WO1999042427A1 - E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol and pharmaceutical compositions thereof - Google Patents
E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol and pharmaceutical compositions thereof Download PDFInfo
- Publication number
- WO1999042427A1 WO1999042427A1 PCT/FI1999/000137 FI9900137W WO9942427A1 WO 1999042427 A1 WO1999042427 A1 WO 1999042427A1 FI 9900137 W FI9900137 W FI 9900137W WO 9942427 A1 WO9942427 A1 WO 9942427A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- diphenyl
- chloro
- enyl
- ethanol
- phenoxy
- Prior art date
Links
- LUMKNAVTFCDUIE-WCWDXBQESA-N 2-[4-[(e)-4-chloro-1,2-diphenylbut-1-enyl]phenoxy]ethanol Chemical compound C1=CC(OCCO)=CC=C1C(\C=1C=CC=CC=1)=C(/CCCl)C1=CC=CC=C1 LUMKNAVTFCDUIE-WCWDXBQESA-N 0.000 title claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 20
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 6
- 230000002265 prevention Effects 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 150000002148 esters Chemical class 0.000 claims description 12
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 12
- 238000002657 hormone replacement therapy Methods 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 18
- 235000012000 cholesterol Nutrition 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 9
- 229960005026 toremifene Drugs 0.000 description 9
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 8
- 229960005309 estradiol Drugs 0.000 description 8
- 229930182833 estradiol Natural products 0.000 description 8
- 210000004291 uterus Anatomy 0.000 description 8
- 241000700159 Rattus Species 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000001833 anti-estrogenic effect Effects 0.000 description 5
- 230000001076 estrogenic effect Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- -1 N,N-dimethylamino Chemical group 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 4
- 229960004622 raloxifene Drugs 0.000 description 4
- OYXIKBMCUBZEPS-NVQSTNCTSA-N (e)-3,4-diphenyl-4-[4-(2-phenylmethoxyethoxy)phenyl]but-3-en-1-ol Chemical compound C=1C=CC=CC=1C(/CCO)=C(C=1C=CC(OCCOCC=2C=CC=CC=2)=CC=1)\C1=CC=CC=C1 OYXIKBMCUBZEPS-NVQSTNCTSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- 239000000328 estrogen antagonist Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- XARXSXPYKRGUFO-NVQSTNCTSA-N 1-[(e)-4-chloro-1,2-diphenylbut-1-enyl]-4-(2-phenylmethoxyethoxy)benzene Chemical compound C=1C=CC=CC=1C(/CCCl)=C(C=1C=CC(OCCOCC=2C=CC=CC=2)=CC=1)\C1=CC=CC=C1 XARXSXPYKRGUFO-NVQSTNCTSA-N 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000013223 sprague-dawley female rat Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FWOHDAGPWDEWIB-UHFFFAOYSA-N 2-bromoethoxymethylbenzene Chemical compound BrCCOCC1=CC=CC=C1 FWOHDAGPWDEWIB-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010027304 Menopausal symptoms Diseases 0.000 description 1
- 208000035327 Oestrogen receptor positive breast cancer Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000008687 biosynthesis inhibition Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 201000007281 estrogen-receptor positive breast cancer Diseases 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001030 gas--liquid chromatography Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000012606 in vitro cell culture Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The present invention relates to E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol useful in lowering serum cholesterol and to pharmaceutical compositions thereof. A method of lowering serum cholesterol and a method for the prevention or treatment of atherosclerosis is also disclosed.
Description
E-2-[4-(4-CHLORO- 1 ,2-DIPHENYL-BUT- 1 -ENYL)PHENOXY]ETHANOL AND PHARMACEUTICAL COMPOSITIONS THEREOF
The present invention relates to E-2-[4-(4-chloro-l,2-diphenyl-but-l- enyl)phenoxy]ethanol (I) having serum cholesterol lowering properties and to pharmaceutical compositions thereof. Compound (I) is useful in reducing serum cholesterol levels and in the treatment of atherosclerosis. It is also potentially useful in the hormone replacement therapy (HRT).
It has been demonstrated that elevated levels of serum cholesterol associated with low density lipoproteins (LDL) are a major contributing factor in the development and progression of atherosclerosis. Therefore it is desirable to provide a method for reducing serum cholesterol levels in patients with hypercholesterolemia or at risk of developing hypercholesterolemia.
International patent application WO 97/32574 describes the use of Z-2-[4-(4-chloro-l,2-diphenyl-but- l-enyl)phenoxy]ethanol for lowering serum cholesterol. The compound has no significant estrogenic side effects in uterine tissue but is able to block the adverse effects of estrogen on uterus. Therefore this compound is especially useful in lowering serum cholesterol. The corresponding E- isomer is not described in this patent application.
Z-2-[4-(4-chloro-l,2-diphenyl-but-l-enyl)phenoxy]ethanol is a metabolite of known antiestrogen drug toremifene. Toremifene (Z-4-chloro-l,2-diphenyl-l-[4-[2- (N,N-dimethylamino)ethoxy]-phenyl]-l-butene) is currently used clinically for the treatment of estrogen receptor positive breast cancer.
Now it has been found that E-2-[4-(4-chloro-l,2-diphenyl-but-l- enyl)phenoxy]ethanol (I) is significantly more potent in lowering serum total cholesterol but approximately equal in uterine effects when compared to the corresponding Z-isomer. This was unexpected since the E-isomer of toremifene is purely estrogenic in uterine tissue. Furthermore, it has been found that the E-isomer of the invention is able to inhibit cholesterol biosynthesis directly whereas the corresponding Z-isomer has not such effect.
Thus, E-2-[4-(4-chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethanol (I) is especially useful in lowering serum cholesterol and in the prevention or treatment of atherosclerosis. Compound (I) is also potentially useful in the hormone replacement therapy (HRT).
2
Accordingly, the invention provides a novel compound useful in lowering serum cholesterol levels said compound being E-2-[4-(4-chloro-l ,2-diphenyl-but-l- enyl)phenoxy]ethanol and having the structure (I)
OH
(I)
or a pharmaceutically acceptable ester thereof.
Pharmaceutically acceptable esters include esters made with aliphatic carboxylic acids, preferably Cι-6 acids, e.g. acetic acid, and made with aroma-tic carboxylic acids, e.g. C -ι2 acids such as benzoic acid. The aliphatic and aromatic acids may optionally be substituted by e.g. one or more C1-4 alkyl.
The invention also provides a pharmaceutical composition comprising E-2-
[4-(4-chloro-l,2-diphenyl-but-l-enyl)phenoxy]ethanol or a pharmaceutically acceptable ester thereof as an active ingredient together with a pharmaceutically acceptable carrier.
The invention also provides a method of lowering serum cholesterol levels which method comprises administering to a patient in need of such treatment an effective amount of E-2-[4-(4-chloro-l,2-diphenyl-but-l-enyl)phenoxy]ethanol or a pharmaceutically acceptable ester thereof.
The invention also provides a method for the prevention or treatment of atherosclerosis which method comprises administering to a patient in need of such treatment an effective amount of E-2-[4-(4-chloro- 1 ,2-diphenyl-but- 1 - enyl)phenoxy]ethanol or a pharmaceutically acceptable ester thereof.
The invention also provides a method of hormone replacement therapy (HRT) which method comprises administering to a patient in need of such therapy an effective amount of E-2-[4-(4-chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethanol or a pharmaceutically acceptable ester thereof.
The compound of the invention may be administered in a variety of ways including orally, parenterally or transdermally using conventional forms of
3 preparations, such as capsules, tablets, granules, powders, suppositories, injections, patches, suspensions and syrups. The term "effective amount" means an amount of compound of the invention which is capable of lowering serum total cholesterol levels or capable of blocking the adverse effects of estrogen particularly on uterus or inhibiting menopausal symptoms. The compound of the invention may be administered according to the method of the invention monthly, weekly or daily or several times a day depending upon the patient's needs. A typical daily oral dosage is within the range of from about 0.5 g to about 1000 mg, preferably from about 10 mg to about 800 mg, of the active compound. However, the dosage may be properly varied depending on the age, body weight and conditions of the patient as well as on the administration method. The compound of the invention may be administered alone or together with other active compounds.
The compositions according to the invention can be prepared by the methods commonly employed in the art. In addition to the active compound the compositions may contain pharmaceutically acceptable additives commonly used in the art, such as carriers, binders, excipients, lubricants, suspending agents and diluents. The amount of the active compound in the compositions of the invention is sufficient to produce the desired therapeutical effect, for example about 0.5 to 1000 mg, preferably about 10 mg to 800 mg, in unit dosage for both oral and parenteral administration.
The following examples illustrate the synthesis of the compound of the invention.
EXAMPLES
Example 1. Preparation of E-2-[4-(4-chloro-l ,2-diphenyl-but-l- enyl)phenoxy]ethanol
a) E-4-[4-(2-benzyloxyethoxy)phenyl]-3,4-diphenyl-but-3-en- 1 -ol
The alkylation of the starting phenol with benzyl-(2-bromoethyl)ether was carried out as described in Example 1 of the International Patent Application WO 96/07402 with the exception that now the starting compound was the other geometric isomer, E-4-(4-hydroxy-l,2-diphenyl-but-l-enyl)-phenol which was prepared by the method described in United States Patent 4,996,225. The product was extracted to toluene. The toluene phases were combined, washed with water, dried and evaporated to dryness. The residue was recrystallized from a minor quantity of toluene and the precipitated product was used in the next step without further purification.
4
1H NMR (300 MHz, CDCI3): 2.8 (2H, t, CH2-C=), 3.6 (2H, dt, CH2OH), 3.8 (2H, t, CH?OBn), 4.2 (2H, t, CH9θPh), 4.6 (2H, s, OCH9Ph), 6.8 - 7.4 (19H, m).
b) E- 1 -[4-(2-benzyloxyethoxy)phenyl]-4-chloro- 1 ,2-diphenyl-but- 1 -ene
The halogenation of E-4-[4-(2-benzyloxyethoxy)phenyl]-3,4-diphenyl-but-3- en-l-ol was carried out as described in Example 2 of the International Patent Application WO 96/07402 but using E-4-[4-(2-benzyloxyethoxy)-phenyl]-3,4- diphenyl-but-3-en-l-ol as the starting compound.
!H NMR (300 MHz, CDCI3): 3.0 (2H, t), 3.4 (2H, t), 3.8 (2H, t), 4.2 (2H, t), 4.6 (2H, s), 6.9 - 7.4 (19H, m).
c) E-2-[4-(4-chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethanol
6.9 g of E- 1 -[4-(2-benzyloxyethoxy)phenyl]-4-chloro- 1 ,2-diphenyl-but- 1 -ene was dissolved in the mixture of ethyl acetate (60 ml) and ethanol (60 ml). Palladium on carbon (5 %, 0.7 g) was added and the solution was stirred vigorously under a hydrogen atmosphere at room temperature until there was not any starting compound left (thin layer chromatography). Palladium on carbon was filtered off through siliceous earth and the filtrate was evaporated to dryness. The residue was crystallized several times from the mixture of ethanol and water.
iH NMR (300 MHz, CDCI3): 3.0 (2H, t), 3.4 (2H, t), 4.0 (2H, m), 4.1 (2H, t), 6.8 - 7.3 (14H, m).
MS-spectrum (+EI, 70 eV, direct inlet): 378 (100%), 342 (8%), 329 (43%), 285 (23%), 284 (28%), 207 (32%), 191 (30%).
EXPERIMENTS
Methods
The estrogenic/antiestrogenic activity of the study drug was tested by measuring the effect on the uterine weight in immature (18 days old) female Sprague-Dawley rats. The compound was given p.o. in a PEG-solution for 3 days (n = 5/group). At the same time the ability of the study drug to inhibit estrogen-induced increase in uterine weight was studied in rats given estradiol 50 μg/kg s.c. Comparison was made with the corresponding Z-isomer.
The effects on cholesterol biosynthesis was studied in vitro in Hep G2 cell cultures using , C-acetate as cholesterol precursor. The test compound was added
5 into the culture medium at concentrations from 0.01 to 10 micromolar. After 2 hours the culture was stopped and the newly synthesized cholesterol was quantitated by thin-layer chromatography. Comparison was made with the Z-isomer.
The effects on uterine weight and on serum cholesterol levels were studied in intact and ovarectomized adult female Sprague-Dawley rats. In the intact rats the study drug was given p.o. at a daily dose of 3.17 mg/kg for two weeks and comparison was made with the equimolar doses of the Z-isomer, toremifene E- isomer, raloxifene or estradiol. In the ovarectomy study the study drug was given p.o. at a daily dose of 0.1 , 1 or 10 mg/kg for 4 weeks and comparison was made with the corresponding Z-isomer and estradiol (100 μg/kg). The serum cholesterol content was determined by an enzymatic method. In the ovarectomy study the serum cholesterol and cholesterol precursor molecule content was determined by gas-liquid chromatography.
Results
In the immature rat uterine weight test the E-isomer of the invention showed approximately equal estrogenic and antiestrogenic effect when compared to the corresponding Z-isomer. The results are shown in Table 1 wherein 1271b (E) means the E-isomer of the invention, 1271a (Z) means the corresponding Z-isomer and E2 means estradiol.
TABLE 1.
Drug dose Average uterine weight (weight after mere E2- (mg/kg) treatment was taken as 1.00)
1271a (Z) 1271a (Z)+E2 1271b (E) 1271b (E)+E2
0 0.25 1.00 0.33 1.00
0.1 0.27 1.18 0.37 0.81
0.5 0.43 1.1 1 0.45 0.82
1 0.53 0.91 0.44 0.57
10 0.75 0.91 0.75 0.83
In the in vitro cell culture system used the E-isomer of the invention inhibited slightly cholesterol biosynthesis but the Z-isomer had an opposite effect as shown in Table 2.
TABLE 2.
Drug concentration Cholesterol biosynthesis level (μM) (% of control) 1271a (Z) 1271b (E)
0.01 143 89
0.1 127 90
1 129 89
10 132 84
In adult female rats 1271b (E), 1271a (Z) and raloxifene decreased relative uterine weight at about the same extent. Instead, estradiol and toremifene E-isomer increased the weight. Of the drugs 1271b (E), toremifene E-isomer, raloxifene and estradiol decreased serum cholesterol level with an approximately equal efficacy (by 50-60%). The 1271a (Z) molecule was less effective. The results are shown in Table 3.
TABLE 3. Drug molecule Relative uterine weight and serum cholesterol content (control level has been taken as 1.00; mean±SD, n=3) Uterus Cholesterol
1271b (E) 0.85±0.07 0.43±0.05 1271a (Z) 0J5±0.06 0.65±0.10
Toremifene (E) 1.09±0.10 0.40±0.18
Raloxifene 0J7±0.21 0.48±0.09
Estradiol 1.29±0.06 0.48±0.09
In the ovarectomy study 1271b (E) increased slightly (1.5-fold) the relative uterus weight, not more than the corresponding Z-isomer. Estradiol increased the weight 3.3-fold. The 1271b (E) decreased serum cholesterol level very efficiently (by up to 77%), 1271a (Z) was clearly less effective (decrease was up to 34%). The results are shown in Table 4.
TABLE 4.
Drug dose Relative uterine weight and serum cholesterol content (mg/kg) (control level has been taken as 1.00)
1271b (E) 1271a (Z) Uterus Cholesterol Uterus Cholesterol
0.1 1.54 0.92 1.22
0.5 - - - 0.90
1 1.50 0.62 1.78 0.96
5 - - - 0.89
10 1.53 0.23 2.04 0.66
Further, in the ovarectomy study it was noticed that 1271b (E) but not 1271a
(Z) increased slightly serum cholesterol precursor molecule level suggesting a direct cholesterol biosynthesis inhibition by 1271b (E).
Discussion
The above data indicate that both 1271a (Z) and 1271b (E) are equivalent in antiestrogenicity in rat uterus. This differs from toremifene as toremifene 's E-isomer is clearly estrogenic in rat uterus and the Z-isomer is antiestrogenic. 1271b (E) is more efficient as a hypolipidemic agent than the corresponding Z-isomer. This is at least partly explained by the ability of 1271b (E) to inhibit cholesterol biosynthesis directly. In summary, the test compound 1271b (E) is an antiestrogenic drug that has also beneficial and potent hypolipidemic properties.
Claims
1. E-2-[4-(4-chloro-l,2-diphenyl-but-l-enyl)phenoxy]ethanol or a pharmaceutically acceptable ester thereof. 2. A pharmaceutical composition which comprises E-2-[4-(4-chloro-l,
2- diphenyl-but-l-enyl)phenoxy]ethanol or a pharmaceutically acceptable ester thereof as an active ingredient together with a pharmaceutically acceptable carrier.
3. A method of lowering serum cholesterol levels which method comprises administering to a patient in need of such treatment an effective amount of E-2-[4-(4- chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethanol or a pharmaceutically acceptable ester thereof.
4. A method for the prevention or treatment of atherosclerosis which method comprises administering to a patient in need of such treatment an effective amount of E-2-[4-(4-chloro-l,2-diphenyl-but-l -enyl)phenoxy]-ethanol or a pharmaceutically acceptable ester thereof.
5. A method of hormone replacement therapy (HRT) which method comprises administering to a patient in need of such therapy an effective amount of E-2-[4-(4- chloro-l,2-diphenyl-but-l-enyl)phenoxy]ethanol or a pharmaceutically acceptable ester thereof.
Priority Applications (20)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU25244/99A AU755798B2 (en) | 1998-02-19 | 1999-02-19 | E-2-{4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy}ethanol and pharmaceutical compositions thereof |
| DK99904899T DK1056701T3 (en) | 1998-02-19 | 1999-02-19 | E-2- [4- (4-Chloro-1,2-diphenyl-but-1-enyl) phenoxy] ethanol and pharmaceutical compositions thereof |
| EP99904899A EP1056701B1 (en) | 1998-02-19 | 1999-02-19 | E-2- 4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol and pharmaceutical compositions thereof |
| UA2000095331A UA57132C2 (en) | 1998-02-19 | 1999-02-19 | E-2-[4-(4-CHLORO-1,2-DIPHENYL-BUT-1-ENYL)PHENOXY]ETHANOL and pharmaceutical compositionS based thereon |
| HU0101354A HUP0101354A3 (en) | 1998-02-19 | 1999-02-19 | E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol itsesters, pharmaceutical compositions thereof and their use |
| CA002321122A CA2321122C (en) | 1998-02-19 | 1999-02-19 | E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol and pharmaceutical compositions thereof |
| BR9907688-8A BR9907688A (en) | 1998-02-19 | 1999-02-19 | E-2- [4- (4-chloro-1,2-diphenyl-but-1-enyl) phenoxy) ethanol and pharmaceutical compositions |
| JP2000532381A JP2002503713A (en) | 1998-02-19 | 1999-02-19 | E-2- [4- (4-Chloro-1,2-diphenyl-but-1-enyl) phenoxy] ethanol and pharmaceutical composition thereof |
| PL342445A PL193315B1 (en) | 1998-02-19 | 1999-02-19 | E-2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethanol and pharmacological compositions containing same |
| NZ505637A NZ505637A (en) | 1998-02-19 | 1999-02-19 | E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol and pharmaceutical compositions useful in lowering serum cholesterol |
| DE69912247T DE69912247T2 (en) | 1998-02-19 | 1999-02-19 | E-2- (4- (CHLORO-1,2-DIPHENYLBUT-1-ENYL) PHENOXY) ETHANOL AND PHARMACEUTICAL COMPOSITIONS THEREOF |
| SK1205-2000A SK285940B6 (en) | 1998-02-19 | 1999-02-19 | E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol and pharmaceutical composition this compound and the compound for medicinal application |
| US09/601,612 US6395785B1 (en) | 1998-02-19 | 1999-02-19 | E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol and pharmaceutical compositions thereof |
| EEP200000473A EE04233B1 (en) | 1998-02-19 | 1999-02-19 | E-2- [4- (4-Chloro-1,2-diphenyl-but-1-enyl) -phenoxy] -ethanol and its pharmaceutical compositions |
| SI9930485T SI1056701T1 (en) | 1998-02-19 | 1999-02-19 | E-2- 4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy)ethanol and pharmaceutical compositions thereof |
| IL13721499A IL137214A (en) | 1998-02-19 | 1999-02-19 | E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl) phenoxy] ethanol and pharmaceutical compositions thereof |
| EA200000851A EA002919B1 (en) | 1998-02-19 | 1999-02-19 | E-2-[4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol and pharmaceutical compositions thereof |
| AT99904899T ATE252531T1 (en) | 1998-02-19 | 1999-02-19 | E-2-(4-(CHLORO-1,2-DIPHENYLBUT-1-ENYL)PHENOXY)ETHANOL AND PHARMACEUTICAL COMPOSITIONS THEREOF |
| NO20003987A NO325595B1 (en) | 1998-02-19 | 2000-08-07 | E-2- [4- (4-chloro-1,2-diphenyl-but-1-enyl) phenoxy] ethanol and pharmaceutical compositions and uses thereof |
| HR20000545A HRP20000545A2 (en) | 1998-02-19 | 2000-08-18 | E-2-/4-(4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy/ethanol and pharmaceutical compositions thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9803521.5 | 1998-02-19 | ||
| GBGB9803521.5A GB9803521D0 (en) | 1998-02-19 | 1998-02-19 | New compounds and pharmaceutical compositions thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999042427A1 true WO1999042427A1 (en) | 1999-08-26 |
Family
ID=10827263
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/FI1999/000137 WO1999042427A1 (en) | 1998-02-19 | 1999-02-19 | E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol and pharmaceutical compositions thereof |
Country Status (33)
| Country | Link |
|---|---|
| US (1) | US6395785B1 (en) |
| EP (1) | EP1056701B1 (en) |
| JP (1) | JP2002503713A (en) |
| KR (1) | KR100755918B1 (en) |
| CN (1) | CN1161314C (en) |
| AR (1) | AR014961A1 (en) |
| AT (1) | ATE252531T1 (en) |
| AU (1) | AU755798B2 (en) |
| BG (1) | BG64471B1 (en) |
| BR (1) | BR9907688A (en) |
| CA (1) | CA2321122C (en) |
| CZ (1) | CZ294315B6 (en) |
| DE (1) | DE69912247T2 (en) |
| DK (1) | DK1056701T3 (en) |
| EA (1) | EA002919B1 (en) |
| EE (1) | EE04233B1 (en) |
| ES (1) | ES2211038T3 (en) |
| GB (1) | GB9803521D0 (en) |
| GE (1) | GEP20022794B (en) |
| HR (1) | HRP20000545A2 (en) |
| HU (1) | HUP0101354A3 (en) |
| ID (1) | ID26857A (en) |
| IL (1) | IL137214A (en) |
| NO (1) | NO325595B1 (en) |
| NZ (1) | NZ505637A (en) |
| PL (1) | PL193315B1 (en) |
| PT (1) | PT1056701E (en) |
| RS (1) | RS49660B (en) |
| SK (1) | SK285940B6 (en) |
| TR (1) | TR200002037T2 (en) |
| UA (1) | UA57132C2 (en) |
| WO (1) | WO1999042427A1 (en) |
| ZA (1) | ZA991232B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001036360A1 (en) * | 1999-11-16 | 2001-05-25 | Hormos Medical Corporation | Triphenylalkene derivatives and their use as selective estrogen receptor modulators |
| EP1705169A2 (en) * | 1999-11-16 | 2006-09-27 | Hormos Medical Ltd. | Triphenylalkene derivatives and their use as selective estrogen receptor modulators |
| US7504530B2 (en) | 2007-02-14 | 2009-03-17 | Hormos Medical Ltd. | Methods for the preparation of fispemifene from ospemifene |
| US7812197B2 (en) | 2007-02-14 | 2010-10-12 | Hormos Medical Ltd. | Method for the preparation of therapeutically valuable triphenylbutene derivatives |
| US7825107B2 (en) | 2006-05-22 | 2010-11-02 | Hormos Medical Ltd. | Method of treating men suffering from chronic nonbacterial prostatitis with SERM compounds or aromatase inhibitors |
| EP2258360A2 (en) | 2003-06-05 | 2010-12-08 | Hormos Medical Ltd. | Method for the treatment or prevention of lower urinary tract symptoms |
| WO2011089385A1 (en) | 2010-01-19 | 2011-07-28 | Cambrex Karlskoga Ab | New processes for producing benzophenone derivatives |
| US9321712B2 (en) | 2012-10-19 | 2016-04-26 | Fermion Oy | Process for the preparation of ospemifene |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150321983A1 (en) * | 2012-10-19 | 2015-11-12 | Fermion Oy | A process for the preparation of ospemifene |
| CN104030896A (en) * | 2013-03-07 | 2014-09-10 | 天津药物研究院 | Method for simply removing specific impurities from ospemifene |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996007402A1 (en) * | 1994-09-07 | 1996-03-14 | Orion-Yhtymä Oy | Triphenylethylenes for the prevention and treatment of osteoporosis |
| WO1997032574A1 (en) * | 1996-03-04 | 1997-09-12 | Orion-Yhtymä Oy | Serum cholesterol lowering agent |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2126576B (en) | 1982-06-25 | 1985-06-19 | Farmos Group Limited | Alkane and alkene derivatives |
-
1998
- 1998-02-19 GB GBGB9803521.5A patent/GB9803521D0/en not_active Ceased
-
1999
- 1999-02-16 AR ARP990100642A patent/AR014961A1/en active IP Right Grant
- 1999-02-16 ZA ZA9901232A patent/ZA991232B/en unknown
- 1999-02-19 CA CA002321122A patent/CA2321122C/en not_active Expired - Fee Related
- 1999-02-19 RS YUP-510/00A patent/RS49660B/en unknown
- 1999-02-19 WO PCT/FI1999/000137 patent/WO1999042427A1/en active IP Right Grant
- 1999-02-19 EP EP99904899A patent/EP1056701B1/en not_active Expired - Lifetime
- 1999-02-19 NZ NZ505637A patent/NZ505637A/en unknown
- 1999-02-19 UA UA2000095331A patent/UA57132C2/en unknown
- 1999-02-19 BR BR9907688-8A patent/BR9907688A/en not_active Application Discontinuation
- 1999-02-19 GE GEAP19995553A patent/GEP20022794B/en unknown
- 1999-02-19 KR KR1020007008982A patent/KR100755918B1/en not_active IP Right Cessation
- 1999-02-19 DK DK99904899T patent/DK1056701T3/en active
- 1999-02-19 CZ CZ20002927A patent/CZ294315B6/en not_active IP Right Cessation
- 1999-02-19 AU AU25244/99A patent/AU755798B2/en not_active Ceased
- 1999-02-19 EA EA200000851A patent/EA002919B1/en not_active IP Right Cessation
- 1999-02-19 ID IDW20001841A patent/ID26857A/en unknown
- 1999-02-19 JP JP2000532381A patent/JP2002503713A/en active Pending
- 1999-02-19 PL PL342445A patent/PL193315B1/en unknown
- 1999-02-19 ES ES99904899T patent/ES2211038T3/en not_active Expired - Lifetime
- 1999-02-19 DE DE69912247T patent/DE69912247T2/en not_active Expired - Fee Related
- 1999-02-19 CN CNB998030139A patent/CN1161314C/en not_active Expired - Fee Related
- 1999-02-19 US US09/601,612 patent/US6395785B1/en not_active Expired - Fee Related
- 1999-02-19 TR TR2000/02037T patent/TR200002037T2/en unknown
- 1999-02-19 AT AT99904899T patent/ATE252531T1/en not_active IP Right Cessation
- 1999-02-19 IL IL13721499A patent/IL137214A/en unknown
- 1999-02-19 EE EEP200000473A patent/EE04233B1/en not_active IP Right Cessation
- 1999-02-19 PT PT99904899T patent/PT1056701E/en unknown
- 1999-02-19 SK SK1205-2000A patent/SK285940B6/en unknown
- 1999-02-19 HU HU0101354A patent/HUP0101354A3/en unknown
-
2000
- 2000-08-07 NO NO20003987A patent/NO325595B1/en unknown
- 2000-08-18 HR HR20000545A patent/HRP20000545A2/en not_active Application Discontinuation
- 2000-08-28 BG BG104713A patent/BG64471B1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996007402A1 (en) * | 1994-09-07 | 1996-03-14 | Orion-Yhtymä Oy | Triphenylethylenes for the prevention and treatment of osteoporosis |
| WO1997032574A1 (en) * | 1996-03-04 | 1997-09-12 | Orion-Yhtymä Oy | Serum cholesterol lowering agent |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ304738B6 (en) * | 1999-11-16 | 2014-09-17 | Hormos Medical Corporation | Triphenylalkene derivatives and their use as selective modulators of estrogen receptors |
| US6875775B2 (en) | 1999-11-16 | 2005-04-05 | Hormos Medical Oy Ltd | Triphenylalkene derivatives and their use as selective estrogen receptor modulators |
| WO2001036360A1 (en) * | 1999-11-16 | 2001-05-25 | Hormos Medical Corporation | Triphenylalkene derivatives and their use as selective estrogen receptor modulators |
| EP1705169A2 (en) * | 1999-11-16 | 2006-09-27 | Hormos Medical Ltd. | Triphenylalkene derivatives and their use as selective estrogen receptor modulators |
| EP1705169A3 (en) * | 1999-11-16 | 2006-11-15 | Hormos Medical Ltd. | Triphenylalkene derivatives and their use as selective estrogen receptor modulators |
| KR100877487B1 (en) * | 1999-11-16 | 2009-01-12 | 호르모스 메디칼 리미티드 | Triphenylalkene derivatives and their use as selective estrogen receptor modulators |
| US6576645B1 (en) | 1999-11-16 | 2003-06-10 | Hormos Medical Oy Ltd | Triphenylalkene derivatives and their use as selective estrogen receptor modulators |
| US10780063B2 (en) | 2003-06-05 | 2020-09-22 | Hormos Medical Ltd. | Method for the treatment or prevention of lower urinary tract symptoms |
| US8962693B2 (en) | 2003-06-05 | 2015-02-24 | Hormos Medical Ltd. | Method for the treatment or prevention of lower urinary tract symptoms |
| US9114106B2 (en) | 2003-06-05 | 2015-08-25 | Hormos Medical Ltd. | Method for the treatment or prevention of lower urinary tract symptoms |
| US9993442B2 (en) | 2003-06-05 | 2018-06-12 | Hormos Medical Ltd. | Method for the treatment or prevention of lower urinary tract symptoms |
| EP2258360A2 (en) | 2003-06-05 | 2010-12-08 | Hormos Medical Ltd. | Method for the treatment or prevention of lower urinary tract symptoms |
| US7825107B2 (en) | 2006-05-22 | 2010-11-02 | Hormos Medical Ltd. | Method of treating men suffering from chronic nonbacterial prostatitis with SERM compounds or aromatase inhibitors |
| US7812197B2 (en) | 2007-02-14 | 2010-10-12 | Hormos Medical Ltd. | Method for the preparation of therapeutically valuable triphenylbutene derivatives |
| US7504530B2 (en) | 2007-02-14 | 2009-03-17 | Hormos Medical Ltd. | Methods for the preparation of fispemifene from ospemifene |
| US8293947B2 (en) | 2007-02-14 | 2012-10-23 | Hormos Medical Ltd. | Method for the preparation of therapeutically valuable triphenylbutene derivatives |
| WO2011089385A1 (en) | 2010-01-19 | 2011-07-28 | Cambrex Karlskoga Ab | New processes for producing benzophenone derivatives |
| US9085519B2 (en) | 2010-01-19 | 2015-07-21 | Cambrex Karlskoga Ab | Processes for producing benzophenone derivatives |
| US9321712B2 (en) | 2012-10-19 | 2016-04-26 | Fermion Oy | Process for the preparation of ospemifene |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5189212A (en) | Triarylethylene carboxylic acids with estrogenic activity | |
| EP0900077B1 (en) | Use of a toremifene metabolite for lowering serum cholesterol level. | |
| EP0779808B1 (en) | Triphenylethylenes for the prevention and treatment of osteoporosis | |
| EP1056701B1 (en) | E-2- 4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol and pharmaceutical compositions thereof | |
| EP0078158B1 (en) | Novel alkane and alkene derivatives and their preparation and use | |
| Pons et al. | Influence of new hydroxylated triphenylethylene (TPE) derivatives on estradiol binding to uterine cytosol | |
| MXPA00008134A (en) | E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol and pharmaceutical compositions thereof | |
| JP2006526002A (en) | Tumor-targeted chemotherapy in the genital organs | |
| AU699845C (en) | Triphenylethylenes for the prevention and treatment of osteoporosis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WWE | Wipo information: entry into national phase |
Ref document number: P-510/00 Country of ref document: YU Ref document number: 99803013.9 Country of ref document: CN |
|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU BA BG BR CA CN CZ EE GE HR HU ID IL IN IS JP KP KR LT LV MK MX NO NZ PL RO RU SG SI SK TR UA US UZ YU |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| WWE | Wipo information: entry into national phase |
Ref document number: 25244/99 Country of ref document: AU |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 137214 Country of ref document: IL Ref document number: 505637 Country of ref document: NZ |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2000/02037 Country of ref document: TR |
|
| WWE | Wipo information: entry into national phase |
Ref document number: PV2000-2927 Country of ref document: CZ |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 12052000 Country of ref document: SK |
|
| ENP | Entry into the national phase |
Ref document number: 2321122 Country of ref document: CA Ref document number: 2321122 Country of ref document: CA Kind code of ref document: A |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 1020007008982 Country of ref document: KR |
|
| WWE | Wipo information: entry into national phase |
Ref document number: P20000545A Country of ref document: HR Ref document number: PA/a/2000/008134 Country of ref document: MX |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 1999904899 Country of ref document: EP Ref document number: IN/PCT/2000/235/KOL Country of ref document: IN Ref document number: IN/PCT/2000/00235/KO Country of ref document: IN |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 09601612 Country of ref document: US |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 200000851 Country of ref document: EA |
|
| WWP | Wipo information: published in national office |
Ref document number: 1999904899 Country of ref document: EP |
|
| WWP | Wipo information: published in national office |
Ref document number: PV2000-2927 Country of ref document: CZ |
|
| WWP | Wipo information: published in national office |
Ref document number: 1020007008982 Country of ref document: KR |
|
| WWG | Wipo information: grant in national office |
Ref document number: 25244/99 Country of ref document: AU |
|
| WWG | Wipo information: grant in national office |
Ref document number: 1999904899 Country of ref document: EP |
|
| WWG | Wipo information: grant in national office |
Ref document number: PV2000-2927 Country of ref document: CZ |