AU1367297A - Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical comp osition for the treatment or prophylaxis of menopausal symptoms - Google Patents
Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical comp osition for the treatment or prophylaxis of menopausal symptomsInfo
- Publication number
- AU1367297A AU1367297A AU13672/97A AU1367297A AU1367297A AU 1367297 A AU1367297 A AU 1367297A AU 13672/97 A AU13672/97 A AU 13672/97A AU 1367297 A AU1367297 A AU 1367297A AU 1367297 A AU1367297 A AU 1367297A
- Authority
- AU
- Australia
- Prior art keywords
- use according
- com
- phenyl
- compound
- treatment
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
Classifications
-
- 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
-
- 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
- A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
Description
Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composi¬ tion for the treatment or prophylaxis of menopausal symptoms
FIELD OF THIS INVENTION
The present invention relates to the use of compounds of the general formula I for the prevention and treatment of menopausal symptoms. The present inventi¬ on also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.
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 climac- teric 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 gra¬ dual but progressive loss of ovarian function and a variety of endocrine, somatic and psycological changes. The median age of the women at the time of cessati- on 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 psy¬ chological 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 estro¬ gen 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 depressi- on and may even in some tissues negate the positive results of estrogen. The hormone replacement theraphy often causes unpleasant effects such as water retention, frequently weight gain and prolonged therapy is associated with an in¬ creased 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 cau- ses less side effects, and preferably brings the woman into a stable post- menopausal state in a reduced period of time than known compounds.
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) 123 (1992), 444 - 450; Grubb, £un £βiπ £bsl≤l Gyo≤cfii 3. ( 1 991 ), 491 - 495; San- karan et al., Contraception 9 ( 1 974), 279 - 289; Indian Patent Specification No. 1 29187). 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 choleste¬ rol lowering pharmaceutical expressed by a significant decrease of the serum concentrations (S.D. Bain et al., J Min Eon fi£S 2 ( 1 994), S 394).
U.S. patent 5,453,442 describes methods of lowering serum cholesterol and in- hibiting 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 treat or prevent menopausal symptoms.
One object of the present invention is to provide compounds which can effecti¬ vely be used in the treatment or prophylaxis of menopausal symptoms.
BRIEF DESCRIPTION OF THIS INVENTION
It has, surprisingly, been found that compounds of the general formula I as sta¬ ted in claim 1 can be used in the prevention and treatment of menopausal symp¬ toms.
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- pyrrolidinoethoxγ)phenyl]-7-methoxychroman) is a partial estrogen antago- nist/agonist and elicits similar actions as estrogen in a range of animal models and is useful in the treatment of climacteric symptoms and complaints without having the adverse effects associated with estrogen treatment.
Within the present invention, compounds of formula I or their pharmaceutically acceptable salts are used for prevention and treatment of menopausal symptoms in a patient.
Within formula I, R1 , R4 and R5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, C,.6 alkyl, C^ alkoxy or (tertiary amino)(C1.6 alkoxy); and R2 and
R3 are individually hydrogen or a C1 -6 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,^ al¬ koxy" 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)(C,.6 alkoxy)" is a C,.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 R ' is C,.6 alkoxy; R2 and R3 are C,.6 alkyl, especially methyl; R4 is hydrogen; and R 5 is (tertiary amino)(C1.6 alkoxy) of the polymethyleneimine type. Within particu¬ larly preferred embodiments, R1 is in the 7-position and is C^ alkoxy, particu¬ larly methoxy; each of R2 and R3 is methyl, R4 is hydrogen, and R5 is in the 4- position and is a (tertiary amino)(C,.6 alkoxy) radical such as 2-(pyrrolidin-1 - yDethoxy 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 inclu- ded.
3,4-diarylchromans are prepared according to known methods, such as those di¬ sclosed 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., Med Chem 12 (1 976), 276 - 279, the contents of which are incorporated herein by reference. Conver¬ sion of the cis isomer to the trans configuration by means of an organometallic
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 disclo¬ sed 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, in- eluding 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 a- cid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorga¬ nic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like. The acid addition salts may be obtained as the di¬ rect products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isola¬ ted 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 vete¬ rinary medicine, for example, in the treatment of patients suffering from meno¬ pausal symptoms. For use within the present invention, 3,4-diarylchromans of formula I and their pharmaceutically acceptable salts are formulated with a phar¬ maceutically acceptable carrier to provide a medicament for parenteral, oral, na- sal, 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 ac-
cordance with accepted practices, such as those disclosed in Remington's Phar¬ maceutical Sciences. Gennaro, ed. , Mack Publishing Co., Easton, PA, 1 990.
Oral administration is preferred. Thus, the active compound of formula I is prepa- red 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 com¬ bined with a carrier and moulded into a tablet. Suitable carriers in this regard in¬ clude starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate and the like. Such compositions may further include one or more auxiliary sub- stances, such as wetting agents, emulsifiers, preservatives, stabilizers, colouring additives, etc.
Pharmaceutical compositions containing a compound of formula I may be admini¬ stered one or more times per day or week. An effective amount of such a phar- maceutical composition is the amount that provides a clinically significant effect against menopausal symptoms. Such amounts will depend, in part, on the parti¬ cular 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.
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 com¬ pound 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 incorpora- ted 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 l-centchroman and d-centchroman enantiomers. Further- more, 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 isola¬ ted 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 fea¬ tures disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realising the in- vention 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 0,001 to 75 mg/kg pa¬ tient 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 systems. 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 men¬ opausal state, in any of the above assays indicates that the compounds of the invention are useful in the treatment of menopausal symptoms.
Claims (20)
1 . The use of compounds of the general formula I
wherein R1 , R4 and R5 are individually hydrogen, hydroxy, halogen, tri- fluoromethyl, C,.6 alkyl, C,.6 alkoxy or (tertiary aminoMC^ alkoxy); and R2 and R3 are individually hydrogen or C,.6 alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier for the manu¬ facture of a pharmaceutical composition for the prevention and treatment of menopausal symptoms.
2. The use, according to claim 1 , wherein R1 in the compound used is C 6 alkoxy, R2 and R3 are C 6 alkyl, R4 is hydrogen and R5 is (tertiary amino) C 6 al¬ koxy.
3. 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 sta¬ ted in formula II below:
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 com¬ pound 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 com¬ pound is an isolated l-enantιomer.
1 2. The use according to claim 1 wherein said compound is centchroman 3,4-trans-2,2-dιmethyl-3-phenyl-4-[4-(2-(pyrrolιdιn-1 -yl)ethoxy)phenyl]-7- methoxychroman having the formula IV as stated below:
13. The use according to claim 1 2 wherein said compound is an isolated I- enantiomer of 3,4-trans-2,2-dιmethyl-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 com¬ position is in a form suitable for oral administration.
1 5. The use according to any one of the preceding claims wherein said com¬ pound is administered as a dose in a range from about 0.001 to 75 mg/kg pa¬ tient 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 com¬ position is in the form of a dermal implant.
1 8. Method for treatment and prophylaxis of menopausal symptoms compris¬ ing 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 phar¬ maceutically acceptable salt thereof in an amount sufficient to treat or prevent menopausal symptoms.
1 9. A method of treating or preventing menopausal symptoms which method comprises administering a clinically effective amount of compounds and pharma¬ ceutically acceptable compositions, according to previous claims to a patient in need of such a treatment.
20. Any novel feature or combination of features described herein.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US983496P | 1996-01-11 | 1996-01-11 | |
US009834 | 1996-01-11 | ||
US67826196A | 1996-07-11 | 1996-07-11 | |
US678261 | 1996-07-11 | ||
PCT/DK1997/000008 WO1997025035A1 (en) | 1996-01-11 | 1997-01-09 | Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of menopausal symptoms |
Publications (1)
Publication Number | Publication Date |
---|---|
AU1367297A true AU1367297A (en) | 1997-08-01 |
Family
ID=26679921
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU13672/97A Abandoned AU1367297A (en) | 1996-01-11 | 1997-01-09 | Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical comp osition for the treatment or prophylaxis of menopausal symptoms |
Country Status (12)
Country | Link |
---|---|
EP (1) | EP0873120A1 (en) |
JP (1) | JP2000506505A (en) |
KR (1) | KR19990077156A (en) |
AU (1) | AU1367297A (en) |
BR (1) | BR9706967A (en) |
CA (1) | CA2241623A1 (en) |
CZ (1) | CZ217298A3 (en) |
HU (1) | HUP9902683A3 (en) |
IL (1) | IL124882A0 (en) |
NO (1) | NO983178L (en) |
PL (1) | PL327831A1 (en) |
WO (1) | WO1997025035A1 (en) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7005428B1 (en) | 1998-06-11 | 2006-02-28 | Endorecherche, Inc. | Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors |
US6465445B1 (en) | 1998-06-11 | 2002-10-15 | Endorecherche, Inc. | Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors |
WO2001049673A2 (en) * | 1999-12-30 | 2001-07-12 | Signal Pharmaceuticals, Inc. | Compounds and methods for modulation of estrogen receptors |
US8080675B2 (en) | 2004-09-21 | 2011-12-20 | Marshall Edwards, Inc. | Chroman derivatives, medicaments and use in therapy |
AU2005287865B2 (en) | 2004-09-21 | 2012-02-16 | Marshall Edwards, Inc. | Substituted chroman derivatives, medicaments and use in therapy |
RS20070166A (en) | 2004-10-20 | 2008-09-29 | Endorecherche Inc., | Sex steroid precursors alone or in combination with a selective estrogen receptor modulator... |
US8268806B2 (en) | 2007-08-10 | 2012-09-18 | Endorecherche, Inc. | Pharmaceutical compositions |
UA96076C2 (en) | 2007-10-16 | 2011-09-26 | Репрос Терапьютикс Инк. | Use of trans-clomiphene |
US20100317635A1 (en) | 2009-06-16 | 2010-12-16 | Endorecherche, Inc. | Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators |
KR20220061258A (en) | 2010-06-16 | 2022-05-12 | 앙도르쉐르슈 인코포레이티드 | Methods of treating or preventing estrogen-related diseases |
EP2635121B1 (en) | 2010-11-01 | 2020-01-08 | MEI Pharma, Inc. | Isoflavonoid compounds and methods for the treatment of cancer |
JP2015508825A (en) | 2012-02-29 | 2015-03-23 | レプロス セラピューティクス インコーポレイティド | Combination therapy to treat androgen deficiency |
PT2953938T (en) | 2014-02-07 | 2017-10-09 | Novogen ltd | Functionalised benzopyran compounds and use thereof |
US9744177B2 (en) | 2014-03-10 | 2017-08-29 | Endorecherche, Inc. | Treatment of male androgen deficiency symptoms or diseases with sex steroid precursor combined with SERM |
PL3253208T3 (en) | 2015-02-02 | 2021-11-08 | Mei Pharma, Inc. | Combination therapies for use in the treatment of breast cancer |
US11633382B2 (en) | 2015-11-10 | 2023-04-25 | Paracrine Therapeutics Ab | Treatment of ER-negative breast cancer with an PDGF-CC inhibitor and anti-estrogen |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4729999A (en) * | 1984-10-12 | 1988-03-08 | Bcm Technologies | Antiestrogen therapy for symptoms of estrogen deficiency |
-
1997
- 1997-01-09 KR KR1019980705294A patent/KR19990077156A/en not_active Application Discontinuation
- 1997-01-09 AU AU13672/97A patent/AU1367297A/en not_active Abandoned
- 1997-01-09 WO PCT/DK1997/000008 patent/WO1997025035A1/en not_active Application Discontinuation
- 1997-01-09 IL IL12488297A patent/IL124882A0/en unknown
- 1997-01-09 EP EP97900200A patent/EP0873120A1/en not_active Withdrawn
- 1997-01-09 PL PL97327831A patent/PL327831A1/en unknown
- 1997-01-09 BR BR9706967A patent/BR9706967A/en not_active Application Discontinuation
- 1997-01-09 JP JP9524768A patent/JP2000506505A/en active Pending
- 1997-01-09 CA CA002241623A patent/CA2241623A1/en not_active Abandoned
- 1997-01-09 CZ CZ982172A patent/CZ217298A3/en unknown
- 1997-01-09 HU HU9902683A patent/HUP9902683A3/en unknown
-
1998
- 1998-07-10 NO NO983178A patent/NO983178L/en unknown
Also Published As
Publication number | Publication date |
---|---|
PL327831A1 (en) | 1999-01-04 |
WO1997025035A1 (en) | 1997-07-17 |
BR9706967A (en) | 1999-05-04 |
CZ217298A3 (en) | 1999-01-13 |
HUP9902683A3 (en) | 2001-08-28 |
CA2241623A1 (en) | 1997-07-17 |
HUP9902683A2 (en) | 2001-04-28 |
IL124882A0 (en) | 1999-01-26 |
KR19990077156A (en) | 1999-10-25 |
NO983178L (en) | 1998-07-10 |
EP0873120A1 (en) | 1998-10-28 |
JP2000506505A (en) | 2000-05-30 |
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