WO2002003992A2 - Therapie pour degenerescence osseuse en rapport avec une prothese - Google Patents

Therapie pour degenerescence osseuse en rapport avec une prothese Download PDF

Info

Publication number
WO2002003992A2
WO2002003992A2 PCT/US2001/021084 US0121084W WO0203992A2 WO 2002003992 A2 WO2002003992 A2 WO 2002003992A2 US 0121084 W US0121084 W US 0121084W WO 0203992 A2 WO0203992 A2 WO 0203992A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
pharmaceutically acceptable
acceptable salt
phenyl
hydroxy
Prior art date
Application number
PCT/US2001/021084
Other languages
English (en)
Other versions
WO2002003992A3 (fr
Inventor
Simon Nicholas Jenkins
Barry Samuel Komm
Christopher Paul Miller
Original Assignee
Wyeth
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wyeth filed Critical Wyeth
Priority to AU2001271784A priority Critical patent/AU2001271784A1/en
Publication of WO2002003992A2 publication Critical patent/WO2002003992A2/fr
Publication of WO2002003992A3 publication Critical patent/WO2002003992A3/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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • 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
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • 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

Definitions

  • This invention relates to methods of using substituted indole compounds optionally in combination with one or more estrogens for the treatment, prevention, inhibition or alleviation of bone prosthesis degeneration. More particularly, this invention provides such methods for treating the degeneration or other damage to tissues surrounding or interacting with prosthetic devices.
  • prosthetic devices has become common in replacement of damage tissues in various joints, including the hip and knee.
  • Prosthetic dental implants have also become quite common for individual or sequential teeth.
  • the use of such prosthetic devices has significantly improved the quality of life for many recipients.
  • estrogenic agents including the treatment of bone loss, cardiovascular disease, maladies associated with or resulting from the proliferation or abnormal development of endometrial or endometrial-like tissues, and disease states or syndromes associated with estrogen deficiency.
  • This invention comprises methods of treating, inhibiting, preventing, or alleviating bone prosthesis degeneration in a mammal, preferably in a human, the methods comprising administering to a mammal in need a pharmaceutically effective amount of a substituted indole compound of the formulae I or ⁇ , below:
  • Z is a moiety selected from the group of:
  • R ⁇ is selected from H, OH or the C1-C 1 2 esters (straight chain or branched) or
  • R 2 , R 3 , R 5 , and R 6 are independently selected from H, OH or the C1-C12 esters
  • R is selected from H, OH or the C1-C1 2 esters (straight chain or branched) or C,-C 12 alkyl ethers (straight chain or branched or cyclic) thereof, benzyloxy, halogens, or C ⁇ C 4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether, cyano, Ci-C ⁇ alkyl (straight chain or branched), or trifluoromethyl;
  • X is selected from H, Ci-C ⁇ alkyl, cyano, nitro, trifluoromethyl, halogen;
  • n is 1, 2 or 3;
  • Y is selected from: a) the moiety:
  • R7 and Rs are independently selected from the group of H, C1-C6 alkyl, or phenyl optionally substituted by CN, C ⁇ -C6 alkyl (straight chain or branched), Ci-C ⁇ alkoxy (straight chain or branched), halogen, -OH, -CF 3 , or -OCF 3 ; or R 7 and R 8 are combined by -(CH 2 )p-, wherein p is an integer of from 2 to 6, so as to form a ring, the ring being optionally substituted by up to three substituents selected from the group of hydroxyl, halo, C ⁇ -C4alkyl, trihalomethyl, C ⁇ -C4alko y, trihalomethoxy, Ci- C4alkylthio, C ⁇ -C4alkylsulfinyl, C ⁇ -C4alkylsulfonyl, hydroxy(C ⁇ -C4)alkyl, -CO 2 H, -CN
  • a five-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of -O-, -NH-, -N(C ⁇ _C4 alkyl)-, -N , and -S(O) m -, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C ⁇ -C4alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C ⁇ -C4acyloxy, C ⁇ -C4alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy(C ⁇ -C )alkyl, -CO 2 H-, -CN-, -CONHR,, -NH 2 , C ⁇ -C 4 alkylamino, di(C ⁇ -C 4 )
  • a six-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of -O-, -NH-, -N( C4 alkyl)-, -N , and -S(O) m -, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C ⁇ -C4alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, C ⁇ -C4acyloxy, C ⁇ -C4alkylthio, C ⁇ -C 4 alkylsulfinyl, C ⁇ -C 4 alkylsulfonyl, hydroxy(C ⁇ -C 4 )alkyl, -CO 2 H, -CN, -CONHR,, -NH 2 , C ⁇ -C 4 alkylamino, di(C ⁇ -C4)alkylamino,
  • a seven-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of -O-, -NH-, -N(C ⁇ _C4alkyl)-, -N , and -S(O) m -, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, -C4 alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, C ⁇ -C 4 acyloxy, C ⁇ -C4alkylthio, C ⁇ -C 4 alkylsulfinyl, C ⁇ -C 4 alkylsulfonyl, hydroxy(C ⁇ -C 4 )alkyl, -CO 2 H, -CN,
  • a bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing up to two heteroatoms selected from the group consisting of -O-, -NH-, -N(C ⁇ _C4alkyl)-, and -S(O) m -, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, C ⁇ -C 4 acyloxy, C ⁇ -C4alkylthio,
  • substituted indole compounds for use in the methods of this invention are those having the general structures I or II, above, wherein:
  • R ! is selected from H, OH or the -C1 2 esters or alkyl ethers thereof, benzyloxy, or halogen;
  • R 2 , R 3 , R 5 , and R 6 are independently selected from H, OH or the -C 12 esters or alkyl ethers thereof, halogen, cyano, Ci-C ⁇ alkyl, or trihalomethyl, preferably trifluoromethyl, with the proviso that, when Ri is H, R 2 is not OH; R is selected from H, OH or the C1-C12 esters or alkyl ethers thereof, benzyloxy, halogen, cyano, Ci-C ⁇ alkyl, or trihalomethyl;
  • X is selected from H, Ci-C ⁇ alkyl, cyano, nitro, trifluoromethyl, halogen; Y is the moiety
  • R 7 and R 8 are selected independently from H, C ⁇ -C6 alkyl, or combined by -(CH 2 )p-, wherein p is an integer of from 2 to 6, so as to form a ring, the ring being optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, C ⁇ -C4alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, Ci-G ⁇ alkyl- thio, C ⁇ -C alkylsulfinyl, Ci- alkylsulf ⁇ nyl, hydroxy(C ⁇ - )alkyl, -CO H, -CN, -CONH(C ⁇ -C 4 )alkyl, -NH 2 , C ⁇ -C 4 alkylamino, di (C 1 -C4 )alkylamino, -NHSO 2 (C ⁇ - C 4 )alkyl, -NHCO(C ⁇ -C 4 )alkyl
  • the rings formed by a concatenated R7 and Rs, mentioned above, may include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneamine or heptamethyleneamine rings.
  • the most preferred compounds of the present invention are those having the structural formulas I or II, above, wherein Ri is OH; R2 - R6 are as defined above; X is selected from the group of Cl, NO 2 , CN, CF3, or CH3; and Y is the moiety
  • R7 and Rs are concatenated together as -(CH 2 )r, wherein r is an integer of from 4 to 6, to form a ring optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C 1 -C4 alkoxy, trihalomethoxy, -C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C ⁇ -C 4 )alkyl, -CO 2 H, -CN, -CONH(C ⁇ -C 4 )alkyl, -NH 2 , - alkylamino, di(C ⁇ - C 4 )alkylamino, -NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C 4 )alkyl, and -NO 2 ; and the pharmaceutically acceptable salts thereof.
  • R7 and Rs are concatenated together as -(CH 2 )p-, wherein p is an integer of from 2 to 6, preferably 4 to 6, the ring so formed is optionally substituted with 1-3 substituents selected from a group containing C1-C3 alkyl, trifluoromethyl, halogen, hydrogen, phenyl, nitro, -CN.
  • the invention includes sulfate, sulfamates and sulfate esters of phenolic groups in these compounds.
  • Sulfates can be readily prepared by the reaction of the free phenolic compounds with sulfur trioxide complexed with an amine such as pyridine, trimethylamine, triethylamine, etc.
  • Sulfamates can be prepared by treating the free phenolic compound with the desired arnino or alkylamino or dialkylamino sulfamyl chloride in the presence of a suitable base such as pyridine.
  • Sulfate esters can be prepared by reaction of the free phenol with the desired alkanesulfonyl chloride in the presence of a suitable base such as pyridine.
  • this invention includes compounds containing phosphates at the phenol as well as dialkyl phosphates.
  • Phosphates can be prepared by reaction of the phenol with the appropriate chlorophosphate.
  • the dialkylphosphates can be hydrolyzed to yield the free phosphates.
  • Phosphinates are also claimed where the phenol is reacted with the desired dialkylphosphinic chloride to yield the desired dialkylphosphinate of the phenol.
  • the invention includes acceptable salt forms of these compounds formed from the addition reaction with either inorganic or organic acids.
  • Inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid useful as well as organic acids such as acetic acid, propionic acid, citric acid, maleic acid, malic acid, tartaric acid, phthalic acid, succinic acid, methanesulfonic acid, toluenesulfonic acid, napthalenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid are useful.
  • this invention includes quaternary ammonium salts of the compounds herein. These can be prepared by reacting the nucleophilic amines of the side chain with a suitably reactive alkylating agent such as an alkyl halide or benzyl halide.
  • the methods of this invention include therapies and pharmaceutical regimens for treatment, prevention, inhibition or alleviation of bone prosthesis degeneration.
  • Such methods include the maintenance and enhancement of the bone and related tissues surrounding or operating in relation to or in contact with the orthopedic or dental prosthetic device in question to facilitate survival or maintenance of the usefulness and utility of the prosthesis over time.
  • the methods of this invention may be utilized remedially or prophylactically, as determined by a medical professional. These methods include maintenance of tissue and inhibition of degeneration associated with prosthetic replacement associated with various joints including, but not limited to, those of the knee, hip, shoulder (humeral), elbow, wrist and ankle.
  • prosthetic devices include those of various materials known in the art, including devices and implants comprised of metal, polymers, ceramics, or other materials.
  • a pharmaceutically effective amount of one or more of the compounds of this invention, or the pharmaceutically acceptable salts thereof is an amount sufficient to provide efficacious results in maintaining the bone and related tissues in question in a healthy state for interaction with the relevant prosthesis or to inhibit, delay, or otherwise counter degeneration or deterioration of the tissues to prolong the period in which the prosthesis may be used.
  • These methods each comprise administering to a mammal in need thereof a pharmaceutically effective amount of a pharmaceutically effective amount of one of the substituted indoles taught herein and optionally one or more estrogens. These administrations may be therapeutic or prophylactic.
  • preferred substituted indole compounds for use in these methods are l-[4-(2-azepan-lyl-ethoxy)-benzyl]-2- (4-hydroxy-phenyl)-3-methyl-lH-indol-5-ol, also known as TSE-424, and 2-(4- hy droxy-pheny l)-3-methyl- 1 -(4-(2-piperidin- 1 -yl-ethoxy)-benzyl]- 1 H-indol-5-ol, also known as ERA-923, or a pharmaceutically acceptable salt of TSE-424 or ERA-923.
  • Estrogens useful in the formulations of this invention include estrone, estriol, equilin, estradiene, equilenin, ethinyl estradiol, 17 ⁇ -estradiol, 17 ⁇ -dihydroequilenin, 17 ⁇ -dihydroequilenin (U.S. Patent 2,834,712), 17 ⁇ -dihydroequilin, 17 ⁇ -dihydro- equilin, menstranol and conjugated estrogenic hormones, such as those in Wyeth- Ayerst Laboratories' Premarin ® products (P.O. Box 8299, Philadelphia, PA 19101, U.S.A.).
  • Phytoestrogens such as equol or enterolactone, may also be used in the present formulations and methods.
  • a preferred embodiment of this invention comprises pharmaceutical compositions and methods of treatment utilizing conjugated estrogenic hormones, such as those in Wyeth-Ayerst Laboratories' Premarin ® products, with one or more compounds of Formulas (I) or (III) listed herein.
  • conjugated estrogenic hormones such as those in Wyeth-Ayerst Laboratories' Premarin ® products, with one or more compounds of Formulas (I) or (III) listed herein.
  • Esterified estrogens such as those sold by Solvay Pharmaceuticals, Inc. under the Estratab® tradename, may also be used with the present formulations.
  • the salts of the applicable estrogens most preferably the sodium salts.
  • Examples of these preferred salts are Sodium estrone sulfate, Sodium equilin sulfate, Sodium 17alpha-dihydroequilin sulfate, Sodium 17alpha-estradiol sulfate, Sodium Delta8,9- dehydroestrone sulfate, Sodium equilenin sulfate, Sodium 17beta-dihydroequilin sulfate, Sodium 17alpha- dihydroequilenin sulfate, Sodium 17beta-estradiol sulfate, Sodium 17beta- dihydroequilenin sulfate, Estrone 3-sodium sulfate, Equilin 3-sodium sulfate, 17alpha-Dihydroequilin 3-sodium sulfate, 3beta-Hydroxy-estra-5(10),7-dien-17-one 3-sodium sul
  • a substituted indole compound selected from l-[4-(2-azepan-lyl- ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-lH-indol-5-ol, also known as TSE- 424, and 2-(4-hydroxy-phenyl)-3-methyl-l-(4-(2-piperidin-l-yl-ethoxy)-benzyl]-lH- indol-5-ol, also known as ERA-923, or a pharmaceutically acceptable salt of TSE-424 or ERA-923; and
  • the conjugated estrogenic hormones such as those of the Premarin ® brand products marketed by Wyeth-Ayerst Laboratories.
  • the present invention includes methods utilizing in conjunction with one or more estrogen, or a pharmaceutically acceptable salt thereof, a first subset or subgroup of substituted indole compounds of the formulas III or IN, below:
  • variable substituents including R, R 2 , R 3 , R 4 , R 5 , R 6 , n, X, and Y are as defined above, or a pharmaceutically acceptable salt thereof.
  • the more preferred compounds of this first subset of indole compounds are those having the general structures III or IV, above, wherein:
  • R j is selected from H, OH or the C1-C12 esters or alkyl ethers thereof, benzyloxy, or halogen;
  • R 2 , R 3 , R 5 , and R 6 are independently selected from H, OH or the C1-C1 2 esters or alkyl ethers thereof, halogen, cyano, C ⁇ -C6 alkyl, or trihalomethyl, preferably trifluoromethyl, with the proviso that, when Ri is H, R2 is not OH;
  • R 4 is selected from H, OH or the C1-C12 esters or alkyl ethers thereof, benzyloxy, halogen, cyano, Ci-C ⁇ alkyl, or trihalomethyl;
  • X is selected from H, Ci-C ⁇ alkyl, cyano, nitro, trifluoromethyl, halogen;
  • Y is the moiety
  • R 7 and R 8 are selected independently from H, alkyl, or combined by -(CH 2 )p-, wherein p is an integer of from 2 to 6, so as to form a ring, the ring being optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, C ⁇ -C4alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, C ⁇ - C4alkylthio, - alkylsulfinyl, Ci- alkylsulfonyl, hydroxy(C ⁇ - )alkyl, -CO 2 H, -C ⁇ , -CO ⁇ H(C ⁇ -C 4 )alkyl, -NH 2 , C ⁇ -C 4 alkylamino, di(C ⁇ -C 4 )alkylamino, -NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C 4 )alkyl, and -NO
  • the most preferred compounds of this first subset of indole compounds are those having the structural formulas I or II, above, wherein Ri is OH; R 2 - Re are as defined above; X is selected from the group of Cl, NO 2 , CN, CF3, or CH3; and Y is the moiety
  • R s and R7 and Rs are concatenated together as -(CH 2 )r, wherein r is an integer of from 4 to 6, to form a ring optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, C ⁇ -C4alkyl, trihalomethyl, C ⁇ -C4alko y, trihalomethoxy, C ⁇ -C4alkylthio, C ⁇ -C4alkylsulfinyl, C ⁇ -C4alkylsulfonyl, hydroxy(C ⁇ -C 4 )alkyl, -CO 2 H, -CN, -CONH(C ⁇ -C 4 )alkyl, -NH 2 , C ⁇ -C 4 alkylamino, di(C ⁇ -C 4 )alkylamino, -NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C )alkyl, and -NO 2 ; and the
  • this first subset of compounds when R7 and Rs are concatenated together as -(CH 2 )p-, wherein p is an integer of from 2 to 6, preferably 4 to 6, the ring so formed is optionally substituted with 1-3 substituents selected from a group containing C1-C3 alkyl, trifluoromethyl, halogen, hydrogen, phenyl, nitro, -CN.
  • the compounds of this first subset or subgroup of indole compounds can be produced by the methods described in EP 0 802 183 Al, published October 22, 1997, and U.S. Patent No. 5,780,497, the subject matter of which is incorporated herein by reference, or by other methods known in the art.
  • Aryloxy-alkyl-dialkylamines or aryloxy-alkyl-cyclic amines useful as intermediates in the production of the compounds above can be produced and used as disclosed in WO 99/19293, published April 22, 1999, the subject matter of which is also incorporated herein by reference.
  • a second subset or subgroup of indole compounds useful with this invention includes those of formulas (V) or (VI), below:
  • variable substituents including R, R 2 , R 3 , R 4 , R 5 , R 6 , n, X, and Y are as defined above, or a pharmaceutically acceptable salt thereof.
  • a third subset of indole compounds useful with the present invention include those of the formulae Nil and NIII:
  • R t is selected from H, OH or the C ⁇ -C ⁇ esters or alkyl ethers thereof, halogen;
  • R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from H, OH or the -C12 esters or alkyl ethers thereof, halogen, cyano, C1-C6 alkyl, or trihalomethyl, preferably trifluoromethyl, with the proviso that, when Ri is H, R 2 is not OH;
  • X is selected from H, Ci-C ⁇ alkyl, cyano, nitro, trifluoromethyl, halogen; Y is the moiety
  • R 7 and R 8 are selected independently from H, C1-C6 alkyl, or combined by -(CH 2 )p-, wherein p is an integer of from 2 to 6, so as to form a ring, the ring being optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, C ⁇ -C4alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, C ⁇ - C alkylthio, C ⁇ -C alkylsulfinyl, C ⁇ -C4alkylsulfonyl, hydroxy(C ⁇ -C )aIkyl, -CO 2 H, -CN, -CONH(C ⁇ -C 4 )alkyl, -NH , C ⁇ -C4alkylamino, di(C ⁇ -C 4 )alkylamino, -NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C 4 )
  • the rings formed by a concatenated R7 and Rs, mentioned above, may include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneamine or heptamethyleneamine rings.
  • indole compounds of the present invention are those having the structural formulas I through NIII, above, wherein Ri is OH; R 2 - R ⁇ are as defined above; X is selected from the group of Cl, ⁇ O 2 , CN, CF3, or CH3; and Y is the moiety
  • R 8 and R7 and Rs are concatenated together as -(CH 2 )r, wherein r is an integer of from 4 to 6, to form a ring optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, -C4 alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, C]-C4alkylthio, C]-C 4 alkylsulfinyl, C ⁇ -C4alkylsulfonyl, hydroxy(C ⁇ -C 4 )alkyl, -CO 2 H, -CN, -CONH(C ⁇ -C 4 )alkyl, -NH 2 , C ⁇ -C 4 alkylamino, di(C ⁇ -C 4 )alkylamino, -NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C )alkyl, and -NO 2 ; and the pharmaceutically acceptable salts
  • R7 and Rs are concatenated together as -(CH 2 )p-, wherein p is an integer of from 2 to 6, preferably 4 to 6, the ring so formed is optionally substituted with 1-3 substituents selected from a group containing C1-C3 alkyl, trifluoromethyl, halogen, hydrogen, phenyl, nitro, -CN.
  • the invention includes acceptable salt forms formed from the addition reaction with either inorganic or organic acids.
  • Inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid useful as well as organic acids such as acetic acid, propionic acid, citric acid, maleic acid, malic acid, tartaric acid, phthalic acid, succinic acid, methanesulfonic acid, toluenesulfonic acid, napthalenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid are useful.
  • this invention includes quaternary ammonium salts of the compounds herein. These can be prepared by reacting the nucleophilic amines of the side chain with a suitably reactive alkylating agent such as an alkyl halide or benzyl halide.
  • the dosage, regimen and mode of administration of these compounds will vary according to the malady and the individual being treated and will be subject to the judgement of the medical practitioner involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
  • Effective administration of these compounds may be given at an effective dose of from about 0.1 mg/day to about 500 mg/day. Preferably, administration will be from about 1 mg/day to about 200 mg/day in a single dose or in two or more divided doses.
  • Such doses may be administered in any manner useful in directing the active compounds herein to the recipient's bloodstream, including orally, parenterally (including intravenous, intraperitoneal and subcutaneous injections), and transdermally.
  • transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
  • the active ingredient in the formulations and methods of this invention is l-[4-(2-Azepan-lyl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl- lH-indol-5-ol, also known as TSE-424, or a pharmaceutically acceptable salt thereof
  • the preferred daily dosage for oral delivery is from about 0.1 to about 50 mg, preferably from about 2.5 to about 40 mg per day.
  • the active ingredient in the formulations and methods of this invention is 2-(4-Hydroxy-phenyl)-3-methyl-l-(4-(2-piperidin-l-yl-ethoxy)-benzyl]-lH-indol-
  • the preferred daily dosage for oral delivery is from about 0.1 to about 200 mg, preferably from about 2.5 to about 100 mg per day.
  • kits or packages of pharmaceutical formulations designed for use in the regimens and methods described herein.
  • These kits are preferably designed for daily oral administration over the specified term or cycle of administration, preferably for the number of prescribed oral administrations per day, and organized so as to indicate a single oral formulation or combination of oral formulations to be taken on each day of the regimen or cycle.
  • each kit will include oral tablets to be taken on each the days specified, in some embodiments one oral tablet will contain each of the combined daily dosages indicated and in other embodiments the administrations of the separate compounds will be present in separate formulations or compositions.
  • the package or kit shall have a calendar or days-of-the-week designation directing the administration of the appropriate compositions on the appropriate day or time.
  • Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions.
  • Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.
  • Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar.
  • pharmaceutically acceptable diluents including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline
  • Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s).
  • Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin.
  • Water soluble suppository bases such as polyethylene glycols of various molecular weights, may also be used.
  • a package or kit of this invention will include individual oral dosage formulations for each of the components of the invention.
  • one daily dosage tablet of an orally administerable formulation of a substituted indole compound of this invention preferably l-[4-(2-Azepan-lyl- ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl- lH-indol-5-ol or 2-(4-Hydroxy- phenyl)-3-methyl- 1 -(4-(2-piperidin- 1 -yl-ethoxy)-benzyl]- 1 H-indol-5-ol or a pharmaceutically acceptable salt thereof, and a once daily dosage Premarin ® conjugated estrogen tablet, for each day of a specified regimen.
  • kit or package comprises a one month supply of the components described herein, i.e. from 28 to 31 daily administration amounts of each component.
  • the estrogens herein may be administered according to the regimens and doses known in the art.
  • the preferred Premarin ® conjugated estrogen tablets may be administered as described in pages 3302-3305 of the Physicians' Desk Reference, 54 Edition, 2000, Medical Economics Company, Inc., Montvale, NJ 07645-1742.
  • estrogens useful with the present invention include OGEN ® (estropipate tablets), ESTRATAB ® (esterified estrogens tablets), ESTRACE ® estradiol vaginal cream, CLIMARA ® (estradiol transdermal system), ESTRADERM ® (transdermal system), MENESTTM (esterified estrogens tablets), ORTHO-EST ® (estropipate tablets), CENES ⁇ NTM (synthetic conjugated estrogens), ALORA ® (estradiol transdermal system), ESTINYL ® (ethynil estradiol), and the VINELLE ® and VIVELLE-DOT ® (estradiol transdermal systems).
  • OGEN ® estropipate tablets
  • ESTRATAB ® estradiol vaginal cream
  • CLIMARA ® estradiol transdermal system
  • ESTRADERM ® transdermal system
  • MENESTTM esterified estrogens tablets
  • ORTHO-EST ® estropi
  • Esterified estrogens 75-80% estrone sulfate Estratab 0.3, 0.625, 1.25, 2.5 mg
  • Estradiol Alora (twice weekly) 0.025, 0.0375, 0.05, 0.075,
  • Estradiol Fematrix 25 50, 75, 100 ⁇ g
  • Estradiol Ortho dienestrol cream 0.625 mg/g
  • Estrace vaginal cream 1.5 mg g . 1.0 mg/g
  • the joint administration of the two groups of compounds in these methods will be determined by a medical professional based upon the condition of the recipient and the malady for which the prophylaxis or treatment is provided. Administration of the two compounds may begin simultaneously or one may be introduced into an ongoing regimen of the other.
  • Solid oral formulations preferably in the form of a film coated tablet or capsule, useful for this invention include the active pharmacological agents disclosed herein in combination with carrier or excipient systems having the components: a) a filler and disintegrant component comprising from about 5% to about 82% by weight (wght) of the total formulation, preferably between about 30% and about 80% of the formulation, of which from about 4% to about 40% by weight of the total formulation comprises one or more pharmaceutically acceptable disintegrants; b) optionally, a wetting agent comprising from about 0.2 to about 5% of the composition (wght), such as selected from the group of sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, sugar esters of fatty acids and glycerides of fatty acids; c) a fill
  • fatty acid esters e.g. sodium stearyl fumarate
  • fatty acids e.g. stearic acid
  • fatty alcohols e.g. glyceryl behenate, mineral oil, parrafins, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates and sodium chloride; and d) optionally, a glidant comprising from about 0.1% to about 10% (wght) of the composition, the glidant selected from those known in the art, including from the group of silicon dioxide, talc, metallic stearates, calcium silicate, or metallic lauryl sulfates.
  • compositions described herein may be used in an uncoated or non- encapsulated solid form, preferably the final compositions are coated or encapsulated.
  • the pharmacological compositions may be optionally coated with a film coating, preferably comprising from about 0.3% to about 8% by weight of the overall composition.
  • Film coatings useful with the present formulations are known in the art and generally consist of a polymer (usually a cellulosic type of polymer), a colorant and a plasticizer. Additional ingredients such as wetting agents, sugars, flavors, oils and lubricants may be included in film coating formulations to impart certain characteristics to the film coat.
  • the compositions and formulations herein may also be combined and processed as a solid, then placed in a capsule form, such as a gelatin capsule.
  • the filler component listed above may utilize the filler or binder components known in the art for solid oral formulations.
  • Pharmaceutically acceptable fillers or binding agents selected from those known in the art including, but not limited to, lactose, microcrystalline cellulose, sucrose, mannitol, calcium phosphate, calcium carbonate, powdered cellulose, maltodextrin, sorbitol, starch, or xylitol.
  • disintegrant agents may be selected from those known in the art, including pregelatinized starch and sodium starch glycolate.
  • Other useful disintegrants include croscarmellose sodium, crospovidone, starch, alginic acid, sodium alginate, clays (e.g.
  • veegum or xanthan gum cellulose floe
  • ion exchange resins or effervescent systems, such as those utilizing food acids (such as citric acid, tartaric acid, malic acid, fumaric acid, lactic acid, adipic acid, ascorbic acid, aspartic acid, erythorbic acid, glutamic acid, and succinic acid) and an alkaline carbonate component (such as sodium bicarbonate, calcium carbonate, magnesium carbonate, potassium carbonate, ammonium carbonate, etc.).
  • the disintegrant(s) useful herein will comprise from about 4% to about 40% of the composition by weight, preferably from about 15% to about 35%, more preferably from about 20% to about 35%.
  • the pharmaceutical formulations and carrier or excipient systems herein preferably also contain an antioxidant or a mixture of antioxidants, most preferably ascorbic acid.
  • antioxidants which may be used include sodium ascorbate and ascorbyl palmitate, preferably in conjunction with an amount of ascorbic acid.
  • a preferable range for the antioxidant(s) is from about 0.5% to about 15% by weight, most preferably from about 0.5% to about 5% by weight.
  • formulations of this invention are pharmaceutical formulations containing a pharmaceutically effective amount of an active pharmacological agent and a carrier or excipient system comprising: a) a filler and disintegrant component comprising between about 50% and about 87% of the formulation, with from about 4% to about 40% of the formulation comprising one or more disintegrant agents; b) a wetting agent comprising between about 0.5% and about 2.7% of the formulation; c) a lubricant comprising between about 0.2% and about 5.5% of the formulation; and d) a glidant comprising between about 0.1% and about 5.5% of the formulation.
  • the percentages listed in the formulations above indicate percentages by weight of the total weight of the components listed from a) to d).
  • the formulations above also preferably contain an optional antioxidant component, preferably ascorbic acid, at a concentration of from about 0.5% to about 5.5% by weight of the formulation.
  • the formulations are also preferably contained within a pharmaceutically acceptable capsule, such as a gel capsule, or coated with a film coating comprising from about 0.3% to about 8% by weight of the formulation.
  • This invention also comprises a pharmaceutical carrier or excipient systems useful in pharmaceutical compositions utilizing as an active ingredient one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, as described herein.
  • These pharmaceutical carrier or excipient systems may comprise, by weight: a) a filler and disintegrant component comprising between about 54% and about 80% of the formulation, with the disintegrant agent(s) therein comprising from about 4% to about 40% by weight of the overall formulation; b) a wetting agent comprising between about 0.55% and about 2.5% of the formulation; c) a lubricant comprising between about 0.2% and about 5.5% of the formulation; and d) a glidant comprising between about 0.1% and about 5.0% of the formulation.
  • the more preferred carrier or excipient systems above also optionally and preferably contain an antioxidant component, preferably ascorbic acid, at a concentration of from about 0.1% to about 5.0% by weight.
  • an antioxidant component preferably ascorbic acid
  • the carrier or excipient systems of this invention are those comprising: a) a filler and disintegrant component, as described above, comprising between about 50% and about 87% of the formulation, the disintegrant(s) therein comprising from about 25% to about 35% of the formulation, by weight; b) a wetting agent comprising between about 0.55% and about 2.7% of the formulation; c) a lubricant comprising between about 0.2% and about 5.5% of the formulation; d) a glidant comprising between about 0.1% and about 5.5% of the formulation; and e) an antioxidant component, preferably ascorbic acid, at a concentration of from about 0.1% to about 5.5% by weight.
  • a filler and disintegrant component as described above, comprising between about 50% and about 87% of the formulation, the disintegrant(s) therein comprising from about 25% to about 35% of the formulation, by weight
  • this invention provides a product or kit of parts comprising a compound of formula I or II as defined above or a pharmaceutically acceptable salt thereof, and one or more estrogens, or a pharmaceutically acceptable salt thereof for administration as a combined preparation for simultaneous, separate or sequential use for inhibiting bone prosthesis degeneration in a mammal.
  • This invention also provides a pharmaceutical composition comprising a compound of formula I or II as defined above or a pharmaceutically acceptable salt thereof, and one or more estrogens, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • this invention also provides use of a substituted indole compound of the formulae I or II as defined above or a pharmaceutically acceptable salt thereof and optionally one or more estrogens in the preparation of a medicament for inhibiting bone prosthesis degeneration in a mammal.
  • Wet granulation of the formulations as described in Table 1 may be carried out by mixing the drug and ascorbic acid with a portion of the lactose, microcrystalline cellulose, pregelatinized starch and sodium starch glycolate.
  • the sodium lauryl sulfate is dissolved in the water and used to granulate the mixture of powders in a high shear mixer.
  • the granulation is dried in a fluid bed dryer to a moisture of 2-3%.
  • the particle size of the dried granulation is controlled by passing through a mill equipped with knife-edged blades and using a 20- or 30-mesh screen.
  • the silicon dioxide and remaining lactose, microcrystalline cellulose, pregelatinized starch, and sodium starch glycolate are mixed with the milled granulation in a tumble- type mixer.
  • the final blend is prepared by adding magnesium stearate to the tumble- type mixer and mixing. Compression is carried out on a rotary tablet press using appropriate size tooling. Coating is performed in conventional coating pans and applying the coating suspension to achieve a suitable film coat.
  • Amount in formula is adjusted for actual potency of TSE-424 as free base. Corresponding adjustment made with Lactose.
  • ERA-923 tablets are compressed to a tablet weight of up to 640 mg to achieve the target dose (up to 100 mg). Tablets may then be film coated.
  • a preferred carrier or excipient system for formulating a granulation of from about 2 to about 8% by weight of one of the active pharmacological agents of this invention, preferably about 5%, may be produced utilizing the carrier or excipient components on a weight percentage; lactose from about 32% to about 38%, microcrystalline cellulose from about 32% to about 38%, pregelatinized starch from about 12% to about 16%, ascorbic acid from about 1% to about 2%, sodium lauryl sulfate from about 1% to about 2%, sodium starch glycolate from about 4% to about 8%, silicon dioxide from about 0.1% to about 0.2% and magnesium stearate from about 0.3% to about 0.7%.
  • a formulation of this invention utilizing TSE-424 as the active ingredient at a 5% granulation was prepared utilizing the components listed below in a granulation part of components and a dry part.
  • TSE-424 tablet weight mg m of film coat applied/tablet

Abstract

Cette invention concerne des méthodes de traitement d'une dégénérescence osseuse en rapport avec une prothèse. Ces méthodes consistent à administrer un composé représenté par la formule (I) ou (II), ou un sel acceptable de ce composé, ou, éventuellement, un oestrogène. Dans la formule (I) ou (II), Z est une fraction prise dans le groupe de formules (a, b ou c) dans lequel: R1 est pris dans H, OH ou les esters en C1-C12 ou des alkyl éthers en C1-C12, ou des halogènes ; ou des éthers halogénés en C1-C4 comprenant un trifluorométhyl éther et un trichlorométhyl éther; R2, R3, R4, R5, et R6 sont H, OH ou des esters en C1-C12 ou des alkyl éthers en C1-C12, des halogènes, ou des éthers halogénés en C1-C4, cyano, alkyle en C1-C6, ou trifluorométhyle, à condition que, quand R1 est H, R2 N'est pas OH; Y est la fraction de la formule (d), R7 et R8 sont un alkyle ou sont concaténés pour former un noyau renfermant de l'azote éventuellement substitué.
PCT/US2001/021084 2000-07-06 2001-06-29 Therapie pour degenerescence osseuse en rapport avec une prothese WO2002003992A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001271784A AU2001271784A1 (en) 2000-07-06 2001-06-29 Therapy for prosthesis-related bone degeneration

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US21640600P 2000-07-06 2000-07-06
US21640700P 2000-07-06 2000-07-06
US60/216,406 2000-07-06
US60/216,407 2000-07-06

Publications (2)

Publication Number Publication Date
WO2002003992A2 true WO2002003992A2 (fr) 2002-01-17
WO2002003992A3 WO2002003992A3 (fr) 2002-06-27

Family

ID=26910981

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/021084 WO2002003992A2 (fr) 2000-07-06 2001-06-29 Therapie pour degenerescence osseuse en rapport avec une prothese

Country Status (2)

Country Link
AU (1) AU2001271784A1 (fr)
WO (1) WO2002003992A2 (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1531807A1 (fr) * 2002-06-13 2005-05-25 Wyeth Schemas therapeutiques du bazedoxifene
US7396855B2 (en) 2002-07-24 2008-07-08 Children's Hospital Medical Center Compositions and products containing S-equol, and methods for their making
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US8153684B2 (en) 2002-10-29 2012-04-10 Colorado State University Research Foundation Use of equol for treating androgen mediated diseases
US8580846B2 (en) 2002-10-29 2013-11-12 Brigham Young University Use of equol for ameliorating or preventing neuropsychiatric and neurodegenerative diseases or disorders
US8668914B2 (en) 2002-07-24 2014-03-11 Brigham Young University Use of equol for treating skin diseases
WO2017059139A1 (fr) 2015-10-01 2017-04-06 Olema Pharmaceuticals, Inc. Médicaments anti-œstrogéniques de type tétrahydro-1h-pyrido[3,4-b]indole
WO2017100715A1 (fr) 2015-12-09 2017-06-15 The Board Of Trustees Of The University Of Illinois Composés régulateurs à la baisse des récepteurs des œstrogènes sélectifs à base de benzothiophène
WO2017197036A1 (fr) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Dégronimères spirocycliques pour la dégradation de protéines cibles
WO2017197046A1 (fr) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Dégronimères de type glutarimide liés au carbone c3 pour la dégradation de protéines cibles
WO2017197055A1 (fr) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Dégronimères hétérocycliques pour la dégradation de protéines cibles
WO2018129387A1 (fr) 2017-01-06 2018-07-12 G1 Therapeutics, Inc. Polythérapie pour le traitement du cancer
US10023335B2 (en) 2010-03-29 2018-07-17 Ferring B.V. Fast dissolving pharmaceutical composition
US10086078B2 (en) 2010-03-29 2018-10-02 Ferring B.V. Fast dissolving pharmaceutical composition
WO2019006393A1 (fr) 2017-06-29 2019-01-03 G1 Therapeutics, Inc. Formes morphiques de git38 et leurs procédés de fabrication
US10208011B2 (en) 2017-02-10 2019-02-19 G1 Therapeutics, Inc. Benzothiophene estrogen receptor modulators
WO2020132561A1 (fr) 2018-12-20 2020-06-25 C4 Therapeutics, Inc. Dégradation ciblée de protéines
US10703747B2 (en) 2016-10-24 2020-07-07 The Board of Directors of the University of Illinois Benzothiophene-based selective mixed estrogen receptor downregulators
EP3858835A1 (fr) 2016-07-01 2021-08-04 G1 Therapeutics, Inc. Agents antiprolifératifs à base de pyrimidine
WO2024030968A1 (fr) 2022-08-03 2024-02-08 Brystol-Myers Squibb Company Composés pour moduler la protéine ret

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996005824A1 (fr) * 1994-08-22 1996-02-29 Eli Lilly And Company Procedes enrayant la degenerescence des protheses osseuses
EP0802184A1 (fr) * 1996-04-19 1997-10-22 American Home Products Corporation N-Benzyl-2-phénylindoles comme agents estrogènes
EP0802183A1 (fr) * 1996-04-19 1997-10-22 American Home Products Corporation Composés oestrogènes
US5880137A (en) * 1996-04-19 1999-03-09 American Home Products Corporation 2-phenyl-1- 4-(amino-1-yl-alk-1-ynyl)-benzyl!-1H-indol-5-ols as estrogenic agents
WO1999059969A1 (fr) * 1998-05-15 1999-11-25 American Home Products Corporation Compositions comprenant des composes a base de 2-phenyl-indole et de formulations d'oestrogenes
WO1999059581A1 (fr) * 1998-05-15 1999-11-25 American Home Products Corporation 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole en combinaison avec des oestrogenes
EP1123717A2 (fr) * 2000-01-26 2001-08-16 Pfizer Products Inc. Compositions contenant des agoniste-antagonistes d' oestrogène et une statine pour le traitement de l'ostéoporose et pour diminuer la valeur du choléstérol dans le sang

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996005824A1 (fr) * 1994-08-22 1996-02-29 Eli Lilly And Company Procedes enrayant la degenerescence des protheses osseuses
EP0802184A1 (fr) * 1996-04-19 1997-10-22 American Home Products Corporation N-Benzyl-2-phénylindoles comme agents estrogènes
EP0802183A1 (fr) * 1996-04-19 1997-10-22 American Home Products Corporation Composés oestrogènes
US5880137A (en) * 1996-04-19 1999-03-09 American Home Products Corporation 2-phenyl-1- 4-(amino-1-yl-alk-1-ynyl)-benzyl!-1H-indol-5-ols as estrogenic agents
WO1999059969A1 (fr) * 1998-05-15 1999-11-25 American Home Products Corporation Compositions comprenant des composes a base de 2-phenyl-indole et de formulations d'oestrogenes
WO1999059581A1 (fr) * 1998-05-15 1999-11-25 American Home Products Corporation 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole en combinaison avec des oestrogenes
EP1123717A2 (fr) * 2000-01-26 2001-08-16 Pfizer Products Inc. Compositions contenant des agoniste-antagonistes d' oestrogène et une statine pour le traitement de l'ostéoporose et pour diminuer la valeur du choléstérol dans le sang

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE DRUGNL [Online] "TSE 424" retrieved from STN Database accession no. 2000:1286 XP002195073 & R&D FOCUS DRUG NEWS, 17 April 2000 (2000-04-17), *

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG162615A1 (en) * 2002-06-13 2010-07-29 Wyeth Corp Bazedoxifene treatment regimens
JP2005531613A (ja) * 2002-06-13 2005-10-20 ワイス バゼドキシフェン治療規則
EP1531807A4 (fr) * 2002-06-13 2007-10-31 Wyeth Corp Schemas therapeutiques du bazedoxifene
EP1531807A1 (fr) * 2002-06-13 2005-05-25 Wyeth Schemas therapeutiques du bazedoxifene
US9173866B2 (en) 2002-07-24 2015-11-03 Children's Hospital Medical Center Compositions and products containing R-equol, and methods for their making
US8668914B2 (en) 2002-07-24 2014-03-11 Brigham Young University Use of equol for treating skin diseases
US7396855B2 (en) 2002-07-24 2008-07-08 Children's Hospital Medical Center Compositions and products containing S-equol, and methods for their making
US8048913B2 (en) 2002-07-24 2011-11-01 Australian Health & Nutrition Assoc. Ltd. Compositions and products containing S-equol, and methods for their making
US9408824B2 (en) 2002-07-24 2016-08-09 Children's Hospital Medical Center Compositions and products containing S-equol, and methods for their making
US7960432B2 (en) 2002-07-24 2011-06-14 Children's Hospital Medical Center Compositions and products containing S-equol, and methods for their making
US9018247B2 (en) 2002-07-24 2015-04-28 Children's Hospital Medical Center Compositions and products containing S-equol, and methods for their making
US9408825B2 (en) 2002-10-29 2016-08-09 Brigham Young University Use of equol for treating androgen mediated diseases
US9889116B2 (en) 2002-10-29 2018-02-13 Bringham Young University Use of equol for treating androgen mediated diseases
US9089547B2 (en) 2002-10-29 2015-07-28 Brigham Young University Use of equol for treating androgen mediated diseases
US10111855B2 (en) 2002-10-29 2018-10-30 Brigham Young University Use of equol for treating androgen mediated diseases
US8450364B2 (en) 2002-10-29 2013-05-28 Brigham Young University Use of equol for treating androgen mediated diseases
US8153684B2 (en) 2002-10-29 2012-04-10 Colorado State University Research Foundation Use of equol for treating androgen mediated diseases
US8580846B2 (en) 2002-10-29 2013-11-12 Brigham Young University Use of equol for ameliorating or preventing neuropsychiatric and neurodegenerative diseases or disorders
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US10512695B2 (en) 2010-03-29 2019-12-24 Ferring B.V. Fast dissolving pharmaceutical composition
US10023335B2 (en) 2010-03-29 2018-07-17 Ferring B.V. Fast dissolving pharmaceutical composition
US10086078B2 (en) 2010-03-29 2018-10-02 Ferring B.V. Fast dissolving pharmaceutical composition
US11229630B2 (en) 2015-10-01 2022-01-25 Olema Pharmaceuticals, Inc. Tetrahydro-1H-pyrido [3,4-b]indole anti-estrogenic drugs
US10624878B2 (en) 2015-10-01 2020-04-21 Olema Pharmaceuticals, Inc. Tetrahydro-1H-pyrido [3,4-b]indole anti-estrogenic drugs
US10292971B2 (en) 2015-10-01 2019-05-21 Olema Pharmaceuticals, Inc. Tetrahydro-1H-pyrido[3,4-b]indole anti-estrogenic drugs
EP3912680A1 (fr) 2015-10-01 2021-11-24 Olema Pharmaceuticals, Inc. Médicaments anti- estrogéniques tétrahydro-1h-pyrido[3,4-b]indole
WO2017059139A1 (fr) 2015-10-01 2017-04-06 Olema Pharmaceuticals, Inc. Médicaments anti-œstrogéniques de type tétrahydro-1h-pyrido[3,4-b]indole
US11672785B2 (en) 2015-10-01 2023-06-13 Olema Pharmaceuticals, Inc. Tetrahydro-1H-pyrido [3,4-b]indole anti-estrogenic drugs
US11447461B2 (en) 2015-12-09 2022-09-20 The Board Of Trustees Of The University Of Illinois Benzothiophene-based selective estrogen receptor downregulators
US10118910B2 (en) 2015-12-09 2018-11-06 The Board Of Trustees Of The University Of Illinois Benzothiophene-based selective estrogen receptor downregulators
US11072595B2 (en) 2015-12-09 2021-07-27 The Board of Trustees of lhe University of Illinois Benzothiophene-based selective estrogen receptor downregulator compounds
US10377735B2 (en) 2015-12-09 2019-08-13 The Board Of Trustees Of The University Of Illinois Benzothiophene-based selective estrogen receptor downregulators
WO2017100712A1 (fr) 2015-12-09 2017-06-15 The Board Of Trustees Of The University Of Illinois Répresseurs du récepteur oestrogénique sélectifs à base de benzothiophène
WO2017100715A1 (fr) 2015-12-09 2017-06-15 The Board Of Trustees Of The University Of Illinois Composés régulateurs à la baisse des récepteurs des œstrogènes sélectifs à base de benzothiophène
US10807964B2 (en) 2015-12-09 2020-10-20 The Board Of Trustees Of The University Of Illinois Benzothiophene-based selective estrogen receptor downregulators
WO2017197055A1 (fr) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Dégronimères hétérocycliques pour la dégradation de protéines cibles
WO2017197046A1 (fr) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Dégronimères de type glutarimide liés au carbone c3 pour la dégradation de protéines cibles
WO2017197036A1 (fr) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Dégronimères spirocycliques pour la dégradation de protéines cibles
EP3858835A1 (fr) 2016-07-01 2021-08-04 G1 Therapeutics, Inc. Agents antiprolifératifs à base de pyrimidine
US10703747B2 (en) 2016-10-24 2020-07-07 The Board of Directors of the University of Illinois Benzothiophene-based selective mixed estrogen receptor downregulators
WO2018129387A1 (fr) 2017-01-06 2018-07-12 G1 Therapeutics, Inc. Polythérapie pour le traitement du cancer
US11364222B2 (en) 2017-01-06 2022-06-21 G1 Therapeutics, Inc. Combination therapy for treatment of cancer
US10981887B2 (en) 2017-02-10 2021-04-20 G1 Therapeutics, Inc. Benzothiophene estrogen receptor modulators
US10633362B2 (en) 2017-02-10 2020-04-28 G1 Therapeutics, Inc. Benzothiophene estrogen receptor modulators
US10208011B2 (en) 2017-02-10 2019-02-19 G1 Therapeutics, Inc. Benzothiophene estrogen receptor modulators
WO2019006393A1 (fr) 2017-06-29 2019-01-03 G1 Therapeutics, Inc. Formes morphiques de git38 et leurs procédés de fabrication
WO2020132561A1 (fr) 2018-12-20 2020-06-25 C4 Therapeutics, Inc. Dégradation ciblée de protéines
WO2024030968A1 (fr) 2022-08-03 2024-02-08 Brystol-Myers Squibb Company Composés pour moduler la protéine ret

Also Published As

Publication number Publication date
AU2001271784A1 (en) 2002-01-21
WO2002003992A3 (fr) 2002-06-27

Similar Documents

Publication Publication Date Title
WO2002003992A2 (fr) Therapie pour degenerescence osseuse en rapport avec une prothese
US20020031548A1 (en) Pharmaceutical compositions of estrogenic agents
AU2001271741A1 (en) Pharmaceutical compositions of estrogenic agents
EP1299093A2 (fr) Combinaisons de bisphosphonates, de substances a action oestrogenique et eventuellement d'oestrogenes
US6358991B2 (en) Methods of treating neuropeptide Y-related conditions
WO2002003977A2 (fr) Combinaisons de statines, d'agents oestrogeniques et eventuellement d'oestrogenes
EP1311293A2 (fr) Combinaisons d'inhibiteurs specifiques de recaptage de la serotonine et d'agents oestrogeniques
WO2002003989A2 (fr) Therapie permettant d'inhiber l'incontinence du sphincter
US20020028805A1 (en) Methods of inhibiting uterotrophic effects of estrogenic agents
US20020016318A1 (en) Methods of treating breast disorders
US6509332B2 (en) Methods of treating excessive intraocular pressure
WO2002003991A2 (fr) Methodes permettant d'accroitre l'activite d'oxyde nitrique- synthase
US6455568B2 (en) Combination therapy for inhibiting sphincter incontinence
US6369051B1 (en) Combinations of SSRI and estrogenic agents
US6635660B2 (en) Methods of inhibiting sphincter incontinence
US20020028800A1 (en) Combination therapy for prosthesis-related bone degeneration
US20020025952A1 (en) Combinations of statins, estrogens and estrogenic agents
US20020028792A1 (en) Combinations of bisphosphonates, estrogens and estrogenic agents
US6465454B2 (en) Combinations of statins and estrogenic agents
US20020022613A1 (en) Methods of treating prosthesis-related bone degeneration
US20020019373A1 (en) Combinations of bisphosphonates and estrogenic agents
EP1656938A1 (fr) Combinaisons d'inhibiteurs spécifiques du recaptage de la sérotonine avec des agents oestrogéniques

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

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 PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW 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 TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

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)
AK Designated states

Kind code of ref document: A3

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 PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW 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 TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP