Benign prostatic hypertrophy

The present invention provides novel uses of compounds of general formula I ##STR1## wherein R.sup.1, R.sup.4 and R.sup.5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); and R.sup.2 and R.sup.3 are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of benign prostatic hypertrophy

Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical 
composition for the treatment or prophylaxis of benign prostatic 
hypertrophy 
This application claims priority under 35 U.S. C. .sctn.119(e) of 
provisional application 60/009,905, filed Jan. 11, 1996, the contents of 
which are incorporated herein by reference. 
FIELD OF THIS INVENTION 
The present invention relates to the use of compounds of the general 
formula I for the treatment of patients suffering from benign prostatic 
hypertrophy and prophylaxis hereof. The present invention also embraces 
pharmaceutical compositions comprising these compounds and methods of 
using the compounds and their pharmaceutical compositions. 
BACKGROUND OF THIS INVENTION 
Benign prostatic hypertrophy is an almost universal phenomenon in aging 
men. It refers to a nodular enlargement of the gland due to hyperplasia of 
both glandular and stromal components. The incidence of this disease is 
only 8% during the fourth decade, but it reaches 50% in the fifth decade 
and 75% in the eighth decade. The disorder is not a major cause of death, 
but it is a leading cause of morbidity in elderly men. The pathogenesis is 
not well-understood, but dihydrotestosterone together with increasing 
levels of estrogen which occur in men act synergistically to induce 
prostatic growth. The treatment is surgical, which, however, can only be 
offered to a small selected number of patients with this disease because 
the majority of men above age 60 have some degree of prostatic 
hyperplasia. No protecting factors other than castraction have been 
identified and no effective pharmacological treatment or profylaxis 
exists. 
Centchroman is a non-steroidal compound known to have antiestrogenic 
activity. It is in use in India as an oral contraceptive (see, for 
example, Salman et al., U.S. Pat. No. 4,447,622; Singh et al., Acta 
Endocrinal (Copenh) 126 (1992), 444-450; Grubb, Curr Opin Obstet Gynecol 3 
(1991), 491-495; Sankaran et al., Contraception 9 (1974), 279-289; Indian 
Patent Specification No. 129187). Centchroman has also been investigated 
as an anti-cancer agent for treatment of advanced breast cancer (Misra et 
al., Int J Cancer 43 (1989), 781-783. Recently, centchroman as a racemate 
has been found as a potent cholesterol lowering pharmaceutical expressed 
by a significant decrease of the serum concentrations (S. D. Bain et al., 
J Min Bon Res 9 (1994), S 394). 
U.S. Pat. No. 5,453,442 describes methods of lowering serum cholesterol and 
inhibiting smoother muscle cell proliferation in humans and inhibiting 
uterine fibroid disease and endometriosis in women by administering 
compounds of formula I as shown therein. Furthermore, U.S. Pat. No. 
5,280,040 describes methods and pharmaceutical compositions for reducing 
bone loss using 3,4-diaryl chromans and their pharmaceutically acceptable 
salts. There is no disclosure in the patents of using the compounds to 
treat or prevent benign prostatic hypertrophy. 
One object of the present invention is to provide compounds which can 
effectively be used in the treatment or prophylaxis of benign prostatic 
hypertrophy. 
BRIEF DESCRIPTION OF THIS INVENTION 
It has, surprisingly, been found that compounds of the general formula I as 
stated in claim 1 can be used in the treatment or prophylaxis of benign 
prostatic hypertrophy. 
DETAILED DESCRIPTION OF THIS INVENTION 
The present invention is based in part on the discovery that a 
representative 3,4-diarylchroman, centchroman 
(3,4-trans-2,2-dimethyl-3-phenyl-4-p-(beta-pyrrolidinoethoxy)phenyl!-7-me 
thoxychroman) is effective against benign prostatic hypertrophy, inter alia 
in rats. An increased prostate weight is the cardinal observation seen in 
patients with prostatic hypertrophy, hence these data thus indicate that 
the 3,4-diarylchromans are useful as therapeutic agents against benign 
prostatic hypertrophy in mammals, including primates such as humans. 
Within the present invention, compounds of formula I as stated in claim 1 
are used for benign prostatic hypertrophy in a patient. Within formula I, 
R.sup.1, R.sup.4 and R.sup.5 are individually hydrogen, hydroxy, halogen, 
trifiuoromethyl, lower alkyl, lower alkoxy or (tertiary amino)(lower 
alkoxy); and R.sup.2 and R.sup.3 are individually hydrogen or a lower 
alkyl. As used herein, the term "lower alkyl" includes straight and 
branched chain alkyl radicals containing from 1 to 6 carbon atoms, such as 
methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl, 
n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like. The term "lower 
alkoxy" includes straight and branched chain alkoxy radicals containing 
from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, 
n-butoxy, tert-butoxy, n-amyloxy, sec-amyloxy, n-hexyloxy, 2-ethylbutoxy, 
2,3-dimethylbutoxy and the like. "Halogen" includes chloro, fluoro, bromo 
and iodo. Herein, the term "(tertiary amino)(lower alkoxy)" is a lower 
alkoxy group which is substituted by a tertiary amino radical. The 
tertiary amino radical may be a N,N-dialkylamine such as a 
N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino and 
N,N-dibutylamino or a polymethyleneimine, e.g., piperidine, pyrrolidine, 
N-methylpiperazine or morpholine. Preferred compounds include those in 
which R.sup.1 is lower alkoxy; R.sup.2 and R.sup.3 are lower alkyl, 
especially methyl; R.sup.4 is hydrogen; and R.sup.5 is (tertiary 
amino)(lower alkoxy) of the polymethyleneimine type. Within particularly 
preferred embodiments, R.sup.1 is in the 7-position and is lower alkoxy, 
particularly methoxy; each of R.sup.2 and R.sup.3 is methyl, R.sup.4 is 
hydrogen, and R.sup.5 is in the 4-position and is a (tertiary amino)(lower 
alkoxy) radical such as 2-(pyrrolidin-1-yl)ethoxy. To be included by this 
invention are all pharmaceutically acceptable salts of the mentioned 
compounds of formula I. 
It is preferred to use the compounds of formula I in the 
transconfiguration. These compounds may be used as racemic mixtures, or 
the isolated d- or l- enantiomers may be used. The trans-I-enantiomers are 
more preferred. 
A particularly preferred compound for use within the present invention is 
centchroman having the formula IV as stated in claim 11. 
Although only one enantiomer is shown, it will be understood that the 
formula IV is used herein to designate the transconfiguration of the 3-and 
4-phenyl groups and that both the d- and I-enantiomers, as well as the 
racemic mixture, are included. 
3,4-diarylchromans are prepared according to known methods, such as those 
disclosed in U.S. Pat. No. 3,340,276 to Carney et al., U.S. Pat. No. 
3,822,287 to Bolger, and Ray et al., J Med Chem 19 (1976), 276-279, the 
contents of which are incorporated herein by reference. Conversion of the 
cis isomer to the trans configuration by means of an organometallic 
base-catalyzed rearrangement is disclosed in U.S. Pat. No. 3,822,287. The 
optically active d- and l-enantiomers may be prepared as disclosed by 
Salman et al. in U.S. Pat. No. 4,447,622 (incorporated herein by 
reference) by forming an optically active acid salt which is subjected to 
alkaline hydrolysis to produce the desired enantiomer. If R2 is different 
from R3 and R4 is different from R5, the general formula I covers 8 
optical isomers. 
Within the present invention, 3,4-diarylchromans of formula I may be 
prepared in the form of pharmaceutically acceptable salts, especially 
acid-addition salts, including salts of organic acids and mineral acids. 
Examples of such salts include salts of organic acids such as formic acid, 
fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, 
pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, 
citric acid, benzoic acid, salicylic acid and the like. Suitable inorganic 
acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric 
and phosphoric acids and the like. The acid addition salts may be obtained 
as the direct products of compound synthesis. In the alternative, the free 
base may be dissolved in a suitable solvent containing the appropriate 
acid, and the salt isolated by evaporating the solvent or otherwise 
separating the salt and solvent. 3,4-diarylchromans of formula I and their 
salts are useful within human and veterinary medicine, for example, in the 
treatment of patients suffering from benign prostatic hypertrophy. For use 
within the present invention, 3,4-diarylchromans of formula I and their 
pharmaceutically acceptable salts are formulated with a pharmaceutically 
acceptable carrier to provide a medicament for parenteral, oral, nasal, 
rectal, subdermal or intradermal or transdermal administration according 
to conventional methods. Formulations may further include one or more 
diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc, 
and may be provided in such forms as liquids, powders, emulsions, 
suppositories, liposomes, transdermal patches, controlled release, derreal 
implants, tablets, etc. One skilled in this art may formulate the 
compounds of formula I in an appropriate manner, and in accordance with 
accepted practices, such as those disclosed in Remington's Pharmaceutical 
Sciences, Gennaro, ed., Mack Publishing Co., Easton, Pa, 1990. 
Oral administration is preferred. Thus, the active compound of formula I is 
prepared in a form suitable for oral administration, such as a tablet or 
capsule. Typically, a pharmaceutically acceptable salt of the compound of 
formula I is combined with a carrier and moulded into a tablet. Suitable 
carriers in this regard include starch, sugars, dicalcium phosphate, 
calcium stearate, magnesium stearate and the like. Such compositions may 
further include one or more auxiliary substances, such as wetting agents, 
emulsifiers, preservatives, stabilizers, colouring additives, etc. 
Pharmaceutical compositions containing a compound of formula I may be 
administered one or more times per day or week. An effective amount of 
such a pharmaceutical composition is the amount that provides a clinically 
significant effect against benign prostatic hypertrophy. Such amounts will 
depend, in part, on the particular condition to be treated, age, weight, 
and general health of the patient, and other factors evident to those 
skilled in the art. A typical daily dose will contain a nontoxic dosage 
range of from about 0.001 to about 75 mg/kg patient per day of a compound 
of the present invention, preferably in a range from about 0.01 to 75, 
more preferably in the range from about 0.01 to 50, and especially in the 
range from about 0. 1 to 25, mg/kg patient per day. 
The pharmaceutical compositions containing a compound of formula I may be 
administered in unit dosage form one or more times per day or week. In the 
alternative, they may be provided as controlled release formulations 
suitable for dermal implantation. Implants are formulated to provide 
release of active compound over the desired period of time, which can be 
up to several years. Controlled-release formulations are disclosed by, for 
example, Sanders et al., J Pharm Sci 73 (1964), 1294-1297, 1984; U.S. Pat. 
No. 4,489,056; and U.S. Pat. No. 4,210,644, which are incorporated herein 
by reference. 
The following examples are offered by way of illustration, not limitation. 
Examples of preferred compounds of formula I are centchroman as a racemic 
mixture and as isolated I-centchroman and d-centchroman enantiomers. 
Furthermore, 
3,4-trans-2,2-dimethyl-3-phenyl-4-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl-7-h 
ydroxychroman is a preferred compound. The more preferred compound is 
isolated I-centchroman 
(I-3,4-trans-2,2-dimethyl-3-phenyl-4-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl! 
-7-methoxychroman). 
Examples of pharmaceutically acceptable acid addition salts are salts with 
non-toxic acids, either inorganic acids such as hydrochloric acid, 
sulphuric acid and phosphoric acid, or organic acids such as formic acid, 
fumaric acid, acetic acid, propionic acid, succinic acid, gluconic acid, 
lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, 
methanesulphonic acid and malonic acid. 
The present invention is further illustrated by the following examples 
which, however, are not to be construed as limiting the scope of 
protection. The features disclosed in the foregoing description and in the 
following examples may, both separately and in any combination thereof, be 
material for realising the invention in diverse forms thereof.

EXAMPLE 1 
Sixty sexually mature male Sprague-Dawley rats were assigned to one of the 
following five treatment groups (12 rats per group): 1)saline, 2) 
I-centchroman 0.025 mg/kg/day, 3) I-centchroman 0.125 mg/kg/day, 4) 
I-centchroman 0.625 mg/kg/day and 5)I-centchroman 3.125 mg/kg/day. The 
doses were administered three times per week for 13 weeks by oral gavage. 
At the conclusion of the experiment and autopsy was performed, the 
prostate gland and testes were isolated and weighed. L-centchroman had no 
effect on the average testis weight between the groups. However, a marked 
and dose-dependent effect on the prostate gland was observed as 
illustrated in Table 1. 
TABLE 1 
______________________________________ 
Effect of I-centchroman on prostate gland weight in Sprague- 
Dawley rats 
Treatment Prostate gland (g) 
______________________________________ 
Saline 0.639 .+-. 0.239 
I-centchroman 0.025 mg/kg/day 
0.669 .+-. 0.149 
I-centchroman 0.125 mg/kg/day 
0.472 .+-. 0.126* 
I-centchroman 0.625 mg/kg/day 
0.430 .+-. 0.122* 
I-centchroman 3.125 mg/kg/day 
0.368 .+-. 0.124* 
______________________________________ 
Values are mean .+-. SD. *indicate significant reduction of prostate glan 
weight compared to saline treated rats.