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WO1998034608A1 - Methods for treatment or prophylaxis of menopausal symptoms - Google Patents

Methods for treatment or prophylaxis of menopausal symptoms Download PDF

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Publication number
WO1998034608A1
WO1998034608A1 PCT/DK1998/000051 DK9800051W WO9834608A1 WO 1998034608 A1 WO1998034608 A1 WO 1998034608A1 DK 9800051 W DK9800051 W DK 9800051W WO 9834608 A1 WO9834608 A1 WO 9834608A1
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WO
WIPO (PCT)
Prior art keywords
acid
compound
formula
treatment
menopausal symptoms
Prior art date
Application number
PCT/DK1998/000051
Other languages
French (fr)
Inventor
Birgitte Hjort Guldhammer
Original Assignee
Novo Nordisk A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU57499/98A priority Critical patent/AU5749998A/en
Publication of WO1998034608A1 publication Critical patent/WO1998034608A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

Definitions

  • the present invention relates to the use of the compound of formula I for the prevention and treatment of menopausal symptoms.
  • the menopause is defined as the final episode of menstrual bleeding in women. However, the term is used commonly to refer to the period of the female climacteric that encompasses the transitional period between the reproductive years up to and beyond the last episode of menstrual bleeding. This period is also referred to as the peri-menopause or the climacterium. During this period there is a grad- ual but progressive loss of ovarian function and a variety of endocrine, somatic and psychological changes. The median age of the women at the time of cessation of menstrual bleeding is 50 to 51 years. Since the life expectancy of women in developed countries is now close to 80 years, approximately one-third of a woman's life-span occurs after cessation of reproductive function.
  • the symptoms associated with declining estrogen levels in the perimenopause include hot flashes and sweats, atrophic vaginitis, headache, dizziness, joint pain, sleeplessness, apathy, lassitude, muscular weakness, palpitations and psychological symptoms such as changes in mood, depression, memory and concen- tration deficits, irritability and problems related to sexual functioning. All of these symptoms are a direct consequence of the declining estrogen production.
  • the compound of formula I is a non-steroidal compound known to have anti- estrogenic properties. From EP 260066 B1 the compound is known to be useful in the treatment of estrogen receptor-positive hormone-dependant cancer. Recently the compound was described to prevent bone loss and reduce serum- cholesterol ( Journal of Bone and mineral research, (Aug 1 996) Vol. 1 1 , Supp.
  • One object of the present invention is to provide compounds which can effectively be used in the treatment or prophylaxis of menopausal symptoms.
  • the present invention relates to the use of 1 -[2-[4-[ 1 -(4-iodophenyl)-2-phenyl-1 butenyl]phenoxy]ethyl]- pyrrolidine of formula I
  • the current invention concerns the discovery that the compounds of formula I are useful for treating menopausal symptoms.
  • the methods of treatment provided by this invention are practised 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 treat menopausal symptoms. Treating is defined to include ameliorating one or more of the symptoms and /or bringing a woman into a stable post- menopausal state in a reduced period of time.
  • the compounds of formula I are useful for treating or preventing menopausal symptoms including e.g.
  • Formula I covers both the (E) and (Z) configurations. It is preferred to use the compound of formula I in the trans (E) configuration.
  • the preparation of the compound of formula I is described in R. McCague, G. Le- clerq, N. Legros, J. Goodman, G.M. Blackburn, M. Jarman and A.B. Foster: J.Med.Chem. _ 2 ( 1 989), 2527-2533.
  • the compound 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.
  • salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyru- vic 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.
  • 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.
  • the compound of formula I and their salts are useful within human and veterinary medicine, for example, in the treatment of patients suffering from menopausal symptoms.
  • the compounds 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, emul- sifiers, 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.
  • the active compound of formula I is prepared in a form suitable for oral administration, such as a tablet or capsule.
  • 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 in- elude 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.
  • 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 menopausal symptoms. 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 0.1 to about 1 000 mg per day of a compound of the present invention and more typically from about 0.5 to about 250 mg per day.
  • 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. Con- trolled-release formulations are disclosed by, for example, Sanders et al., J Pharm Sci 73 ( 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 pharmaceutically acceptable acid addition salts are salts with nontoxic 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.
  • inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid
  • 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.
  • a compound of the invention is given in the amount of 0.5 to 250 mg per day and the frequency of vasomotor symptoms are closely monitored together with the variables laid down in the Green Scale or Kupperman Indeks monitoring sys- tems. The dosing of the compound of the invention continues for a period of 4 weeks.
  • This test is ran as Test 1 , except the dosing period is for a period of 6 months.
  • Activity defined as either total cessation of one or more sequellae of the patient, or reduced severity or occurrence thereof, or a more rapid advancement to menopausal state, in any of the above assays indicates that the compounds of the invention are useful in the treatment of menopausal symptoms.
  • TST tail skin temperature
  • Naloxone administration to morphine-dependent female rats produces a significant and sustained increase in tail skin temperature (TST) .
  • TST tail skin temperature
  • the ability of the compound of formula I (idoxifen) to attenuate this increase will be studied.
  • Three groups of rats will be administered idoxifen s.c. in different doses once daily for one week. Ovarectomized female rats are used.
  • morphine dependency will be induced in all groups by the subcutaneous implantation of a 75mg pellet of morphine free base. Two days after the initial pellet implantation another pellet will be implanted in each animal.
  • the rats Two days after the implantation of the last morphine pellet, the rats will be connected to a temperature probe to measure TST. Following a 30 min. equilibration period, the morphine addiction will be withdrawn by injection of 0.25mg/kg naloxone. Temperature measurements are recorded every 5 min. for 1 hr. under ketamine anesthesia (80mg/kg).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides novel uses of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment or prevention of menopausal symptoms.

Description

Methods for treatment or prophylaxis of menopausal symptoms
FIELD OF THIS INVENTION
The present invention relates to the use of the compound of formula I for the prevention and treatment of menopausal symptoms.
BACKGROUND OF THIS INVENTION
The menopause is defined as the final episode of menstrual bleeding in women. However, the term is used commonly to refer to the period of the female climacteric that encompasses the transitional period between the reproductive years up to and beyond the last episode of menstrual bleeding. This period is also referred to as the peri-menopause or the climacterium. During this period there is a grad- ual but progressive loss of ovarian function and a variety of endocrine, somatic and psychological changes. The median age of the women at the time of cessation of menstrual bleeding is 50 to 51 years. Since the life expectancy of women in developed countries is now close to 80 years, approximately one-third of a woman's life-span occurs after cessation of reproductive function.
The symptoms associated with declining estrogen levels in the perimenopause include hot flashes and sweats, atrophic vaginitis, headache, dizziness, joint pain, sleeplessness, apathy, lassitude, muscular weakness, palpitations and psychological symptoms such as changes in mood, depression, memory and concen- tration deficits, irritability and problems related to sexual functioning. All of these symptoms are a direct consequence of the declining estrogen production.
Currently the treatment of these disorders involves different regimens of estrogen administration with or without concomitant progestin administration. Estro- gen alone and in different combinations is often associated with unacceptable side effects. The effects of progestin are often poorly tolerated causing depres- sion and may even in some tissues negate the positive results of estrogen. The hormone replacement therapy often causes unpleasant effects such as water retention, frequently weight gain and prolonged therapy is associated with an increased risk of endometrial cancer. Thus there is a need for a new compound, which ameliorates the symptoms of the menopause, but which is safe and causes less side effects, and preferably brings the woman into a stable post- menopausal state in a reduced period of time than known compounds.
The compound of formula I is a non-steroidal compound known to have anti- estrogenic properties. From EP 260066 B1 the compound is known to be useful in the treatment of estrogen receptor-positive hormone-dependant cancer. Recently the compound was described to prevent bone loss and reduce serum- cholesterol ( Journal of Bone and mineral research, (Aug 1 996) Vol. 1 1 , Supp.
1 ). There is no disclosure in the prior art of using the compound to treat or prevent menopausal symptoms.
One object of the present invention is to provide compounds which can effectively be used in the treatment or prophylaxis of menopausal symptoms.
DETAILED DESCRIPTION OF THIS INVENTION
The present invention relates to the use of 1 -[2-[4-[ 1 -(4-iodophenyl)-2-phenyl-1 butenyl]phenoxy]ethyl]- pyrrolidine of formula I
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for prevention or treatment of menopausal symptoms in a patient.
The current invention concerns the discovery that the compounds of formula I are useful for treating menopausal symptoms. The methods of treatment provided by this invention are practised 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 treat menopausal symptoms. Treating is defined to include ameliorating one or more of the symptoms and /or bringing a woman into a stable post- menopausal state in a reduced period of time. Thus the compounds of formula I are useful for treating or preventing menopausal symptoms including e.g. hot flushes, sweats, atrophic vaginitis, headache, dizziness, joint pain, sleeplessness, apathy, lassitude, muscular weakness, palpitations and psychological symptoms such as changes in mood, depression, memory and concentration deficits, irritability and problems related to sexual functioning. To be included by this invention are all pharmaceutically acceptable salts of the compound of formula I.
Formula I covers both the (E) and (Z) configurations. It is preferred to use the compound of formula I in the trans (E) configuration. The preparation of the compound of formula I is described in R. McCague, G. Le- clerq, N. Legros, J. Goodman, G.M. Blackburn, M. Jarman and A.B. Foster: J.Med.Chem. _ 2 ( 1 989), 2527-2533.
The compound 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, pyru- vic 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.
The compound of formula I and their salts are useful within human and veterinary medicine, for example, in the treatment of patients suffering from menopausal symptoms. For use within the present invention, the compounds 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, emul- sifiers, 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. Typi¬ cally, 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 in- elude 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 menopausal symptoms. 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 0.1 to about 1 000 mg per day of a compound of the present invention and more typically from about 0.5 to about 250 mg 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. Con- trolled-release formulations are disclosed by, for example, Sanders et al., J Pharm Sci 73 ( 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 pharmaceutically acceptable acid addition salts are salts with nontoxic 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
Between 3 and 20 women of the age of 45-50 years are selected as a test group. The women exhibit at least one of the sequellae of impending menopause. A compound of the invention is given in the amount of 0.5 to 250 mg per day and the frequency of vasomotor symptoms are closely monitored together with the variables laid down in the Green Scale or Kupperman Indeks monitoring sys- tems. The dosing of the compound of the invention continues for a period of 4 weeks.
Test 2
The same test as in Test 1 is carried out, however, the administration period is for a time of 3 months.
Test 3
This test is ran as Test 1 , except the dosing period is for a period of 6 months. Activity, defined as either total cessation of one or more sequellae of the patient, or reduced severity or occurrence thereof, or a more rapid advancement to menopausal state, in any of the above assays indicates that the compounds of the invention are useful in the treatment of menopausal symptoms.
Test 4
The effects of idoxifen administration on the tail skin temperature (TST) following naloxone induced withdrawal in OVX rats addicted to morphine .
Naloxone administration to morphine-dependent female rats produces a significant and sustained increase in tail skin temperature (TST) . The ability of the compound of formula I (idoxifen) to attenuate this increase will be studied. Three groups of rats will be administered idoxifen s.c. in different doses once daily for one week. Ovarectomized female rats are used.
In the third day of the experiment, morphine dependency will be induced in all groups by the subcutaneous implantation of a 75mg pellet of morphine free base. Two days after the initial pellet implantation another pellet will be implanted in each animal.
Two days after the implantation of the last morphine pellet, the rats will be connected to a temperature probe to measure TST. Following a 30 min. equilibration period, the morphine addiction will be withdrawn by injection of 0.25mg/kg naloxone. Temperature measurements are recorded every 5 min. for 1 hr. under ketamine anesthesia (80mg/kg).
Group 1 1 -6 OVX placebo naloxone 0.25mg/kg
Group 2 7-1 2 OVX idoxifen 1 nmol/g naloxone 0.25mg/kg
Group 3 1 3-1 8 OVX idoxifen 1 0nmol/g naloxone 0.25mg/kg
Group 4 1 3-1 8 OVX idoxifen 50nmol/g naloxone 0.25mg/kg
Group 5 1 9-24 OVX estrogen 0. 1 mg/kg naloxone 0.25mg/kg

Claims

1 . The use of a compound of formula I
Figure imgf000010_0001
or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of menopausal symptoms.
2. The use according to claim 1 wherein said compound is in the trans (E) configuration.
3. The use according to any one of the preceding claims wherein said composition is in a form suitable for oral administration.
4. The use according to any one of the preceding claims wherein said composition is administered one or more times per day or week.
PCT/DK1998/000051 1997-02-11 1998-02-10 Methods for treatment or prophylaxis of menopausal symptoms WO1998034608A1 (en)

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DK15297 1997-02-11
DK0152/97 1997-02-11

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0178862A2 (en) * 1984-10-12 1986-04-23 BCM Technologies, INC. Antiestrogen therapy for symptoms of estrogen deficiency
EP0260066A1 (en) * 1986-09-11 1988-03-16 National Research Development Corporation Tamoxifen derivatives
WO1998009519A1 (en) * 1996-09-06 1998-03-12 Smithkline Beecham Corporation Method of treating post menopausal diseases, including osteoporosis

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0178862A2 (en) * 1984-10-12 1986-04-23 BCM Technologies, INC. Antiestrogen therapy for symptoms of estrogen deficiency
EP0260066A1 (en) * 1986-09-11 1988-03-16 National Research Development Corporation Tamoxifen derivatives
WO1998009519A1 (en) * 1996-09-06 1998-03-12 Smithkline Beecham Corporation Method of treating post menopausal diseases, including osteoporosis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PROMT ON STN, PROMT No. 97:523083, "Idoxifene SmithKline Beecham Phase Change III, USA, Europe (Osteoporosis) Tamoxifen Derivative, Idoxifene, for Osteoporosis, has Entered Phase III Trials in US & Europe"; & R & D FOCU DRUG NEWS, 6 Oct. 1997. *

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AU5749998A (en) 1998-08-26

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