Weight loss abstract
A method of inhibiting weight gain or inducing or facilitating
weight loss comprising administering to a human an effective amount
of a compound having the formula ##STR1## wherein R.sup.1 and R.sup.3
are independently hydrogen, --CH.sub.3, ##STR2## wherein Ar is optionally
substituted phenyl; R.sup.2 is selected from the group consisting
of pyrrolidino, hexamethyleneamino, and piperidino; or a pharmaceutically
acceptable salt of solvate thereof.
Weight loss claims
1. A method of inhibiting weight gain or inducing weight loss comprising
administering to a human an effective amount of a compound having
the formula ##STR5## wherein R.sup.1 and R.sup.3 are independently
hydrogen, --CH.sub.3, ##STR6## wherein Ar is optionally substituted
phenyl; R.sup.2 is piperidino; or a pharmaceutically acceptable
salt of solvate thereof.
2. The method of claim 1 wherein said compound is the hydrochloride
3. The method of claim 1 wherein said administration is prophylactic.
4. The method of claim 1 wherein said compound is ##STR7## or its
5. The method of claim 1 wherein said human is a post-menopausal
Weight loss description
BACKGROUND OF THE INVENTION
Western society places great emphasis on personal appearance and
in particular one's weight. Diets and weight loss programs are extensively
advertised and utilized by many people with varying degrees of success.
There continues to be a search for new and effective means to facilitate
Obesity is the most prevalent, chronic, medical condition in our
society. Being overweight or obese is directly or indirectly associated
with a vast number of diseases including hypertension, diabetes,
cardiovascular disease, and gallstones, for example. Also, diminished
self-image with consequent psychological maladjustments are linked
to being overweight. As such, those who are overweight often experience
more health problems and shortened life expectancies.
SUMMARY OF THE INVENTION
This invention provides methods for inhibiting weight gain or inducing
weight loss comprising administering to a human an effective amount
of a compound of formula I ##STR3## wherein R.sup.1 and R.sup.3
are independently hydrogen, --CH.sub.3, ##STR4## wherein Ar is optionally
R.sup.2 is selected from the group consisting of pyrrolidino, hexamethyleneimino,
and piperidino; and pharmaceutically acceptable salts and solvates
Also encompassed by the invention is a method of suppressing or
inhibiting appetite which comprises administering to a human a compound
of formula 1.
DETAILED DESCRIPTION OF THE INVENTION
The current invention concerns the discovery that a select group
of 2-phenyl-3-aroylbenzothiophenes (benzothiophenes), those of formula
I, are useful for inhibiting weight gain or inducing or facilitating
weight loss, or inhibiting appetite. The methods of use provided
by this invention are practiced by administering to a human a dose
of a compound of formula I or a pharmaceutically acceptable salt
or solvate thereof, effective to inhibit weight gain or induce weight
loss, or inhibit appetite. The present method includes both medical
therapeutic and/or prophylactic treatment, as appropriate.
The term "inhibit weight gain or induce weight loss"
is defined to include its generally accepted meaning which includes
administration to a human subject to weight gain, and holding in
check or reducing a human's weight. The term "inhibit appetite"
includes suppression or reduction of appetite. Also encompassed
by the invention is the treatment of an obese human, inducement
of weight loss in a human of relatively normal weight, and the maintenance
of weight control.
Raloxifene, a preferred compound of this invention is the hydrochloride
salt of a compound of formula 1, wherein R.sup.1 and R.sup.3 are
hydrogen and R.sup.2 is 1-piperidinyl, and is a nuclear regulatory
Generally, the compound is formulated with common excipients, diluents
or carriers, and compressed into tablets, or formulated as elixirs
or solutions for convenient oral administration, or administered
by the intramuscular or intravenous routes. The compounds can be
administered transdermally, and may be formulated as sustained release
dosage forms and the like.
The compounds used in the methods of the current invention can
be made according to established procedures, such as those detailed
in U.S. Pat. Nos. 4,133,814, 4,418,068, and 4,380,635 all of which
are incorporated by reference herein. In general, the process starts
with a benzo[b]thiophene having a 6-hydroxyl group and a 2-(4-hydroxyphenyl)
group. The starting compound is protected, acylated, and deprotected
to form the formula I compounds. Examples of the preparation of
such compounds are provided in the U.S. patents discussed above.
Optionally substituted phenyl includes phenyl or phenyl substituted
once or twice with C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxy,
hydroxy, nitro, chloro, fluoro, or tri(chloro or fluoro)methyl.
The compounds used in the methods of this invention form pharmaceutically
acceptable acid and base addition salts with a wide variety of organic
and inorganic acids and bases and include the physiologically acceptable
salts which are often used in pharmaceutical chemistry. Such salts
are also part of this invention. Typical inorganic acids used to
form such salts include hydrochloric, hydrobromic, hydroiodic, nitric,
sulfuric, phosphoric, hypophosphoric and the like. Salts derived
from organic acids, such as aliphatic mono and dicarboxylic acids,
phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic
acids, aromatic acids, aliphatic and aromatic sulfonic acids, may
also be used. Such pharmaceutically acceptable salts thus include
acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate,
chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate,
methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide,
isobutyrate, phenylbutyrate, .beta.-hydroxybutyrate, butyne-1,4-dioate,
hexyne-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate,
formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate,
maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate,
isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate,
propiolate, propionate, phenylpropionate, salicylate, sebacate,
succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite,
sulfonate, benzene-sulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate,
ethanesutfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate,
naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate,
and the like. A preferred salt is the hydrochloride salt.
The pharmaceutically acceptable acid addition salts are typically
formed by reacting a compound of formula I with an equimolar or
excess amount of acid. The reactants are generally combined in a
mutual solvent such as diethyl ether or benzene. The salt normally
precipitates out of solution within about one hour to 10 days and
can be isolated by filtration or the solvent can be stripped off
by conventional means.
Bases commonly used for formation of salts include ammonium hydroxide
and alkali and alkaline earth metal hydroxides, carbonates, as well
as aliphatic and primary, secondary and tertiary amines, aliphatic
diamines. Bases especially useful in the preparation of addition
salts include ammonium hydroxide, potassium carbonate, methylamine,
diethylamine, ethylene diamine and cyclohexylamine.
The pharmaceutically acceptable salts generally have enhanced solubility
characteristics compared to the compound from which they are derived,
and thus are often more amenable to formulation as liquids or emulsions.
Pharmaceutical formulations can be prepared by procedures known
in the art. For example, the compounds can be formulated with common
excipients, diluents, or carriers, and formed into tablets, capsules,
suspensions, powders, and the like. Examples of excipients, diluents,
and carriers that are suitable for such formulations include the
following: fillers and extenders such as starch, sugars, mannitol,
and silicic derivatives; binding agents such as carboxymethyl cellulose
and other cellulose derivatives, alginates, gelatin, and polyvinyl
pyrrolidone; moisturizing agents such as glycerol; disintegrating
agents such as calcium carbonate and sodium bicarbonate; agents
for retarding dissolution such as paraffin; resorption accelerators
such as quaternary ammonium compounds; surface active agents such
as cetyl alcohol, glycerol monostearate; adsorptive carriers such
as kaolin and bentonite; and lubricants such as talc, calcium and
magnesium stearate, and solid polyethyl glycols.
The compounds can also be formulated as elixirs or solutions for
convenient oral administration or as solutions appropriate for parenteral
administration, for instance by intramuscular, subcutaneous or intravenous
routes. Additionally, the compounds are well suited to formulation
as sustained release dosage forms and the like. The formulations
can be so constituted that they release the active ingredient only
or preferably in a particular part of the intestinal tract, possibly
over a period of time. The coatings, envelopes, and protective matrices
may be made, for example, from polymeric substances or waxes.
The particular dosage of a compound of formula I required to inhibit
weight gain or induce or facilitate weight loss, or inhibit appetite,
according to this invention, will depend upon the severity of the
condition, the route of administration, and related factors that
will be decided by the attending physician. Generally, accepted
and effective daily doses will be from about 0.1 to about 1000 mg/day,
and more typically from about 50 to about 200 mg/day. Such dosages
will be administered to a subject in need of treatment from once
to about three times each day, or more often as needed.
It is usually preferred to administer a compound of formula I in
the form of an acid addition salt, as is customary in the administration
of pharmaceuticals bearing a basic group, such as the piperidino
ring. It is also advantageous to administer such a compound by the
oral route to an aging human (e.g. a post-menopausal female). For
such purposes the following oral dosage forms are available.
In the formulations which follow, "active ingredient"
means a compound of formula I.
______________________________________ Formulation 1: Gelatin Capsules
Hard gelatin capsules are prepared using the following: Ingredient
Quantity (mg/capsule) ______________________________________ Active
ingredient 0.1-1000 Starch, NF 0-650 Starch flowable powder 0-650
Silicone fluid 350 centistokes 0-15 ______________________________________
The ingredients are blended, passed through a No. 45 mesh U.S.
sieve, and filled into hard gelatin capsules.
Examples of specific capsule formulations of raloxifene that have
been made include those shown below:
______________________________________ Ingredient Quantity (mg/capsule)
______________________________________ Formulation 2: Raloxifene
capsule Raloxifene 1 Starch, NF 112 Starch flowable powder 225.3
Silicone fluid 350 centistokes 1.7 Formulation 3: Raloxifene capsule
Raloxifene 5 Starch, NF 108 Starch flowable powder 225.3 Silicone
fluid 350 centistokes 1.7 Formulation 4: Raloxifene capsule Raloxifene
10 Starch, NF 103 Starch flowable powder 225.3 Silicone fluid 350
centistokes 1.7 Formulation 5: Raloxifene capsule Raloxifene 50
Starch, NF 150 Starch flowable powder 397 Silicone fluid 350 centistokes
The specific formulations above may be changed in compliance with
the reasonable variations provided.
A tablet formulation is prepared using the ingredients below:
______________________________________ Formulation 6: Tablets Ingredient
Quantity (mg/tablet) ______________________________________ Active
ingredient 0.1-1000 Cellulose, microcrystalline 0-650 Silicon dioxide,
fumed 0-650 Stearate acid 0-15 ______________________________________
The components are blended and compressed to form tablets.
Alternatively, tablets each containing 0.1-1000 mg of active ingredient
are made up as follows:
______________________________________ Formulation 7: Tablets Ingredient
Quantity (mg/tablet) ______________________________________ Active
ingredient 0.1-1000 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone
4 (as 10% solution in water) Sodium carboxymethyl cellulose 4.5
Magnesium stearate 0.5 Talc 1 ______________________________________
The active ingredient, 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 granules so produced are dried at
50.degree.-60.degree. 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 U.S. sieve, are then added to the granules
which, after mixing, are compressed on a tablet machine to yield
Suspensions each containing 0.1-1000 mg of medicament per 5 mL
dose are made as follows:
______________________________________ Formulation 8: Suspensions
Ingredient Quantity (mg/5 ml) ______________________________________
Active ingredient 0.1-1000 mg Sodium carboxymethyl cellulose 50
mg Syrup 1.25 mg Benzoic acid solution 0.10 mL Flavor q.v. Color
q.v. Purified water to 5 mL ______________________________________
The medicament is passed through a No. 45 mesh U.S. sieve and mixed
with the sodium carboxymethyl cellulose and syrup to form a smooth
paste. The benzoic acid solution, flavor, and color are diluted
with some of the water and added, with stirring. Sufficient water
is then added to produce the required volume.
Between three and fifty rats (250-300 g) are individually housed
in metal wire hanging cages. The animals are divided into one of
three dosing groups: vehicle (20% cyclodextrin (CDX)); ethynyl estradiol
(EE.sub.2)(0.1 mg/kg) or a compound of formula 1 (10 mg/kg). The
rats are given daily oral gavages for four consecutive days while
having ad lib access to food and water. After the fourth daily dose,
all food is removed from each of the animals' cages for a 24 hour
period. After the food deprivation period, the animals are given
a fifth oral gavage of the appropriate agent. Thirty minutes later,
a pre-weighed allotment of lab chow is placed on the cage floor.
The animals are allowed to feed for 2 hours after which any remaining
food on the cage floor is collected along with large pieces which
fall through the wire mesh floor. A second allotment is then given
to each animal for an additional two hour period, and the residual
food is collected as before. Food intake for each two hour period,
and the four hour total, is calculated algebraically.
For a compound of formula 1 wherein R.sup.1 and R.sup.3 are hydrogen
and R.sup.2 is 1-pyrrolidino ("Compound A"), the following
data is collected.
______________________________________ TIME (hr) FOOD INTAKE (g)
______________________________________ Control Group 2 4.83 .+-.
0.38 (12 rats) 4 7.17 .+-. 0.47 EE.sub.2 Group 2 0.00 .+-. 0.00*
(6 rats) 4 1.50 .+-. 0.00* Compound A 2 1.35 .+-. 0.87* Group (6
rats) 4 2.12 .+-. 1.00* ______________________________________ *
= p .ltoreq. 0.05 vs CDX control
Ovariectomized or sham surgeried rats are group housed in metal
wire hanging cages Immediately following surgery, animals are given
either control vehicle (1.5% carboxymethylcellulose), ethynyl estradiol
(0.1 mg/kg) or a compound of formula 1 (0.01 to 10 mg/kg) by daily
oral gavage. The animals have ad lib access to food and water. Body
weight is determined after 35 days of dosing.
For raloxifene ("Ral") the following data is collected.
______________________________________ BODY WEIGHT GROUP CHANGE
(g).sup.a ______________________________________ Intact Control
77.4 .+-. 3.1* OVX Control 120.3 .+-. 3.8 OVX + EE.sub.2 18.0 .+-.
4.0* (0.1 mg/kg) OVX + Ral 108.6 .+-. 4.0 (0.01 mg/kg) OVX + Ral
70.5 .+-. 3.7* (0.1 mg/kg) OVX + Ral 62.2 .+-. 3.0* (1 mg/kg) OVX
+ Ral 53.7 .+-. 2.8* (10 mg/kg) ______________________________________
.sup.a = mean body weight .+-. SEM for for 28(intact control), 29(OVX
control), 12 (EE.sub.2), or 30 (each raloxifene dose) rats per group.
* = p .ltoreq. 0.05 vs OVX control by Scheffe range test.
Other feeding paradigms
Nocturnal (12 hr) feeding and daytime feeding induced by insulin
(10 mg/kg) is also assessed in estrogen and Compound A treated rats.
Spontaneous nocturnal feeding is significantly suppressed by ethynyl
estradiol (0.1 mg/kg), but Compound A treated rats (10 mg/kg) did
not exhibit significant suppression. Insulin-induced feed is not
significantly affected by either ethynyl estradiol or Compound A.
This indicates an inhibition of feeding, yet the type of hyperphagic
stimulus is important.
Five to fifty women are selected for the clinical study. The women
are post-menopausal, i.e., have ceased menstruating for between
6 and 12 months prior to the study's initiation, are in good general
health, and are overweight (at least 15% above acceptable weight
for the person's height). The study has a placebo control group,
i.e., the women are divided into two groups, one of which receives
the active agent of this invention and the other receives a placebo.
Women in the test group receive between 50-200 mg of the active
agent per day by the oral route. They continue this therapy for
3-12 months. Accurate records are kept as to the weights of the
patients in both groups and at the end of the study these results
are compared. The results are compared both between members of each
group and also the results for each patient are compared to the
weights reported by each patient before the study began.
Utility of the compounds of the invention is illustrated by the
positive impact they have on weight gain/loss or appetite inhibition
when used in at least one study above.