WO2003063859A1 - Suppression de la degradation du cartilage a l'aide du recepteur des oestrogenes - Google Patents

Suppression de la degradation du cartilage a l'aide du recepteur des oestrogenes Download PDF

Info

Publication number
WO2003063859A1
WO2003063859A1 PCT/EP2003/000241 EP0300241W WO03063859A1 WO 2003063859 A1 WO2003063859 A1 WO 2003063859A1 EP 0300241 W EP0300241 W EP 0300241W WO 03063859 A1 WO03063859 A1 WO 03063859A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
chroman
cis
serm
methoxy
Prior art date
Application number
PCT/EP2003/000241
Other languages
English (en)
Inventor
Claus Christiansen
Stephan Christgau
Original Assignee
Nordic Bioscience 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
Priority claimed from GB0200743A external-priority patent/GB0200743D0/en
Priority claimed from GB0209495A external-priority patent/GB0209495D0/en
Application filed by Nordic Bioscience A/S filed Critical Nordic Bioscience A/S
Priority to JP2003563549A priority Critical patent/JP2005524630A/ja
Priority to EP03702427A priority patent/EP1465619A1/fr
Publication of WO2003063859A1 publication Critical patent/WO2003063859A1/fr

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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/352—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 condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the pharmaceutical use of selective estrogen receptor modulators (SERMs) alone or in combination with other pharmaceutical agents, especially progestins, for the treatment or prevention of a wide range of diseases but especially those associated with elevated cartilage degradation.
  • SERMs selective estrogen receptor modulators
  • this invention relates in part to the pharmaceutical use of chroman derivatives for the treatment or prevention of osteoarthritis or rheumatoid arthritis.
  • Osteoarthritis which is also called “degenerative joint disease”
  • OA osteoarthritis
  • the prevalence of this chronic disease increases with age and it is a prominent cause of disability and poor quality of life among the elderly.
  • the prevalence of the disease is higher in women than in men, and in women the incidence of osteoarthritis increases after the menopause.
  • RA Rheumatid arthritis
  • RA is an inflammatory condition where articular cartilage of affected joints are being degraded.
  • the etiology of RA is complex and a number of environmental 5 and genetic factors have been suggested a role in the development of the disease.
  • RA is more prevalent in woman.
  • estrogen may also have a potential beneficial effect in RA, as estrogen has a positive role as an inhibitor of inflammation.
  • Studies in humans and animal models of OA an RA have demonstrated a progressive depletion of articular cartilage matrix macromolecules as the disease develops.
  • cartilage degeneracy and osteophytes small abnormal bone outgrowths in the affected joints
  • Symptoms of OA are pain, swelling and stiffness of the articulation.
  • RA the cartilage degradation tends to occur more rapidly.
  • the progression of joint destruction varies widely between individual patients with a marked cyclical pattern characterized by periods of elevated disease activity 5 (flare ups) intermittent with more 'silent' periods. This cyclical pattern of disease activity is especially prominent for RA.
  • NSAJD non-steroidal anti- inflammatory agents
  • DMARD's disease modifying anti-rheumatic drugs
  • the aim of current therapies of these diseases is mainly to relieve pain and disease symptoms.
  • NSAJD and DMARD's have proven effectiveness in relieving the symptoms of OA and RA but their effect on decreasing cartilage catabolism has not been well documented.
  • Some of them, 5 like sodium salicylate, have shown inhibiting properties in relation to proteoglycan synthesis which may jeopardize the cartilage repair process.
  • Doxycycline a member of the tetracycline family, was also shown to reduce, in vivo, the severity of O A lesions in the dog ACL model while reducing metalloprotease activity, (Yu LP Jr et al. Arthritis Rheum 35:1150-1159, 1992). Recent data suggests that the action of corticosteroids is associated with a reduction in the synthesis of stromelysin-1 by chondrocytes. (see: Pelletier et al., J Arthritis Rheum 37:414-423, 1994; and Pelletier et al., J Lab Invest 72:578-586, 1995).
  • estrogen and compounds acting through the estrogen receptor may have a potential beneficial effect.
  • SERMs Selective Estrogen Receptor Modulators
  • a SERM is a synthetic compound that possesses some, but not all, of the actions of estrogen.
  • raloxifene is classified as a SERM because it prevents bone loss and lowers serum cholesterol as an estrogen agonist but act as an estrogen antagonist by not stimulating the endometrial lining of the uterus.
  • bone tissue tend to be less selective in their antagonistic action on tissues such as the endometrium.
  • many potent SERM's are not used as drugs in prevention, treatment of e.g. osteoporosis because of unwanted side effects.
  • An example of this is the chroman compound levormeloxifene as disclosed in patent No. US 3822287 and US 5977158.
  • Progestins includes progesterone related steroid hormones, their derivatives and compounds having progestogenic effect. They are widely used in hormone replacement therapy in combination with other steroid hormones to reduce the (side) effect on the endometrium lining growth. Only recently progestins have been proposed for the treatment of bone related diseases as disclosed in WO 00/74684 and EPO 0474374. It has been found that the combination of the SERM raloxifene and the progestin norethinedrone acetate has a synergistic effect on osteoporosis by increasing the bone mass index significantly as disclosed in EPO 0665015.
  • This invention provides in a first aspect a method of preventing, treating or alleviating conditions involving elevated cartilage degradation comprising administering to a subject an effective amount of a selective estrogen receptor modulator (SERM) selected from droloxifene, levormeloxifene, chroman derivatives, nafoxidine, miproxifene, arzoxifene, 2 o lasofoxifene, basedoxifene, MDL-103323, EM-800, fulvestrant, ICI 183,780, ICI 164,384, 19-nor-testosterone derivatives and pharmaceutically acceptable esters, ethers and salts thereof.
  • SERM selective estrogen receptor modulator
  • the SERM comprises one or more of levormeloxifene, a chroman derivative, or 5 a 19-nor-testosterone derivative or a pharmaceutically acceptable salt thereof.
  • progestin or progestin agent means a compound having progestational activity (i.e., induce the formulation of a secretory endometrium), such as, for example, norethindrone (also referred to as norethisterone), ethynodiol, desogestrel, levonorgestrel, 0 norgestrel, norgestimate, medroxyprogesterone, danazol, lynoestrenol, dydrogesterone, chlormadinone, promegesterone, gestrinone, algestone acetophenide, allyloestrenol, cyproterone acetate, demegestone, gestodene, osaterone, hydroxyprogesterone hexanoate, medrogestone, megestrol, nomegestrol, ethynylnortestosterone, no regneninolone, NSC
  • Progestin agents are well described in the art (See, for example, Martindale: The Extra Pharmacopoeia, 30th edition, 1993 incorporated herein by reference).
  • Preferred salts are acetate salts.
  • a more preferred progestin agent is norethindrone, with norethindrone acetate being most preferred.
  • a progestin agent is also referred to as a progestogen, a gestagen or a progestational hormone.
  • Osteoarthritis or “OA” is a type of arthritis that is caused by breakdown of cartilage with eventual loss of the cartilage of the joints.
  • Cartilage is a protein substance that serves as a “cushion” between the bones of the joints.
  • Osteoarthritis is also known as degenerative arthritis.
  • RA rheumatoid arthritis
  • RA rheumatoid arthritis
  • the etiology of RA is complex and a number of environmental and genetic factors have been suggested a role in the development of the disease.
  • SERM selective estrogen receptor modulator
  • chromens means 3,4-chroman derivatives.
  • coumarins means 2-chromen-2-one derivatives, [is 'one' correct?]
  • cartilage specific biochemical marker means a metabolite of cartilage catabolism which can be quantified in a body fluid, where said metabolite is indicative of 5 systemic cartilage degradation.
  • the selective estrogen receptor modulator is selected from chroman derivatives. Any chroman derivatives presently known in the art, or subsequently developed may be used in l o practising the claimed methods.
  • the synthesis of exemplary receptor antagonists is described, by way of example only, in U.S. Pat. Nos. 5,919,817; 6,043,269; and EP 937057; EP 937060; and EP 937062, incorporated herein by reference in their entireties.
  • the selective estrogen receptor modulator 15 is selected from a group of chroman derivatives of the formula I
  • R 1 is H, SO 2 NR 2 4 , SO 2 NHR 4 ,C1, CH 3 or benzyl;
  • R 2 is phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of OH, halogen, nitro, cyano, SH, SR 4 , trihalo-C ⁇ -C6 alkyl, C ⁇ -C 6 -alkyl, d-C ⁇ alkoxy and phenyl; 5
  • R is phenyl substituted with — X ⁇ (CH2) n — Y, wherein: X is a valency bond, O or S,
  • n is an integer in the range of 1 to 12,
  • Y is H, halogen, OH, OR 4 , NHR 4 , NR 2 4 , NHCOR 4 , NHS0 2 R 4 ,C0NHR 4 ,
  • CONR 4 COOH, COOR 4 , SO 2 R 4 , SOR 4 , SONHR 4 , SONR 2 4 , a pyrrolidinyl ring, optionally being substituted with 1 to 3 substituents independently selected from the group consisting of H, OH, halogen, nitro, cyano, SH, SR 4 , trihalo-d -C 6 -alkyl, Ci -C 6 -alkyl and Ci -C 6 -alkoxy; and
  • R 4 is d -Ce -alkyl
  • the present invention is concerned with use of the compound of the formula I wherein:
  • R 1 is H, SO 2 NR 2 4 ,C1, CH 3 or SO 2 NHR 4 ;
  • R 2 and R 3 are arranged in cis-configuration
  • R 2 is phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of OH, halogen, nitro, cyano, SH, SR 4 , trihalo-d -C 6 -alkyl, d -C 6 -alkyl and CI -C6 -alkoxy;
  • R 3 is phenyl substituted with ⁇ X ⁇ (CH 2 ) n ⁇ Y, wherein:
  • X is a valency bond, O or S
  • n is an integer in the range of 1 to 12,
  • Y is H, OH, OR l 44 ,, NNHHRR44,, NNRR 22 * 4 ,, NHCOR 4 , NHSO 2 R 4 , CONH 4 , CONR 2 4 , COOH,
  • R 4 is Ci -Q; -alkyl
  • the present invention is concerned with use of compound of the formula
  • R 1 , R 2 and R 3 are as defined above.
  • the present invention is concerned with use of the compound of the formula
  • R 1 is as defined above and m is an integer from 0 to 10.
  • the present invention is concerned with use of the compound of the formula
  • R 1 is as defined above and R 6 represents one or more of the following substituents: methoxy, hydroxy, trifluormethyl, fluoro and chloro.
  • This invention includes, the use of a SERM as defined above for the preparation of a 5 medicament for use in the treatment, prevention, or alleviation of a condition involving elevated cartilage degradation.
  • the present invention relates to a method for preventing, treating or alleviating conditions involving elevated cartilage degradation comprising administering to a l o subject an effective amount of the combination of
  • SERM selective estrogen receptor modulator
  • the invention also provides pharmaceutical formulations for treatment of arthritis comprising (1) a chroman or a coumarin derivative or a pharmaceutically acceptable salt or solvate thereof; and (2) a progestin or a salt thereof and other compounds having progestational activity; in amounts such that the combination inhibits OA or RA, together 2 o with one or more pharmaceutically acceptable carriers.
  • the present invention relates to a method for treating or alleviating arthritis comprising administering to a subject an effective amount of the combination of a selective estrogen receptor modulator (SERM) selected from the group consisting of raloxifene, droloxifene, tamoxifen, 4-hydroxy-tamoxifen, 4'-iodotamoxifen, toremifene, (deaminohydroxy)toremifene, chlomiphene, levormeloxifene, chroman derivatives, coumarin derivatives, idoxifene, nafoxidine, miproxifene (TAT-59), arzoxifene (LY-353381), lasofoxifene (CP-336156), MDL-103323, EM-800, fulvestrant (0-182,780) ICI 183,780, ICI 164,384, diethylstilbesterol, genistein, nafoxidine, GW 5638, panom
  • Preferred SERM's include droloxifene, tamoxifen, levormeloxifene, chroman derivatives, nafoxidene, toremifene, TAT-59, LY-353381, CP-336156, MDL-103323, EM-800, ICI-182, ICI 183,780 and 19-nor-testosteone derivatives or a pharmaceutically acceptable salt thereof.
  • This aspect of the present invention is in particular related to the observation that the side effects of hormone replacement therapy administering specific selective estrogen receptor modulators (SERMs) alone such as increased incidence of breast cancer and growth of the endometrial lining can be reduced by combined administration of progestins.
  • SERMs selective estrogen receptor modulators
  • a long lasting and continued administration of an effective inhibitor of cartilage degradation is mandatory.
  • side effects of said inhibitor may have dramatic impact on the patients health over time and must be avoided or minimized to improve the life value of patients and save the 5 health system for expensive complications.
  • the selective estrogen receptor modulator is selected from chroman derivatives.
  • said progestin is progesterone, norethindrone acetate, ethynodiol, desogestrel, levonorgestrel, norgestrel, norgestimate, medroxyprogesterone and its esters or a pharmaceutically acceptable salt thereof.
  • said progestin is norethindrone or norethindrone acetate and its esters or a pharmaceutically acceptable salt thereof.
  • the present invention is concerned with a pharmaceutical composition for o use in the therapeutic or prophylactic treatment of diseases wherein decreased estrogen production is a factor, said composition comprising an effective amount of the combination of a 3,4 chroman or coumarin derivative or a pharmaceutical acceptable salt thereof and a progestin or a pharmaceutical acceptable salt thereof and a pharmaceutical carrier or diluent. 5
  • the invention is related to the use of said pharmaceutical composition for the therapeutic or prophylactic treatment of conditions such as is breast cancer, testicular cancer, osteopenias or osteoporosis induced bone loss, endometriosis, cardiovascular disease, hypercholesterolemia, prostatic hypertrophy, prostatic carcinomas, 0 obesity, hot flashes, skin effects, mood swings, memory loss, urinary incontinence, hairloss, cataracts, natural hormonal imbalances, and adverse reproductive effects associated with exposure to environmental chemicals.
  • conditions such as is breast cancer, testicular cancer, osteopenias or osteoporosis induced bone loss, endometriosis, cardiovascular disease, hypercholesterolemia, prostatic hypertrophy, prostatic carcinomas, 0 obesity, hot flashes, skin effects, mood swings, memory loss, urinary incontinence, hairloss, cataracts, natural hormonal imbalances, and adverse reproductive effects associated with exposure to environmental chemicals.
  • the invention is concerned with a pharmaceutical composition for use in the therapeutic or prophylactic treatment of diseases wherein elevated cartilage degradation is a factor, said composition comprising an effective amount of the combination of a 3,4 chroman or a coumarin derivative or a pharmaceutical acceptable salt thereof and a progestin or a pharmaceutical acceptable salt thereof and a pharmaceutical carrier or diluent.
  • the present invention is concerned with a pharmaceutical composition for use in the therapeutic or prophylactic treatment of diseases wherein elevated cartilage degradation is a factor, said composition comprising an effective amount of the combination of a 3,4 chroman or a coumarin derivative or a pharmaceutical acceptable salt thereof and norethindrone or norethindrone acetate or a pharmaceutical acceptable salt thereof and a pharmaceutical carrier or diluent.
  • the present invention is concerned with a pharmaceutical composition for use in the therapeutic or prophylactic treatment of diseases wherein elevated cartilage degradation is a factor, said composition comprising an effective amount of a cis-3,4 diarylchromane or a pharmaceutical acceptable salt thereof in combination with an effective amount of norethindrone or norethindrone acetate or a pharmaceutical acceptable salt thereof and a pharmaceutical carrier or diluent.
  • the effective amount of said selective estrogen receptor modulator or a pharmaceutical acceptable salt thereof from 0.01 to about 100 mg per individual per day, preferably from 0.1 to about 10 mg per individual per day and most preferably from 0.2 to about 1.0 mg per individual per day.
  • the effective amount of said progestin or a pharmaceutical acceptable salt thereof and a pharmaceutical carrier or diluent thereof is from 0.01 to about 100 mg per individual per day, preferably from 0.1 to about 10 mg per individual per day and most preferably from 0.2 to about 1.0 mg per individual per day.
  • the effective amount of said progestin or a pharmaceutical acceptable salt thereof and a pharmaceutical carrier or diluent thereof is in an amount sufficient to significantly reduce SERM induced estrogenic side effects.
  • the invention is concerned with the pharmaceutical l o composition as described above in the form of an oral dosage unit or parenteral dosage unit.
  • the invention is concerned with administering to a mammal in need thereof a therapeutically effective amount compound I in combination 15 with a progestin.
  • the invention is concerned with administering to a human in need thereof a therapeutically effective amount compound I in combination with norethindrone or norethindrone acetate.
  • the invention in another embodiment relates to a method of treating osteoarthritis or rheumatoid arthritis, said method comprising administering to a human in need thereof a therapeutically effective amount of a compound (I) in combination with a progestin.
  • the invention is concerned with use of a cartilage specific biochemical marker for titration of the doses described above. Titration of a therapeutically effective dose is based on quantification of one or more fragments of a cartilage matrix protein as described above. Different doses of the pharmaceutically composition is given to a mammal for at least 2-4 weeks, and the cartilage degradation response is assayed for each dose for selection of o the minimally therapeutic effective dose. Therapeutically effective dose is defined as the dose giving a significant decrease in the cartilage specific biomarker.
  • said therapeutically effective dose leads to a reduction of the cartilage specific biomarker of 20-90 %, more preferably 30-70% and most preferably 40- 50% of the control level.
  • said marker is CartiLaps ELISA as disclosed by Christgau etal. 2001.
  • the invention is concerned with the use of a composition for preventing, treating or alleviating conditions involving elevated cartilage degradation
  • a composition for preventing, treating or alleviating conditions involving elevated cartilage degradation comprising a selective estrogen receptor modulator (SERM) selected from droloxifene, tamoxifen, levormeloxifene, chroman derivatives, coumarin derivatives, idoxifene, nafoxidine, toremifene, TAT-59, LY-353381, CP-336156, MDL-103323, EM-800, ICI-182, ICI 183,780 and 19-nor-testosteone derivatives or a pharmaceutically acceptable salt thereof.
  • SERM selective estrogen receptor modulator
  • the present invention relates to a method of preventing, treating or alleviating conditions involving elevated cartilage degradation comprising administering to a subject a selective estrogen receptor modulator (SERM) selected from droloxifene, tamoxifen, levormeloxifene, chroman derivatives, coumarin derivatives, idoxifene, nafoxidine, toremifene, TAT-59, LY-353381, lasofoxifene, MDL-103323, EM-800, ICI- 182 j ⁇ 183,780, ICI 164,384, ICI 183,780, GW 5638, 19-nor-testosteone derivatives and pharmaceutically acceptable esters, ethers and salts thereof in amounts such that the combination decreases cartilage degradation.
  • SERM selective estrogen receptor modulator
  • the present invention relates to a method of preventing, treating or alleviating conditions involving elevated cartilage degradation comprising administering to a subject an effective amount of a selective estrogen receptor modulator (SERM) selected from droloxifene, levormeloxifene, chroman derivatives, nafoxidine, TAT-59, LY-353381, lasofoxifene, MDL-103323, EM-800, ICI-182,780, ICI 183,780, ICI 164,384, GW 5638, ICI 183,780, 19-nor-testosteone derivatives and pharmaceutically acceptable esters, ethers and salts thereof.
  • SERM selective estrogen receptor modulator
  • SERM'S which contain the core structure shown below as Formula 2:
  • the dotted bond indicates a single or double bond.
  • Each extension at a position R may be any structure attached to the core structure of Formula 2 to produce a SERM.
  • a SERM for use in the invention in any of its aspects should have a binding affinity Ki for the estrogen receptor alpha of not less than 10 ⁇ M, preferably not less than 1 ⁇ M, andor a binding affinity for the estrogen receptor beta of not less than 10 ⁇ M, preferably not less than 1 ⁇ M.
  • said SERM comprises levormeloxifene, chroman derivatives and 19-nor-testosteone derivatives or pharmaceutically acceptable salts thereof.
  • GW 5638 3-[4-(l,2-diphenylbut-l-enyl) ⁇ henyl]acrylic acid
  • the compounds of the invention may be prepared by resorting to the chroman chemistry which is well-known in the art, for example in P. K. Arora, P. L. Kole and S. Ray, Indian J. Chem. 20 B, 41-5, 1981; S. Ray, P. K. Grover and N. Anand, Indian J. Chem. 9, 727- 5 8,1971; S. Ray, P. K. Grover, V. P. Kamboj, S. B. Betty, A. B. Kar and N. Anand, J. Med. Chem. 19, 276-9, 1976; Md. Salman, S. Ray, A. K.
  • the invention is furthermore concerned with a general method for the preparation of compounds of formula (I) as described in US 6043269.
  • the present invention also relates to pharmaceutical compositions comprising an effective 5 amount of a compound according to the invention and a pharmaceutical carrier or diluent.
  • Such compositions are preferably in the form of an oral dosage unit or parenteral dosage unit.
  • the compounds with which the invention is concerned may also be prepared for administration by any route consistent with their pharmacokinetic properties.
  • the orally o administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, 5 sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, o emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate, or acacia
  • non-aqueous vehicles which may include edible oils
  • almond oil fractionated coconut oil
  • oily esters such as glycerine, propy
  • the dosage unit involved in oral administration may contain from about 0.01 to 100 mg, preferably from about 0.1 to 10 mg, and most preferably from about 0.2 to 1 mg of a compound of the invention.
  • a suitable daily dose for a mammal may vary widely depending on the condition of the patient. However, a dose of a compound of general formula I of about 0.1 to 10 mg/kg body weight, particularly from about 0.2 to 1 mg/kg body weight may be appropriate.
  • the drug may be made up into a cream, lotion or ointment.
  • Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
  • the active ingredient may also be administered parenterally in a sterile medium.
  • the drug can either be suspended or dissolved in the vehicle.
  • adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the drug may include, in addition to the conventional vaginal suppositories, soft capsules containing a liquid oily base or ointment and tubes containing same for injection when in use.
  • a liquid oily base or ointment exemplified are oily base, water-soluble base, emulsion base, ointment-like base and so on.
  • the oily base includes fats and oils such as peanut oil, olive oil, corn oil, castor oil, cacao butter, laurin fat, glycerol fatty acid ester, specifically Pharmasol (product of NOF Corp.), Witepsol (product of Dinamite Nobel Inc.), SB-base (product of Kaneka Corp.) and lanolin fat.
  • water- soluble base examples include polyethylene glycol, polypropylene glycol, glycerin and glycerogelatin.
  • the base emulsion is an emulsified base of water-soluble base and oily base and may be of an O/W type or W/O type.
  • an oily base is preferably used, by which PG is highly stabilized and superior pharmacological effects of PG can be achieved.
  • These bases may be used solely or in an appropriate combination.
  • the compounds of the invention may also be included in an implant, a vaginal ring, a patch, a gel, and any other preparation for sustained release.
  • Nasal administration may be applied from solution as a nasal spray and may be dispensed as a spray by a variety of methods known to those skilled in the art.
  • Preferred systems for dispensing liquids as a spray are disclosed in U.S. Pat. No.4,511,069. Such systems were used in carrying out the work described in the examples set forth hereinafter.
  • Such nasal spray solutions comprise the drug or drug to be delivered, a nonionic surfactant which enhances absorption of the drug, polysorbate-80, and one or more buffers.
  • the nasal spray solution further comprises a propellant.
  • the pH of the nasal spray solution is preferably between pH 6.8 and 7.2.
  • FIG. 1 Cartilage erosion in the four different condyles in 5-month-old (top) and 7-month- old (bottom) female rats maintained for 9 weeks after OVX or sham treatment. The erosion is expressed as percentage of total cartilage surface. The erosion is presented as mean erosion + SEM values for the two groups (ovx - dark green, sham - light green). Each of the four condyles were scored: Medial Tibia (Medial T), Medial Femur (Medial F), Lateral Tibia (Lateral T), and Lateral Femur (Lateral F). Finally the average of all four areas are presented (Total).
  • FIG. 1 Cartilage and bone turnover in the OVX and sham treated rats. Cartilage turnover was assessed using the CTX-II marker (panels A, B) and bone resorption was determined by measurement of RatLaps (CTX-I) (panels C, D).
  • CTX-I RatLaps
  • the left panels (A, C) are measurement from rats that were 5-month old at start and followed for 9 weeks.
  • the right panels (B, D) are measurements from rats that were 7-month old at start and followed for 9 weeks.
  • the X-axis indicates weeks after OVX.
  • Figure 4 Percentage of erosion in animals with low or high CartiLaps values (at week 4) in the 7-month old cohort.
  • FIG. 8 CartiLaps (left panel) and RatLaps (right panel) levels in 6 month old OVX rats treated with three doses of (-)-cis-3,4-diaryl-hydroxychromane (SERM #0781), as well as vehicle and estradiol.
  • FIG. 9 Area under curve (AUC) measurements of the CartiLaps data in figure 8. Student's T-test was performed to test significance of the difference to the vehicle treated group, *) p>0.05; **) p ⁇ 0.01; NS) not significant.
  • FIG. 10 Spleen weights at the termination of the CIA-2 experiment.
  • Figure 11 Cumulative incidence of arthritis in CIA animals treated with or without SERM #0781 A) low dose SERM #0781, B) medium dose SERM #0781, C) high dose SERM #0781, E) estrogen, S) Sham, V) vehicle. Values are presented as mean within the group. Arthritis index is the mean clinical arthritis score for all rats in the group. The X- axis indicates days after immunization with collagen type II (performed 1 week after OVX).
  • Figure 12 Average survival time in CIA animals treated with or without SERM #0781 A) low dose SERM #0781 , B) medium dose SERM #0781 , C) high dose SERM #0781 , E) estrogen, S) Sham , V) vehicle. Values are presented as percent surviving rats within each group. The X-axis indicates days after immunization with collagen type II (performed 1 week after OVX). Figure 13. A) Levels of CartiLaps in CIA animals treated with or without SERM #0781 A) low dose SERM #0781, B) medium dose SERM #0781, C) high dose SERM #0781, E) estrogen, S) Sham, V) vehicle.
  • the groups are labelled as follows: A) low dose SERM #0781, B) medium dose SERM #0781, C) high dose SERM #0781, E) estrogen, S) Sham, V) vehicle. Values are presented as mean creatinine corrected values with SD for each group.
  • Figure 15 Changes in the cartilage degradation marker urinary CartiLaps measuring degradation products of collagen type II C-telopeptides during treatment with Raloxifene (upper panel) and Levormeloxifene (lower panel). Designs and treatment groups are described in methods. Error bars represent SEM.
  • Example 1 Cartilage erosion is induced by ovariectomv.
  • the animals in this study consisted of two cohorts of 20 female Sprague-Dawley rats (obtained from Charles River laboratory, Germany). One cohort was 5-month old animals, and in the second cohort the animals were 7-month old. Each cohort was divided in two groups, 10 in each group, and kept for 9 weeks. The animals were received in the animal facilities 2 months prior to study start to enable a thorough acclimatization. At baseline the weight was determined and the animals were randomised to the two groups. Ovarectomy is performed on all rats by first anaesthetising with Hypnorm-Dormicum (1 part Hypnorm® + 1 part Dormicum® + 2 part sterile de-ionized water).
  • the rats are given 0.15-0.2 ml/100 g body weight) and a standard sham operation or ovariectomy are performed.
  • the weight of the animals was determined weekly throughout the experiment.
  • the animals were weighed, and blood as well as urine samples taken at regular intervals.
  • Urine samples were taken as spot urine samples, by either inducing urination by gently rubbing the belly of the animal or by placing it in a metabolic cage for 30 - 60 min and collecting the resulting urine sample.
  • the knees were isolated and the cartilage analysed for erosion by histology.
  • the knees were decalcified in 10% formic acid, 2% formaldehyde.
  • the decalcified knee joints were cleaved along the medial collateral ligament into two sections and embedded in paraffin.
  • the embedded knees were then cut in three different depths (0, 250, and 500 ⁇ m) from the medial collateral ligament each section was then stained in Toluidine Blue.
  • the cartilage sections were scored blinded for the following parameters: Erosion, loss of proteoglycan, black dead chondrocytes, loss of chondrocytes, cysts, fibrillation, and bone formation in the cartilage. All changes were measured as percentage of total cartilage surface and the incidence of erosion in the groups (OVX/sham) were also calculated.
  • RatLaps (CTX-I, bone resorption) and CartiLaps (CTX-II, cartilage degradation) levels were measured in serum and urine samples respectively.
  • CartiLaps ELISA is measured in urine using a competitive ELIS A employing a monoclonal antibody (MabF46) specific for collagen type ⁇ C-telopeptide fragments (Christgau et al 2001).
  • the assay was performed by first incubating biotinylated collagen type II C-telopeptide derived peptide (EKGPDP) on a streptavidine microtitre plate and then sample as well as primary antibody was added.
  • EKGPDP biotinylated collagen type II C-telopeptide derived peptide
  • Monoclonal antibody MabF46 specific for collagen type U C-telopeptide fragments was used in a competitive ELISA format developed for measurement of urine samples.
  • EKGPDP Biotinylated collagen type II C-telopeptide derived peptide
  • RatLaps ELISA measures collagen type I C-telopeptide degradation products using a 0 specific monoclonal antibody in a competitive ELISA form.
  • the assay is applicable for measurement of both urine and serum samples, but only serum samples were assessed in this study.
  • the assay is commercially available (Nordic Bioscience Diagnostics, Herlev, Denmark). All serum samples measured in the assay were from animals, which had been fasting for at least 6 hours prior to sampling. Briefly described, the assay is performed by 5 incubating a biotinylated form of a synthetic peptide representing the C-telopeptide epitope
  • EKSQDGGR EKSQDGGR. This is followed by addition of sample and primary antibody and after overnight incubation; the amount of bound antibody is visualized using a peroxidase labeled secondary antibody and a chromogenic peroxidase substrate.
  • concentrations in the samples were determined from construction of a calibration curve based on o measurement of synthetic peptide standards .
  • OVX induced a highly significant increase in CTX-I and CTX-II levels (Fig. 2).
  • the results are in accordance with the histology data.
  • FIG. 4 Another way to assess the association between CartiLaps and erosion quantified by histology is to evaluate the association between levels as well as changes in CartiLaps levels and subsequent cartilage erosion.
  • the data for the 7-month-old cohort has been processed in this way.
  • the animals were divided into two groups according to CartiLaps at week 4 after the OVX: Low CartiLaps (28-75 ng mmol) and high values (97 - 520 ng/mmol).
  • the animals with low CartiLaps data have only small erosion whereas the animals with high CartiLaps values have a higher percentage of erosion (fig. 4) as well as higher incidence of erosion. Similar results were obtained when data from the 5-month-old animals were analysed.
  • the results demonstrate that significant increases in both bone and cartilage turnover is induced in OVX treated rats, and that cartilage erosion appears in OVX treated rats after 9 weeks. This points to the important role of estrogen and compounds acting through the estrogen receptor for maintaining normal cartilage turnover and it points to a cartilage preserving potential of estrogen and SERM's as demonstrated in the following examples. Furthermore, the results validate the use of the OVX model as a relevant in vivo model of postmenopausal OA. Finally the results demonstrate that the CartiLaps assay may be used as a relevant biochemical marker of subsequent articular cartilage degradation in rat models of arthritis.
  • Example 2 Levormeloxifene is a potent inhibitor of cartilage degradation in the ovariectomized rat.
  • Levormeloxifene was assessed in the OVX model of postmenopausal OA (see example 1) to assess potential cartilage protective effects of this SERM. Seventy 6-month old female Sprague-Dawley rats were obtained from Charles River, Germany and used in the study. 10 animals were subjected to sham operation and the remainder (60 animals) were ovarectomized. The ovarectomy and handling of animals were performed as described in example 1. The OVX animals were divided in 5 groups of 12 animals treated with vehicle, 17 ⁇ -ethynyl-estradiol (Sigma, E-8875, Lot # 21K1267) 0.1 mg/kg day or three doses of levormeloxifene (0.2, 1 or 5 mg/kg day).
  • Example 3 Levormeloxifene, and levormeloxifene + Norethisterone acetate (NETA) are potent inhibitors of cartilage degradation, but have no effect on uterus weight in 314-month old ovariectomised rats.
  • NETA Norethisterone acetate
  • Norethisterone acetate was assessed in the OVX model of postmenopausal OA in young animals (314 month) to assess potential uterus and cartilage protective effects. Fifty 314-month old female Sprague-Dawley rats were obtained and used in this study. 10 animals were subjected to sham operation and the remainders (40 animals) were ovariectomised. The ovarectomy and handling of animals were performed as described in example 1.
  • the OVX animals were divided in 4 groups of 10 animals treated with vehicle, levormeloxifene (1.0 mg/kg/day given 5 days a week), NETA (1.0 mg/kg/day given 5 days a week) or levormeloxifen + NETA (both compounds given as 1.0 mg/kg/day given 5 days a week) and treated for 5 weeks. All treatments were administered orally in suspension (50% propylene glycol, 0.075 M NaCl) daily for 5 days a week, with no administration in the weekend. Throughout the study the animals were weighed, and blood/urine samples taken at regular intervals.
  • Urine samples were taken as spot urine samples, by either inducing urination by gently rubbing the belly of the animal or by placing it in a metabolic cage for 30 - 60 min and collecting the resulting urine sample.
  • Treatment with levormeloxifene showed an identical development in body weight as sham animals, whereas the levormeloxifene + NETA treatment lowered the growth in the animals.
  • Treatment with vehicle or NETA increased the bodyweight with the vehicle group having the highest growth rate (table 1).
  • Treatment with levormeloxifene, levormeloxifene + NETA, or NETA did not have any effect on uterus weight in OVX rats compared to the vehicle treated rats (table 1).
  • the sham rats had an increased uterus weight compared to the OVX rats, which 5 is due to endogenous estrogen production.
  • Treatment with levormeloxifene, NETA or levormeloxifen + NETA induced a significant reduction in CartiLaps levels in the OVX animals to the same level as those seen in the sham animals (Fig. 6).
  • Fig. 6 When comparing the CartiLaps and RatLaps data to examples 1, 2 and 4, it must be taken into account that the cohort in this experiment was much younger (314 months at study start), and thus have a 0 substantial skeletal growth which will contribute to the measurement both in the RatLaps assay and in the CartiLaps assay due to the presence of collagen type U in the growth plate.
  • gestagene analogue NETA to levormeloxifene does not impair the potential chondro-protective effects of this SERM.
  • This " potential combination therapy may hold clinical advantages in human subjects where estrogenic effects on uterus and breast tissues of SERMs is a significant concern, and thus addition of a gestagene 5 analogue could be desirable as this provides a well recognized method of preventing estrogenic stimulation of these tissues.
  • Example 4 (-)-cis-3,4-diaryl-hvdroxychromane is a potent inhibitor of cartilage degradation in the ovariectomized rat.
  • the chroman SERM compound (-)-cis-3,4-diaryl-hydroxychromane was assessed in the OVX model of postmenopausal OA (see example 1) to assess potential cartilage protective effects of this SERM. Seventy 6-month old female Sprague- Dawley rats were obtained and used in the study. 10 animals were subjected to sham operation and the remainder (60 animals) were ovariectomized. The ovarectomy and handling of animals were performed as described in example 1.
  • the OVX animals were divided in 5 groups of 12 animals treated with either vehicle, 17 -ethynyl-estradiol (Sigma, E-8875, Lot # 21K1267) 0.1 mg/kg/day given 5 days a week or three doses of (-)-cis-3,4- diaryl-hydroxychromane (0.2, 1 or 5 mg kg/day given 5 days a week). All treatments were administered orally in suspension (50% propylene glycol, 0.075 M NaCl) daily for 5 days a week, with no administration in the weekend. Throughout the study the animals were weighed, and blood/urine samples taken at regular intervals.
  • Urine samples were taken as spot urine samples, by either inducing urination by gently rubbing the belly of the animal or by placing it in a metabolic cage for 30 - 60 min and collecting the resulting urine sample.
  • RatLaps and CartiLaps measurements demonstrate a significant effect of the compound on both bone resorption and cartilage turnover. Whereas the highest dose of the SERM suppressed CartiLaps levels to the level of estrogen or sham animals (fig. 8 left panel), it was not able to suppress bone resorption to the same extent as estrogen. This indicates that this compound has a stronger action on cartilage than on bone, and thus may exert a potential chondro-protective role in the treatment of postmenopausal OA.
  • Example 5 Delay of onset and reduction in severity and incidence of inflammatory arthritis induced by (-)-cis-3,4-diarvI-hvdroxychromane in collagen type II immunized Lewis rats.
  • CIA Lewis-rat Collagen Induced Arthritis
  • joint inflammation is induced by immunization with collagen type II which provoke a severe inflammatory response to joint cartilage apparent as paw joint swelling and subsequent destruction of joints when histological analysis is performed.
  • SERM #0781 ((-)-cis-3,4-diaryl-hydroxychromane, fig. 7) on the disease development and severity in CIA.
  • Arthritis was monitored by macroscopic scoring of swelling and redness of the paws.
  • Cartilage and bone erosion was monitored by quantifying urinary levels of CartiLaps and serum levels of RatLaps.
  • the uterine weights of the animals were determined to assess estrogenicity of the estrogen.
  • the study cohort comprised 66 female Lewis HanHsd rats (Harlan, The Netherlands). After 1-week acclimatization ovarectomy is performed on 55 of the rats by first anaesthetising with Hypnorm-Dormicum (1 part Hypnorm® + 1 part Dormicum® + 2 part sterile de-ionised water). The rats are given 0.15-0.2 ml/100 g body weight) and a standard ovariectomy are performed. Eleven rats are subjected to sham operation using the same anaesthesia procedure. The rats are immunized 1 week after OVX. Each rat is immunized with 150 ⁇ g bovine collagen type II (Cat. Nr.
  • the compound When a homogenous suspension is obtained the compound is diluted in the same amount (1:1) of 0.15M NaCl.
  • the compounds were given orally by gavages for five days a week, with no administration during weekends.
  • Treatment with vehicle, estrogen and SERM #0781 in three different doses was started the day after OVX, i.e. prior to collagen type II immunization.
  • Uterus weights were measured at the end of the experiments to determine the uterotrophic effect of SERM #0781. Highest weights were observed in the sham animals (S) representing normal uterus weights.
  • OVX resulted in a more the 50% reduction of uterus weight as seen in the vehicle treated groups (V).
  • Estrogen treatment restores the uterus weight to some extent, however not completely.
  • SERM #0781 treated rats show a slight increase in uterus weight regardless of dose compared to vehicle treated rats. Spleen weights were determined at the end of the CIA experiment. Spleen weights were reduced in all SERM #0781 treated groups and the estrogen group compared to the sham and vehicle groups.
  • the great impact of arthritis on the CartiLaps levels shown in figure 13 B explains the large variability in the CartiLaps levels in figure 13 A.
  • OVX two weeks after immunisation with collagen type H
  • the time point of immunisation, week 1 in figure 13, is one week after OVX.
  • Rats that remain healthy during the six weeks of observation have an endpoint value of 26,5 % of the baseline level of CartiLaps.
  • RA inflammatory arthritis
  • FIG 14 shows the absolute values of CartiLaps at the end of the CIA experiment.
  • the different treatment groups are shown separately. This demonstrates that also the absolute values of CartiLaps reflect the arthritis status of the rat.
  • OVX OA model an increase of CartiLaps levels were induced by OVX (see examples 1 - 4). This homeostatic imbalance was restored within six weeks and could be prevented by estrogen levormeloxifene or SERM #0781 treatment. This period of imbalance in cartilage metabolism following OVX may be the reason for increased susceptibility to develop cartilage erosions and CIA during this period.
  • Additional beneficial effect of the SERM treatment as exemplified by the effect of SERM #0781 in this experiment may be that they result in a general immunosuppressive effect (see fig. 10), which may also have a significant therapeutic potential for treatment of inflammatory arthritis.
  • Example 6 Suppression of cartilage turnover in humans induced by selective estrogen receptor modulators.
  • Table 3 demonstrates the physical demographics and relevant biomarker levels of the participants at baseline. Both studies were performed according to the Helsinki Declaration II and the European standard for Good Clinical Practice. 5 Designs: The raloxifene study included five treatment groups and lasted five years.
  • BMI Body mass index
  • Serum CrossLaps ELISA Serum CrossLaps was included for comparison.
  • the Serum CrossLaps One Step ELISA is a sensitive indicator of bone resorption and the assay was 5 performed as described by the manufacturer (Nrodic Bioscience Diagnostics, Herlev,
  • Serum CrossLaps measurements were performed at baseline and after 3, 6 and 12 months of treatment in both trials.
  • Table 3 provides the baseline values for the two study populations divided into the treated 5 groups and their controls. Independent T-tests performed between the raloxifene study population and the levormeloxifene study population demonstrated a slight difference between the two groups with regard to age. The levormeloxifene group was thus 1.1 ⁇ 0.5 years (p ⁇ 0.05) older compared to the raloxifene group and had on average been postmenopausal for a corresponding ⁇ 0.5 years (p ⁇ 0.05) longer than the raloxifene l o group. Serum CrossLaps values reflecting osteoclast mediated bone resorption were in accordance with this slight difference in age and YSM statistically higher in the levormeloxifene group. There were no statistically significant differences between the two study populations with regard to BMI and urinary CartiLaps levels reflecting cartilage collagen type II degeneration. The variance between the listed parameters in table 1 was
  • CartiLaps levels in placebo treated women showed a slight increase during the five-year study period.
  • the treated groups reached a plateau of the CartiLaps marker after 12 months with no apparent dose response.
  • 5 Results of CartiLaps measurements from the levormeloxifene study are shown in the lower panel of figure 15. In this study a 50 % decrease in CartiLaps levels was observed after 3 to 6 months of levormeloxifene treatment. There were only relatively small and nonsignificant differences between the responses in the four treatment-groups during the 12 months of therapeutic intervention. After cessation of the levormeloxifene treatment all
  • the study populations included in the two studies comprise postmenopausal women that were not selected according to a specific degree of OA.
  • postmenopausal women experience an increased incidence of OA. If cartilage degradation is reduced in postmenopausal women this would probability involve a reduced risk of developing OA.
  • postmenopausal women that have not been selected to have symptomatic OA, represent a relevant group for investigating preventive chondroprotective therapies.
  • Postmenopausal women also represent the key target group for SERM therapy, as the documented and approved indications for such a therapy includes prevention of postmenopausal osteoporosis.
  • the raloxifene treated study population was followed for five years.
  • Bone resorption is reduced by both raloxifene and levormeloxifene, measured by biomarkers and in the case of raloxifene also by a long-term reduction in fracture occurrence rates.
  • the SERMs effect on bone resorption as assessed with the CrossLaps ELISA was of a similar magnitude as the effect on cartilage degradation we here demonstrate with the CartiLaps assay.

Abstract

L'invention concerne l'utilisation pharmaceutique de modulateurs des récepteurs des oestrogènes sélectifs seuls ou combinés aux progestines, pour le traitement ou la prévention de maladies associées à une dégradation élevée du cartilage. L'invention porte notamment sur l'utilisation pharmaceutique de dérivés de chromane combinés à la noréthindrone, pour le traitement ou la prévention de l'osthéoarthite ou de la polyarthrite rhumatoïde.
PCT/EP2003/000241 2002-01-14 2003-01-13 Suppression de la degradation du cartilage a l'aide du recepteur des oestrogenes WO2003063859A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2003563549A JP2005524630A (ja) 2002-01-14 2003-01-13 エストロゲン受容体を介する軟骨破壊の抑制
EP03702427A EP1465619A1 (fr) 2002-01-14 2003-01-13 Suppression de la degradation du cartilage a l'aide du recepteur des oestrogenes

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US34873002P 2002-01-14 2002-01-14
US60/348,730 2002-01-14
GB0200743.3 2002-01-14
GB0200743A GB0200743D0 (en) 2002-01-14 2002-01-14 Suppression of cartilage degradation via the estrogen receptor
GB0209495.1 2002-04-25
GB0209495A GB0209495D0 (en) 2002-04-25 2002-04-25 Suppression of cartilage degradation via the estrogen receptor

Publications (1)

Publication Number Publication Date
WO2003063859A1 true WO2003063859A1 (fr) 2003-08-07

Family

ID=27669900

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/000241 WO2003063859A1 (fr) 2002-01-14 2003-01-13 Suppression de la degradation du cartilage a l'aide du recepteur des oestrogenes

Country Status (3)

Country Link
EP (1) EP1465619A1 (fr)
JP (1) JP2005524630A (fr)
WO (1) WO2003063859A1 (fr)

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006082072A1 (fr) * 2005-02-04 2006-08-10 Peter Heger Utilisation de principes actifs contenant de l'hydroxystilbene pour la prevention et/ou le traitement de l'osteoporose
EP1809618A1 (fr) * 2004-09-21 2007-07-25 Novogen Research Pty Ltd Dérivés de chromane, médicaments et utilisation à des fins thérapeutiques
WO2008002490A3 (fr) * 2006-06-23 2008-06-26 Radius Health Inc Traitement de symptômes vasomoteurs par des modulateurs des récepteurs d'œstrogène sélectifs
EP2034984A2 (fr) * 2006-06-02 2009-03-18 Pear Tree Women's Health Care Procédé de traitement de la vaginite atrophique
US7601855B2 (en) 2004-09-21 2009-10-13 Novogen Research Pty Ltd Substituted chroman derivatives, medicaments and use in therapy
WO2010045674A1 (fr) * 2008-10-22 2010-04-29 Novogen Research Pty Ltd Méthodes pour provoquer une mort cellulaire programmée
WO2010054758A1 (fr) * 2008-11-11 2010-05-20 Bayer Schering Pharma Aktiengesellschaft Combinaison pharmaceutique synergique contenant un antagoniste du récepteur des oestrogènes et une progestine
US8080675B2 (en) 2004-09-21 2011-12-20 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US8703810B2 (en) 2010-06-10 2014-04-22 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US20150216876A1 (en) * 2008-06-02 2015-08-06 Novelmed Therapeutics, Inc. Method for treating inflammatory conditions
CN104902904A (zh) * 2013-04-18 2015-09-09 西安力邦医药科技有限责任公司 7-α-[9-(4,4,5,5,5-五氟戊基亚硫酰基)壬基]-雌甾-1,3,5(10)-三烯-3,17β-二醇及其衍生物的用途
US9187460B2 (en) 2011-12-14 2015-11-17 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US20160060288A1 (en) * 2013-04-18 2016-03-03 Xi'anlibang Pharmaceutical Technology Co., Ltd. Ester derivatives of 7-alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl)-estra-1,3,5(10)-triene-3,17beta-diol having anticancer activity and preparation method thereof
WO2017000081A1 (fr) * 2015-06-30 2017-01-05 上海交通大学 Utilisation de l'étonorgestrel dans la préparation d'un produit permettant de lutter contre l'adénocarcinome de la prostate
US9555014B2 (en) 2010-05-12 2017-01-31 Radius Health, Inc. Therapeutic regimens
US9663484B2 (en) 2010-11-01 2017-05-30 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US9701655B2 (en) 2014-02-07 2017-07-11 Novogen Limited Functionalised benzopyran compounds and use thereof
US9920044B2 (en) 2010-09-28 2018-03-20 Radius Pharmaceuticals, Inc. Selective androgen receptor modulators
US10071066B2 (en) 2014-03-28 2018-09-11 Duke University Method of treating cancer using selective estrogen receptor modulators
US10385008B2 (en) 2017-01-05 2019-08-20 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US10420734B2 (en) 2014-03-28 2019-09-24 Duke University Method of treating cancer using selective estrogen receptor modulators
US10980774B2 (en) 2015-02-02 2021-04-20 Mei Pharma, Inc. Combination therapies
WO2021118629A1 (fr) * 2019-12-12 2021-06-17 Accutar Biotechnology Inc. Nouveaux dérivés de chromane ayant une activité de dégradation des récepteurs des oestrogènes et leurs utilisations
US11642342B2 (en) 2019-12-23 2023-05-09 Accutar Biotechnology Combinations of estrogen receptor degraders and cyclin-dependent kinase inhibitors for treating cancer
US11643385B2 (en) 2018-07-04 2023-05-09 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCl
US11771682B2 (en) 2016-06-22 2023-10-03 Ellipses Pharma Ltd. AR+ breast cancer treatment methods
US11819480B2 (en) 2015-04-29 2023-11-21 Radius Pharmaceuticals, Inc. Methods for treating cancer
WO2023172608A3 (fr) * 2022-03-08 2023-12-07 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Amélioration du récepteur alpha des oestrogènes dans l'arthrose

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0888775A2 (fr) * 1997-07-03 1999-01-07 Medical College Of Hampton Roads Régulation des modulateurs sélectifs du récepteur oestrogénique
US5861438A (en) * 1996-02-28 1999-01-19 Pfizer Inc. Combination therapy to prevent bone loss parathyroid hormone and estrogen agonists
US5977158A (en) * 1996-11-28 1999-11-02 Novo Nordisk A/S Pharmaceutical formulations comprising levormeloxifene compounds
WO2000074684A1 (fr) * 1999-06-04 2000-12-14 The General Hospital Corporation Formulations pharmaceutiques pour traiter des femmes en periode de postmenopause et de perimenopause, et leur utilisation
EP1090639A2 (fr) * 1999-10-06 2001-04-11 Medical College Of Hampton Roads Composition pharmaceutique contenant un corticoide progestatif et un modulateur sélectif du récepteur oestrogénique
WO2002091993A2 (fr) * 2001-05-10 2002-11-21 Merck & Co., Inc. Modulateurs des recepteurs des oestrogenes

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5861438A (en) * 1996-02-28 1999-01-19 Pfizer Inc. Combination therapy to prevent bone loss parathyroid hormone and estrogen agonists
US5977158A (en) * 1996-11-28 1999-11-02 Novo Nordisk A/S Pharmaceutical formulations comprising levormeloxifene compounds
EP0888775A2 (fr) * 1997-07-03 1999-01-07 Medical College Of Hampton Roads Régulation des modulateurs sélectifs du récepteur oestrogénique
WO2000074684A1 (fr) * 1999-06-04 2000-12-14 The General Hospital Corporation Formulations pharmaceutiques pour traiter des femmes en periode de postmenopause et de perimenopause, et leur utilisation
EP1090639A2 (fr) * 1999-10-06 2001-04-11 Medical College Of Hampton Roads Composition pharmaceutique contenant un corticoide progestatif et un modulateur sélectif du récepteur oestrogénique
WO2002091993A2 (fr) * 2001-05-10 2002-11-21 Merck & Co., Inc. Modulateurs des recepteurs des oestrogenes

Cited By (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9381186B2 (en) 2004-09-21 2016-07-05 Mei Pharma, Inc. Substituted chroman derivatives, medicaments and use in therapy
EP1809618A4 (fr) * 2004-09-21 2008-11-19 Novogen Res Pty Ltd Dérivés de chromane, médicaments et utilisation à des fins thérapeutiques
US9198895B2 (en) 2004-09-21 2015-12-01 Mei Pharma, Inc. Chroman derivatives, medicaments and use in therapy
US8957109B2 (en) 2004-09-21 2015-02-17 Mei Pharma, Inc. Chroman derivatives, medicaments and use in therapy
US9138478B2 (en) 2004-09-21 2015-09-22 Mei Pharma, Inc. Substituted chroman derivatives, medicaments and use in therapy
US7601855B2 (en) 2004-09-21 2009-10-13 Novogen Research Pty Ltd Substituted chroman derivatives, medicaments and use in therapy
EP1809618A1 (fr) * 2004-09-21 2007-07-25 Novogen Research Pty Ltd Dérivés de chromane, médicaments et utilisation à des fins thérapeutiques
US8697891B2 (en) 2004-09-21 2014-04-15 Marshall Edwards, Inc. Substituted chroman derivatives, medicaments and use in therapy
US8080675B2 (en) 2004-09-21 2011-12-20 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US8084628B2 (en) 2004-09-21 2011-12-27 Marshall Edwards, Inc. Substituted chroman derivatives, medicaments and use in therapy
EP2407462A1 (fr) * 2004-09-21 2012-01-18 Marshall Edwards, Inc. Dérivés de chromane substitués, médicaments et utilisation en thérapie
EP2436680A3 (fr) * 2004-09-21 2012-08-15 Marshall Edwards, Inc. Dérivés de chromane, médicaments et utilisation à des fins thérapeutiques
US8461361B2 (en) 2004-09-21 2013-06-11 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
WO2006082072A1 (fr) * 2005-02-04 2006-08-10 Peter Heger Utilisation de principes actifs contenant de l'hydroxystilbene pour la prevention et/ou le traitement de l'osteoporose
EP2034984A2 (fr) * 2006-06-02 2009-03-18 Pear Tree Women's Health Care Procédé de traitement de la vaginite atrophique
US9693953B2 (en) 2006-06-02 2017-07-04 Janet A. Chollet Method of treating atrophic vaginitis
EP2034984A4 (fr) * 2006-06-02 2013-03-06 Pear Tree Women S Health Care Procédé de traitement de la vaginite atrophique
WO2008002490A3 (fr) * 2006-06-23 2008-06-26 Radius Health Inc Traitement de symptômes vasomoteurs par des modulateurs des récepteurs d'œstrogène sélectifs
US8933130B2 (en) 2006-06-23 2015-01-13 Radius Health, Inc. Treatment of vasomotor symptoms with selective estrogen receptor modulators
US20150216876A1 (en) * 2008-06-02 2015-08-06 Novelmed Therapeutics, Inc. Method for treating inflammatory conditions
WO2010045674A1 (fr) * 2008-10-22 2010-04-29 Novogen Research Pty Ltd Méthodes pour provoquer une mort cellulaire programmée
WO2010054758A1 (fr) * 2008-11-11 2010-05-20 Bayer Schering Pharma Aktiengesellschaft Combinaison pharmaceutique synergique contenant un antagoniste du récepteur des oestrogènes et une progestine
US9555014B2 (en) 2010-05-12 2017-01-31 Radius Health, Inc. Therapeutic regimens
US9078871B2 (en) 2010-06-10 2015-07-14 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US8703810B2 (en) 2010-06-10 2014-04-22 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US9920044B2 (en) 2010-09-28 2018-03-20 Radius Pharmaceuticals, Inc. Selective androgen receptor modulators
US10973799B2 (en) 2010-11-01 2021-04-13 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US9981936B2 (en) 2010-11-01 2018-05-29 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US11583514B2 (en) 2010-11-01 2023-02-21 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10369132B2 (en) 2010-11-01 2019-08-06 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US11723893B2 (en) 2010-11-01 2023-08-15 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US9663484B2 (en) 2010-11-01 2017-05-30 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10105346B2 (en) 2010-11-01 2018-10-23 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US9708283B2 (en) 2010-11-01 2017-07-18 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US9193714B2 (en) 2011-12-14 2015-11-24 Seragon Pharmaceuticals, Inc. Fluorinated estrogen receptor modulators and uses thereof
US9187460B2 (en) 2011-12-14 2015-11-17 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
EP2987492A4 (fr) * 2013-04-18 2016-09-14 Xi An Libang Medical Technology Co Ltd Utilisation de 7-a-[9-(4,4,5,5,5-pentafluoro-pentyl-sulfinyl)nonyl]-estra-1,3,5(10)-triène-3,17b-diol et de ses dérivés
CN104902904A (zh) * 2013-04-18 2015-09-09 西安力邦医药科技有限责任公司 7-α-[9-(4,4,5,5,5-五氟戊基亚硫酰基)壬基]-雌甾-1,3,5(10)-三烯-3,17β-二醇及其衍生物的用途
AU2013386726B2 (en) * 2013-04-18 2019-08-01 Xi'an Libang Pharmaceutical Technology Co., Ltd. Use of 7-alpha-[9-(4,4,5,5,5 - pentafluoro-pentyl-sulfinyl)nonyl]-estra-1,3,5(10)-triene-3,17beta-diol and derivatives thereof
US20160038439A1 (en) * 2013-04-18 2016-02-11 Xi'anlibang Pharmaceutical Technology Co., Ltd. Use of 7-a-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-estra-1,3,5(10)- triene-3,17B-diol and derivatives thereof
US20160060288A1 (en) * 2013-04-18 2016-03-03 Xi'anlibang Pharmaceutical Technology Co., Ltd. Ester derivatives of 7-alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl)-estra-1,3,5(10)-triene-3,17beta-diol having anticancer activity and preparation method thereof
US9701655B2 (en) 2014-02-07 2017-07-11 Novogen Limited Functionalised benzopyran compounds and use thereof
US10370349B2 (en) 2014-02-07 2019-08-06 Kazia Therapeutics Limited Functionalised benzopyran compounds and use thereof
US10420734B2 (en) 2014-03-28 2019-09-24 Duke University Method of treating cancer using selective estrogen receptor modulators
US10071066B2 (en) 2014-03-28 2018-09-11 Duke University Method of treating cancer using selective estrogen receptor modulators
US11951080B2 (en) 2014-03-28 2024-04-09 Duke University Method of treating cancer using selective estrogen receptor modulators
US11779552B2 (en) 2014-03-28 2023-10-10 Duke University Method of treating cancer using selective estrogen receptor modulators
US10980774B2 (en) 2015-02-02 2021-04-20 Mei Pharma, Inc. Combination therapies
US11819480B2 (en) 2015-04-29 2023-11-21 Radius Pharmaceuticals, Inc. Methods for treating cancer
US10441591B2 (en) 2015-06-30 2019-10-15 Shanghai Jiao Tong University Applications for etonogestrel in preparing anti-prostate cancer products
WO2017000081A1 (fr) * 2015-06-30 2017-01-05 上海交通大学 Utilisation de l'étonorgestrel dans la préparation d'un produit permettant de lutter contre l'adénocarcinome de la prostate
US11771682B2 (en) 2016-06-22 2023-10-03 Ellipses Pharma Ltd. AR+ breast cancer treatment methods
US10385008B2 (en) 2017-01-05 2019-08-20 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US11708318B2 (en) 2017-01-05 2023-07-25 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US11643385B2 (en) 2018-07-04 2023-05-09 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCl
WO2021118629A1 (fr) * 2019-12-12 2021-06-17 Accutar Biotechnology Inc. Nouveaux dérivés de chromane ayant une activité de dégradation des récepteurs des oestrogènes et leurs utilisations
US11642342B2 (en) 2019-12-23 2023-05-09 Accutar Biotechnology Combinations of estrogen receptor degraders and cyclin-dependent kinase inhibitors for treating cancer
WO2023172608A3 (fr) * 2022-03-08 2023-12-07 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Amélioration du récepteur alpha des oestrogènes dans l'arthrose

Also Published As

Publication number Publication date
JP2005524630A (ja) 2005-08-18
EP1465619A1 (fr) 2004-10-13

Similar Documents

Publication Publication Date Title
WO2003063859A1 (fr) Suppression de la degradation du cartilage a l'aide du recepteur des oestrogenes
Christgau et al. Suppression of elevated cartilage turnover in postmenopausal women and in ovariectomized rats by estrogen and a selective estrogen-receptor modulator (SERM)
US8835413B2 (en) Sex steroid precursors alone or in combination with a selective estrogen receptor modulator and/or with estrogens and/or a type 5 cGMP phosphodiesterase inhibitor for the prevention and treatment of vaginal dryness and sexual dysfunction in postmenopausal women
JP6197292B2 (ja) 閉経を処置するためのｄｈｅａ組成物
Brown et al. Daily low-dose mifepristone has contraceptive potential by suppressing ovulation and menstruation: a double-blind randomized control trial of 2 and 5 mg per day for 120 days
US10201611B2 (en) Pharmaceutical composition comprising estetrol derivatives for use in cancer therapy
Goldstein et al. Raloxifene effect on frequency of surgery for pelvic floor relaxation
Seed Postmenopausal hormone replacement therapy, coronary heart disease and plasma lipoproteins
JPH06234632A (ja) ベンゾチオフェン類を含有する医薬組成物
KR100880564B1 (ko) 갱년기나 그 이후 여성의 갱년기 장애 치료 방법
KR20200108505A (ko) 선택적 에스트로겐 수용체 조절자와 복합된 성 스테로이드 전구체에 의한 알츠하이머병, 인지 상실, 기억 상실 및 치매의 치료
Martel et al. Prevention of bone loss by EM-800 and raloxifene in the ovariectomized rat
Zahradnik et al. Efficacy, safety and sustainability of treatment continuation and results of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg chlormadinone acetate, in long-term usage (up to 45 cycles)—an open-label, prospective, noncontrolled, office-based Phase III study
NO336612B1 (no) Anvendelse av en forbindelse for fremstilling av en farmasøytisk sammensetning for hemming av urininkontinens i en kvinne
Geiser et al. A new selective estrogen receptor modulator with potent uterine antagonist activity, agonist activity in bone, and minimal ovarian stimulation
Bjarnason et al. Raloxifene reduces atherosclerosis: studies of optimized raloxifene doses in ovariectomized, cholesterol‐fed rabbits
Silfen et al. Selective estrogen receptor modulators: tissue selectivity and differential uterine effects
Warming et al. Adverse effects of a SERM (Levormeloxifene): safety parameters and bone mineral density 12 months after treatment withdrawal
Lawrence et al. Clinical development of estrogen modulators for breast cancer chemoprevention in premenopausal vs. postmenopausal women
Kallner et al. Effect of letrozole on uterine tonus and contractility: a randomized controlled trial
Zanni et al. Animal models for the effective development of atrophic vaginitis therapies: Possibilities and limitations
Soulez et al. Polycystic ovary syndrome: a multidisciplinary challenge
Delmanto et al. Effect of raloxifene on the vaginal epithelium of postmenopausal women
Paschou et al. Polycystic ovary syndrome
CN100545158C (zh) 具有雌激素活性的(3r,4r)-反-3,4-二芳基苯并二氢吡喃衍生物

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2003702427

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2003563549

Country of ref document: JP

WWP Wipo information: published in national office

Ref document number: 2003702427

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 2003702427

Country of ref document: EP