EP1299093A2 - Combinations of bisphosphonates, estrogenic agents and optionally estrogens - Google Patents

Combinations of bisphosphonates, estrogenic agents and optionally estrogens

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Publication number
EP1299093A2
EP1299093A2 EP01952365A EP01952365A EP1299093A2 EP 1299093 A2 EP1299093 A2 EP 1299093A2 EP 01952365 A EP01952365 A EP 01952365A EP 01952365 A EP01952365 A EP 01952365A EP 1299093 A2 EP1299093 A2 EP 1299093A2
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EP
European Patent Office
Prior art keywords
alkyl
pharmaceutically acceptable
acceptable salt
phenyl
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP01952365A
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German (de)
French (fr)
Inventor
Simon Nicholas Jenkins
Barry Samuel Komm
Christopher Paul Miller
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Wyeth LLC
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Wyeth LLC
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Publication of EP1299093A2 publication Critical patent/EP1299093A2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—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
    • A61K31/44—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
    • A61K31/55—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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61P35/00—Antineoplastic agents

Definitions

  • 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, preventing, alleviating or inhibiting bone disorders, including osteoporosis or Paget's disease in a mammal, preferably in a human, the methods comprising administering to a mammal in need thereof a pharmaceutically effective combination of:
  • a pharmaceutically effective amount of a bisphosphonate compound such as, but not limited to, Alendronate, Risedronate, Tiludronate, Ibandronate,
  • R x is selected from H, OH or the C1- 2 esters (straight chain or branched) or C,-C 12 (straight chain or branched or cyclic) alkyl ethers thereof, benzyloxy, or halogens; or C C 4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether.
  • R 2 , R 3 , R 5 , and R 6 are independently selected from H, OH or the -C12 esters
  • R 4 is selected from H, OH or the C1-C12 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, C ⁇ -C6 alkyl, cyano, nitro, trifluoromethyl, halogen; n is 1, 2 or 3; Y is selected from: a) the moiety:
  • R 7 and Rs are independently selected from the group of H, C 1 -C6 alkyl, or phenyl optionally substituted by CN, C1-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 ⁇ -C4alkoxy, trihalomethoxy, Ci-
  • 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, Ci-G-tacyloxy, C ⁇ -C4alkylthio,
  • a six-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, C ⁇ -C4alkoxy, trihalomethoxy, C ⁇ -C4acyloxy, C ⁇ -C4alkylthio, C ⁇ -C 4 alkylsulfinyl, C ⁇ -C 4 alkylsulfonyl, hydroxy(C ⁇ -C )alkyl, -CO 2 H, -CN, -CONHR., -NH 2 , C ⁇ -C 4 alkylamino, di(C ⁇ -C 4 )alky
  • R 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 -C 12 esters or alkyl ethers thereof, halogen, cyano, Ci-C ⁇ alkyl, or trihalomethyl, preferably trifluoromethyl, with the proviso that, when Ri is H, R2 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, 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, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 alkylthio, -C4 alkylsulfinyl, -C4 alkylsulfonyl, hydroxy(C ⁇ -C 4 )alkyl, -CO 2 H, -CN, -CONH(C ⁇ -C 4 )alkyl, -NH 2 , C ⁇ -C 4 alkylamino, di-(C ⁇ -C4)alkylamino, -NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C )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.
  • substituted indole compounds of the present invention are those having the structural formulas I or II, above, wherein Ri is OH; R2 - Re are as defined above; X is selected from the group of CI, NO2, CN, CF3, or CH3; and Y is the moiety
  • R 8 and R7 and Rs are concatenated together as -(CH2)r.
  • 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, C1-C4 alkoxy, trihalomethoxy, Ci-G-talkylthio, C ⁇ -C4alkylsulfinyl, C ⁇ -C4alkylsulfonyl, hydroxy (C ⁇ -C 4 )alkyl, -CO 2 H, -CN, -CONH(C ⁇ -C 4 )alkyl, -NH 2 , C ⁇ -C4alkylamino, di-(C ⁇ - C 4 )alkylamino, -NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C 4 )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-C 3 alkyl, trifluoromethyl, halogen, hydrogen, phenyl, nitro, -CN.
  • the invention includes sulfate, sulfamates and sulfate esters of phenolic groups of the substituted indoles. 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 amino 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 the substituted indole 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 present invention includes methods for strengthening bone and for inhibiting, alleviating, preventing or treating bone disorders including Paget's disease, osteoporosis, including steroid-induced osteoporosis and post-menopausal osteoporosis, tumor-induced hypercalcemia and malignant osteolytic bone disease, bone degradation due to metastases from cancers, such as breast and prostate cancer, and bone destruction characteristic of multiple myeloma, disorders of bone remodeling, tumor induced hypercalcemia, and malignant osteolytic bone disease.
  • the administration of the regimens of this invention may also be used in methods for reducing the fracture risk and occurrence in a recipient.
  • These methods each comprise administering to a mammal in need thereof a bisphosphonate and a pharmaceutically effective amount of one of the substituted indoles taught herein and optionally a pharmaceutically effective amount of one or more estrogens. These administrations may be therapeutic or prophylactic.
  • 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-Hydroxy-phenyl)-3-methyl-l-(4-(2-piperidin-l-yl- ethoxy)-benzyl]-lH-indol-5-ol, also known as ERA-923.
  • the present invention includes methods utilizing, in conjunction with a bisphosphonate compound and, optionally, an estrogen, a first subset or subgroup of substituted indole compounds of the formulas III or IN, below:
  • variable substituents including R, R 2 , R-, R 4 , R 5 , R 6 , n, X, and Y are as defined above, or a pharmaceutically acceptable salt thereof.
  • Rj 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 -C12 esters or alkyl ethers thereof, halogen, cyano, 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 2 esters or alkyl ethers thereof, benzyloxy, halogen, cyano, C ⁇ -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, Ci-Cg 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, C ⁇ -C 4 alkylsulfinyl, C ⁇ -C4alkylsulfonyl, hydroxy(C ⁇ -C )alkyl, -CO 2 H, -CN, -CONH(C ⁇ -C 4 )alkyl, -NH 2 , C ⁇ -C 4 alkylamino, diC ⁇ -C 4 alkylamino, -NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C 4 )alky
  • the rings formed by a concatenated R7 and R$, mentioned above, may include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneamine or heptamethyleneamine rings.
  • substituted indole compounds of this first subset of compounds are those having the structural formulas I or II, above, wherein Ri is OH; R2 - R ⁇ are as defined above; X is selected from the group of CI, NO2, CN, CF3, or CH3; and Y is the moiety
  • R 8 and R7 and R_ are concatenated together as -(CH2)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, C1-C4 alkoxy, 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 ⁇ -C4)alkyl and -NO 2 ; and the pharmaceutically acceptable salts thereof
  • this first subset of compounds when R7 and Rs are concatenated together as -(CH2)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 -Chalky!, trifluoromethyl, halogen, hydrogen, phenyl, nitro, -CN.
  • substituents selected from a group containing -Chalky!, trifluoromethyl, halogen, hydrogen, phenyl, nitro, -CN.
  • 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 substituted indole compounds useful with this invention includes those of formulas (N) or (NI), below:
  • variable substituents including Rphenol 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 substituted indole compounds useful with the present invention include those of the formulae Nil and NDI:
  • n 1, 2 or 3 and the variable substituents including R réelle 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 compounds of this third subset or subgroup of substituted indole compounds can be produced by the methods described in U.S. Patent No. 5,880,137 (Miller et al.), which is incorporated herein by reference, or by other methods known in the art.
  • Ri is selected from H, OH or the C1-C12 esters or alkyl ethers thereof, halogen;
  • R 2 , R 3 , R , R 5 , and R 6 are independently selected from H, OH or the C1-C 2 esters or alkyl ethers thereof, halogen, cyano, Cj-C ⁇ alkyl, or trihalomethyl, preferably trifluoromethyl, with the proviso that, when Ri is H, R2 is not OH;
  • X is selected from H, C ⁇ -C alkyl, cyano, nitro, trifluoromethyl, halogen;
  • Y is the moiety
  • the rings formed by a concatenated R7 and R_, mentioned above, may include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneamine or heptamethyleneamine rings.
  • substituted indole compounds of the present invention are those having the structural formulas I through VIII, above, wherein Ri is OH; R 2 - Re are as defined above; X is selected from the group of CI, NO2, CN, CF3, or CH3; and
  • Y is the moiety
  • R 8 and R7 and R_ are concatenated together as -(CH2) .
  • 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, C1-C4 alkoxy, trihalomethoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C ⁇ -C 4 )alkyl, -CO 2 H, -CN, -CONH(C ⁇ -C 4 )alkyl, -NH 2 , C1-C4 alkylamino, di(C ⁇ - C 4 )alkylamino, -NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C 4 )alkyl, and -NO 2 ; and the pharmaceutically acceptable salt
  • the invention includes sulfate, sulfamates and sulfate esters of phenolic groups.
  • 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 amino 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 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.
  • 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 ⁇ -dihydroequilin, 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)J-dien-17-one 3-sodium sulf
  • 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 b) a bisphosphonate compound selected from the group of , Alendronate,
  • the dosage, regimen and mode of administration of these compounds will vary according to the extent of 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 bisphosphonates and substituted indole 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
  • 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- 5-ol, also known as ERA-923, or a pharmaceutically acceptable salt form thereof
  • 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.
  • 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, micro
  • 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.
  • the pharmaceutically effective doses for the bisphosphonates and substituted indoles and the estrogens when used herein will be understood to be those sufficient to provide a desirable diminution in the risk or prevalence of the bone disease or disorder in question.
  • the compounds will be administered at a dose effective to maintain or increase bone mass density in the recipient, as directed by a medical professional.
  • the bisphosphonate compounds of these methods may be administered in regimens and at dosages known in the art.
  • alendronate sodium which is sold by Merck & Co., Inc. under the Fosamax ® name, has a recommended dosage of
  • Tiludronate sodium marketed by Sanofi Pharmaceuticals under the Skelid ® brandname, may be taken as a single 400 mg daily oral dose.
  • Etidronate sodium offered by MGI Pharma,
  • 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), CENESTINTM (synthetic conjugated estrogens), ALORA ® (estradiol transdermal system), ESTINYL ® (ethynil estradiol), and the VIVELLE ® 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 ® estropipat
  • 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 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. For shorter term bisphosphonate administrations, such as the infusion of etidronate sodium, an initial regimen of the substituted indole compound may be preferred, which may continue through the term of bisphosphonate administration and beyond.
  • the joint administration of the three groups of compounds in the methods of this invention will likewise be determined by a medical professional based upon the condition of the recipient and the malady for which the prophylaxis or treatment is provided.
  • prophylaxis such as the combination of one of the substituted indoles herein and alendronate and one or more estrogens
  • administration of all compounds of the regimen may begin simultaneously or one may be introduced into an ongoing regimen of the other.
  • bisphosphonate administrations such as the infusion of etidronate sodium
  • an initial regimen of the substituted indole compound and one or more estrogens may be preferred, which may continue through the term of bisphosphonate administration and beyond.
  • the pharmaceutical compositions of the methods herein are supplied in unit dosage form, e.g. as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • the substituted indole compound(s) and bisphosphonate(s), and estrogens when utilised, of the present formulations may be administered in separate dosage units, such as separate pills, tablets, powders, etc., or combined into one formulation.
  • optimum dosages for the indole compounds and the bisphosphonates of these formulations have been determined, it may preferable to incorporate both into a single formulation for ease of administration.
  • the formulations herein may or may not include other pharmaceutically active components.
  • This invention also includes kits or packages of pharmaceutical formulations designed for use in the regimens and methods described herein.
  • 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. It is most preferable that 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.
  • 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 a bisphosphonate selected Alendronate, Risedronate, Tiludronate, Ibandronate, Etidronate, Clodronate, Minodronate, Pamidronate, Zoledronate, Incadronate, Olpadronate or Neridronate, or a pharmaceutically acceptable salt thereof and one orally administerable formulation for 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-l-(4-(2-pi ⁇ eridin-l-yl-ethoxy)-benzyl]-lH-indol-5-ol or a pharmaceutically acceptable salt
  • 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.
  • 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.
  • 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%.
  • Some components may have multiple functions in the formulations of this invention, acting e.g. as both a filler and a disintegrant, such a component may be referred to as a filler disintegrant and its function in a specific formulation may be singular even though its properties may allow multiple functionality.
  • 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 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.
  • this invention further provides a product comprising a compound of formula I or II as defined above or a pharmaceutically acceptable salt thereof and a bisphosphonate or a pharmaceutically acceptable salt thereof, and optionally one or more estrogens, or a pharmaceutically acceptable salt thereof for administration as a combined preparation for simultaneous, separate or sequential use in treatment of bone disorders in a mammal.
  • This invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or II as defined above or a pharmaceutically acceptable salt thereof, and a bisphosphonate or a pharmaceutically acceptable salt thereof and optionally one or more estrogens, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Example 1. TSE-424 Acetate -Rapid Dissolution Formulations
  • 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.
  • a Amount in formula is adjusted for actual potency of TSE-424 as free base. Corresponding adjustment made with Lactose. b Used in process but does not appear in the final product.
  • 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 mg of film coat applied/tablet

Abstract

This invention comprises methods of treating bone disorders and lowering blood LDL levels comprising administration of a bisphosphonate, and compound of the formula (I) or (II), wherein Z is a moiety selected from the group of (a), (b), or (c); wherein: R1 is selected from H, OH or the C1-C12 alkyl ethers thereof, benzyloxy, or halogen; or C1-C4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether; R2, R3, R4, R5, and R6 are H, OH or C1-C12 esters or C1-C12 alkyl ethers thereof, halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl, or trifluoromethyl, with the proviso that, when R1 is H, R2 is not OH; Y is the moiety (1); R7 and R8 are alkyl or concatenated together to form an optionally substituted, nitrogen-containing ring; or a pharmaceutically acceptable salt thereof, and optionally an estrogen.

Description

COMBINATIONS OF BISPHOSPHONATES. ESTROGENIC AGENTS AND
OPTIONALLY ESTROGENS
This invention relates to methods of using substituted indole compounds in the combination with a bisphosphonate and optionally one or more estrogens for strengthening of bone and the treatment, prevention, inhibition or alleviation of bone disorders, including osteoporosis and Paget's disease, and related pharmaceutical compositions and kits.
Background of the Invention
EP 0 802 183 A 1 and U.S. Patent No. 5,780,497 describe substituted indole
as well as their use as 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.
EP 0 802 184 Al, published October 22, 1997, describes comparable uses for substituted indole compounds of the formulae below.
Analogous indole compounds having the general structures:
are described in U.S. Patent No. 5,880,137 (Miller et al.).
Filipponi P et al: Cyclical clodronate is effective in preventing post- menopausal bone loss: A comparative study with transcutaneous hormone replacement therapy. J Bone Min Res 10:697-703, 1995.
Description of the Invention
This invention comprises methods of treating, preventing, alleviating or inhibiting bone disorders, including osteoporosis or Paget's disease in a mammal, preferably in a human, the methods comprising administering to a mammal in need thereof a pharmaceutically effective combination of:
i) a pharmaceutically effective amount of a bisphosphonate compound, such as, but not limited to, Alendronate, Risedronate, Tiludronate, Ibandronate,
Etidronate, Clodronate, Minodronate, Pamidronate, Zoledronate, Incadronate, Olpadronate or Neridronate, or a pharmaceutically acceptable salt of these bisphosphonate compounds;
and ii) a pharmaceutically effective amount of a substituted indole compound of the formulae I or π, below:
I II wherein Z is a moiety selected from the group of:
or -(CH2)n Y
wherein:
Rx is selected from H, OH or the C1- 2 esters (straight chain or branched) or C,-C12 (straight chain or branched or cyclic) alkyl ethers thereof, benzyloxy, or halogens; or C C4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether.
R2, R3, R5, and R6 are independently selected from H, OH or the -C12 esters
(straight chain or branched) or Cj-C.., alkyl ethers (straight chain or branched or cyclic) thereof, halogens, or C.-C4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether, cyano, C1-C6 alkyl (straight chain or branched), or trifluoromethyl, with the proviso that, when Ri is H, R2 is not OH;
R4 is selected from H, OH or the C1-C12 esters (straight chain or branched) or C,-C12 alkyl ethers (straight chain or branched or cyclic) thereof, benzyloxy, halogens, or C,-C4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether, cyano, Ci-Cβ alkyl (straight chain or branched), or trifluoromethyl;
X is selected from H, Cχ-C6 alkyl, cyano, nitro, trifluoromethyl, halogen; n is 1, 2 or 3; Y is selected from: a) the moiety:
-A \ 7
R8 wherein R7 and Rs are independently selected from the group of H, C1-C6 alkyl, or phenyl optionally substituted by CN, C1-C6 alkyl (straight chain or branched), Ci-Cβ alkoxy (straight chain or branched), halogen, -OH, -CF3, or -OCF3; or R7 and R8 are combined by -(CH2)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, Cι-C4alkyl, trihalomethyl, Cι-C4alkoxy, trihalomethoxy, Ci-
C4alkylthio, Cι-C4alkylsulfinyl, C -C4alkylsulfonyl, hydroxy(Cι-C4)alkyl, -CO2H, -CN, -CONH(Cι-C4)alkyl, -NH2, Cι-C4alkylamino, di-(Cι- C4)alkylamino, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C4)alkyl and -NO2;
b) a five-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of -O-, -NH-, -N(Cι_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, Ci-G-tacyloxy, Cι-C4alkylthio,
C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy(Cι-C4)alkyl, -CO2H-, -CN-, -CONHR., -NH2, Cι-C4alkylamino, di(Cι-C4)alkylamino, -NHSO2R„ -NHCOR,, -CONH(Cι-C4)alkyl, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C4)alkyl, -NO2, and phenyl optionally substituted with 1-3 (Cι-C4)alkyl;
c) a six-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of -O-, -NH-, -N(Cι_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, Cι-C4alkoxy, trihalomethoxy, Cι-C4acyloxy, Cι-C4alkylthio, Cι-C4alkylsulfinyl, Cι-C4alkylsulfonyl, hydroxy(Cι-C )alkyl, -CO2H, -CN, -CONHR., -NH2, Cι-C4alkylamino, di(Cι-C4)alkylamino, -NHSO2R,, -NHCOR,, -CONH(Cι-C4)alkyl, -NHSO2(Cι~C4)alkyl, -NHCO(Cι-C )alkyl, -NO2, and phenyl optionally substituted with 1-3 (Cι-C4)alkyl; d) a seven-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of -O-, -NH-, -N(Cι_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, C1-C4 alkyl, trihalomethyl, Cι-C4alkoxy, trihalomethoxy, Cι-C4acyloxy, Cι~C4alkylthio, Cι-C4alkylsulfinyl, Cι-C alkylsulfonyl, hydroxy(Cι-C )alkyl, -CO2H, -CN, -CONHR,, -NH2, Cι-C4alkylamino, di(Cι-C4)alkylamino, -NHSO2R„ -NHCOR,, -CONH(Cι-C4)alkyl, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C4)alkyl,
-NO2, and phenyl optionally substituted with 1-3 (Cι-C4)alkyl; or
e) 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(Cι_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, Cι-C4alkoxy, trihalomethoxy, Cι-C4acyloxy, Cι-C4alkylthio, Cι-C4alkylsulfinyl, Cι-C4alkylsulfonyl, hydroxy(Cι-C4)alkyl, -CO2H-, -CN, -CONHR,, -NH2, Cι-C4alkylamino, di(Cι-C4)alkylamino, -NHSO2R,,
-NHCOR,, -CONH(Cι-C4)alkyl, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C4)alkyl, -NO2, and phenyl optionally substituted with 1-3 (C1-C4) alkyl; and the pharmaceutically acceptable salts thereof; and, optionally iii) a pharmaceutically effective amount of one or more estrogens, or a pharmaceutically acceptable salt thereof.
The more preferred substituted indole compounds of this invention are those having the general structures I or II, above, wherein: R] is selected from H, OH or the C1-C12 esters or alkyl ethers thereof, benzyloxy, or halogen;
R2, R3, R5, and R6 are independently selected from H, OH or the -C 12 esters or alkyl ethers thereof, halogen, cyano, Ci-Cβ alkyl, or trihalomethyl, preferably trifluoromethyl, with the proviso that, when Ri is H, R2 is not OH; R is selected from H, OH or the C1-C12 esters or alkyl ethers thereof, benzyloxy, halogen, cyano, Ci-Cβ alkyl, or trihalomethyl; X is selected from H, Ci-Cό alkyl, cyano, nitro, trifluoromethyl, halogen; Y is the moiety
\
R8 ;
R7 and R8 are selected independently from H, C1-C6 alkyl, or combined by -(CH2)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, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 alkylthio, -C4 alkylsulfinyl, -C4 alkylsulfonyl, hydroxy(Cι-C4)alkyl, -CO2H, -CN, -CONH(Cι-C4)alkyl, -NH2, Cι-C4alkylamino, di-(Cι-C4)alkylamino, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C )alkyl, and -NO2; and the pharmaceutically acceptable salts thereof.
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 substituted indole compounds of the present invention are those having the structural formulas I or II, above, wherein Ri is OH; R2 - Re are as defined above; X is selected from the group of CI, NO2, CN, CF3, or CH3; and Y is the moiety
-A \
R8 and R7 and Rs are concatenated together as -(CH2)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, C1-C4 alkoxy, trihalomethoxy, Ci-G-talkylthio, Cι-C4alkylsulfinyl, Cι-C4alkylsulfonyl, hydroxy (Cι-C4)alkyl, -CO2H, -CN, -CONH(Cι-C4)alkyl, -NH2, Cι-C4alkylamino, di-(Cι- C4)alkylamino, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C4)alkyl, and -NO2; and the pharmaceutically acceptable salts thereof.
In another embodiment of this invention, when R7 and Rs are concatenated together as -(CH2)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 of the substituted indoles. 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 amino 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. Additionally, 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 the substituted indole 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. It is known that compounds possessing a basic nitrogen can be complexed with many different acids (both protic and non-protic) and usually it is preferred to administer a compound of this invention in the form of an acid addition salt. Additionally, 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 present invention includes methods for strengthening bone and for inhibiting, alleviating, preventing or treating bone disorders including Paget's disease, osteoporosis, including steroid-induced osteoporosis and post-menopausal osteoporosis, tumor-induced hypercalcemia and malignant osteolytic bone disease, bone degradation due to metastases from cancers, such as breast and prostate cancer, and bone destruction characteristic of multiple myeloma, disorders of bone remodeling, tumor induced hypercalcemia, and malignant osteolytic bone disease. The administration of the regimens of this invention may also be used in methods for reducing the fracture risk and occurrence in a recipient.
These methods each comprise administering to a mammal in need thereof a bisphosphonate and a pharmaceutically effective amount of one of the substituted indoles taught herein and optionally a pharmaceutically effective amount of one or more estrogens. These administrations may be therapeutic or prophylactic. Among the 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-Hydroxy-phenyl)-3-methyl-l-(4-(2-piperidin-l-yl- ethoxy)-benzyl]-lH-indol-5-ol, also known as ERA-923.
The present invention includes methods utilizing, in conjunction with a bisphosphonate compound and, optionally, an estrogen, a first subset or subgroup of substituted indole compounds of the formulas III or IN, below:
(πi) (IV) wherein the variable substituents including R,, R2, R-, R4, R5, R6, n, X, and Y are as defined above, or a pharmaceutically acceptable salt thereof.
The more preferred substituted indole compounds of this first subset of compounds are those having the general structures III or IN, above, wherein: Rj is selected from H, OH or the C1-C12 esters or alkyl ethers thereof, benzyloxy, or halogen;
R2, R3, R5, and R6 are independently selected from H, OH or the -C12 esters or alkyl ethers thereof, halogen, cyano, alkyl, or trihalomethyl, preferably trifluoromethyl, with the proviso that, when Ri is H, R2 is not OH; R4 is selected from H, OH or the -C12 esters or alkyl ethers thereof, benzyloxy, halogen, cyano, C\-C§ alkyl, or trihalomethyl; X is selected from H, Ci-Cβ alkyl, cyano, nitro, trifluoromethyl, halogen;
Y is the moiety
\ / R7
\
R8 ;
R7 and R8 are selected independently from H, Ci-Cg alkyl, or combined by -(CH2)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, Cι-C4alkyl, trihalomethyl, Cι-C4alkoxy, trihalomethoxy, C\- C4alkylthio, Cι-C4alkylsulfinyl, Cι-C4alkylsulfonyl, hydroxy(Cι-C )alkyl, -CO2H, -CN, -CONH(Cι-C4)alkyl, -NH2, Cι-C4alkylamino, diCι-C4alkylamino, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C4)alkyl, and -NO2; and the pharmaceutically acceptable salts thereof.
The rings formed by a concatenated R7 and R$, mentioned above, may include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneamine or heptamethyleneamine rings.
The most preferred substituted indole compounds of this first subset of compounds are those having the structural formulas I or II, above, wherein Ri is OH; R2 - Rό are as defined above; X is selected from the group of CI, NO2, CN, CF3, or CH3; and Y is the moiety
\ /R7 \
R8 and R7 and R_ are concatenated together as -(CH2)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, C1-C4 alkoxy, trihalomethoxy, Cι-C4alkylthio, Cι-C4alkylsulfinyl, Cι-C4alkylsulfonyl, hydroxy(Cι-C4)alkyl, -CO2H, -CN, -CONH(Cι-C4)alkyl, -NH2, Cι-C4alkylamino, di(Cι-C4)alkylamino, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C4)alkyl and -NO2; and the pharmaceutically acceptable salts thereof.
In another embodiment of this first subset of compounds, when R7 and Rs are concatenated together as -(CH2)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 -Chalky!, trifluoromethyl, halogen, hydrogen, phenyl, nitro, -CN. Among the preferred compounds of this first subset of substituted indoles are the following:
5~Benzyloxy-2-(4-ethoxy-phenyl)-3-methyl-l-[4-(2-piperidin-l-yl-ethoxy)- benzyl]- lH-indole;
5-Benzyloxy-2-phenyl-3-methyl- 1 -[4-(2-azepan- 1 -yl-ethoxy)-benzyl]- 1 H- indole;
5-Benzyloxy-2-(4-benzyloxy-phenyl) ■3-methyl- 1 -[4-(2-azepan- 1 -yl-ethoxy)- benzyl] - 1 H-indole ; 5-Benzyloxy-2-(4-benzyloxy-phenyl) •3 -methyl- 1 - [4-(2-diisopropylamino- 1 - yl-ethoxy)-benzyl] - 1 H-indole ;
5-Benzyloxy-2-(4-benzyloxy-phenyl) -3-methyl- 1 -[4-(2-butyl-methylamino- 1 - ylethoxy)-benzyl]- lH-indole;
5-Benzyloxy-2-(4-benzyloxy-phenyl) •3-methyl- 1 - { 4-dimethylamino)ethoxy]- benzyl }-lH-indole;
5-Benzyloxy-2-(4-benzyloxy-phenyl) -3 -methyl- 1 - { 4- [2-(2-methyl-piperidin- 1 -y l)-ethoxy] -benzyl } - 1 H-indole ;
5-Benzyloxy-2-(4-benzyloxy-phenyl) -3-methyl- 1 - { 4- [2-(3 -methyl-piperidin- 1 -yl)-ethoxy]-benzyl } - 1 H-indole; 5-Benzyloxy-2-(4-benzyloxy-phenyl) -3-methyl- 1 - { 4-[2-(4-methyl-piperidin-
1 -yl)-ethoxy] -benzyl } - 1 H-indole ;
5-Benzyloxy-2-(4-benzyloxy-phenyl) •3-methyl- 1 {4-[2-((cis)-2,6-Dimethyl- piperidin- 1 -yl)-ethoxy]-benzyl } - 1 H-indole;
5-Benzyloxy-2-(4-benzyloxy-phenyl) ■3-methyl-{4-[2-(l,3,3-trimethyl-6-aza- bicyclo[3.2. l]oct-6-yl)-ethoxy]-benzyl } - lH-indole;
( 1 S ,4R)-5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl { 4- [2-(2-Aza-bicyclo [2.2.1] hept-2-yl)-ethoxy]-benzyl } - lH-indole;
5-Benzyloxy-2-(4-fluoro-phenyl)-3-methyl- 1 - [4-(2-azepan- 1 -yl-ethoxy)- benzyl] -lH-indole; 5-Benzyloxy-2-(4-fluoro-phenyl)-3-methyl- 1 - [4-(2-piperidin- 1 -yl-ethoxy)- benzyl] - 1 H-indole;
5-Benzyloxy-2-(4-chloro-phenyl)-3-methyl- 1 - [4-(2-piperidin- 1 -yl-ethoxy)- benzyl]-lH-indole; 5-B enzyloxy-2- [3 ,4-methylenedioxy-phenyl]-3 -methyl- 1 - [4-(2-piperidin- 1 -y 1- ethoxy)-benzyl] - 1 H-indole ;
5-Benzyloxy-2-[4-isopropoxy-phenyl]-3-methyl-l-[4-(2-piperidin-l-yl- ethoxy)-benzyl]- lH-indole; 5-Benzyloxy-2-[4-methyl-phenyl]-3-methyl-l-[4-(2-piperidin-l-yl-ethoxy)- benzyl]- 1 H-indole; l-[4-(2-Azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-benzyloxy-phenyl)-3- methyl- lH-indole;
5-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-l-[4-(2-piperidin-l- yl-ethoxy)-benzyl]-lH-indole;
5-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-l-[4-(2-azepan-l-yl- ethoxy)-benzyl]- lH-indole;
5-Benzyloxy-2-(3-methoxy-phenyl- 1 - [4-(2-piperidin- 1 -yl-ethoxy)-benzyl]-3- methyl- lH-indole; 5-B enzyloxy-3 -methyl- 1 -[4-(2-piperidin- 1 -yl-ethoxy)-benzyl]-2-(4-trifluoro- methoxy-phenyl)-lH-indole;
(2-{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-l-ylmethyl]- phenoxy } -ethyl)-cyclohexyl-amine ;
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl- 1 - { 4-methylpiperazin- 1 -yl)- ethoxy] -benzyl } - 1 H-indole; l-[4-(2-Azepan-l-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-methoxy-phenyl)-3- methyl- 1 H-indole;
4- { 3-Methyl- l-[4-(2-piperidin- l-yl-ethoxy)-benzyl]- lH-indole } ;
4- { 3-Methyl- 1 - [4-(2-piperidin- 1 -yl-ethoxy)-benzyl]- 1 H-indol-2-yl } -phenol ; 3-Methyl-2-phenyl- 1 -[4-(2-piperidine- 1 -yl-ethoxy)-benzyl]- 1 H-indol-5-ol;
4- { 5-Methoxy-3-methyl- l-{4-[2-(piperidin- 1 -yl)-ethoxy]-benzyl } - lH-indol-2- yl) -phenol;
2-(4-methoxy-phenyl)-3-methyl- 1 - { 4- [2-(piperidin- 1 -yl)-ethoxy]-benzyl } - 1H- indol-5-ol; 5-Methoxy-2-(4-methoxy-phenyl)-3-methyl- 1 -[4-(2-piperidin- 1 -yl-ethoxy)- benzyl] - 1 H-indole ; l-[4-(2-Azepan-l-yl-ethoxy)-benzyl]-5-methoxy-2-(4-methoxy-phenyl)-3- methy 1- 1 H-indole ; 2-(4-Ethoxy-phenyl)-3 -methyl- 1 - [4-(2-piperidin- 1 -yl-ethoxy)-benzyl] - 1 H- indol-5-ol;
1 - [4-(2- Azepan- 1 -yl-ethoxy)-benzyl] -2-(4-ethoxy-phenyl)-3 -methyl- 1 H-indol- 5-ol; 4- { 5 -Fluoro-3 -methyl- 1 - [4-(2-piperidin- 1 -yl-ethoxy )-benzyl] - 1 H-indol-2-y 1 } - phenol; l-[4-(2-Azepan-l-yl-ethoxy)-benzyl]-3-methyl-2-phenyI-lH-indol-5-ol;
2-(4-Hydroxy-phenyl)-3-methyl-l-[4-(2-pyrollidin-l-yl-ethoxy)-benzyl]-lH- indol-5-ol; 1 - [4-(2- Azepan- 1 -yl-ethoxy)-benzyl] -2-(4-hy droxy-phenyl)-3 -methyl- 1 H- indol-5-ol;
1 - [4-(2- Azepan- 1 -yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl- 1 H- indol-5-ol; l-[4-(2-Azocan-l-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-lH- indol-5-ol;
2-(4-Hydroxy-phenyl)-3-methyl- 1 -[4-(2-dimethyl- 1 -yl-ethoxy)-benzyl]- 1H- indol-5-ol;
2-(4-Hydroxy-phenyl)-3-methyl-l-[4-(2-diethyl-l-yl-ethoxy)-benzyl]-lH- indol-5-ol; l-[4-(2-Dipropylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-lH- indol-5-ol; l-[4-(2-Dibutylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-lH- indol-5-ol; l-[4-(2-Diisopropylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl- lH-indol-5-ol; l-{4-[2-(Butyl-methyl-amino)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-3- methyl-lH-indol-5-ol;
2-(4-Hydroxy-phenyl)-3-methyl-l-{4-[2-(2-methyl-piperidin-l-yl)-ethoxy]- benzyl}-1H-indol-5-ol; 2-(4-Hydroxy-phenyl)-3-methyl-l-{4-[2-(3-methyl-piperdin-l-yl)-ethoxy]- benzyl}-1H-indol-5-ol;
2-(4-Hydroxy-phenyl)-3-methyl-l-{4-[2-(4-methyl-piperidin-l-yl)-ethoxy]- benzyl}-1H-indol-5-ol; l-{4-[2-(3,3-Dimethyl-piperidin-l-yl)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)- 3 -methyl- 1 H-indol-5-ol ; l-{4-[2-((cis)-2,6-Dimethyl-piperidin-l-yl)-ethoxy]-benzyl}-2-(4-hydroxy- phenyl)-3-methyl-lH-indol-5-ol; 2-(4-Hydroxy-phenyl)- 1 - { 4-[2-(4-hydroxy-piperidin- 1 -yl)-ethoxy] -benzyl } -3- methyl- 1 H-indol-5-ol ;
( 1 S,4R)- 1 - { 4-[2-(2-Aza-bicyclo [2.2.1] hept-2-yl)-ethoxy]-benzyl } -2-(4- hydroxy-phenyl)-3-methyl-lH-indol-5-ol;
2-(4-Hydroxy-phenyl)-3-methyl-l-{4-[2-(l,3,3-trimethyl-6-azabicyclo[3.2.1]- oct-6-yl)-ethoxy]-benzyl } - 1 H-indol-5-ol;
2-(4-Fluoro-phenyl)-3-methyl- 1 -[4-(2-piperidine- 1 -yl-ethoxy )-benzyl]- 1 H- indol-5-ol; l-[4-(2-Azepan-l-yl-ethoxy)-benzyl]-2-(4-fluoro-phenyl)-3-methyl-lH-indol- 5-ol; 2-(3-Methoxy-4-hydroxy-phenyl)-3-methyl-l-[4-(2-piperidin-l-yl-ethoxy)- benzyl]-lH-indol-5-ol;
2-Benzo [ 1 ,3] dioxol-5 -yl-3 -methyl- 1 - [4-(2-piperidin- 1 -yl-ethoxy)-benzyl] - 1 H- indol-5-ol;
2-(4-Isopropoxy-phenyl)-3-methyl-l-[4-(2-piperidin-l-yl-ethoxy)-benzyl]-lH- indol-5-ol; l-[4-(2-Azepan-l-yl-ethoxy)-benzyl]-2-(4-isopropoxy-phenyl)-3-methyl-lH- indol-5-ol;
2-(4-Cyclopentyloxy-phenyl)-3-methyl- 1 -[4-(2-piperidin- 1 -yl-ethoxy)- benzyl]-lH-indol-5-ol; 3-Methyl- 1 - [4-(2-piperidin- 1 -yl-ethoxy)-benzyl]-2-(4-trifluoromethylphenyl)- lH-indol-5-ol;
3-Methyl-l-[4-(2-piperidin-l-yl-ethoxy)-benzyl]-2-p-tolyl-lH-indol-5-ol;
2-(4-Chloro-phenyl)-3 -methyl- 1 - [4-(2-piperidin- 1 -yl-ethoxy)-benzyl] - 1 H- indol-5-ol; 2-(2,4-Dimethoxy-phenyl)-3-methyl- 1 - [4-(2-ρiperidin- 1 -yl-ethoxy)-benzyl]- lH-indol-5-ol;
2-(3-Hydroxy-phenyl)-3-methyl-l-[4-(2-piperidin-l-yl-ethoxy)-benzyl]-lH- indol-5-ol; l-[4-(2-Azepan-l-yl-ethoxy)-benzyl]-2-(3-hydroxy-phenyl)-3-methyl-lH- indole-5-ol;
2-(3-Fluoro-4-hydroxy-phenyl)-3-methyl-l-[4-(2-piperidin-l-yl-ethoxy)- benzyl]-lH-indol-5-ol; 2-(3 -Fluoro-4-hy droxy-phenyl)-3 -methyl- 1 - [4-(azepan- 1 -yl-ethoxy )-benzyl] - lH-indol-5-ol;
2-(3-Methoxy-phenyl)-3-methyl- 1 -[4-(2-piperidin- 1 -yl-ethoxy)-benzyl]- 1 H- indole-5-ol;
3-Methyl-l-[4-(2-piperidin-l-yl-ethoxy)-benzyl]-2-(4-trifluoromethoxy- phenyl)-lH-indole-5-ol;
3-Chloro-2-(4-hydroxy-phenyl)- 1 - [4-(2-pyrrolidin- 1 -yl-ethoxy)-benzyl]- 1 H- indol-5-ol;
3-Chloro-2-(4-hydroxy-phenyl)-l-[4-(2-piperidin-l-yl-ethoxy)-benzyl]-lH- indol-5-ol; 3 -Chloro-2-(4-hydroxy-phenyl)- 1 - [4-(2-azepan- 1 -yl-ethoxy)-benzyl] - 1 H- indol-5-ol;
3-Chloro-2-(4-hydroxy-2-methyl-phenyl)-l-[4-(2-piperidin-l-yl-ethoxy)- benzyl]-lH-indol-5-ol;
2-(4-Hydroxy-phenyl)-3-ethyl-l-[4-(2-piperidin-l-yl-ethoxy)-benzyl]-lH- indol-5-ol;
5-Hydroxy-2-(4-Hydroxy-phenyl)- 1 -[4-(2-piperidin- 1 -yl-ethoxy)-benzyl]- 1H- indole-3-carbonitrile; l-[4-(2-Azepan-l-yl-ethoxy)-benzyl]-5-hydroxy-2-(4-hydroxy-phenyl)-lH- indole-3-cabonitrile; 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-l-[4-(2-piperidin-l-yl-ethoxy)- benzyl]-lH-indole;
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-l-[4-(2-azepan-l-yl-ethoxy)- benzyl]- 1 H-indole;
5-Benzyloxy-2-(2-methyl-4-benzyloxy-phenyl)-3-chloro-l-[4-(2-piperidin-l- yl-ethoxy )-benzyl]-l H-indole;
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-ethyl- 1 - [4-(2-piperidin- 1 -yl-ethoxy)- benzyl] - 1 H-indole; 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-cyano-l-[4-(2-piperidin-l-yl-ethoxy)- benzyl] - 1 H-indole;
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-cyano-l-[4-(2-azepan-l-yl-ethoxy)- benzyl]-lH-indole; Di-propionate of 1 - [4-(2- Azepan- 1 -yl-ethoxy)-benzyl] -2-(4-hy droxy-phenyl)-
3-methyl-lH-indol-5-ol;
Di-pivalate of 1 - [4-(2- Azepan- 1 -yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3- methyl- lH-indol-5-ol;
5-Benzyloxy-2-(4-benzyloxy-phenyl)- 1 - [4-(3-piperidin- 1 -yl-propoxy)benzyl]- 3-methyl-lH-indole;
2-(4-Hy droxy-phenyl)-3 -methyl- 1 - { 4- [3 -(piperidin- 1 -yl)-propoxy] -benzyl } - lH-indol-5-ol;
2-(4-Hydroxy-phenyl)- 1 -[3-methoxy-4-(2 -piperidin- 1 -yl-ethoxy)-benzyl]~3- methyl-lH-indol-5-ol; 2-(4-Hydroxy-phenyl)-l-[3-methoxy-4-(2-azepan-l-yl-ethoxy)-benzyl]-3- methyl- lH-indol-5-ol;
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-[3-Methoxy-4-(2-piperidin- 1 -yl-ethoxy)-benzyl] - 1 H-indole ;
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl- 1 -[2-Methoxy-4-(2-azepan- 1 - yl-ethoxy)-benzyl]-lH-indole;
2-(4-Hydroxy-phenyl)-3-methyl- 1 -[4-(2-piperidin- l-yl-ethoxy)-benzyl]- 1H- indol-5-ol; or the pharmaceutically acceptable salts thereof.
The compounds of this first subset or subgroup of 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 substituted indole compounds useful with this invention includes those of formulas (N) or (NI), below:
wherein the variable substituents including R„ R2, R3, R4, R5, R6, n, X, and Y are as defined above, or a pharmaceutically acceptable salt thereof.
Among the preferred substituted indole compounds of this second subset or subgroup are the following:
(E)-Ν,Ν-Diethyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-l- ylmethyl] -phenyl } -acrylamide; l(E)-N-tert-butyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-l- ylmethyl]-phenyl}-acrylamide; (E)-Pyrollidino-3- { 4- [5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol- 1 - ylmethyl] -phenyl } -acrylamide;
(E)-N,N-Dimethyl-3- { 4- [5-hydroxy-2-(4-hydroxy-ρhenyl)-3-methyl-indol- 1 - ylmethyl]-phenyl } -acrylamide;
(E)-N,N-Dibutyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-l- ylmethyl]-phenyl} -acrylamide;
(E)-N-Butyl,N'-methyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl- indol- 1 -ylmethyl] -phenyl } -acrylamide ;
(E)-Morpholinino-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-l- ylmethyl]-phenyl } -acrylamide; (E)-3- { 4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol- 1 -ylmethyl]- phenyl } -acrylamide;
(E)-N,Methyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-l- ylmethyl]-phenyl } -acrylamide; (E)-N,N-Dibutyl-3- { 4- [5-hydroxy-2-(4-fluoro-phenyl)-3-methyl-indol- 1 - ylmethyl] -phenyl } -acrylamide;
(E)-N-Butyl,N'-Methyl-3-{4-[5-hydroxy-2-(4-fluoro-phenyl)-3-methyl-indol- 1 -ylmethyl] -phenyl } -acrylamide ; as well as the pharmaceutically acceptable salts and esters thereof.
The compounds of this second subset or subgroup of substituted indole compounds can be produced by the methods described in EP 0 802 184 Al, published October 22, 1997, which is incorporated herein by reference, or by other methods known in the art.
A third subset of substituted indole compounds useful with the present invention include those of the formulae Nil and NDI:
(Nil) (VIII) wherein n is 1, 2 or 3 and the variable substituents including R„ R2, R3, R4, R5, R6, n, X, and Y are as defined above, or a pharmaceutically acceptable salt thereof.
Among the preferred compounds of this third subset of substituted indoles are:
2-(4-Hydroxy-phenyl)-3-methyl- 1 -[4-(3-Ν,Ν-dimethyl-l -yl-prop- 1 -ynyl)- benzyl] - 1 H-indol-5 -ol ;
2-(4-Hydroxy-phenyl)-3-methyl- 1 -[4-(3-piperidin- 1 -yl-prop- 1 -ynyl)-benzyl]- lH-indol-5-ol; and 2-(4-Hydroxy-phenyl)-3-methyl-l-[4-(3-pyrrolidin-l-yl-prop-l-ynyl)-benzyl]- lH-indol-5-ol; or pharmaceutically acceptable salts or esters thereof.
The compounds of this third subset or subgroup of substituted indole compounds can be produced by the methods described in U.S. Patent No. 5,880,137 (Miller et al.), which is incorporated herein by reference, or by other methods known in the art.
Within each of the first, second and third subsets of substituted indole compounds of this invention are further subdivisions of more preferred substituted indole compounds having the general structures I through NHI, above, wherein:
Ri is selected from H, OH or the C1-C12 esters or alkyl ethers thereof, halogen; R2, R3, R , R5, and R6 are independently selected from H, OH or the C1-C 2 esters or alkyl ethers thereof, halogen, cyano, Cj-Cό alkyl, or trihalomethyl, preferably trifluoromethyl, with the proviso that, when Ri is H, R2 is not OH;
X is selected from H, C\-C alkyl, cyano, nitro, trifluoromethyl, halogen;
Y is the moiety
\ /R7 Ν
\ R8 ;
R7 and R8 are selected independently from H, Ci-Cβ alkyl, or combined by -(CH2)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, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (Cι-C4)alkyl, -CO2H, -CΝ, -COΝH(Cι-C4)alkyl, -NH2, -C4 alkylamino, diCι-C4alkylamino, -NHSO2(Cι-C4)alkyl, -NHCO(C1-C4)alkyl, and -NO2; and the pharmaceutically acceptable salts thereof.
The rings formed by a concatenated R7 and R_, mentioned above, may include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneamine or heptamethyleneamine rings.
The most preferred substituted indole compounds of the present invention are those having the structural formulas I through VIII, above, wherein Ri is OH; R2 - Re are as defined above; X is selected from the group of CI, NO2, CN, CF3, or CH3; and
Y is the moiety
\ /R7 N
\
R8 and R7 and R_ are concatenated together as -(CH2) . 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, C1-C4 alkoxy, trihalomethoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (Cι-C4)alkyl, -CO2H, -CN, -CONH(Cι-C4)alkyl, -NH2, C1-C4 alkylamino, di(Cι- C4)alkylamino, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C4)alkyl, and -NO2; and the pharmaceutically acceptable salts thereof.
In another embodiment of the substituted indoles of this invention, when R7 and Rg are concatenated together as -(CH2)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. 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 amino 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. Additionally, 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 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. It is known that compounds possessing a basic nitrogen can be complexed with many different acids (both protic and non-protic) and usually it is preferred to administer a compound of this invention in the form of an acid addition salt. Additionally, 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.
When an estrogen is used estrogens useful in the formulations of this invention include estrone, estriol, equilin, estradiene, equilenin, ethinyl estradiol, 17β-estradiol, 17α-dihydroequilenin, 17β-dihydroequilenin (U.S. Patent 2,834,712), 17α-dihydroequilin, 17β-dihydroequilin, 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. Esterified estrogens, such as those sold by Solvay Pharmaceuticals, Inc. under the Estratab® tradename, may also be used with the present formulations. Also preferred for use with the present invention are 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)J-dien-17-one 3-sodium sulfate, 5alpha-Pregnan-3beta-20R-diol 20-sodium sulfate, 5alpha-Pregnan- 3beta,16alpha-diol-20-one 3-sodium sulfate, delta(8,9)-Dehydroestrone 3-sodium sulfate, Estra-3beta, 17alpha-diol 3-sodium sulfate, 3beta-Hydroxy-estr-5(10)-en-17- one 3-sodium sulfate or 5alpha-Pregnan-3beta,16alpha,20R-triol 3-sodium sulfate. Preferred salts of estrone include, but are not limited to, the sodium and piperate salts. Among the most preferred estrogens for use with this invention are the conjugated estrogens of the Premarin® brand products.
Among the most preferred embodiments of this invention are methods combining the administration in a mammal of pharmaceutically effective amounts of: a) 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 b) a bisphosphonate compound selected from the group of , Alendronate,
Risedronate, Tiludronate, Ibandronate, Etidronate, Clodronate, Minodronate, Pamidronate, Zoledronate, Incadronate, Olpadronate or Neridronate, or a pharmaceutically effective salt of one of these bisphosphonate compounds, and optionally c) the conjugated estrogenic hormones, such as those of the Premarin® brand products marketed by Wyeth-Ayerst Laboratories.
It is understood that the dosage, regimen and mode of administration of these compounds will vary according to the extent of 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 bisphosphonates and substituted indole 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. For the purposes of this disclosure, 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).
When 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.
When 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- 5-ol, also known as ERA-923, or a pharmaceutically acceptable salt form thereof, 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.
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. 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. The pharmaceutically effective doses for the bisphosphonates and substituted indoles and the estrogens when used herein will be understood to be those sufficient to provide a desirable diminution in the risk or prevalence of the bone disease or disorder in question. Preferably the compounds will be administered at a dose effective to maintain or increase bone mass density in the recipient, as directed by a medical professional.
The bisphosphonate compounds of these methods may be administered in regimens and at dosages known in the art. For instance, alendronate sodium, which is sold by Merck & Co., Inc. under the Fosamax® name, has a recommended dosage of
10 mg per day for treatment of osteoporosis in postmenopausal women and 5 mg per day for the prevention of osteoporosis in postmenopausal women. Tiludronate sodium, marketed by Sanofi Pharmaceuticals under the Skelid® brandname, may be taken as a single 400 mg daily oral dose. Etidronate sodium, offered by MGI Pharma,
Inc. under the Didronel® name, has a recommended daily intravenous infusion dose of
7.5 mg/kg body weight/day for three successive days. Risedronate (ActonelTM; jointly marketed by Procter and Gamble Pharmaceuticals and Hoechst Marion
Roussel) has been approved by the FDA for use in Paget's disease of the bone (30-mg tablets) Risedronate was shown to be effective in clinical trials.
The estrogens herein may be administered according to the regimens and doses known in the art. For instance, 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. Other commercially available 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), MENEST™ (esterified estrogens tablets), ORTHO-EST® (estropipate tablets), CENESTIN™ (synthetic conjugated estrogens), ALORA® (estradiol transdermal system), ESTINYL® (ethynil estradiol), and the VIVELLE® and VIVELLE-DOT® (estradiol transdermal systems). Each of these commercially available estrogen products can be administered as described in their relevant portions of the Physicians' Desk Reference, 54 Edition, 2000. The following table lists estrogen replacement therapies and dosage strengths available in the United States and/or Europe
Generic Name Brand Name Strength
Oral estrogens
Conjugated equine estrogens (natural) Premarin 0.3, 0.625, 0.9, 1.25, 2.5 mg
Conjugated estrogens (synthetic) Cenestin 0.625, 0.9 mg
Esterified estrogens (75-80% estrone sulfate Estratab 0.3, 0.625, 1.25, 2.5 mg
6-15% equilin sulfate derived from plant sterols)
Estropipate (Piperazine estrone sulfate) Ogen Ortho-Est 0.625, 1.25, 2.5 mg
Micronized estradiol Estrace 0.5, 1.0, 2.0 mg
Raloxifene (selective estrogen receptor modulator) Evista 60 mg
Esterified estrogens and methylestosterone Estratest 1.25 mg esterified estrogen and 2.5 mg methylestosterone
Estratest HS 0.625 mg esterified estrogen and 1.25 mg methylestosterone
Estradiol valerate Climaval 1 mg, 2 mg
Estradiol Elleste Solo 1 mg, 2 mg
Estradiol Estrofem 2 mg
Estradiol Estrofem Forte 4 mg
Piperazine esterone sulfate Harmogen 1.5 mg
Combination: Estrone Hormonin 1.4 mg
Estradiol 0.6 mg
Estriol 0.27 mg
Estradiol valerate Progynova 1 mg, 2 mg
Estradiol Zumenon 1 mg, 2 mg
Transdermal estrogens
Estradiol Alora (twice weekly) 0.025, 0.0375, 0.05, 0.075,
Climara (weekly) 0.1 mg of estradiol released
Estraderm (2x weekly) daily (dose options for
Fem Patch (weekly) various
Vivelle (twice weekly) products)
Estradiol Dermestril
Estradiol Estraderm 25, 50, 100 μg
Estradiol Evorel (Systen) 25, 50, 100 μg
Estradiol Fematrix 25, 50, 75, 100 μg
Estradiol Menorest 40, 80 μg
Progynova TS 25, 37.5, 50, 75 μg
Estradiol And TS Forte
(Climara) 50, 100 μg
Vaginal estrogens
Conjugated equine estrogens Premarin vaginal
Dienestrol cream
Estradiol Ortho dienestrol cream 0.625 mg/g
Estropipate Estring 0.1 mg/g
Micronized estradiol Ogen vaginal cream 7.5 μg
Estrace vaginal cream 1.5 mg/g 1.0 mg g The joint administration of 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. For shorter term bisphosphonate administrations, such as the infusion of etidronate sodium, an initial regimen of the substituted indole compound may be preferred, which may continue through the term of bisphosphonate administration and beyond.
The joint administration of the three groups of compounds in the methods of this invention will likewise be determined by a medical professional based upon the condition of the recipient and the malady for which the prophylaxis or treatment is provided. For prophylaxis, such as the combination of one of the substituted indoles herein and alendronate and one or more estrogens, for prevention of osteoporosis, administration of all compounds of the regimen may begin simultaneously or one may be introduced into an ongoing regimen of the other. For shorter term bisphosphonate administrations, such as the infusion of etidronate sodium, an initial regimen of the substituted indole compound and one or more estrogens may be preferred, which may continue through the term of bisphosphonate administration and beyond.
Preferably, the pharmaceutical compositions of the methods herein are supplied in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
The substituted indole compound(s) and bisphosphonate(s), and estrogens when utilised, of the present formulations may be administered in separate dosage units, such as separate pills, tablets, powders, etc., or combined into one formulation. When optimum dosages for the indole compounds and the bisphosphonates of these formulations have been determined, it may preferable to incorporate both into a single formulation for ease of administration. It is also understood that the formulations herein may or may not include other pharmaceutically active components. This invention also includes 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. Preferably 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. It is most preferable that 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.
In a preferred embodiment, a package or kit of this invention will include individual oral dosage formulations for each of the components of the invention. For instance one daily dosage tablet of a bisphosphonate selected Alendronate, Risedronate, Tiludronate, Ibandronate, Etidronate, Clodronate, Minodronate, Pamidronate, Zoledronate, Incadronate, Olpadronate or Neridronate, or a pharmaceutically acceptable salt thereof, and one orally administerable formulation for 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-l-(4-(2-piρeridin-l-yl-ethoxy)-benzyl]-lH-indol-5-ol or a pharmaceutically acceptable salt thereof, and optionally one daily dosage Premarin® conjugated estrogen tablet, for each day of a specified regimen. It will be understood that any or each of these components may be divided in the kit or package into multiple doses to be administered over the course of each day. In another preferred embodiment, the 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.
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 lubricant comprising from about 0.2% to about 10% of the composition (wght), such as selected from the group of magnesium stearate or other metallic stearates (e.g. calcium stearate or zinc stearate), fatty acid esters (e.g. sodium stearyl fumarate), fatty acids (e.g. stearic acid), fatty alcohols, 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.
While the formulations 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.
In conjunction with or in place of the materials listed above for the filler component, the present formulations utilize disintegrant agents. These disintegrants 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%. Some components may have multiple functions in the formulations of this invention, acting e.g. as both a filler and a disintegrant, such a component may be referred to as a filler disintegrant and its function in a specific formulation may be singular even though its properties may allow multiple functionality.
The pharmaceutical formulations and carrier or excipient systems herein preferably also contain an antioxidant or a mixture of antioxidants, most preferably ascorbic acid. Other 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.
Among the 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 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.
Among 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.
Accordingly this invention further provides a product comprising a compound of formula I or II as defined above or a pharmaceutically acceptable salt thereof and a bisphosphonate or a pharmaceutically acceptable salt thereof, and optionally one or more estrogens, or a pharmaceutically acceptable salt thereof for administration as a combined preparation for simultaneous, separate or sequential use in treatment of bone disorders in a mammal.
This invention further provides a pharmaceutical composition comprising a compound of formula I or II as defined above or a pharmaceutically acceptable salt thereof, and a bisphosphonate or a pharmaceutically acceptable salt thereof and optionally one or more estrogens, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Example 1. TSE-424 Acetate -Rapid Dissolution Formulations
* Amount in formula is adjusted for actual potency of TSE-424 as free base. Corresponding adjustment made with Lactose.
The formulations given above in Table 1 were prepared by incorporating a portion of the excipients in the granulation and a portion is also added in the final blending steps as dry powders. A dissolution profile generated for the formulations demonstrated almost 90% release of the drug in 30 minutes. Thus, the unique combination of disintegrants and soluble diluents plus the incorporation of both granulated and powdered solids into the composition ensures the fastest release of drug.
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.
Example 2. Modified TSE-424 formulation
%w/w
a Amount in formula is adjusted for actual potency of TSE-424 as free base. Corresponding adjustment made with Lactose. b Used in process but does not appear in the final product.
Example 3. ERA-923 formulations
%w/w
a As the Hydrochloride Monohydrate. Quantity is adjusted based on the actual potency (theory = 89.34%). b Used in process but does not appear in the final product.
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.
Example 4. TSE-424 at 5 % Granulation
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.
Item No. Ingredients Mg Unit ranuli ition Part:
1 TSE-424 acetate 5.00
2 Lactose NF 26.60
3 Microcrystalline Cellulose NF 25.00
4 Pregelatinized Starch NF 10.00
5 Ascorbic Acid USP 1.50
6 Sodium Lauryl Sulfate NF 1.50
7 Sodium Starch Glycolate NF 4.00
8 Water, Purified USP Q.S.
73.60
Dry Part: 9 Lactose NF (fast flo) 9.75
10 Microcrystalline Cellulose NF 10.00
11 Pregelatinized Starch NF 4.00
12 Sodium Starch Glycolate NF 2.00
13 Silicon Dioxide NF 0.15 14 Magnesium Stearate NF 0.50
100.00
A film coat of White Opadry I (YS-1-18027-A) was applied to the tablets, which were compressed as follows:
Dose of TSE-424 tablet weight. mg mg of film coat applied/tablet
5 mg 100 6.0
10 mg 200 8.0
20 mg 400 13.0

Claims

CLAIMS:
1. A method for treatment of bone disorders in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a: i) a bisphosphonate, or a pharmaceutically acceptable salt thereof; ii) a substituted indole compound of the formulae I or II:
I π wherein Z is a moiety selected from the group of:
or -(CH2)n Y wherein:
Rx is selected from H, OH or the -C12 esters or CrC12 alkyl ethers thereof, benzyloxy, or halogen; or C,-C4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether;
R2, R3, R5 and R6 are independently selected from H, OH or the C1-C12 esters or C,-C12 alkyl ethers thereof, halogens, or C,-C4 halogenated ethers, cyano, C1-C6 alkyl, or trifluoromethyl, with the proviso that, when Ri is H, R2 is not OH;
R4 is selected from H, OH or the C1-C12 esters or C.-C12 alkyl ethers thereof, halogens, or C.-C4 halogenated ethers, benzyloxy, cyano, Cj-Cβ alkyl, or trifluoromethyl;
X is selected from H, C1-C6 alkyl, cyano, nitro, trifluoromethyl, halogen; n is 1, 2 or 3; Y is selected from: a) the moiety:
-A \ 7
R8 wherein R7 and Rs are independently selected from the group of H, C1-C6 alkyl, or phenyl optionally substituted by CN, Ci-Cβ alkyl, C1-C6 alkoxy (straight chain or branched), halogen, -OH, -CF3, of -OCF3; ;or R7 and
R8 are combined by -(CH2)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, Cι-C4alkyl, trihalomethyl, C\- C4alkoxy, trihalomethoxy, Cι-C4alkylthio, Cι-C4alkylsulfinyl, Cι-C4alkyl- sulfonyl, hydroxy(Cι-C4)alkyl, -CO2H, -CN, -CONH(Cι-C4)alkyl, -NH2, Ci- C4alkylamino, di-(Cι-C4)alkylamino, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C4)- alkyl and -NO2;
b) a five-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of -O-, -NH-, -N(Cι_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, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, Cι-G-|.acyloxy, Cι-C4alkylthio,
Cι-C4alkylsulfinyl, Cι-C4alkylsulfonyl, hydroxy(Cι-C4)alkyl, -CO2H, -CN-, -CONHR,, -NH2, Cι-C4alkylamino, di(Cι-C4)alkylamino, -NHSO2R„ -NHCOR,, -CONH(Cι-C4)alkyl, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C4)alkyl, -NO2, and phenyl optionally substituted with 1-3 (Cι-C4)alkyl;
c) a six-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of -O-, -NH-, -N(Cι_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, Cι-C4alkoxy, trihalomethoxy, C2-C4acyloxy, Cι-C4alkylthio, Cι-C4alkylsulfinyl, Cι-C4alkylsulfonyl, hydroxy(Cι-C )alkyl, -CO2H, -CN, -CONHR,, -NH , Cι-C4alkylamino, di(Cι-C4)alkylamino, -NHSO2R„ -NHCOR,, -CONH(Cι-C4)alkyl, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C4)alkyl, NO2, and phenyl optionally substituted with 1-3 (Cι-C4)alkyl; d) a seven-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of -O-, -NH-, -N(Cι_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, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C2-G acyloxy, Cι-C4alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (Cι-C )alkyl, -CO2H-, -CN-, -CONHR,, -NH2, Cι-C4alkylamino, di(Cι-C4)alkylamino, -NHSO2R,-, -NHCOR,, -CONH(Cι-C4)alkyl, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C4)alkyl,
-NO2, and phenyl optionally substituted with 1-3 (Cι-C4)alkyl; or
e) 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(CιC4 alkyl)-, 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, C1-C4 alkoxy, trihalomethoxy, Cι-C4acyloxy, Cι-C4alkylthio, C1-C4 alkylsulfinyl, Cι-C4alkylsulfonyl, hydroxy(Cι-C4)alkyl, -CO2H-, -CN-, -CONHR,-, -NH2-, C1-C4 alkylamino, di(Cι-C4)alkylamino,
-NHSO2R„ -NHCOR,, -CONH(Cι-C4)alkyl, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C4)alkyl, -NO2, and phenyl optionally substituted with 1-3 (Ci- C4) alkyl; or a pharmaceutically acceptable salt thereof. and, optionally iii) one or more estrogens, or a pharmaceutically acceptable salt thereof;
2. The method of Claim 1 wherein in the compound of the formulae I or II:
R1 is selected from H, OH or the C1-C12 esters or alkyl ethers thereof, benzyloxy, or halogen; R2, R3, R5, and R6 are independently selected from H, OH or the C1-C12 esters or alkyl ethers thereof, halogen, cyano, Ci-Cβ alkyl, or trihalomethyl; with the proviso that, when R\ is H, R2 is not OH;
R is selected from H, OH or the C1-C12 esters or alkyl ethers thereof, benzyloxy, halogen, cyano, -Cό alkyl, or trihalomethyl; X is selected from H, -C6 alkyl, cyano, nitro, trifluoromethyl, halogen; Y is the moiety:
-A \
R8 •
R7 and R8 are selected independently from H, Ci-Cβ alkyl, or combined by -(CH2)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, C1-C4 alkyl, trihalomethyl, Cι-C4alkoxy, trihalomethoxy, Ci- C4alkylthio, Ci- alkylsulfinyl, Ci- alkylsulfσnyl, hydroxy(Cι-C4)alkyl, -CO2H, -CN, -CONH(Cι-C4)alkyl, -NH , Cι-C4alkylamino, di(Cι-C4)alkylamino, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C4)alkyl, and -NO2; or a pharmaceutically acceptable salt thereof.
3. The method of Claim 2 wherein, in the compound of the formulae I or II, the ring formed by a the combination of R7 and R_ by -(CH2)p- is selected from aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneamine or heptamethylene- amine.
4. The method of Claim 1 utilizing a compound of the formulae I or II, wherein Ri is OH; R2 - Rό are as defined in Claim 1 ; X is selected from the group of CI, NO2, CN, CF3, or CH3; and Y is the moiety:
and R7 and R_ are concatenated together as -(CH2)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, Cι-C4alkyl, trihalomethyl, Cι-C4alkoxy, trihalomethoxy, Cι-C4alkylthio, Cι-C4alkylsulfinyl, Cι-C4alkylsulfonyl, hydroxy(Cι-C4)alkyl, -CO2H, -CN, -CONH(Cι-C4)alkyl, -NH2, Cι-C4alkylamino, di(Cι-C4)alkylamino, -NHSO2(Cι-C4)alkyl, -NHCO(Cι-C4)alkyl, and -NO2; or a pharmaceutically acceptable salt thereof.
5. A method for treatment of bone disorders in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a bisphosphonate, or a pharmaceutically acceptable salt thereof, and optionally one or more estrogens, or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of a compound of the formulae III or IN:
(III) (IN) wherein R„ R-, Rj, R4, R5, R6, n, X, and Y are as defined in Claim 1, or a pharmaceutically acceptable salt thereof.
6 A method for treatment of bone disorders in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a bisphosphonate, or a pharmaceutically acceptable salt thereof, and optionally one or more estrogens, or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of a compound of the formulae (N) or (VI):
wherein R,, R2, R3, R4, R5, R6, X, and Y are as defined in Claim 1, or a pharmaceutically acceptable salt thereof.
7. A method for treatment of bone disorders in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a bisphosphonate, or a pharmaceutically acceptable salt thereof, and optionally one or more estrogens, or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of a compound of the formulae Nil and VIII:
(VII) (vπi) wherein R,, R2, R3, R4, R5, R6, n, X,. and Y are as defined in Claim 1, or a pharmaceutically acceptable salt thereof.
8. A method according to Claim 1 in which the compound of formula I or la is 1 -[4-(2-azepan- lyl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl- 1 H-indol-5- ol, or a pharmaceutically effective salt thereof, or
2-(4-hydroxy-phenyl)-3-methyl-l-(4-(2-piperidin-l-yl-ethoxy)-benzyl]-lH-indol-5-ol, or a pharmaceutically effective salt thereof.
9. A method according to any one of claims 1 to 8 wherein the bisphosphonate is selected from the group of Alendronate, Risedronate, Tiludronate, Ibandronate, Etidronate, Clodronate, Minodronate, Pamidronate, Zoledronate, Incadronate, Olpadronate or Neridronate.
10. A method according to any one of claims 1 to 9 wherein the one or more estrogens are selected from the group of estrone, estriol, equilin, estradiene, equilenin, ethinyl estradiol, 17β-estradiol, 17α-dihydroequilenin, 17β-dihydro- equilenin, 17α-dihydroequilin, 17β-dihydroequilin, menstranol, conjugated estrogenic hormones, equol, enterolactone, or a pharmaceutically acceptable salt thereof.
11. A method according to any one of claims 1 to 10 wherein the bone disorder is osteoporosis.
12. A method according to any one of claims 1 to 10 wherein the bone disorder is Paget's disease.
13. A method according to any one of claims 1 to 10 wherein the bone disorder is malignant osteolytic bone disease.
14. A method according to any one of claims 1 to 10 wherein the bone disorder is bone degradation due to metastases from cancer.
15. A method for treatment of bone disorders in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of 1 -[4-(2-azepan- lyl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl- 1H- indol-5-ol, or a pharmaceutically effective salt thereof, a pharmaceutically effective amount of a bisphosphonate, or a pharmaceutically effective salt thereof, and optionally one or more estrogens, or a pharmaceutically acceptable salt thereof,.
16. A method for treatment of bone disorders in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of 2-(4-hydroxy-phenyl)-3-methyl-l-(4-(2-piρeridin-l-yl-ethoxy)-benzyl]-lH- indol-5-ol, or a pharmaceutically effective salt thereof, a pharmaceutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof, and optionally, one or more estrogens or a pharmaceutically effective salt thereof.
17. The method of Claim 15 or Claimlό wherein the bisphosphonate is selected from the group of Alendronate, Risedronate, Tiludronate, Ibandronate, Etidronate, Clodronate, Minodronate, Pamidronate, Zoledronate, Incadronate, Olpadronate or Neridronate, or a pharmaceutically acceptable salt thereof.
18. The method of Claim 15, 16 or Claim 17 wherein the one or more estrogens are conjugated estrogenic hormones.
19. A product comprising a compound of formula I or π as defined in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a bisphosphonate or a pharmaceutically acceptable salt thereof, and optionally one or more estrogens, or a pharmaceutically acceptable salt thereof for administration as a combined preparation for simultaneous, separate or sequential use in treatment of bone disorders in a mammal.
20. A pharmaceutical composition comprising a compound of formula I or II as defined in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a bisphosphonate or a pharmaceutically acceptable salt thereof, and optionally one or more estrogens, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
EP01952365A 2000-07-06 2001-06-29 Combinations of bisphosphonates, estrogenic agents and optionally estrogens Withdrawn EP1299093A2 (en)

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