preferably from about 0.1
mg to about 10 g, most preferably from about 0.1 to about
g.
J
In the practice of the present invention the
aminoalkylenephosphonate may be administered per se or as
a component of a pharmaceutically acceptable composition.
l0 Thus, the present invention may be practiced with the
aminoalkylenephosphonate being provided in pharmaceutical
formulation, both for veterinary and for human medical
use. Such pharmaceutical formulations comprise the active
agent (the aminoalkylenephosphonate) together with one or
more pharmaceutically acceptable carriers thereof and
optionally any other therapeutic ingredients. The
carriers) must be pharmaceutically acceptable in the
sense of being compatible with the other ingredients) in
the formulation and not unsuitably deleterious to the
2o recipient thereof. The aminoalkylenephosphonate is
provided in an effective amount, as described above, and
in a quantity appropriate to achieve the desired dose.
The formulations include those suitable for oral,
rectal, topical, nasal, ophthalmic, or parenteral
(including subcutaneous, intramuscular, and intravenous)
administration. Formulations may be prepared by any
methods well known in the art of pharmacy. Such methods
include the step of bringing the aminoalkylenephosphonate
into association with a carrier, which constitute one or
more accessory ingredients. In general, the formulation
may be prepared by uniformly and intimately bringing the
aminoalkylenephosphonate into association with a liquid
carrier, a finely divided solid carrier, or both, and
then, if necessary, shaping the product into desired
formulation. In addition, the formulations of this
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invention may further include one or more accessory
ingredients) selected from diluents, buffers, flavoring
agents, binders, disintegrants, surface active agents,
thickeners, lubricants, preservatives.
The following Examples are provided to illustrate the
present invention, and should not be construed as limiting
thereof.
l0 Example 1
Eleven week old Female Sprague-Dawley laboratory rats
(75) were fed a commercial rat diet and were allowed to
drink water ad libitum. They were housed in pairs in an
air-conditioned environment, and were allowed to enjoy 14
hours of illumination per day. Ten rats were sham-
operated and were used as "non-osteopenic" control rats.
All of the other rats were ovariectomized at 12 weeks of
age. All surgeries were done under injectable anesthesia.
Ten of the ovariectomized rats were used as an "osteopenic
but non-treated" control, and did not receive any
phosphonate treatments. The remaining rats were given
various phosphonate compounds in groups of ten.
Phosphonates (5 mg/kg) were administered
subcutaneously (to insure better bioavailability). The
rats were given doses three times during the first week
and once a week thereafter.
Structures of the compounds tested are shown below in
Figure 1.
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Figure 1. Structures of Compounds Tested (Example 1)
i
Nf 1, !-1,0;!'-~ n ~ PO'!-!-
N N N
H,O~!'~N N~POaIh
H,O P- -PO H, CN N
_ a ~ _ N
bH ll,a,!'-~ U ~PO,EI,
Po,H
Alendronatc DOTMP PCTMP
H,O;P N~--~~~P03Hz H=OAP N~PO3Ii,
H,03P~ ' ~P03H, H,O~P~ ~- P03H,
P03Hz
D);TA-Phosphonate EDTMP
to Bone mineral density was determined by single photon
absorptiometry while the rats were under injectable
anesthesia. The distal femoral metaphysis of all rats
were scanned at weekly intervals for ten weeks.
Figure 2 below shows the average drop in bone mineral
density, normalized to the sham-operated control group,
for the ovariectomized (OVX) control group and for the
treatment groups.
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Figure 2. Average Change in BMD
(Normalized to sham-operated control - 0)
0.010
o.ooo
-0.010
-~-EDTMP
N
E -0.020 f DETA
_u
-0.030 f DOTMP
a ~--Alendronate
o~
m -0.040 ~ PCTMP
r
V + OVX
-0.050
- SHAM
-0.060
-0.070
-0.080 . ._ ...... .. ._.. .... ... _. .. . . _,_-_
0 1 2 3 4 5 6 7 8 9 10
Week
As can be seen, relative to the sham-operated
control, the OVX group loses bone mineral density (BMD)
l0 over time. Three aminomethylenephosphonates, DOTMP,
EDTMP, and DETA-Phosphonate, all lost more BMD than the
OVX group (at this dose level). Both the alendronate and
PCTMP groups maintained BMD. (Because of the difference
in molecular weight, PCTMP was actually used at a lower
dose level than alendronate on a mole basis.)
By week 10, there are three statistical groupings.
The sham operated controls, alendronate, and PCTMP are all
statistically equivalent. The ovariectomized controls are
in a group by themselves, as are the other three
aminomethylenephosphonates.
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Example 2:
A second study was undertaken to explore the effect
of structural changes in PCTMP. The structures of the
compounds tested are shown below in Figure 3. Included in
the study was DOTMP at one tenth the dose, that is, 0.5
mg/kg. All other compounds were dosed at 5 mg/kg. In
this study, bone mineral density was determined by dual
energy X-ray absorptiometry (DEXA). Other aspects of the
l0 study were substantially the same as in Example 1. The
results of the study are shown in Figure 4 below.
Again, it can be seen that, relative to the sham-
operated controls, the OVX control group lost significant
BMD over the study period. As before, PCTMP shows an
improvement over the OVX group. AMPDMP and BP2MP both
look even better, but the best compound tested was DOTMP
at 0.5 mg/kg. At this dose level it was equivalent to the
sham-operated control.
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I'iaure 3. Structures of Compounds ~l'ested
i ~ /~ ~ 1'031 h
~N ~ ~v. -1'011,
N
N N
11
O
1' ~
~ 1'0
11
? AMPDMI'
~
N
?
3
w ~i
P0311~
1'C'IMP
\
N
1y031' p03H2 ~N N_..\
H?031' N PO;Ho
~ ~
~
FIZ03P
~>
POgH~
N
BAMPDMP BP2MP
H203P PO~IIz
~N~-- NJ
CN N
Hz03P~ U ~ 03Hz
DOTMP
Figure 4. Average Change in BMD
(Normalized to sham-operated control - 0)
o.oio -
o.ooo
-o.o~o
n + AMPDMP
B ~-OVX
a
m -0.020 +BAMPTMP
0
-Sham
-0.030 -31E- DOTMP/10
o~
f PCTMP
r
v +BP2MP
-0.040
-0.050 -.
-0.060
0 1 2 3 4 5 6 7 8
Week
