Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/12—Radicals substituted by oxygen atoms
• • 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
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/30—Oestrogens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• the present invention relates to new N-substituted benzoyl indole compounds which are useful as estrogenic agents, as well as pharmaceutical compositions and methods of treatment utilizing these compounds and processes for preparing them.
• Estrogen replacement therapy has been well established as the treatment of choice in women for the prevention of osteoporosis. [C. Christiansen, R. Lindsay, Estrogen , Bone Loss and Preservation, Osteoporosis International, 1, 15-21 (1990)]
• the downside to this therapy is that when estrogen is given alone i.e. without the opposing effects of progestins, proliferative effects on the uterus may result and thereby can put the patient at risk for endometrial cancer.
• hormone replacement therapy has been implicated in increasing the incidence of breast tumor formation.
• Non-steroidal antiestrogen drugs such as tamoxifen have been used in the treatment of breast cancer.
• the drug also is known to maintain bone mass, acting as a bone-sparing estrogen agonist, however it is also an agonist in uterine tissue.
• WO A 95 17383 (Kar Bio AB) describes indole antiestrogens with long straight chains.
• Another related patent WO A 93 10741 describes 5-hydroxyindole with a generic descriptor incorporating other side chains.
• U.S. Patent No. 5,496,844 (Inai, et al.) teaches substituted N-indole compounds having potent antiestrogenic activity which are useful in the treatment of estrogen-dependent diseases, such as anovulatory infertility, prostatic hypertrophy, osteoporosis, breast cancer, endometrial cancer and melanoma.
• the compounds described in the present invention are mixed estrogen agonists/antagonists and have potential use in treating osteoporosis, endometriosis, prostatic hypertrophy, breast cancer and endometrial cancer. Description of the Invention
• the present invention provides N-substituted indoles of Formula (I):
• Ri, R 2 and R 3 are independently selected from hydrogen, halogen, C ⁇ -Cj 2 alkoxy (straight chain or branched or cyclic), -CF 3 , -NO 2 , cyano, C ⁇ -C 6 alkyl (straight chain or branched), trifluoromethyl, -OH or the C ⁇ -C ⁇ 2 esters (straight chain or branched) thereof, or C ⁇ -C 6 halogenated ethers, preferably Cj-C 3 halogenated ethers, including trifluoromethyl ether and trichloromethyl ether;
• R and R 5 are independently selected from H or benzyl, the benzyl group being optionally substituted by C ⁇ -C alkyl, Cj-C 6 alkoxy, -CF 3 , or halogen;
• X is H, C ⁇ -C 6 alkyl, or CF 3 ;
• Z is O or S;
• n is 2 or 3;
• Y is selected from:
• R' is C C 6 lower alkyl the same or different; or b) a moiety selected from the group of:
• Examples of Ri, R 2 and R 3 when esters are C -C ⁇ 2 alkyl esters such as -O(C O)(C ⁇ -C 6 alkyl).
• alkyl groups are methyl, ethyl, n-propyl, isopropyl and n-butyl.
• alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
• Ri and R 2 are H, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy -CF 3 and NO 2 .
• R 3 and R 4 are H.
• An example of X is methyl.
• a preferred group of this invention are those compounds of Formula I wherein R], R and R are independently selected from hydrogen, Cj-C 6 alkyl, C ⁇ -C 6 alkoxy, - CF 3 , or -NO 2 ; and R 4 , R 5 , X, Z, n, and Y are as defined above, or a pharmaceutically acceptable salt thereof.
• Another preferred group of compounds of this invention are those in which Z is oxygen and Rj, R 2 , R , and R 4 are H, or a pharmaceutically acceptable salt thereof.
• R 5 is H.
• Y is a piperidine ring.
• This 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 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, naphthalenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid are useful.
• HC1, HBr, and acetate salts are preferred salts.
• the compounds of the invention are partial estrogen agonists and display high affinity for the estrogen receptor. Unlike many estrogens, however, many of these compounds do not cause the increases in uterine wet weight normally associated with natural or synthetic estrogens. These compounds are antiestrogenic in the uterus and antagonize the trophic effects of estrogen agonists in uterine tissue. In addition, the compounds may be used as estrogen agonists in bone tissue. Due to the tissue selective nature of these compounds, they are useful in treating or preventing in a mammal disease states or syndromes which are caused or associated with an estrogen deficiency or an excess of estrogen.
• the present compounds have the ability to behave like estrogen agonists by lowering cholesterol and preventing bone loss. These compounds are useful for treating many maladies which result from estrogen excess or deficiency including osteoporosis, prostatic hypertrophy, male pattern baldness, ovarian cancer, infertility, breast cancer, endometrial cancer, cardiovascular disease, contraception, Alzheimer's disease, cognitive decline and other CNS disorders, as well as certain cancers, including melanoma, prostrate cancer, cancers of the colon, CNS cancers, among others. Additionally, these compounds can be used for hormone replacement therapy in post-menopausal women or in other estrogen deficiency states where estrogen supplementation would be beneficial.
• the compounds of this invention may also be used in methods of treatment for bone loss, which may result from an imbalance in an individual's formation of new bone tissues and the resorption of older tissues, leading to a net loss of bone.
• bone depletion results in a range of individuals, particularly in post-menopausal women, women who have undergone hysterectomy, those receiving or who have received extended corticosteroid therapies, those experiencing gonadal dysgenesis, and those suffering from Cushing's syndrome.
• Special needs for bone replacement can also be addressed using these compounds in individuals with bone fractures, defective bone structures, and those receiving bone-related surgeries and/or the implantation of prosthesis.
• these compounds can be used in treatments for osteoarthritis, hypocalcemia, hypercalcemia, Paget's disease, osteomalacia, osteohalisteresis, multiple myeloma and other forms of cancer having deleterious effects on bone tissues.
• Methods of treating the maladies listed herein are understood to comprise administering to an individual in need of such treatment a pharmaceutically effective amount of one or more of the compounds of this invention or a pharmaceutically acceptable salt thereof.
• This invention also includes pharmaceutical compositions utilizing one or more of the present compounds, and/or the pharmaceutically acceptable salts thereof, along with one or more pharmaceutically acceptable carriers, excipients, etc.
• the dosage, regimen and mode of administration of these compounds will vary according to the malady and the individual being treated and will be subject to the judgement of the medical practitioner involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
• Effective administration of these compounds may be given at an effective dose of from about 0.1 mg/day to about 1,000 mg/day. Preferably, administration will be from about 10 mg/day to about 600 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).
• Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions.
• Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.
• Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar.
• pharmaceutically acceptable diluents including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline
• Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s).
• Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin.
• Water soluble suppository bases such as polyethylene glycols of various molecular weights, may also be used.
• This invention also provides processes for preparing the compounds of formula I which processes comprises one of the following:
• hal represents a halogen e.g chlorine or bromine, with an amine of formula:
• the initial indole synthesis for 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl- lH-indole is accomplished by heating an appropriately substituted alpha-bromo ketone (b) with the desired aniline (a) in DMF to form the indole (c).
• the (aminoethoxy)benzoic acid side chains of the present compounds may be prepared by the general methods taught by Jones et al., J. Med. Chem., 1984, Vol. 27, No. 8, pp. 1057-1066 or as shown in Scheme 2 and coupled to the core indoles via the method of Scheme 3.
• Receptor Preparation CHO cells overexpressing the estrogen receptor are grown in 150 mm dishes in DMEM+ 10% dextran coated charcoal, stripped fetal bovine serum. The plates are washed twice with PBS and once with 10 mM Tris-HCl, pH 7.4, 1 mM EDTA. Cells are harvested by scraping the surface and then the cell suspension is placed on ice. Cells are disrupted with a hand-held motorized tissue grinder using two, 10-second bursts.
• the crude preparation is centrifuged at 12,000 x g for 20 min. followed by a 60 min spin at 100,000 x g to produce a ribosome-free cytosol.
• the cytosol is frozen and stored at -80 deg C. Protein concentration of the cytosol is estimated using the BCA assay with BSA as the reference standard protein.
• the competition assay is performed in a 96-well plate (polystyrene*) which binds ⁇ 2.0% of the total input [3H]-17 ⁇ -estradiol. Each data point is gathered in triplicate. 100 ⁇ g/100 ⁇ l of the receptor preparation is aliquoted per well. A saturating dose of 2.5 nM [3H]17 ⁇ -estradiol + competitor (or buffer) in a 50 ⁇ l volume is added in the preliminary competition when lOOx and 500x competitor concentrations are evaluated. For an IC 50 determination, where 12 concentrations of competitor are evaluated, only 0.8 nM [3H]17 ⁇ -estradiol is used. The plate is incubated at room temperature for 2.5 h.
• CPM Counts per minute
• IC 50 curves For the generation of IC 50 curves, % binding is plotted vs [compound]. IC 5 o's are generated for compounds that show >10% competition at up to a 500x competitor concentration.
• estradiol 0.08 ⁇ M tamoxifen: 4.50 ⁇ M raloxifene 0.04 ⁇ M 17 -dihydroequilin 0.15 ⁇ M
• Example No.2 was tested against the standards tamoxifen, also named (Z)-2-[4- (l,2-Diphenyl-l-butenyl)-phenoxy]-N,N-dimethylethanamine, and raloxifene, also named [6-Hydroxy-2-(4-hydroxy-phenyl)-benzo [b]thiophene-3 -yl] - [4-(2-piperidin- 1 - yl-ethoxy)-phenyl]-methanone. It is understood that 17 ⁇ -estradiol as a standard has 100%> binding in the Receptor Binding Assay.

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• 2000
  • 2000-02-22 JP JP2000602211A patent/JP2002538141A/ja active Pending
  • 2000-02-22 EP EP00917652A patent/EP1159268A1/de not_active Withdrawn
  • 2000-02-22 MX MXPA01008911A patent/MXPA01008911A/es unknown
  • 2000-02-22 WO PCT/US2000/004386 patent/WO2000051983A1/en not_active Application Discontinuation
  • 2000-02-22 AU AU38594/00A patent/AU3859400A/en not_active Abandoned
  • 2000-02-22 CA CA002364914A patent/CA2364914A1/en not_active Abandoned
  • 2000-02-22 CN CN00804545A patent/CN1342144A/zh active Pending
  • 2000-03-01 AR ARP000100898A patent/AR022797A1/es not_active Application Discontinuation

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