Methods for alleviating symptoms of premenstrual syndrome and late luteal phase dysphoric disorder

The present invention provides novel methods of inhibiting the symptoms of premenstrual syndrome comprising administering to a human in need of treatment an effective amount of a compound of formula I ##STR1## wherein R.sup.1 and R.sup.2 may be the same or different provided that, when R.sup.1 and R.sup.2 are the same, each is a methyl or ethyl group, and, when R.sup.1 and R.sup.2 are different, one of them is a methyl or ethyl group and the other is hydrogen or a benzyl group; or a pharmaceutically acceptable salt thereof.

This is a continuation of provisional application 60/012,410 filed Feb. 28, 
1996, the benefit of which is hereby claimed under 37 C.F.R. 
.sctn.1.78(a)(3). 
BACKGROUND OF THE INVENTION 
Each month, for a few days prior to the onset of menstruation, many 
millions of otherwise-healthy women develop symptoms of disturbed mood and 
appetite that can be strikingly similar to those reported by patients with 
Seasonal Affective Disorder (SAD), carbohydrate-craving obesity, or the 
non-anorexic variants of bulimia. This syndrome was first termed 
"premenstrual tension" by R. T. Frank in 1931 and is a very common 
phenomenon. According to Guy Abraham of UCLA, of every ten patients to 
walk into a gynecologist's office, three or four will suffer from 
premenstrual tension and, in some, the symptoms will be of such severity 
as to include attempts at suicide. Current Progress in Obstetrics and 
Gynecology, 3:5-39 (1980). 
Initial descriptions of the Premenstrual Syndrome (PMS) focused on its 
association with nervous tension, headache, and weight gain. The weight 
gain observed was initially attributed to excessive retention of salt and 
water, which does indeed occur in some PMS patients. However, it soon 
became evident that it was also a consequence of the widespread tendency 
of individuals suffering from PMS to crave and overconsume carbohydrates, 
particularly foods with a sweet taste. PMS is also now referred to as late 
luteal phase syndrome (or late luteal phase dysphoric disorder). D.N.S. 
III, Revised, American Psychiatric Association (1987). 
There have been numerous suggestions made about the etiology of PMS. For 
example, some hypothesized that it was caused by a uterine toxin. Others 
suggested its cause was overconsumption of sweets, which was presumably 
followed by excessive insulin secretion, hypoglycemia, and inadequate 
brain glucose, and resulted in the often observed depression and anxiety. 
It also has been postulated that the behavioral symptoms result from the 
tissue edema often observed and that the psychological changes result from 
feelings of loss or the social complexities generated by the discomforts 
of menstruation. 
However, none of these theories has been substantiated: PMS can persist 
after hysterectomy and, hence, uterine toxins cannot be its cause; the 
hyperinsulinism of PMS is not associated with low blood glucose levels, 
and is probably the consequence of a behavioral aberration (i.e., the 
tendency of premenstrual women to chose high-carbohydrate diets, which 
potentiate insulin secretion) rather than the cause; the mood and 
appetitive changes of PMS are poorly correlated with the tissue swelling; 
and subhuman primates who are presumably exempt from the psychodynamic or 
social complexities of human life also exhibit characteristic behavioral 
changes premenstrually. 
There have been many treatments suggested for overcoming or reducing the 
symptoms of PMS. These include carbohydrate-free diets, vitamin 
supplements, ovarian hormones, detoxifying agents, irradiation of the 
ovaries and pituitary, and use of diuretics. These approaches have all had 
limited success, however. 
Late Luteal Phase Dysphoric Disorder (LLPDD) is the current term associated 
with Premenstrual Syndrome (PMS). Many females report a variety of 
physical and emotional changes associated with specific phases of the 
menstrual cycle. For most of these females, these changes are not severe, 
cause little distress, and have no effect on social or occupational 
functioning. In contrast, the essential feature of LLPDD is a pattern of 
clinically significant emotional and behavioral symptoms that occur during 
the last week of the luteal phase and remit within a few days after the 
onset of the follicular phase. In most females, these symptoms occur in 
the week before and remit within a few days after the onset of menses. 
LLPDD is diagnosed only if the symptoms are sufficiently severe to cause 
marked impairment in social or occupational functioning and have occurred 
during a majority of menstrual cycles in the past year. 
Among the most commonly experienced symptoms are marked affective lability 
(e.g., sudden episodes of tearfulness, sadness, or irritability), 
persistent feelings of irritability, anger, or tension, feelings of 
depression, and self-deprecating thoughts. Also common are decreased 
interest in usual activities, fatigability and loss of energy, a 
subjective sense of difficulty in concentration, changes in appetite, 
craving for specific foods (especially carbohydrates), and sleep 
disturbance. Other physical symptoms, such as breast tenderness or 
swelling, headaches, joint or muscle pain, a sensation of bloating, and 
weight gain, also may be present. 
Generally, non-steroidal anti-inflammatory drugs are administered to LLPDD 
patients, but these only are effective for some of the physical symptoms. 
The physical manifestations of PMS, if severe, may be treated 
symptomatically. Water retention may be relieved by diet or antidiuretic 
medication, but severity of water retention does not always correlate with 
psychological symptoms. Recent studies have suggested that spironolactone 
(Aldactone, Searle) may also be effective in relieving depression and 
crying spells. 
Other drugs, including progesterone, lithium carbonate, thiazide, 
diuretics, antidepressants and bromocriptine (Parlodel.RTM., Sandoz), have 
been tried with uncertain success. 
U.S. Pat. No. 5,389,670 describes the use of certain benzothiophenes for 
treatment of LLPDD/PMS. 
In view of the drawbacks and inadequacies with existing methods of treating 
PMS/LLPDD, new therapies are sought. 
SUMMARY OF THE INVENTION 
The present invention relates to methods for inhibiting the symptoms of 
PMS/LLPDD comprising administering to a human in need of treatment an 
effective amount of a compound of formula I 
##STR2## 
wherein 
R.sup.1 and R.sup.2 may be the same or different provided that, when 
R.sup.1 and R.sup.2 are the same, each is a methyl or ethyl group, and, 
when R.sup.1 and R.sup.2 are different, one of them is a methyl or ethyl 
group and the other is hydrogen or a benzyl group; or a pharmaceutically 
acceptable salt thereof. A preferred compound of formula I is that in 
which R.sup.1 and R.sup.2 are methyl. A preferred salt is the citrate salt 
.

DETAILED DESCRIPTION OF THE INVENTION 
The present invention concerns methods for inhibiting the symptoms of PMS 
and LLPDD. The term "inhibit" is defined to include its generally accepted 
meaning which includes prophylactically treating a subject to prevent the 
occurrence of one or more of these disease states, holding in check the 
symptoms of such a disease state, and/or treating such symptoms. Thus, the 
present methods include both medical therapeutic and/or prophylactic 
treatment, as appropriate. 
The methods of this invention are practiced by administering to an 
individual in need of treatment an effective amount of a compound formula 
I 
##STR3## 
wherein R.sup.1 and R.sup.2 may be the same or different provided that, 
when R.sup.1 and R.sup.2 are the same, each is a methyl or ethyl group, 
and, when R.sup.1 and R.sup.2 are different, one of them is a methyl or 
ethyl group and the other is hydrogen or a benzyl group; or a 
pharmaceutically acceptable salt thereof. 
Compounds of formula I are known in the art and essentially are prepared 
via the methods described in U.S. Pat. No. 5,047,431, which is hereby 
incorporated herein by reference. 
A preferred formula I compound is that in which R.sup.1 and R.sup.2 each 
are methyl. This preferred compound is known as droloxifene, 
(E)-1-4'-(2-Dimethylaminoethoxy)phenyl!-1-(3-hydroxyphenyl)-2-phenylbut-1 
-ene, which previously has been described as an antiestrogenic agent and is 
useful for the treatment of hormone dependent mammary tumors (U.S. Pat. 
No. 5,047,431), and for the relief of bone diseases caused by the 
deficiency of estrogen or the like (U.S. Pat. No. 5,254,594). Furthermore, 
droloxifene is known to have less uterotrophic effect than other 
antiestrogenic compounds such as tamoxifen. 
Although the free-base form of formula I compounds can be used in the 
methods of the present invention, it is preferred to prepare and use a 
pharmaceutically acceptable salt form. Thus, the compounds used in the 
methods of this invention form pharmaceutically acceptable acid and base 
addition salts with a wide variety of inorganic and, preferably, organic 
acids 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, terephthalate, phosphate, monohydrogenphosphate, 
dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, 
phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, 
bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, 
p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 
2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, 
naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, 
and the like. A preferred salt is the citrate 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. 
The pharmaceutically acceptable salts of formula I compounds 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. 
Once prepared, the free base or salt form of formula I compounds can be 
administered to an individual in need of treatment for the methods herein 
described. The following nonlimiting test examples illustrate the methods 
of the present invention. 
For the methods of the present invention, compounds of Formula I are 
administered continuously, or from 1 to 4 times daily. 
As used herein, the term "effective amount" means an amount of compound of 
the methods of the present invention which is capable of inhibiting the 
symptoms of the pathological conditions herein described. The specific 
dose of a compound administered according to this invention will, of 
course, be determined by the particular circumstances surrounding the case 
including, for example, the compound administered, the route of 
administration, the state of being of the patient, and the severity of the 
pathological condition being treated. A typical daily dose will contain a 
nontoxic dosage level of from about 0.25 mg to about 100 mg/day of a 
compound of the present invention. Preferred daily doses generally will be 
from about 1 mg to about 40 mg/day. 
The compounds of this invention can be administered by a variety of routes 
including oral, rectal, transdermal, subucutaneous, intravenous, 
intramuscular, and intranasal. These compounds preferably are formulated 
prior to administration, the selection of which will be decided by the 
attending physician. Typically, a formula I compound, or a 
pharmaceutically acceptable salt thereof, is combined with a 
pharmaceutically acceptable carrier, diluent or excipient to form a 
pharmaceutical formulation. 
The total active ingredients in such formulations comprises from 0.1% to 
99.9% by weight of the formulation. By "pharmaceutically acceptable" it is 
meant the carrier, diluent, excipients, and/or salt must be compatible 
with the other ingredients of the formulation, and not deleterious to the 
recipient thereof. 
Pharmaceutical formulations containing a compound of formula I can be 
prepared by procedures known in the art using well known and readily 
available ingredients. For example, the compounds of formula I 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 also can be formulated as elixirs or solutions for convenient 
oral administration or as solutions appropriate for parenteral 
administration, for example, 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 
physiological location, possibly over a period of time. The coatings, 
envelopes, and protective matrices may be made, for example, from 
polymeric substances or waxes. 
Compounds of formula I generally will be administered in a convenient 
formulation. The following formulation examples only are illustrative and 
are not intended to limit the scope of the present invention. 
In the formulations which follow, "active ingredient" means a compound of 
formula I, or a salt thereof. 
______________________________________ 
Formulation 1: Gelatin Capsules 
Hard gelatin capsules are prepared using the following: 
Ingredient Quantity (mg/capsule) 
______________________________________ 
Active ingredient 
0.25-100 
Starch, NF 0-650 
Starch flowable powder 
0-50 
Silicone fluid 350 centistokes 
0-15 
______________________________________ 
A tablet formulation is prepared using the ingredients below: 
______________________________________ 
Formulation 2: Tablets 
Ingredient Quantity (mg/tablet) 
______________________________________ 
Active ingredient 
0.25-100 
Cellulose, microcrystalline 
200-650 
Silicon dioxide, fumed 
10-650 
Stearate acid 5-15 
______________________________________ 
The components are blended and compressed to form tablets. 
Alternatively, tablets each containing 0.25-100 mg of active ingredient are 
made up as follows: 
______________________________________ 
Formulation 3: Tablets 
Ingredient Quantity (mg/tablet) 
______________________________________ 
Active ingredient 0.25-100 
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 tablets. 
Suspensions each containing 0.25-100 mg of medicament per 5 ml dose are 
made as follows: 
______________________________________ 
Formulation 4: Suspensions 
Ingredient Quantity (mg/5 ml) 
______________________________________ 
Active ingredient 0.25-100 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 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. An aerosol solution is prepared containing the 
following ingredients: 
______________________________________ 
Formulation 5: Aerosol 
Ingredient Quantity (% by weight) 
______________________________________ 
Active ingredient 0.25 
Ethanol 25.75 
Propellant 22 (Chlorodifluoromethane) 
70.00 
______________________________________ 
The active ingredient is mixed with ethanol and the mixture added to a 
portion of the propellant 22, cooled to 30.degree. C., and transferred to 
a filling device. The required amount is then fed to a stainless steel 
container and diluted with the remaining propellant. The valve units are 
then fitted to the container. 
Suppositories are prepared as follows: 
______________________________________ 
Formulation 6: Suppositories 
Ingredient Quantity (mg/suppository) 
______________________________________ 
Active ingredient 
250 
Saturated fatty acid glycerides 
2,000 
______________________________________ 
The active ingredient is passed through a No. 60 mesh U.S. sieve and 
suspended in the saturated fatty acid glycerides previously melted using 
the minimal necessary heat. The mixture is then poured into a suppository 
mold of nominal 2 g capacity and allowed to cool. 
An intravenous formulation is prepared as follows: 
______________________________________ 
Formulation 7: Intravenous Solution 
Ingredient Quantity 
Active ingredient 
20 mg 
Isotonic saline 1,000 mL 
______________________________________ 
The solution of the above ingredients is intravenously administered to a 
patient at a rate of about 1 mL per minute. 
TEST PROCEDURE 
Three to fifty women are selected for the clinical study. The women have 
regular menses, are in good general health, and suffer from one or more of 
the above mentioned PMS/LLPDD symptoms. Because of the somewhat 
idiosyncratic and subjective nature of these symptoms, the study has a 
placebo control group, i.e., the woman 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 10-100 mg of the drug per 
day by the oral route. They continue this therapy for 1-3 months. Accurate 
records are kept as to the number and severity of the symptoms 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 symptoms reported by each patient before 
the study began. See U.S. Pat. No. 5,389,670. 
Utility of the compounds of the invention for inhibiting the symptoms of 
PMS/LLPDD is illustrated by the positive impact they have on one or more 
of the symptoms when used in a study as above.