Note: Descriptions are shown in the official language in which they were submitted.
CA 02335134 2000-12-14
WO 99165486 PCT/IB99/01117
THERAPEUTIC COM$INATIONS OF (SELECTIVE) ESTROGEN RECEPTOR MODULATORS (SERM)
AND GROWTH
HORMONE SECRETAGOGUES (GHS) FOR TREATING MUSCULOSKELETAL FRAILTY
BACKGROUND OF THE INI~rENTION
This invention relates to a pharmaceutical! combination of a selective
estrogen receptor modulator (SERM) and a growth hormone secretagogue (GHS)
that stimulates bone formation, increases bone mass, decreases serum lipid
levels
and increases muscle mass. The invention also r~alates to kits containing such
combinations and the use of such combinations to treat musculoskeletal
frailty,
including osteoporosis, osteoporotic fracture, low bone mass, frailty, low
muscle
mass and the like in mammals, including humans.. tn particular, this invention
relates to a combination of (-)-cis-6-phenyl-5-{4-(2-ipyrrolidin-1-yl-ethoxy)-
phenyl)-
5,6,7,8-tetrahydronaphthalene-2-of or a pharrnace~rticatly acceptable salt
thereof
and 2-amino-N-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3, 3a, 4,6,7-hexahydro-
pyrazoto-[4,3-c]pyridin-5-yl)-9(R)-benzyloxymethyl-2-~oxo-ethyt)-isobutyramide
or a
pharmaceutically acceptable salt thereof, kits contaiining such a combination
and
the use of such a combination to treat mus~,~.uloskeletal frailty, including
osteoporosis, osteoporotic fracture, low bone mass, frailty; low muscle mass
and
the like in mammals, including humans.
Osteoporosis is' a systemic skeletal disease, characterized by t~nr bone
mass and deterioration of bone tissue, with a conseduent increase in bone
fragility
and susceptibility to fracture. In the U.S., the condition affects more than
25
million people and causes more than 1.3 million fractures each year, including
500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures
are the most serious, with 5-20% of patients dying vwithin one year, and over
50%
of survivors being incapacitated.
The elderly are at greatest r7sk of osteoiparosis, and the problem is
therefore predicted to increase significantly with tlhe aging of the
population.
Worldwide fracture incidence is forecast to increase three-fold over the next
60
years, and one study estimates that there will be 4.5 million hip fractures
worldwide in 2050.
Although both men and women are susceptible to musculoskeletal frailty,
including osteoporosis, women are at greater risk of osteoporosis than men.
Women experience a sharp acceleration of bone loss immediately following
CA 02335134 2000-12-14
WO 99/65486 2 PCTIIB99101117
menopause. Other factors that increase bone loss leading to osteoporosis
include
smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.
Estrogen is the agent of choice in preventing osteoporosis or post
menopausal bone loss in women. in addition, Black, et al. in EP 0605193A1
report that estrogen, particularly when taken orally, lowers plasma levels of
LDL
and raises those of the beneficial high density lipoproteins (HDL's). Long-
term
estrogen therapy, fiowever, has been implicated in a variety of disorders,
including
an increase in the risk of uterine cancer, endometrial cancer and possibly
breast
cancer, causing many women to either avoid this treatment or take the
medica#ion
for only a short period of time. Although the risk of endometrial cancer is
thought
to be reduced by a concurrent use of a progesterone, there is still concern
about
possible increased risk of breast cancer with the use of estrogen. Recently
suggested therapeutic regimens, which seek to lessen the cancer risk, such as
administering combinations of progesterone and estrogen, cause the patient to
experience unacceptable bleeding. Furthermore, combining progesterone with
estrogen seems to blunt the serum cholesterol lowering effects of estrogen.
The
sign~cant undesirable side effects associated with estrogen therapy support
the
need to develop alternative Therapies for osteoporosis that have the desirable
benefiaal effect on serum LDL but do not cause undesirable side effects.
Recently, a number of selective estrogen receptor modulators have been
proposed for treatment of osteoporosis. It has been reported (Osteoporosis
Conference Scrip No. 1812113 April 16!20, 1993, p. 29) that raloxifene, 6-
hydroxy-
2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy} benzoyl] benzo[bj thiophene,
mimics
the favorable action of estrogen on bone and lipids but, unlike estrogen, has
minimal uterine stimulatory effect. [Black, L.J. ei: al., Raloxifene (LY139481
Hd)
Prevents Bone Loss and Reduces Serum Cholesterol Without Causing Uterine
Hypertrophy in Ovariectomized Rats, J. Clin. lnveat., 1994, 93:63-fig and
Delmas,
P.D. et al., Effects of Raioxifene on Bone Mineral Density, Serum Cholesterol
Concentration, and Uterine Endometrium in Postmenopausal Women, New
England Journal of Medicine, 1997, 337:1641-164.7j.
Agents such as droioxifene, U.S. pat. no. 6,254,595, prevent bone loss and
thereby reduce the risk of fracture without estrogen's side effects. However,
estrogen and estrogen agonists alone are only expected to reduce The fracture
risk
CA 02335134 2000-12-14
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3
by about 50% leaving approximately 50°/° of osteopenic women
still at risk for an
osteoporotic fracture.
Commonly assigned U.S. P at.No . 5,552,4'I2, -
discloses SERM compounds of the formula
,Y
wherein the variables are defined as set forth therein.
Growth hormone (GH), which is secreted from the pituitary gland,
stimulates growth of alt tissues of the body that are capable of growing. tn
addition, GH is known to have the following basic effects on the metabolic
process
of the body:
1. increased rate of protein synthesis in substantially all cells of the
body;
2. Decreased rate of carbohydrate utilization in cells of the body;
3. Increased mobilization of free fatty acids and use of fatty acids for
energy.
Defiaency in GH results in a variety of medical disorders. In children, it
causes dwarfism. tn adults, the consequences of acquired GH deficiency inGude
profound reduction in lean body mass and concomitant increase in total body
fat,
particularly in. the tFUncal region: . Decreased- stceletat .and cardiac
ntus~e~-mass
and muscle strength lead to a significant reduction in exerase capacity. Bone
density is also reduced. Administration of exogenous. GH has been shovm to
reverse many of the metabolic changes. Additional. benefits of therapy have
included reduction in LDL cholesterol and improved psychological well-being.
In cases where increased levels of GH were desired, the problem was
generailx~sotved. by providing exage~ous...Gk -or- by administering arr agent-
wpyi~y.
stimulated GH production andlor release. In either case the peptidyl nature of
the
compound necessitated that it be administered by injectiion. Initially the
source of
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WO 99/654$6 PCT/IB99/01117
4
GH was the extraction of the pituitary glands of cadavers. This resulted in an
expensive product, and carried with it the risk that a disease associated with
the
source of the pituitary gland could be transmitted to the recipient of the GH
(e.g.,
Jacob-Creutzfetd disease). Recently, recombinant GH has become available
which, while no longer carrying any risk of disease transmission, is still a
very
expensive product which must be given by injection or by~a nasal spray.
Most GH defiaencies are caused by defects in GH release, not primary
defects in pituitary synthesis of GH. Therefore, an alternative strategy for
normalixing serum GH levels is by stimulating il:s release from somatotrophs.
1~ Increasing GH secretion can be achieved by :stimulating or inhibiting
various
neurotransmitter systems in the brain and hypothalamus. As a resutt, the
development of synthetic GH-releasing agents to stimulate pituitary GH
secretion
are being pursued, and may have several advantages over expensive arid
inconvenient GH replacement therapy. By acting along physiologic regulatory
pathways, the most desirable agents would stimulate pulsatile GH secretion,
and
excessive Levels of GH that have been associated with the undesirable side
effects of exogenous GH administration would !be avoided by virtue of intact
negative feedback loops.
Physiologic and pharmacologtc stimulators of GH secretion include
2t7 arginine, L-3,4dihydroxyphenylalanine (L-DOPA), glucagan, vasopressin, and
insulin induced hypoglycemia, as welt as activities such as sleep and
exercise,
indirectly cause GH to be released from the pituttairy by acting in some
fashion on
the hypothalamus pefiaps either to decrease somatos#atin secretion or to
increase the secretion of the known secretagogue GH releasing factor (GHRF) or
an~ unknown endogenous GH-reteasing hormone or' all of these.
Commonly assigned International Patent Application Publication Number
W0971243fi9, designating, inter olio, the United States; discloses GH
secretagogues of the formula
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72222-421
Rt ~~ Rs
Y (Cf"!?~e (C1"!?~n C ~ ~ R6 R~
.C/ \N/
'R$
R2/~ ~ N~ (Cti~w R O
wherein the variables are defined as set forth therein.
Tang et at., Restorino and Maintainino Bone in Osteogenic Female Rat
5 Skeleton: t_ Chanoes in Bone Mass and Strvctmrp, ~, gone Mineral Research 7
(9),
p1093-'1104, 1992 disUoses data for the lose, restore and maintain (LRM)
concept, a practical approach for reversing existing osteoporosis. The LRM
concept uses anabolic agents to restore bone mass and architecture (+ phase)
and then switches to an agent with the established abiliify to maintain bone
mass,
to keep the new bone (+I phase). The rat study utilized PGEz and risedronate,
a
bisphosphonate, to show that most of the new canc;ettous and cortical bone
induced by PGEz can be maintained for at least 60 days after discontinuing
PGEz
by administering risedronate.
Shen et al., Effects of Reciprocal Treatment with Estrogen and Estrogen
1 ~ plus Parathyroid Hormone on Bone Structure and Sh~ength in Ovariectomi2ed
Rats, J. Clinical Investigation, 1995, 96:2331-2338 disGoses data for the
combination andJor sequential use of anti-resorptive agents and anabolic
agents
for the treatment of osteoporosis.
Commonly assigned lntemational Patent Applicaation Publication Number
WOg7/31640, designating, inter olio, the United States, discloses the use of
certain GH secretagogues in combination with cE:rtain SERMS to treat
osteoporosis.
SUMMARY OF THE 1NVENT10N
This invention is directed to a pharmaceutical composition comprising:
a. a first compound, the first compound beinci ( ~cs$phenyl-5,.(ø(2-
PY~tidin-~l-y1-ethoxy~phenyt)-5,fi,7.8-tetrahydronaphthaie~ne-2-of or a
pharmaceutically acceptable salt thereof; and
72222-421
CA 02335134 2001-O1-18
6
b. a second compound, which is 2-amino-N-(2-{3a(R)-
benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexa:hydropyrazolo[4,3-
c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxoethyl)isobutyramide
or a pharmaceutically acceptable salt thereof.
This invention is further directed to a
pharmaceutical composition as recited i:n the immediately
preceding paragraph additionally comprising a pharmaceutical
carrier.
This invention is also directed to a pharmaceutical
composition as described in either of t:he first two paragraphs
of this summary, wherein the first compound is {-)-cis-6
phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-Lohenyl)-5,6,7,8-
tetrahydronaphthalene-2-of D-tartrate a:nd the second compound
is 2-amino-N-(2-(3a(R)-benzyl-2-methyl-.3-oxo-2,3,3a,4,6,7-
hexahydropyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-
oxoethyl)isobutyramide L-tartrate.
This invention is still further directed to a method,
designated Method A, for treating a mammal suffering from
musculoskeletal frailty, comprising administering to the mammal
a pharmaceutical composition as recited in any of the first
three paragraphs of this summary.
A preferred method within Method A, designated Method
B, is wherein the mammal is suffering from osteoporosis.
Another preferred method within Method A, designated
Method C, is wherein mammal is suffering from osteotomy,
childhood idiopathic bone loss or bone :Loss associated with
periodontitis.
This invention is still further directed to a method,
designated Method Al, for treating a ma~unal suffering from
r , CA 02335134 2001-O1-18
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7
musculoskeletal frailty, comprising administering to the
mamma 1:
a. a first compound, which is (-)-cis-6-phenyl-5-(4-(2-
pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-
2-0l or a pharmaceutically acceptable salt thereof; and
b. a second compound, which is 2~-amino-N-(2-(3a(R)-
benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexalzydropyrazolo[4,3-
c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxoethyl)isobutyramide
or a pharmaceutically acceptable salt thereof.
This invention is particularly directed to a method
of Method A1 wherein the first compound and the second compound
are administered substantially simultaneously.
This invention is also particularly directed to a
method of Method A1, hereinafter termed Method D, wherein the
second compound is administered for a pESriod of from about
three months to about three years.
This invention is more particularly directed to a
method of Method D followed by administration of the first
compound for a period of from about three months to about three
years without the administration of the second compound during
the period of from about three months to about three years.
This invention is also more particularly directed to
a method of Method D followed by administration of the first
compound for a period greater than about. three years without
the administration of the second compound during the greater
than about three year period.
This invention is also directed to a method,
hereinafter termed Method E, for treating musculoskeletal
frailty in a mammal suffering therefrom, comprising
administering to the mammal a therapeutically effective amount
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8
of a composition as recited in any of the first three
paragraphs of this summary.
A preferred method within Method E is wherein bone
healing following facial reconstruction,, maxillary
reconstruction or mandibular reconstruction is enhanced,
vertebral synostosis is induced, long bone extension is
enhanced, the healing rate of a bone gra ft or a long bone
fracture is enhanced or prosthetic ingrowth is enhanced.
Additionally preferred is a method comprising administering to
the mammal:
a. a first compound which is (-)--cis-6-phenyl-5-(4-(2-
pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8--tetrahydronaphthalene-
2-0l or a pharmaceutically acceptable s<~lt thereof; and
b. a second compound, which is 2--amino-N- (2- (3a (R) -
benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-
c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxoethyl)isobutyramide
or a pharmaceutically acceptable salt thereof.
This invention is also directed to a method for
increasing muscle mass in a mammal, comprising administering to
the mammal a muscle mass increasing effective amount of a
composition as recited in any of the first three paragraphs of
this summary. Additionally preferred is a method comprising
administering to the mammal:
a. a first compound which is (-)--cis-6-phenyl-5-(4-(2-
pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8--tetrahydronaphthalene-
2-0l or a pharmaceuticaly acceptable sa7_t thereof; and
b. a second compound, which is 2--amino-N-(2-(3a(R)-
benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-
c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxoethyl)isobutyramide
or a pharmaceutically acceptable salt thereof.
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8a
In all of the methods of this invention, it is
particularly preferred that the mammal is a human.
This invention is also directed to a kit comprising a
treatment for a mammal suffering from musculoskeletal frailty
comprising:
a. a therapeutically effective amount of (-)-cis-6-
phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-;phenyl)-5,6,7,8-
tetrahydonaphthalene-2-of or a pharmaceutically acceptable salt
thereof and a pharmaceutically acceptable carrier in a first
unit dosage form;
b. a therapeutically effective amount of 2-amino-N-(2-
(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-
[4,3-c]pyridin-5-yl)-1(R)-benzyloxymeth;yl-2-oxo-ethyl)-
isobutyramide or a pharmaceutically acceptable salt thereof and
a pharmaceutically acceptable carrier in a second unit dosage
form; and
c. a container.
This invention is particularly directed to a kit as
described in the immediately preceding paragraph, wherein the
first unit dosage form comprises (-)-cia-6-phenyl-5-(4-(2-
pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-
2-0l D-tartrate and the second unit dosage form comprises 2-
amino-N-(2-(3a(R)-benzyl-2-methyl-3-oxo--2,3,3a,4,6,7-hexahydro-
pyrazolo [4, 3-c] pyridin-5-yl) -1 (R) -benzy:Loxymethyl-2-
oxoethyl)isobutyramide L-tartrate.
In all of the composition, mei~hods and kits of this
invention, it is particularly preferred that the D-tartrate
salt-of (-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-
phenyl)-5,6,7,8-tetrahydronaphthalene-2--of is used and that the
L-
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WO 99/6548b 9 PCT/IB99/OI I I7
tartrate salt of 2-amino-N-{2-(3a(R)-benzyl-2:-methyl-3-oxo-2,3, 3a, 4,6,7-
hexahydro-pyrazolo-[4, 3-cjpyridin-5-yl)-1 {R)-benzyloxymethyl-2-oxo-ethyl)-
isobutyramide is used.
The phrase "condition which presents wiith low bone mass" refers to a
condition where the level of bone mass is below the age specfic normal as
defined in standards by the World Health Organization "Assessment of Frachrre
Risk and its Application to Screening for Postmenopausal Osteoporosis (9994),
Report of a World Health Organization Study Group. World Health Organization
Technical Series 843". . Childhood idiopathic an<i primary osteoporosis are
also
included. Included in the treatment of osteoporosis is the prevention or
attenuation of long term complications such as curvature of the spine, toss of
height, prosthetic surgery, and prevention of prostate malfunctioning. Also
included is increasing the bone fracture healing rate and enhancing the rate
of
successful bone grafts. Also included is periodontal disease and alveolar bone
loss.
The phrase "condition which presents with tow bone mass" also refers to a
mammal known to have a significantly higher than average chance of developing
such diseases as are described above inGu~ding osteoporosis {e.g., post-
menopausai women, men over the age of 60, <~nd persons being treated with
drugs known to cause osteoporosis as a side effect (such as glucocorticoid)).
Those skilled in the art will recognize that the term bone mass actually
refers to bone mass per unit area which is sometimes (although not strictly
correctly) referred to as bone mineral density.
The phrase "musculoskeletal frailty refers to a condition wherein a subject
has low bone mass andlor low muscle mass, and inGudes such diseases,
disorders and conditions such as, but not limited to, conditions which present
with
low bone mass, osteoporosis, conditions which present with low muscle mass,
osteotomy, childhood idiopathic bone toss, bone loss associated with
periodontitES,
bone healing following facial reconstruction, maxillary reconstruction,
mandibular
reconstruction and bone fracture. Further, musculoskeleta# frailty encompasses
such conditions as intertaces between newly attached prostheses and bone which
require bone ingrowth.
CA 02335134 2000-12-14
WO 99/65486 PCT/IB991(t1117
The term "treating", "treat" or "treatment" as used herein includes curative,
preventative (e.g., prophylactic) and palliative treatrnent.
The parenthetical negative or positive sign used herein in the nomenclature
denotes the direction ptane polarized light is rotates! by the particular
stereoisomer.
5 The compositions of this invention may include hydrates of the~compounds
used therein.
The pharmaceutical compositions and methods of this invention result in a
more rapid and higher magnitude bone mass gain than is achievable with the
same doses of (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-
10 tetrahydro-naphthalene-2-of as described above alone or 2-amino-N-j2-(3a-
(R)-
benzy!-2-methyl-3-oxo-2, 3,3a,4,6,7-hexahydro-pyra;zoto-[4, 3-cjpyridin-5-yl)_
1.(R~.
benzyloxyrriethyl-2-oxo-ethyl]-isobutyr~amide as described above alone.
Further,
these combinations increase bone density and muscle mass while at the same
time reducing fat mass and total serum cholesterol. Thus, these combinations
increase bone mass and decrease fracture rates to a greater extent than is
achievable through use of either agent alone. This invention makes a
significant
contribution to the art by providing compositions and methods that increase
and
maintain bone mass resulting in prevention, retardation, and/or regression of
osteoporosis and related bone disorders.
Other features and advantages will be appairent from the speciftcation and
claims which describe the invention.
DETAILED DESCRIPTION OF TFIE INVENTION
The first compound of this invention is (-)-cns-6-phenyl-5-j4-(2-pyrrolidin-1
yl-ethoxyrphenyl]-5,fi,7,8-tetrahydro-naphthalene-2-of or a pharmaceutically
acceptable salt thereof, which has the structure of Formula I:
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72222-421
11
HO
1
(-~-Cis-6-phenyl-5-[4-{2-pyrroiidin-1-yl-ethoxy~-pheny!)-5,6,7,8-tetrahydto-
naphthalene-2-of and the pharmaceutically acceptable sall;s thereof are
prepared
as described in commonly assigned US Patent Number 5,:552,412, which is
referenced above.
{-~-Cis-~6-phenyl-5-[4-{2-pyrrotidin-1-yI-ethoxy}-phenyi~-5,6,7, 8-tetrahydro-
naphthalene-2-of D-tartrate is prepared as set forth in the immediately
preceding
paragraph or, altemativeiy, as set forth in lntema~onal Patent Application
Publication Number W097116434 .
The second compound of this invention is 2-amino-N-[2-(3a-{R~-benzyl-2-
methyf-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazofo-[4,3-cJpyrid!in-5-yl)-1-(RJ-
benzyioxymethyt-2-oxo-e#hyt]-isabutyramide or a pharmaceutically acceptable
salt
thereo#, which has the structure of Formula ti:
Me
nne she
-.
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WO 99/65486 PCT/IB99/01117
12
2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazoto-
[4,3-
c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-is~obutyramide and
pharmaceutically acceptable salts thereof are prep<~red as set forth in
commonly
assigned International Patent Application Publica6a~n Number W097/24369, which
is referenced above.
In addition, when the compounds or the pham~aceutically acceptable salts
thereof of this invention form hydrates or solvates they are also within the
scope of
the invention.
The pharmaceutical combinations and methods of this invention are all
adapted to therapeutic use as agents that either activate bone turnover or
prevent
bone resorption or increase bone formation in m~ammais, particularly humans.
Since these functions are dosely related to the development of osteoporosis
and
bone related disorders, these combinations, by virtue of their action on bone,
prevent, arrest, regress or reverse osteoporosis.
The utility of the compositions and methods of the present invention as
medical agents in the treatment of muscutoskeletal frailty (e.g., conditions
which
present with low bone mass or low muscle ma~,ss including osteoporosis} in
mammals (e.g. humans) is demonstrated by the activity of the compounds of this
invention in conventional assays as set forth in U.S. Patent Number 5,552,412
and
International Patent Application Publication Number W097I24369. Further
evidence of the utility of the instant combination is sEa forth in Example One
below.
Such assays also provide a means whereby' the activities of the compounds of
this invention can be compared between themselves and with the activities of
other knovm compounds. The results of these comparisons are useful for
determining dosage levels in mammals, including humans, for the treatment of
such diseases.
Administration of the compounds of this invE:ntion can be via any method
which delivers a compound of the combination of thi:> invention systemically
and/or
locally. These methods include oral routes, parenteral, intraduodenal routes,
etc.
Generally, the compounds of this invention are administered orally, but
parenteral
administration (e.g., intravenous, intramuscular, transcutaneous, subcutaneous
or
intramedullary) may be utilized, for example, vvhere oral administration is
inappropriate for the instant target or where the patient is unable to ingest
the
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13
drug. The two different compounds of this invention can be co-administered
simultaneously or sequentially in any order, or ,a single phamtaceutical
composition comprising a first compound as described above and a second
compound as described above in a pharmaceutically acceptable carrier can be
administered.
In any event the amount and timing of compounds administered wilt, of
course, be dependent on the subject being treated, on the severity of the
afFlic~ion,
on the manner of administration and on the judgrnent of the prescribing
physician.
Thus, because of patient to patient variability, the dosages given. below are
a
guideline and the physician may titrate doses of the drug to achieve the
activity
(e.g., bone mass augmentation) that the physician considers appropriate for
the
individual patient. In considering the degree of activity desired, the
physician must
balance a variety of factors such as bone mass starting level, age of the
patient,
presence of preexisting disease, as well as pnesence of other diseases (e.g.,
cardiovascular). For example, the administraition of (-)-cis-6-phenyt-5-(4-(2-
pyrrolidin-1-yl-ethoxy)-phenyl}-5,6,7,&tetrahydron~aphthalene-2-of can provide
cardiovascular benefits, par6culacly for post menopausal women. The following
paragraphs provide preferred dosage ranges for the various components of this
invention.
An effective dosage for ~ (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-
phenyl]-5,6,7;&tetrahydro-naphthalene-2-of is in the range of 0.0001 to 100
mg/kglday, preferably 0.001 to 10 mg!!cg/day.
An effective dosage for 2-amino-N-(2-(3a(Ft)'benzyl-2-methyl-3-oxo-2,3, 3a,
4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1 (R)-benzyloxymethyl-2-oxo-
ethyl)-
isobutyramide is in the range of 0.0001 to 100 mg/kglday, preferably 0.01 to 5
mg/kgJday.
Where the tartrate salt or other pharmaceutically acceptable salt of either
of the above compounds is used in this invention, the skilled person will be
able to
calculate effective dosage amounts by calculating the molecular weight of the
salt
form and performing simple stoichiometric ratios.
The' compounds of the present invention acre generally administered in the
form of a pharmaceutical composition comprising <~t least one of the compounds
or
pharmaceutically acceptable salts thereof of i;his invention together with a
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WO 99/65486 PCT/IB99101117
14
pham~aceu~cally acceptable vehicle or diluent. Thus, the compounds and
pharmaceutically acceptable salts thereof of this invention can be
administered
separately or together in any conventional oral, p;arenteral or transdennal
dosage
form. When administered separately, the administration of the other compound
or
a pharmaceutically acceptable salt thereof of the invention follows.
For oral administration a pharmaceutical c~~mposition can take the form of
solutions, suspensions, tablets, pills, capsules, powders, and the tike.
Tablets
containing various excipients such as sodium citrate, calcium carbonate and
calcium phosphate are employed along with various disintegrants such as starch
and preferably potato or tapioca starch and certain complex silicates,
together with
binding agents such as polyvinytpyrrolidone, sucrose, gelatin and acacia.
Additionally, lubricating agents such as magnesium stearate, sodium lauryl
sulfate
and talc are often useful for tabletting purposes. Solid compositions of a
similar
type are also employed as fillers in soft and hard-filled gelatin capsules;
preferred
'I5 materials in this connection also include lactose or milk sugar as well as
high
molecular weight polyethylene glycols. When aquE:ous suspensions and/or
elixirs
are desired for oral administration, the compaunds~ or pharmaceutically
a~p~bte
salts thereof of this invention can be combined with various sweetening
agents,
flavoring agents, coloring agents, emulsifying agents andlor suspending
agents,
as wail as such diluents as water, ethanol, propylene glycol, glycerin and
various
tike combina#ions thereof.
For purposes of parenteral administration, solutions in sesame or peanut oil
or in aqueous propylene glycol can be employed, as well as sterile aqueous
solutions of the corresponding water-soluble salts. Such aqueous solutions may
be suitably buffered, if necessary, and the liquid dilueryt first rendered
isotonic with
sufficient saline or glucose. These aqueous solutions are especially suitable
for
intravenous, intramuscular, subcutaneous and intraperitoneal injection
purposes.
In this connection, the sterile aqueous media employed are all readily
obtainable
by standard techniques well-known to those skilled in the art
For purposes of transdermal (e.g.,topical) administration, dilute sterile,
aqueous or partially aqueous solutions (usually in about 0.1'/o to 5%
concentration), otherwise similar to the above parenteral solutions, are
prepared.
CA 02335134 2000-12-14
WO 99/65486 PCT/IB99/01117
Methods of preparing various pharmaceutical compositions with a certain
amount of each active ingredient are known, or will be apparent in light of
this
.disclosure, to those skilled in this art. For examples, see Remington_'s
Pharmaceutical Saences, Mack Publishing Company, Easton, Pa., 19th ~ Edition
5 {1990).
Pharmaceutical compositions according to the invention may contain 0.1 %-
95% of a combination of the compounds or -pharmaceutically acceptable salts
thereof of this invention, preferably 1~°-70%. In any event, the
composition or
formulation to be administered will contain a nquantity of the compounds or
10 pharmaceutically acceptable salts thereof of the invention in an amount
effective
to treat the diseaselcondition of the subject being treated.
Since the present invention relates to treai;ment with a combination of the
two active ingredients which may be administered separately, the invention
also
relates to combining separate pharmaceutical compositions in kit form. The kit
15 inGudes two separate pharmaceutical compositions: (-)-cis-6..phenyt-5-{4-(2-
pyn-olidin-1-yl-ethoxy~.phenyl)-5,6,7,8-tetrahydronaphthalene-2-o! or a
pharmaceutically acceptable salt thereof and 2-amino-N-(2-(3a(R)-benzyl-2-
methyl-3-oxo-2,3, 3a, 4,6,7-hexahydro-F~yrazolo-j4,3-c]pyridin-5-yl)-1(R)-
benzyloxymethyl-2-oxo-ethylrisobutyramide or a pharmaceutically acceptable
salt
thereof. The kit includes a container for containing the separate compositions
such
as a divided bottle or a divided foil packet, however, the separate
compositions
may also be contained within a single, undivided container. Typically the kit
inGudes directions for the administration of the ,>eparate components. The kit
form is particularly advantageous when the separate components are preferably
administered in different dosage forms (e.g., oral and parenteral), are
administered
at different dosage intervals, or when titration of the individual components
of the
combination is desired by the prescribing physician.
An example of such a kit is a so-called blister pack. Blister packs are well
known in the packaging industry and are being wiidely used for the packaging
of
pharmaceutical unit dosage forms {tablets, capsules, and the like). Blister
packs
generally consist of a sheet of relatively stiff material covered with a foil
of a
preferably transparent plastic material. During the packaging process recesses
are formed in the plastic foil. The recesses have the size and shape ~of the
tablets
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16
or capsules to be packed. Next, the tablets or capsules are pfaced in the
recesses
and the sheet of relatively stiff material is sealed aigainst the plastic foil
at the face
of the foil which is opposite from the direction in which the recesses were
formed.
As a result, the tablets or capsules are seated in tihe recesses between the
plastic
foil and the sheet. Preferably the strength of the sheet is such that the
tablets or
capsules can be removed from the blister pack by manually applying pressure on
the recesses whereby an opening is formed in the sheet at the place of the
recess.
The tablet or capsule can then be removed via said opening.
It is desirable to provide a memory aid on a card insert, e.g., in the form of
numbers next to the tablets or capsules whereby the numbers correspond with
the
days of the regimen which the tablets or capsules :>o speafied should be
ingested.
Another example of such a memory aid is a calendar printed on the card e.g.,
as
follows "First Week, Monday, Tuesday, ...etc;.... Second Week; Monday,
Tuesday,..." etc. Other variations of memory aids will be readily apparent. A
'daily
dose" can be a single tablet or capsule or several spills or capsules to be
taken on
a given day. Also a daily dose of SERM can consi:>t of one tablet or capsule
white
a daily dose of a GH secretagogue can consist of s~everat tablets or capsules.
The
memory aid should retied this.
In another speafic embodiment of the invention a dispenser designed to
dispense the daily doses one at a time in the order of their intended use is
provided. Preferably, the dispenser is equipped with a memory-aid, so as to
further facilitate compliance with the regimen. An example of such a memory-
aid
is a mechanical counter which indicates the number of daily doses that has
been
dispensed. Another example of such a memory-aid is a battery-powered micro
chip memory coupled with a liquid crystal readout, or audible reminder signal
which, for example, reads out the date that the last daily dose has been taken
and/or reminds one when the next dose is to be takE:n.
The following assay is used to show that the combination and methods of
this invention increases lean body mass and decr~aases fat body mass whereas
the GH secretagogue alone would be expected to decrease #at body mass with no
change in lean body mass and the SERM alone would be expected to increase
both lean and fat body mass. Further, the combination increases bone density
and decreases total serum cholesterol.
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17
Example One
Female S-D rats (Harian) were sham-operated or ovariectomized (OVX) at
3.5 months of age. Drug administration started v~~fien the rats were 9 months
of
age and 5.5 months post surgery. The sham-opeu~ated rats received daily gavage
of vehicle (10% ethanol in water), while the OV:~C rats received daily gavage
of
vehide, or 2-amino-N-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-
pyrazolo-[4,3-c)pyridin-5-yt)-1 (R)-benzyloxymethyt-2-oxoethyl~.isobutyramide
at 5
mg/kgJd alone, or (-)cis-6-phenyl-5-(4-(2-PYrrolidin-1-yl-ethoxy)-phenyl)-
5,6,7,$-
tetrahydronaphthalene-2-of at 0.1 mg/kgld atone, or co-treatment of 2-amino-N-
(2-
(3a(R}-benzyt-2-methyl-3-oxo-2,3,3a,4,6,7-hexahycfro-pyrazolo-[4,3-c]pyndin-5-
yI)-
1 (R~benzyioxymethyt-2-oxoethylrisobutyramide and (-)cis-6-phenyl-5-(4-(2_
pyrrolidin-1-yl-ethoxy)-phenyly-5,6,7,&tetrahydronaphthalene-2-o! for 4 weeks.
In
the combination group, 2-amino-N-{2-(3a(R)-ben;zyl-2-methyl-3-oxo-2,3,3a,4,6,7-
hexahydro-pyrazolo-[4,3-cjpyridin-5-yl)-1 (R)-benzyloxymethyt-2-oxoethyt)-
isobutyramide was given 2 hours prior to {-)cis~-6-phenyl-5-(4-(2-py~olidin-1-
y!-
ethoxyrphenytr5,6,7,8-tetrahydronaphthalene-2-ol. There were $ to 10 rats per
each subgroup. Ail rats were given subcutaneous injections. with 10 mg/kg of
calcein (Sigma Chemical Co., St. Louis, MO) on 13 and 3 days before autopsy.
It
wits be recognized by those skilled in the art that the compounds used in this
assay
may be administered in the form of a pharmaceutically acceptable salt and that
the
dosage amount can be readily determined by calculating the molecular weight of
the salt and performing simple ratios.
Before autopsy on the terminal day of the assay, all rats under
ketaminelxylazine anesthesia underwent dual-enercty X ray absorptiornetry
(DXA,
QDR-10001W, Hologic Inc., Waltham, MA) equipped with Rat Whole Body Scan
software (Hotogic Inc.; Waltham, MA) for lean and 'fat body mass
determination.
The rats were then autopsied and blood was obtained by cardiac puncture. Total
serum cholesterol was determined using a high pertormance cholesterol
colorometic assay (Boehringer Mannheim Biochennicals, fndianapolis, IN). Tlie
body weight gain was calculated as body weight at .autopsy minus body weight
at
day 0. The 'uterine wet weight was determined immediately at autopsy.
The right femur from each rat was removed at autopsy and scanned using
dual energy x-ray absorptiometry (DXA, QDR 1000N'd, Hologic inc., Wattham, MA)
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WO 99165486 PCT/IB99/Oll1'7
18
equipped with "Regional High Resolution Scan" software (Holcgic Inc., Wattham,
MA). The scan field size was 5.08 x 1.902 cm, rE~solution is 0.0254 x 0.0127
cm
and scan speed was 7.25 mmlsecond. The femoral scan images were analyzed
and total femoral bone area, bone mineral conteni~ and bone mineral density
were
determined according to the method described in H. Z. Ke et al., Droloxifene,
a
New Estrogen AntagonistlAgonist, Prevents Bone Loss in Ovariectomized Rats.
ENDOCRINOLOGY 136;2435-2441, 1995.
Study Results and Discussion
Compared to the controls, 2-amino-N-{2-(3a(R)-benzyi-2-methyl-3-oxo-
2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-y!;)-1 (R)-benzybxymethyl-2-
oxoethyl)-isobutyramide alone increased both tean and fat body mass; while (
)cis-
6-phenyl-5-{4-{2-pyrrolidin-1-yt-ethoxy)-phenyl)-5,6"7,8-tetrahydronaphthalene-
2-al
alone decreased fat body mass with no change in lean body mass. Combination
of 2-amino-N-(2-(3a(Rj-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-
[4,3-c]pyridin-5-yl)-1 (R)-benzyloxymethyl-2-oxoethy!)-isobutyramide and (
)cis.6-
phenyl-5-{4-(2-pynofidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-
of
increased lean body mass and decreased fat body mass. Therefore, combination
of both compounds have a better body composiition profile than 2-amino-N-(2-
{3a{R)-benzy!-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydlro-pyrazolo-[4,3-c]pyridin-5-
yl)-
1 (R)-benzyloxymethyl-2-oxoethyl)-isobutyramide alone or (-)as-6-phenyl-
5..(4.(2-
pyn-olidin-1-yl-ethoxy)-phenyl)-5,fi,7,8-tetrahydronaphthalene-2-of alone.
A 5-6% increase in total femoral bone area was observed in subjects
receiving the combination relative to those subjects who received placebo.
This
result is similar to the increase in total femoral bone area which was
observed in
subjects receiving either (-)cis-6-phenyl-5-(4-(c!-pYrrolidin-1-yl-ethoxy)-
phenyl)_
5,6,7,8-tetrahydronaphthalene-2-o! or 2-amino-N-(:?-(3a(R)-benzyl-2-methyl_3-
oxo-
2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)..1 (R)-benzyloxymethyl-2-
oxoethyl)-isobutyramide and {-)cis-6-phenyl-5-(4.(2;-pyrrofidin-1-yl-ethoxy)-
phenyt)-
5,6,7,8-tetrahydronaphthalene-2-of alone. Total fiernoral bone mineral content
increased by 8.5% in 2-amino-N-(2-(3a(R)-bent:yl-2-methyl-3-oxo..2,3,3a,4,6,7-
hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1 (R)-benzyfa~xymethy-2-oxoethyt)-
isobutyramide alone and 7.7°~ in (-)cis-6-phenyl-5-(4-(2-pyrrolidin-1-
yl_ethoxy}-
phenyl)-5,6,7,8-tetrahydronaphthaiene-2-of alone. However; in the ~
combination
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WO 99!65486
19
group, total femoral bane mineral content increased by 12.5%, which was a
significant increase compared to either alone. A similar pattern was found in
the
tots! femoral bone mineral density.
Total serum cholesterol decreased in (-)cis-6-phenyl-5-(4-(2-pyrrblidin-1-yl
ethoxy)-phenyl)-5,6,7,8-tetrahydronaphthalene-2-o1 alone group and the
combination group.
These data indicated that combination of 2-amino-N-(2-(3a(R~benzyt-2-
methyt-3-axo-2,3,3a,4,6,7-hexahydro-pyrazolo-j4,3-cjpyridin-5-yl)-1 (R)-
benzyloxymethyl-2-oxoethyl)-isobutyramide and ( )cis-6-phenyl-5-(4-(2-
pyrrolidin-1-
yl-ethoxy)-phenyl)-5,fi,7,8-tetrahydronaphthaiene-2-of, have multiple benefts.
These benefits include an increase in Lean mass and a decrease in fat mass and
senrm lipid. Further, an increase in bone mass was observed.
It should be understood that the invention is not limited to the particular
embodiments described herein, but that various changes and modifications may
be made vri~thout departing from the spirit and scope: of this invention as
defined by
the following clairris.
