WO1998033499A1

WO1998033499A1 - Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for increasing libido in post-menopausal women

Info

Publication number: WO1998033499A1
Application number: PCT/DK1998/000031
Authority: WO
Inventors: Michael Shalmi; Malcolm Sheardown; Birgitte Hjort Guldhammer
Original assignee: Novo Nordisk A/S
Priority date: 1997-01-29
Filing date: 1998-01-28
Publication date: 1998-08-06
Also published as: AU5550298A

Abstract

The present invention provides novel uses of compounds of general formula (I) wherein R?1, R4 and R5¿ are individually hydrogen, hydroxy, halogen, trifluoromethyl, C¿1-6? alkyl, C1-6 alkoxy or (tertiary amino) (C1-6 alkoxy); and R?2 and R3¿ are individually hydrogen or C¿1-6? alkyl, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for increasing libido in post-menopausal women.

Description

Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for increasing libido in post-menopausal women

FIELD OF THIS INVENTION

The present invention relates to the use of compounds of the general formula I for increasing libido in post-menopausal women. The present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.

BACKGROUND OF THIS INVENTION

The medical advances made in the second half of this century have resulted in increases in both the length and the quality of life. One result of this trend is a rapidly ageing population and an increasing demand for new therapies to treat the problems which result from the ageing process.

One such problem is that of sexuality in peri- and post-menopausal women. While there is a decline in libido with age in women, an accelerated reduction oc- curs with the menopause. Several studies have shown that between one third and one half of menopausal women complain of a problem in one or more aspects of sexual functioning. Kinsey,A,C, et al (Sexual Behaviour in the Human Female, Saunders;PA, 1 953) showed a 53% reduction in frequency of coitus in menopausal women, whilst a longitudinal study of women in Sweden found a 52% decrease in sexual interest and a 20% decrease in orgasm (Hallstrom,T, Sexuality in the climacteric. Clin Obstet Gynecol 1 977;4:227-239). This study established statistically that these decrements in sexual functioning were related to the menopause and not ageing per se. Other survey studies of menopausal women have confirmed decreases in sexual interest of 33% (Hallstrom,T, Sam- uelsson,S, Changes in women's sexual desire in middle life : the longitudinal study of women in Gothenburg. Arch Sex Behav 1 990; 1 9:259-268), 85% (McCoy, N.L., Davidson, J.M., A longitudinal study of the effects of menopause on sexuality .Maturitas 1 985;7:203-210) and 39% (Sarrel,P.M., Whitehead,M.I., Maturitas;7:21 7-224). Pfeiffer, E., Etal (Terminus of sexual behaviour in middle and old age , Journal of the American geriatric society 1 972;pg 21 51 -21 58 ) showed the most dramatic change in sexuality took place postmenopausaly be- tween the ages of 50 - 60years. A recent study (Davis, S:R., Etal Testosterone enhances estradiol's effects on postmenopausal bone density Maturitas 1 995;21 : pg 227-236) documented both the loss of sexuality in post- menopausal women and the beneficial effects of estradiol.

While there is no proven direct link between declining oestrogen levels and declining sexual function, it may be hypothesised that as sex hormone levels fall following natural and surgical menopause this fall may contribute to the negative changes in sexuality in this population of women.

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. Patent Specification No. 4,447,622; Singh et al., Acta Endocrinal (Copenh) 1 26 ( 1 992), 444 - 450; Grubb. Curr Opin Obstet Gynecol 3 (1 991 ), 491 - 495; Sankaran et al., Contraception 9 ( 1 974), 279 - 289; Indian Patent Specification No. 1 291 87). Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int J Cancer 43 (1 989), 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., _ Min Ben Qss. 3 (1 994), S 394).

U.S. patent 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, US patent 5,280,040 describes methods and phar- maceutical 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 increase libido in post-menopausal women. There remains a need in the art for compositions and methods useful for increasing libido in post-menopausal women.

DETAILED DESCRIPTION OF THIS INVENTION

This invention provides the use of a compound having the formula

wherein R\ R⁴ and R⁵ are individually hydrogen, hydroxy, halogen, tri- fluoromethyl, C,.₆ alkyl, C^ alkoxy or (tertiary aminoXC,^ alkoxy); and R² and R³ are individually hydrogen or C ._e alkyl, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for increasing li- bido in post-menopausal women.

The current invention concerns the discovery that the compounds of formula I are useful for increasing libido. The methods of treatment provided by this invention are practiced by administering to a human in need a dose of a compound of formula I or a pharmaceutically acceptable salt thereof, that is effective to increase libido.

The term "post-menopausal women" is defined to include not only women of advanced age who have passed through menopause, but also women who have been oophorectomised, hysterectomized or oophorohysterectomised or for some other reason have suppressed estrogen production, such as those who have un- dergone long-term administration of corticosteroids, suffer from Cushions' syndromes or have gonadal dysgenesis.

The expression "libido" as used herein refers to those aspects of the human psy- che which are related to sexual interest and drive. Additionally, the expression "libido" refers to related psychic attitudes concerned with mental well-being and which refer to such characteristics as mental alertness and activity, creativity, enthusiasm, sociability and an awareness of interpersonal relationships. Libido is generally recognized to be the result of a complex interaction of factors in which genetic, anatomic, neurologic, psychologic and biochemical factors all play prominent roles. The exact mechanism by which the compounds of the present invention achieve this effect is not understood except to the extent that it is attributable to a biochemical mechanism.

Within formula I, R , R^ and R° are individually hydrogen, hydroxy, halogen, trifluoromethyl, C,.₆ alkyl, C,.₆ alkoxy or (tertiary ammoMC^ alkoxy); and R^ and

R^ are individually hydrogen or a C,^ alkyl. As used herein, the term "C,^ 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 "C,.₆ 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)(C₁.₆ alkoxy)" is a C_1-6 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 R¹ is C_1-6 alkoxy; R² and R³ are C^ alkyl, especially methyl; R⁴ is hydrogen; and R 5 is (tertiary aminoMC^e alkoxy) of the polymethyleneimine type. Within particularly preferred embodiments, R ' is in the 7-position and is C,.₆ alkoxy, particularly methoxy; each of R² and R³ is methyl, R^ is hydrogen, and R^ is in the 4- position and is a (tertiary aminoMC^e alkoxy) radical such as 2-(pyrrolidin-1 - yl)ethoxy with formula II

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 I- enantiomers may be used. The trans-l-enantiomers are more preferred.

A particularly preferred compound for use within the present invention is cen- tchroman having the formula IV

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 l-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. Patent Specification No. 3,340,276 to Carney et al., U.S. Patent Specification No. 3,822,287 to Bolger, and Ray et al., J Med Chem 1 9 ( 1 976), 276 - 279, the contents of which are incorporated herein by reference. Conversion of the cis isomer to the trans configuration by means of an or- ganometallic base-catalyzed rearrangement is disclosed in U.S. Patent Specification No. 3,822,287. The optically active d- and l-enantiomers may be prepared as disclosed by Salman et al. in U.S. Patent Specification 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, maleic 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. A preferable salt is the hydrogen fumarate salt.

3,4-diarylchromans of formula I and their salts are useful within human medicine in the treatment of patients suffering from a decline in libido. 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, dermal 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, 1 990.

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 admin- istered one or more times per day or week. An effective amount of such a pharmaceutical composition is the amount required to increase libido, according to this invention. 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 dos- age range of from about 0.001 to about 75 mg/kg patient per day of a compound of the present invention.

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 al- ternative, 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. Con- trolled-release formulations are disclosed by, for example, Sanders et al., _ Pharm Sci 7_3_ ( 1 964), 1 294 - 1 297, 1 984; U.S. Patent Specification No. 4,489,056; and U.S. Patent Specification No. 4,210,644, which are incorporated herein by reference.

Examples of preferred compounds of formula I are centchroman as a racemic mixture and as isolated l-centchroman and d-centchroman enantiomers. Furthermore, 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl]-7- hydroxychroman is a preferred compound. The more preferred compound is iso- lated l-centchroman (l-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.

EXAMPLES

Test 1

The animals used are ovariectomized Sprague Dawley rats (Møllegaard Denmark) weighing 250-300 grams Food and water are available ad libitum. A compound of the invention (or oestrogen) is administered to one group of rats, and the other group is maintained as a control. Behavioural observations are made by placing each female with a cage adapted, sexually experienced male and measuring the number of females exhibiting lordosis (dorsi-flexion of the spine). In each female exhibiting lordosis the lordosis quotient (L.Q. = ratio of the number of lordoses to the number of mounts x 100) was calculated. Only the females being mounted at least once by the male were included in the L.Q. calculations. Tests were concluded when the females had received 1 0 mounts or after 1 5 min whichever came first. The tests were carried out in subdued lighting. Activity is shown as a positive effect on either of the above measures.

Claims

The use of compounds of the general formula I

wherein R\ R⁴ and R⁵ are individually hydrogen, hydroxy, halogen, tri- fluoromethyl, C,^ alkyl, C^ alkoxy or (tertiary amino)(C₁.₆ alkoxy); and R² and R³ are individually hydrogen or C ₆ alkyl, or a pharmaceutically acceptable salt thereof , for the manufacture of a pharmaceutical composition for increasing libido in post-menopausal women.

2. The use, according to claim 1 , wherein R¹ in the compound used is C_1-6 alkoxy, R² and R³ are C,^ alkyl, R⁴ is hydrogen and R⁵ is (tertiary amino) C^ alkoxy.

The use according to any one of claims 1 or 2 wherein R¹ is methoxy.

4. The use according to any one of claims 1 -3 wherein R² is methyl.

5. The use according to any one of claims 1 -4 wherein R³ is methyl.

6. The use according to any one of claims 1 -5 wherein R⁴ is hydrogen.

7. The use according to any one of claims 1 -6 wherein R⁵ is a group as stated in formula II below:

(II)

8. The use according to any one of claims 1 -7 wherein said compound is an isolated d- or l-enantiomer.

9. The use according to any one of the preceding claims wherein said com- pound has the general formula III as stated below:

wherein R\ R², R³, R⁴ and R⁵ each are as defined in above claim 1 .

10. The use according to anyone of the preceding claims wherein said compound is 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl]- 7-hydroxychroman.

1 1 . The use according to anyone of the preceding claims wherein said compound is an isolated l-enantiomer.

1 2. The use according to claim 1 wherein said compound is centchroman 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl]-7- methoxychroman having the formula IV as stated below:

1 3. The use according to claim 1 2 wherein said compound is an isolated I- enantiomer of 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl]-7-methoxychroman.

14. The use according to any one of the preceding claims wherein said composition is in a form suitable for oral administration.

1 5. The use according to any one of the preceding claims wherein said compound is administered as a dose in a range from about 0.001 to 75 mg/kg patient per day.

1 6. The use according to any one of the preceding claims wherein said com- position is administered one or more times per day or week.

1 7. The use according to any one of the preceding claims wherein said composition is in the form of a dermal implant.

1 8. Method for increasing libido in post-menopausal women comprising administering to a patient a clinically effective amount of a compound of above formula I stated to be used in any of the preceding use claims, or a pharmaceutically acceptable salt thereof in an amount sufficient to increase libido in post- menopausal women.

1 9. A method of increasing libido in post-menopausal women which method comprises administering a clinically effective amount of compounds and pharmaceutically acceptable compositions, according to previous claims to a patient in need of such a treatment.