Current major diseases or conditions of bone which are of
public concern include post-menopausal osteoporosis, senile
osteoporosis, patients undergoing long-term treatment of
corticosteroids, side effects from glucocorticoid or steroid
treatment, patients suffering from Cushings's syndrome, gonadal
dysgensis, periarticular erosions in rheumatoid arthritis,
osteoarthritis, Paget's disease, osteohalisteresis,
osteomalacia, hypercalcemia of malignancy, osteopenia due to
bone metastases, periodontal disease, and hyperparathyroidism.
All of these conditions are characterized by bone loss,
resulting from an imbalance between the degradation of bone
(bone resorption) and the formation of new healthy bone. This
turnover of bone continues normally throughout life and is the
mechanism by which bone regenerates. However, the conditions
stated above will tip the balance towards bone loss such that
the amount of bone resorbed is inadequately replaced with new
bone, resulting in net bone loss.
One of the most common bone disorders is post-menopausal
osteoporosis which affects an estimated 20 to 25 million women
in the United States alone. Women after menopause experience an
increase in the rate of bone turnover with resulting net loss of
bone, as circulating estrogen levels decrease. The rate of bone
turnover differs between bones and is highest in sites enriched
with trabecular bone, such as the vertebrae and the femoral
head. The potential for bone loss at these sites immediately
following menopause is 4-5% per year. The resulting decrease in
bone mass and enlargement of bone spaces leads to increased
fracture risk, as the mechanical integrity of bone deteriorates
rapidly.
At present, there are 20 million people with detectable
vertebral fractures due to osteoporosis and 250,000 hip
fractures per year attributable to osteoporosis in the U.S. The
latter case is associated with a 12% mortality rate within the
first two years and 30% of the patients will require nursing
home care after the fracture. Therefore, bone disorders are
characterized by a noticeable mortality rate, a considerable
decrease in the survivor's quality of life, and a significant
financial burden to families.
Essentially all of the conditions listed above would
benefit from treatment with agents which inhibit bone
resorption. Bone resorption proceeds by the activity of
specialized cells called osteoclasts. Osteoclasts are unique in
their ability to resorb both the hydroxyapatite mineral and
organic matrix of bone. They are somewhat similar to the
cartilage resorbing cells, termed chondroclasts. It is for this
reason that potent inhibitors of osteoclastic bone resorption
may also inhibit the cell-mediated degradation of cartilage
observed in rheumatoid arthritis and osteoarthritis.
Therapeutic treatments to impede net bone loss include the
use of estrogens. Estrogens have been shown clearly to arrest
the bone loss observed after menopause and limit the progression
of osteoporosis; but patient compliance has been poor because of
estrogen side-effects. These side effects include resumption of
menses, mastodynia, increase in the risk of uterine cancer, and
possibly an increase in the risk of breast cancer.
Alternatively, calcitonxn has been used to treat
osteoporotic patients. Salmon calcitonin has been shown to
directly inhibit the resorption activity of mammalian
osteoclasts and is widely prescribed in Italy and Japan.
However, calcitonins are prohibitively expensive to many and
appear to be short-lived in efficacy. That is, osteoclasts are
able to "escape" calcitonin inhibition of resorption by down-
regulating calcitonin receptors. Therefore, recent clinical
data suggest that chronic treatment with calcitonin may not have
long term effectiveness in arresting the post-menopausal loss of
bone. There continues to be great interest in research directed
to novel therapies to inhibit bone loss.
This invention provides a novel method for
inhibiting bone loss comprising administering to a human in need
thereof a first compound selected from 1) triarylethylenes; 2)
2,3-diaryl-2H-1-benzopyrans, 3) 1-aminoalkyl-2-phenylindoles; 4)
2-phenyl-3-aroylbenzothiophenes, 5) 1-substituted-2-aryl-
dihydronaphthalenes; or 6) benzofurans; and a second compound
being a bisphosphonate, or pharmaceutically acceptable salts and
solvates thereof.
Also encompassed by the invention are combination
pharmaceutical formulations and salts.
This invention concerns the discovery that combination
therapy for humans, comprising administering a component from
the first group of compounds, as defined above, with a
bisphosphonate, is useful in the inhibition of bone loss. The
therapy may be sequential, concurrent or simultaneous, with the
latter two being preferred.
The general chemical terms used in the description of
the compounds of this invention have their usual meanings. For
example, the term "alkyl" by itself or as part of another
substituent means a straight or branched chain alkyl radical
having the stated number of carbon atoms such as methyl, ethyl,
propyl, and isopropyl and higher homologues and isomers where
indicated.
The term "alkoxy" means an alkyl group having the
stated number of carbon atoms linked to the parent moiety by an
oxygen atom, such as methoxy, ethoxy, propoxy, butoxy,
pentyloxy, and hexyloxy and also includes branched chain
structures such as, for example, isopropoxy and isobutoxy.
The term "substituted alkyl" includes an alkyl
substituted once or more with substitutents known in the art.
As this term is used in conjunction with the bisphosphonates,
those references in this art would disclose such substitutents.
The term "C1-C7-alkanoyloxy" means a group -O-C(O)-Ra
where Ra is hydrogen or C1-C6 alkyl and includes formyloxy,
acetoxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy,
and the like and also includes branched chain isomers such as,
for example, 2,2-dimethylpropanoyloxy, and 3,3-
dimethylbutanoyloxy.
Analogously, the term C4-C7 cycloalkanoyloxy" means a
group -O-C(O)-(C3-C6 cycloalkyl) where the C3-C6 alkyl group
includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "(C1-C6-alkoxy)-C1-C7-alkanoyloxy" means a
group -O-C(O)-Rb-O-(C1-C6 alkyl) where Rb is a bond (C1-C6
alkoxycarbonyloxy) or C1-C6 alkanediyl and includes, for
example, methoxycarbonyloxy, ethoxycarbonyloxy,
propoxycarbonyloxy, butoxycarbonyloxy, methoxyacetoxy,
methoxypropanoyloxy, methoxybutanoyloxy, methoxy-pentanoyloxy,
methoxyhexanoyloxy, ethoxyacetoxy, ethoxypropanoyloxy,
ethoxybutanoyloxy, ethoxypentanoyloxy, ethoxyhexanoyloxy,
propoxyacetoxy, propoxypropanoyloxy, propoxybutanoyloxy, and the
like.
The term "unsubstituted or substituted aroyloxy" means
a group -O-C(O)-aryl where aryl is a phenyl, naphthyl, thienyl
or furyl group that is, as to each group, unsubstituted or
monosubstituted with a hydroxyl, halo, C1-C3 alkyl, or C1-C3
alkoxy.
The term "unsubstituted or substituted
aryloxycarbonyloxy" means a group -O-C(O)-O-aryl where aryl is a
phenyl, naphthyl, thienyl or furyl group that is, as to each
group, unsubstituted or monosubstituted with a hydroxyl, halo,
C1-C3 alkyl or C1-C3 alkoxy.
The term "halo" means chloro, fluoro, bromo or iodo.
The term "inhibit" is defined to include its generally
accepted meaning which includes preventing, prohibiting,
restraining, and slowing, stopping or reversing progression, or
severity, and holding in check and/or treating existing
characteristics. The present method includes both medical
therapeutic and/or prophylactic treatment, as appropriate.
The term "pharmaceutically acceptable salts" refers to
salts of the compounds of the above classes which are
substantially non-toxic to living organisms. Typical
pharmaceutically acceptable salts include those salts prepared
by reaction of a compound of the above class with a
pharmaceutically acceptable mineral or organic acid, or a
pharmaceutically acceptable alkali metal or organic base,
depending on the types of substituents present on the compound.
Examples of pharmaceutically acceptable mineral acids
which may be used to prepare pharmaceutically acceptable salts
include hydrochloric acid, phosphoric acid, sulfuric acid,
hydrobromic acid, hydroiodic acid, phosphorous acid and the
like. Examples of pharmaceutically acceptable organic acids
which may be used to prepare pharmaceutically acceptable salts
include aliphatic mono and dicarboxylic acids, oxalic acid,
carbonic acid, citric acid, succinic acid, phenyl-substituted
alkanoic acids, aliphatic and aromatic sulfonic acids and the
like. Such pharmaceutically acceptable salts prepared from
mineral or organic acids thus include hydrochloride,
hydrobromide, nitrate, sulfate, pyrosulfate, bisulfate, sulfite,
bisulfite, phosphate, monohydrogenphosphate,
dihydrogenphosphate, metaphosphate, pyrophosphate, hydroiodide,
hydrofluoride, acetate, propionate, formate, oxalate, citrate,
lactate, p-toluenesulfonate, methanesulfonate, maleate, and the
like.
Many compounds of the above classes which contain a
carboxy, carbonyl, or hydroxy or sulfoxide group may be
converted to a pharmaceutically acceptable salt by reaction with
a pharmaceutically acceptable alkali metal or organic base.
Examples of pharmaceutically acceptable organic bases which may
be used to prepare pharmaceutically acceptable salts include
ammonia, amines such as triethanolamine, triethylamine,
ethylamine, and the like. Examples of pharmaceutically
acceptable alkali metal bases included compounds of the general
formula MOZ, where M represents an alkali metal atom, e.g.
sodium, potassium, or lithium, and Z represents hydrogen or C1-
C4 alkyl.
It should be recognized that the particular anion or
cation forming a part of any salt of this invention is not
critical, so long as the salt, as a whole, is pharmacologically
acceptable and as long as the anion or cationic moiety does not
contribute undesired qualities.
In addition, some of the compounds disclosed as useful
in the methods of the present invention may form solvates with
water or common organic solvents. Such solvates are included
within the scope of the present invention and solvates thereof.
The class of compounds known as bisphosphonates
includes those compounds which contains a di-phosphonic acid
moiety separated by a carbon link and include a variety of side-
chains, usually containing a basic function. The compounds have
the following general structure:

Y1, R1 and R2 may be those substitutents as defined in US Patent
5,139,786, and EPO Publication 0416689A2, published March 13,
1991, incorporated herein by reference, although not limited to
such.
Pharmacologically, these compounds have been shown to slow
or stop bone resorption by inhibiting osteoclast cell function.
Several compounds of this class are currently undergoing
clinical evaluation for the treatment of post-menopausal
osteoporosis. Many of these compounds are also being evaluated
for the treatment of Paget's Disease and hypercalcemia
malignancy and several have been approved.
The art refers to three different generations of
bisphosphonates. The first generation usually refers to the
compound etidronate. This compound is being marketed for the
treatment of Paget's disease and hypercalcemia malignacy.
The second generation of bisphosphonates refers to the
compounds clodronate and pamidronate. Clodronate is marketed
for Paget's disease and hypercalcemia maligancy. Pamidronate
will probably be approved for osteoporosis in some European
countries in the near future.
The third generation of bis-phosphonates refer to
alendronate, residronate, and tiludronate and a host of lesser
known compounds. Pharmacologically, these compounds are much
more potent and are claimed to have fewer side-effects.
The structures of some bisphosphonate compounds are as
follows:
Preferred are alendronate, pamidronate, risedronate,
cycloheptylaminomethylidene bis phosphonate, and 3-pyrolidenyl-
1-hydroxy-propylidene bisphosphosphonate, and salts and solvates
thereof.
Bisphosphonates appear to have the potential of treating
osteoporosis; however, they also apppear to have potential
detrimental side-effects:
1) they have the potential of inhibiting bone formation as
well as resorption;
2) they are poorly adsorbed via oral adminstration and are
known to cause G.I. irritation;
3) they have extremely long half-lives in bone;
4) they may all have the potential for causing
osteomalacia; and
5) there is concern as to the bio-mechanical strength of
the bones treated with bis-phosphonates.
In general, it is felt that these compounds may have great
promise for treating osteoporosis; however, there is concern as
to their long term effects
Therefore, it is reasonable that the minimal exposure of
the osteoporotic patient to these compounds would be desirable.
Reducing exposure without sacrificing efficacy might be
achievable by either using the bis-phosphonates for a limited
period of time (cyclically) or by enhancing their efficacy by
the inclusion of another anti-resorptive agent, working by a
different mechanism of action.
The first class of compounds to be therapeutically
combined with a bisphosphonate comprises triarylethylenes.
These compounds are widely known and are disclosed in and
prepared according to procedures described in U. S. Patent
4,536,516; U.S. Patent No. 2,914,563; Ogawa, et al., Chem.
Pharm. Bull., 39(4), 911 (1991) which are all incorporated by
reference herein, in their entirety. Specific illustrative
compounds within this class include Tamoxifene, Clomiphene and
(Z)-4-[1-[4-[2-dimethylamino)ethoxy]phenyl]-2-(4-
isopropylphenyl)-1-butenyl]phenyl monophosphate.
The triarylethylenes include compounds having the
formula

where R is a basic ether group of the formula -OCnH2nA where n
is 2, 3 or 4 and A is a dialkylamino group where the alkyl
groups independently contain from 1 to 4 carbon atoms or a
cyclic structure selected from N-piperidinyl, N-pyrrolidinyl, N-
morpholinyl, and N-hexamethyleneimino; each R1 is independently
hydrogen, hydroxy, halogen or methoxy; and pharmaceutically
acceptable salts and solvates thereof.
U.S. Patent 4,536,516 describes Tamoxifene, a
triarylethylene having the formula

and pharmaceutically acceptable acid addition salts and solvates
thereof, and discloses methods of synthesis.
Similarly, U.S. Patent 2,914,563 describes
triarylethylenes having the formula

where
R is a basic ether group of the formula -OCnH2nA where
n is 2,3 or 4 and A is a dialkylamino group where the alkyl
groups independently contain from 1 to 4 carbon atoms or a
cyclic structure such as N-piperidinyl, N-pyrrolidinyl or N-
morpholinyl group. The group -OCnH2nA is bonded to the phenyl
ring para to the carbon atom bonded to the ethylene group. Each
R1 is independently hydrogen, hydroxy, halogen or methoxy; X is
halogen; and pharmaceutically acceptable salts and solvates
thereof. Methods of synthesizing these compound are disclosed
therein.
In Ogawa et al., supra, triarylethylenes are disclosed
having the formula

where R2 and R3 are independently selected from hydrogen and
methyl;
R4 is isopropyl, isopropen-2-yl, or mono or dihydroxy
isopropyl;
R5 is hydroxy or phosphate (-OPO3H2); and
pharmaceutically acceptable salts and solvates thereof.
This article also discloses synthesis of these compounds.
In addition, US Patent 5,254,594 and EPO 054,168 describe
droloxifene, a triarylethylene having the formula

A second class of compounds comprises the 2,3-diaryl-
2H-1-benzopyrans. These compounds are disclosed in and prepared
according to procedures described in EP 470 310A1. and Sharma,
et al., J. Med. Chem., 33. 3210, 3216, 3222 (1990) which are
incorporated by reference herein in their entirety. Specific
illustrative compounds within this class include 2-[4-[2-(1-
piperidinyl)ethoxy]phenyl]-3-[4-hydroxyphenyl]-2H-1-benzopyran;
2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-3-phenyl-7-methoxy-2H-1-
benzopyran; 2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-3-[4-
hydroxyphenyl]-7-hydroxy-2H-1-benzopyran.
EP 47 0 310 Al describes benzopyrans having the formula

where
R6 and R7 are the same or different hydrogen hydroxy,
C1-C17 alkoxy or C2-C18 alkanoyloxy;

and pharmaceutically acceptable salts and solvates thereof.
Synthesis of these benzopyrans is described therein.
A third class of compounds comprises the 1-aminoalkyl-
2-phenylindoles. These compounds are disclosed in and prepared
according to procedures described in von Angerer, et al., J.
Med. Chem., 33, 2635 (1990) which is incorporated by reference
herein in its entirety.
The 1-aminoalkyl-2-phenylindoles described in von
Angerer et al., supra, are those having the formula

where
R9 is hydrogen or methyl;
R10 and R11 are methoxy or hydroxy;
m is 4 to 8;
Y is NR12R13 where R12 and R13 are independently
selected from hydrogen, methyl and ethyl or one of R12 or R13 is
hydrogen and the other is benzyl or are combined with the
nitrogen atom to constitute a pyrrolidinyl, piperidinyl or
morpholinyl group, and pharmaceutically acceptable salts and
solvates thereof. Procedures for synthesizing these compound
are specifically disclosed or referenced therein.
A fourth class of compounds comprises the 2-phenyl-3-
aroylbenzo[b]thiophenes; (Z-triarylpropenones). These compounds
are disclosed in and prepared according to procedures described
in U.S. Patent No. 4,133,814; U.S. Patent No. 4,418,068; and
Jones, et al., J. Med. Chem. , 27., 1057-1066 (1984) which are all
incorporated by reference herein in their entirety. specific
illustrative compounds within this class include Raloxifene [6-
hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-
piperidinyl)ethoxy]phenyl]methadone hydrochloride, formerly
keoxifene; and [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-
yl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone Hydrochloride.
The 2-phenyl-3-aroylbenzo[b]thiophenes are exemplified
by those in U.S. Patent 4,133,814 and have the formula

where
R16 is hydrogen, hydroxy, C1-C5 alkoxy, C1-C7
alkanoyloxy, C3-C7 cycloalkanoyloxy, (C1-C6 alkoxy)-C1-C7
alkanoyloxy, substituted or unsubstituted aroyloxy, or
substituted or unsubstituted aryloxycarbonyloxy;
R17 is hydrogen, hydroxy, C1-C5 alkoxy, adamantoyloxy,
chloro, bromo, C1-C7 alkanoyloxy, C3-C7 cycloalkanoyloxy, (C1-C6
alkoxy)-C1-C7 alkanoyloxy, substituted or unsubstituted
aroyloxy, or substituted or unsubstituted aryloxycarbonyloxy;
R18 is -O-CH2-CH2-X'-NR19R20; x' is a bond or -CH2-,
R19 and R20 are independently C1-C4 alkyl or are taken together
with the nitrogen atom to which they are bonded to constitute a
pyrrolidinyl, piperidinyl, hexamethyleneiminyl, or morpholinyl
ring; and pharmaceutically acceptable acid addition salts and
solvates thereof.
Methods of synthesizing these compounds are disclosed
in U.S. Patent 4,133,814. Raloxifene, and its preparation, are
described in U.S. Patent 4,418,068.
A fifth class of compounds comprises the 1-
substituted-2-aryl-dihydronaphthalenes. These compounds are
disclosed in and prepared according to procedures described in
U.S. Patent Nos. 4,400,543; 4,323,707; 4,230,862; and 3,274,213
which are all incorporated by reference herein in their
entirety. Specific illustrative compounds within this class
include Nafoxidene and Trioxifene.
The l-substituted-2-aryl-dihydronaphthalenes are
exemplified by U.S. Patent 4,230,862 that describes compounds
having the formula:

where
Z is -CH2-CH2- or -CH=CH-;
R16 is hydrogen, hydroxy or C1-C5 alkoxy;
R17 is hydrogen, hydroxy, C1-C5 alkoxy, C1-C5 acyloxy,
C1-C5 alkoxycarbonyloxy, benzyloxy, adamantoyloxy, chloro, or
bromo
R18 is C1-C5 alkoxy or -O-CH2-CH2-NR19R20; and R19 and
R20 are independently C1-C4 alkyl or are taken together with the
nitrogen atom to which they are bonded to constitute a
pyrrolidinyl, piperidinyl, hexamethyleneimino, or morpholinyl
ring; and pharmaceutically acceptable acid addition salts and
solvates thereof.
Methods of synthesizing these compound are disclosed
in U.S. Patent 4,230,862.
The l-substituted-2-aryl-dihydronaphthalenes are also
exemplified by U.S. Patent 3,274,213 that describes compounds
having the formula

where
R19 and R20 are C1-C8 alkyl or are taken together with
the nitrogen atom to which they are bonded to form a 5 to 7
membered saturated heterocyclic radical selected from
pyrrolidinyl, 2-methylpyrrolidinyl, 2,2 dimethylpyrrolidinyl,
piperazinyl, 4-methylpiperazinyl, 2,4-dimethylpiperazinyl,
morpholinyl, piperidinyl, 2-methylpiperidinyl, 3-
methylpiperidinyl, hexamethyleneiminyl, homopiperazinyl, and
homomorpholinyl;
q is 2 to 6;
p is 1 to 4;
R21 is C1-C8 alkoxy; and
pharmaceutically acceptable salts and solvates thereof.
Methods of synthesizing these compounds are disclosed
therein.
A sixth class of compounds comprises the 2-
substituted-3-aryl-benzofurans. These compounds are disclosed
in and prepared according to procedures described in Teo et al.,
J. Med. Chem., 35 , 1330-1339 which is incorporated by reference
herein in its entirety.
The 2-substituted-3-aryl-benzofurans described in Teo
et al., J. Med. Chem., 35, 1330-1339 (1992) includes those
having the formula

where X2 is halo;
Y2 is a bond or -CH2-;
R22 is hydrogen or methyl;
R23 is a group -NR19R20, where R19 and R20 are
independently C1-C4 alkyl or are taken together with the
nitrogen atom to which they are bonded to constitute a
pyrrolidinyl, piperidinyl, hexamethyleneiminyl or morpholinyl
ring; and
pharmaceutically acceptable salts and solvates
thereof.
Methods of synthesizing these compound are also
disclosed therein.
The preferred class of compounds useful in the methods
of the present invention are the benzothiophenes. More
preferred are benzothiopenes having the formula:

wherein
X1 is a bond or -CH2-;
R16 is hydroxyl, methoxy, C1-C7 alkanoyloxy, C3-C7
cycloalkanoyloxy, (C1-C6 alkoxy)-C1-C7 alkanoyloxy, substituted or
unsubstituted aroyloxy, or substituted or unsubstituted
aryloxycarbonyloxy;
R17 is hydrogen, hydroxyl, chloro, bromo, methoxy, C1-C7
alkanoyloxy, C3-C7 cycloalkanoyloxy, (C1-C6 alkoxy)-C1-C7
alkanoyloxy, substituted or unsubstituted or aroyloxy, or
substituted or unsubstituted aryloxycarbonyloxy;
Y1 is a heterocyclic ring selected from the group
consisting of pyrrolidinyl, piperidinyl, or hexamethyleneiminyl;
and pharmaceutically acceptable salts and solvates thereof.
Particularly preferred are raloxifene and its pyrrolidinyl
analog.
Included within the scope of this invention are salt
formation products, preferably consisting of one molecule of the
acidic bis-phosphonate and one molecule of the basic compound of
the first group. Preferred salts are raloxifene/alendronate;
raloxifene/pamidronate; raloxifene/risedronate;
raloxifene/cycloheptyl amino methylidene bisphosphonate, and
raloxifene/3-pyrolidenyl-1-hydroxy propylidene bisphosphonate.
The compounds utilized in the method of the present
invention are effective over a wide dosage range. For example,
dosages of compounds of the first group per day will normally
fall within the range of about 0.01 to about 1000 mg/kg of body
weight. In the treatment of adult humans, the range of about 10
to about 600 mg/day, in single or divided doses, is preferred.
The amount of bisphonate will fall within 5 mg/day at 400
mg/day. However, it will be understood that the amount of the
compounds actually administered will be determined by a
physician in light of the relevant circumstances including the
condition to be treated, the choice of compounds to be
administered, the age, weight, and response of the individual
patient, the severity of the patient's symptoms and the chosen
route of administration. Therefore, the above dosage ranges are
not intended to limit the scope of the invention in any way.
While the present compounds are preferably administered orally,
the compounds may also be administered by a variety of other
routes such as the transdermal, subcutaneous, intranasal,
intramuscular and intravenous routes.
While it is possible to administer the compounds
directly, the compounds are preferably employed in the form of a
pharmaceutical formulation comprising a pharmaceutically
acceptable carrier, diluent or excipient and a compound of the
invention. Such formulations will contain from about 0.01
percent to about 99 percent of the compounds.
In making the formulations of the present invention,
the active ingredients will usually be mixed with at least one
carrier, or diluted by at least one carrier, or enclosed within
a carrier which may be in the form of a capsule, sachet, paper
or other container. When the carrier serves as a diluent, it
may be a solid, semi-solid or liquid material which acts as a
vehicle, excipient or medium for the active ingredient. Thus,
the formulations can be in the form of tablets, granules, pills,
powders, lozenges, sachets, cachets, elixirs, emulsions,
solutions, syrups, suspensions, aerosols (as a solid or in a
liquid medium) and soft and hard gelatin capsules.
Examples of suitable carriers, diluents and excipients
include lactose, dextrose, sucrose, sorbitol, mannitol,
starches, gum acacia, calcium phosphate, alginates, liquid
paraffin, calcium silicate, microcrystalline cellulose,
polyvinyl pyrrolidone, cellulose, tragacanth, gelatin, syrup,
methyl cellulose, methyl- and propyl-hydroxybenzoates, vegetable
oils, such as olive oil, injectable organic esters such as ethyl
oleate, talc, magnesium stearate, water and mineral oil. The
formulations may also include wetting agents, lubricating,
emulsifying and suspending agents, preserving agents, sweetening
agents, perfuming agents, stabilizing agents or flavoring
agents. The formulations of the invention may be formulated so
as to provide quick, sustained or delayed release of the active
ingredient after administration to the patient by employing
procedures well-known in the art.
For oral administration, the compounds can be admixed
with carriers and diluents and molded into tablets or enclosed
in gelatin capsules.
The compositions are preferably formulated in a unit
dosage form, each dosage containing from about 1 to about 500
mg, more usually about 5 to about 300 mg, of the active
ingredient. The term "unit dosage form" refers to physically
discrete units suitable as unitary dosages for human subjects
and other mammals, each unit containing a predetermined quantity
of active material calculated to produce the desired therapeutic
effect, in association with a suitable pharmaceutical carrier,
diluent or excipient therefor.
More particularly, there are three different, basic
formulations envisioned within this invention.
1) Separate, co-administered dosage formulations
This formulation consists of each drug separately formulated for
parenteral or oral adminstration in manners well known to those
skilled in the art and as particularly taught in references of
each of the compounds cited. Because two separate formulations
are being co-adminstered, each formulation, especially those by
the oral route, would be color-coded or otherwise easily
indentifiably labelled to avoid confusion by both patient or
physician. Since a concept of this invention is to minimize the
exposure of the patient to high doses of the bisphosphonate
while maximizing the efficacy, the envisioned protocols for use
of this invention would necessiate a short term or cyclic use of
the bis-phosphonate and a continous use of a compound of the
first group.
2) Single Mixture Formulations
One way to avoid possible confusion and which would
allow for various strengths of the two different drugs would be
to combine the two entities in a simple mixture in forms well
known and taught in the art. A patient could an orange tablet
containing 50 mg of, for example, raloxifene and 25 mg of
risedronate, once a day, for two weeks, followed in continuance
of the blue tablet of 50mg of raloxifene.
3) Single Molar Defined Salt Formulations
This formulation, where each drug is preferably the
counter ion for the other, would lead to a salt of defined
chemical composition. This would aid in consistancy and
homogeneity of the preparation and may aid in absorption of the
bis-phosphonate by oral adminstration.
Since there is a great deal of concern about the side-
effects of bis-phosphonate therapy, prolonged, continous use of
the bis-phosphonate would not be recommended, rather a cyclic
regiment would be more appropriate. An example of such a cyclic
protocol is taught in the art in regard to the use of bis-
phosphonates in the treatment of Paget's Disease and
specifically for the treatment of osteoporosis in "Watts, N.B.,
et al., The New England J. of Medicine, 323(2), p.73-79.
In order to more fully illustrate the operation of
this invention, the following examples of formulations are
provided. The examples are illustrative only and are not
intended to limit the scope of the invention. The formulations
may employ as active ingredients any of the compounds described
above.

The above ingredients are mixed and filled into hard
gelatin capsules in 460 mg quantities.
The active ingredient(s), cellulose, starch and
magnesium stearate are blended, passed through a No. 45 mesh
U.S. sieve and filled into a hard gelatin capsule.
FORMULATION 3
Capsules each containing 100 mg of active
ingredient(s) are made as follows:
The above ingredients are thoroughly mixed and placed
in an empty gelatin capsule.
The active ingredient(s), starch and cellulose are passed
through a No. 45 mesh U.S. sieve and mixed thoroughly. The
solution of polyvinylpyrrolidone is mixed with the resultant
powders which are then passed through a No. 14 mesh U.S. sieve.
The granule so produced is dried at 50°-60°C and passed through
a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch,
magnesium stearate and talc, previously passed through a No. 60
mesh U.S. sieve, are then added to the granule which, after
mixing, is compressed on a tablet machine to yield a tablet
weighing 100 mg.
The components are blended and compressed to form
tablets each weighing 665 mg.
The medicament is passed through a No. 45 mesh U.S.
sieve and mixed with the sodium carboxymethylcellulose and syrup
to form a smooth paste. The benzoic acid solution, flavor and
color is diluted with some of the water and added, with
stirring. Sufficient water is then added to produce the
required volume.

The active compound(s) are mixed with ethanol and the
mixture added to a portion of the propellant 22, cooled to -30°C
and transferred to a filling device. The required amount is
then fed to a stainless steel container and diluted further with
the remaining amount of propellant. The valve units are then
fitted to the container.
The following is an example of the preparation of a salt
formula between a bisphosphonate and a compound from group 1.
Combination Salt of [2-(4-Hydroxyphenyl)-6-hydroxybenzo[B]thien-
3-yl] [4-[2-(1-piperidenyl)ethoxylphenyl]methanone and 4-amino-
1-hydroxybutyl-1,1-bis phosphonate
2.37g of [2-(4-hydroxyphenyl)-6-hydroxybenzo[B]thien-3-
yl]4-[2-(1-piperidenyl)ethoxy]phenyl] methanone (0.0 05 mol) was
dissolved in 25 mL of EtOH.
1.36g of 4-amino-1-hydroxybutyl-1, 1-bisphosphonate mono
sodium (0.005 mol) was dissolved in 25 mL of water and 5 mL of
1N HCl (0.005) was added. The reaction mixture was evaporated
to a gummy white solid and redissolved in 10 mL of water. This
aqueous solution was then added to the EtOH solution prepared
above. This reaction mixture was heated on a steam bath for one
hour in order to dissolve all the components. The reaction
mixture was evaporated to a white amorphous powder and dried
under vaccuum at room temperature for 24-hours.
This yielded 3.6 g of the title compound as a white
amorphous powder.
MS: m/e=780 (M-1)
474 (Raloxifene base +1)
309 (Bis-phosphonate-NaCl +1)
EA: Clac: C, 49.21; h,5.16; N,3.59 Found: C,41.80; H, 5.06;
N,3.57.
In the following, a model of post-menopausal
osteoporosis was used in which effects of different treatments
upon femur density were determined.
Seventy-five day old female Sprague Dawley rats
(weight range of 225 to 275 g) were obtained from Charles River
Laboratories (Portage, MI). They were housed in groups of 3 and
had ad libitum access to food (calcium content approximately 1%)
and water. Room temperature was maintained at 22.2° ± 1.7° C
with a minimum relative humidity of 40%. The photoperiod in the
room was 12 hours light and 12 hours dark.
One week after arrival, the rats underwent bilateral
ovariectomy under anesthesia (44 mg/kg Ketamine and 5 mg/kg
Xylazine (Butler, Indianapolis, IN) administered
intramuscularly). Treatment with vehicle or the indicated
compound was initiated either on the day of surgery following
recovery from anesthesia or 35 days following the surgery.
Oral dosage was by gavage in 0.5 mL of 1%
carboxymethylcellulose (CMC).
Body weight was determined at the time of surgery and
weekly during the study, and the dosage was adjusted with
changes in body weight. Vehicle-treated ovariectomized (ovex)
rats and non-ovariectomized (intact) rats were evaluated in
parallel with each experimental group to serve as negative and
positive controls.
The rats were treated daily for 3 5 days (6 rats per
treatment group) and sacrificed by decapitation on the 36th day.
The 35-day time period was sufficient to allow maximal reduction
in bone density, measured as described infra. At the time of
sacrifice, the uteri were removed, dissected free of extraneous
tissue, and the fluid contents were expelled before
determination of wet weight in order to confirm estrogen
deficiency associated with complete ovariectomy. Uterine weight
was routinely reduced about 75% in response to ovariectomy. The
uteri were then placed in 10% neutral buffered formalin to allow
for subsequent histological analysis.
The right femurs are excised and scanned at the distal
metaphysis proximal from the growth plate region by grey scale
image analysis of digitalized X-ray generation on a Nicolet NXR-
1200 real time X-ray imaging system. Additional image analysis
was performed with NIH Image (1.45) software Relative density
of bone was assayed over the lower end of the grey scale
(therefore highest density range to demonstrate activity).
One of the major concepts put forth in the IDM of the use
of Raloxifene and Bis-phosphonates for the treatment of
osteoporosis was the concept of limiting the exposure of the
patient to the potential side-effects of bis-phosphonates. We
have done some further studies combinding other hormonally
acting drugs with bis-phosphonates to see if Raloxifene has a
unique profile when used in this modality. The data presented
below demonstrate that raloxifene when used in combination with
alendronate does have a different and more beneficial profile.
In Table 1, Alendronate (ALN) was combind with Provera (a
synthetic Progestin) and tested in the 5-week ovex rat model of
post-menopausal osteoporosis. As can be seen, at the two doses
of Provera (1 and 10 mg/kg) and ALN at 0.1mg/kg, there was no
protection from bone loss. The high dose of ALN (lmg/kg) had to
be used to gain protection, even though at 10 mg/kg of provera
had a protective effect by itself. This in contrast to RAL and
ALN (93-11), where the low dose of RAL (O.lmg/kg) and ALN
(O.lmg/kg) gave some protection from bone loss. At the high
doses of either compound when given in combination, there seems
to be little contribution by the Provera.
In Table 2, Alendronate was combined with ethynylestradiol
(EE2, a synthetic estrogen), these results were similar to the
raloxifene and alendronate combination, except that the total
protection with Raloxifene and alendronate was superior. Again
keeping in mind the concept of iimiting the exposure to
alendronate, EE2 at both 30 and 100 ug/kg and alendronate at
0.1mg/kg could not achieve the complete protection of bone loss
seen with the intact controls. The dose of Alendronate had to
be increased to see that level of activity. In contast, in
Table 3, virtually complete protection could be achieved with
Raloxifene at 1 mg/kg and alendronate at 0.1 mg/kg.
In summary, each of the four agents tested could afford
some level of protection against bone loss in this model when
used alone. Alendronate and Provera demonstrated the least
interactive effects. EE2 and raloxifene plus alendronate did
show interactive effects. However, raloxifene and alendronate
in combination demonstrated the greatest protection from bone
loss with the lowest exposure to the potentially undesirable
side-effects of alendronate.
(It should be noted that when viewing the attached
biological data @0.1mg/kg of alendronate and 0.1 mg/kg of
raloxifene, this combination gave good anti-resorptive activity
even though each compound separately was inactive. The molar
ratio of the two compounds was 1:2 (raloxifene:alendronate) in
this assay. It would seem very likely that a salt form with a
1:1 molar ratio, given at a slightly higher dose would be
effective, whereas the two compounds if given separately might
not.)
WE CLAIM
1. A pharmaceutical formulation adapted for
inhibiting bone loss in conjunction with a bisphosphonate
in humans which comprises as an active ingredient a first
compound selected from 1) triarylethylenes; 2) 2,3-diaryl-
2H-1-benzopyrans, 3) 1-aminoalkyl-2-phenylindoles; 4) 2-
phenyl-3-aroylbenzothiophenes, 5) 1-substituted-2-aryl-
dihydronaphthalenes; and 6) benzofurans, and
pharmaceutically acceptable salts and solvates thereof.
2. The pharmaceutical formulation of Claim 1
wherein said bisphosphnate is selected from alendronate,
pomidronate, risedronate, cycloheptyl amino methyl idine
bisphosphonate, and 3-pyrolidonyl-1-hydroxy propylidene
bisphosphonate.
3. The formulation of Claim 1 wherein said
first compound is a 2-phenyl-3-aroylbenzo[b]thiophene
having the formula

where
R16 is hydrogen, hydroxy or C1-C5 alkoxy C1-C7
alkanoyloxy, C3-C7 cycloalkanoyloxy, (C1-C6 alkoxy)-C1-C7
alkanoyloxy, substituted or unsubstituted aroyloxy, or
substituted or unsubstituted aryloxycarbonyloxy;
R17 is hydrogen, hydroxy, C1-C5 alkoxy,
adamantoyloxy, chloro, bromo, C1-C7 alkanoyloxy, C3-C7
cycloalkanoyloxy, (C1-C6 alkoxy)-C1-C7 alkanoyloxy,
substituted or unsubstituted aroyloxy, or substituted or
unsubstituted aryloxycarbonyloxy;
R18 is -O-CH2-CH2-X'-NR19R20;
X' is a bond or -CH2-, R19 and R20 are independently C1-C4
alkyl or are taken together with the nitrogen atom to which
they are bonded to constitute a pyrrolidinyl, piperidinyl,
hexamethyleneiminyl, or morpholinyl ring; and
pharmaceutically acceptable acid addition salts and
solvates thereof.
4. The formulation of Claim 3 wherein said 2-
phenyl-3-aroylbenzo[b]thiophene is [6-hydroxy-2-(4-
hydroxyphenyl)benzo [b] thien-3-yl][4-[2-(1-
piperidinyl)ethoxy]phenyl]methanone and, pharmaceutically
acceptable salts and solvates thereof.
5. The formulation of Claim 3 wherein said 2-
phenyl-3-aroylbenzo[b]thiophene is and [6-hydroxy-2-(4-
hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-
pyrrolidinyl)ethoxy]phenyl]methanone and pharmaceutically
acceptable salts and solvates thereof.
6. A pharmaceutical formulation adapted for
inhibiting bone loss in a human which comprises a
bisphosphonate and a first compound, as defined in Claim 1.

The present invention provides a method for inhibiting
bone loss comprising administering to a human in need thereof a
first compound selected from 1) triarylethylenes; 2) 2,3-diaryl-
2H-1-benzopyrans, 3) l-aminoalkyl-2-phenylindoles; 4) 2-phenyl-
3-aroylbenzothiophenes, 5) l-substituted-2-aryl-
dihydronaphthalenes; or 6) benzofurans, and a second compound
being a bisphosphonate: or pharmaceutically acceptable salts and
solvates thereof. Also encompassed by the invention are
combination pharmaceutical formulations and salts.