Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • 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
• • 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
• • 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

Definitions

• the present invention relates to the use of 3-[4-(2-phenyl-Indole-l-ylmethyl)- Phenyl]-Acrylamide compounds and 2-phenyl-l-[4-(amino-l-yl-alk-l-ynyl)-benzyl]- lH-indol-5-ol compounds which are useful as selective estrogen receptor modulating agents, in conjunction with estrogens, as well as pharmaceutical compositions and methods of treatment utilizing these compounds.
• hormone replacement therapy for bone loss prevention in post- menopausal women is well precedented.
• the normal protocol calls for estrogen supplementation using such formulations containing estrone, estriol, ethynyl estradiol, 17 ⁇ -estradiol, esterified estrogens, or conjugated estrogens isolated from natural sources (i.e. Premarin® conjugated estrogens from Wyeth-Ayerst) or synthetic estrogens.
• therapy may be contraindicated due to the proliferative effects of unopposed estrogens (estrogens not given in combination with progestins) have on uterine tissue. This proliferation is associated with increased risk for endometriosis and/or endometrial cancer.
• Raloxifene a benzothiophene antiestrogen
• tissue selective estrogens is seen in the article "Tissue-Selective Actions Of Estrogen Analogs", Bone Vol. 17, No. 4, October 1995, 181S-190S.
• the use of indoles as estrogen antagonists has been reported by Von Angerer, Chemical Abstracts, Vol. 99, No. 7 (1983), Abstract No. 53886u. Also, see, J.Med.Chem. 1990, 33, 2635-2640; J.Med.Chem. 1987, 30, 131-136. Also see Ger.
• WO A 95 17383 (Karo Bio AB) describes indole antiestrogens with long straight chains.
• Another related patent WO A 93 10741 describes 5-Hydroxyindoles with a broad range of side chains.
• WO 93/23374 (Otsuka Pharmaceuticals, Japan) describes compounds sharing structural similarities with those of the present invention, except with the structure referred to as R 3 in the present formulas I and II, below, is defined as thioalkyl and the reference discloses no such compounds having chains from the indole nitrogen having the same structure as the ones provided by the present invention.
• U.S. Patent No. 4,894,373 (Young) teaches the use of antiestrogens, including clomiphene and its isomers, citrates and derivatives, in the absence of estrogen for treating menopausal symptoms and treating or preventing osteoporosis.
• U.S. Patent No. 5,552,401 (Cullinan et al.) describes benzothiophene compounds as useful for the treatment of various medical indications associated with post-menopausal syndrome, and uterine fibroid disease, endometriosis, and aortal smooth muscle cell proliferation, the compounds being used in pharmaceutical formulations optionally containing estrogen or progestin.
• 5,646,137 and 5,591,753 discloses methods of treating osteoporosis with formulations of raloxefine- type arylbenzothiophene compounds in conjunction with a progestin selected from medroxyprogesterone, norethindrone or norethynodrel, or pharmaceutically acceptable salts thereof.
• a progestin selected from medroxyprogesterone, norethindrone or norethynodrel, or pharmaceutically acceptable salts thereof.
• 5,550,107 claims an invention comprising the treatment of breast or endometrial cancer with an antiestrogen together with at least one compound selected from the group of an androgen, a progestin, at least one inhibitor of sex steroid formation, expecially 17 ⁇ -hydroxysteroid dehydrogenase and aromatase activity, at least one inhibitor of prolactin secretion, one inhibitor of growth hormone secretion and one inhibitor of ACTH secretion.
• U.S. Pat. No. 5,672,609 discloses pyridine compounds useful in treating post menopausal syndrome and formulations therefore containing estrogen or progestin.
• U.S. Pat. No. 5,534,527 Black et al. teaches the use of aroylbenzothiophenes and estrogens in the inhibition of bone loss.
• the present invention provides pharmaceutical formulations, and methods for using them, comprising compounds of formulas (I) and (II), below, in conjunction with estrogens, preferably in conjunction with one or more pharmaceutically acceptable carriers or excipients.
• the uses of the present formulations is alleviating the symptoms of post-menopausal syndrome in women, including peri-menopausal and post-menopausal symptoms.
• the present formulations and methods of treatment can be used to minimize undesirable side effects of estrogen treatment or therapy and may be used to minimize the amounts of estrogen(s) necessary for a particular regimen.
• Compounds of the general structure type shown in formulas (I) and (II) are estrogen agonists/antagonists useful for the treatment of diseases associated with estrogen deficiency disclosed in EP-A-0802184, the contents of which are inco ⁇ orated herein by reference in their entirety.
• the compounds used in the present invention show strong binding to the estrogen receptor and are capable of antagonizing the effects of 17 ⁇ - estradiol while showing little uterine stimulation when dosed alone.
• the present invention includes compounds of formulas (I) and (II), below:
• R. ! is selected from H, OH or the C 1 -C 4 esters or alkyl ethers thereof, or halogen;
• R 2 , R 3 , R 4 , R 5 , and R6 are independently selected from H, OH or the C 1 -C 4 esters or alkyl ethers thereof, halogen, cyano, C 1 -C6 alkyl, or trifluoromethyl, with the proviso that, when Ri is H, R2 is not OH;
• X is selected from H, C1-C6 alkyl, cyano, nitro, trifluoromethyl, halogen;
• Y is selected from:
• Y is selected from: a) the moiety
• R7 and Rs are independently selected from the group of H, -C6 alkyl, phenyl 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 hydroxyl, halo, C 1 -C4 alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, C1-C4 alkylthio, Ci- alkylsulfinyl, C ⁇ -C4alkylsulfonyl, hydroxy (Ci-GOalkyl, -CO2H, - CN, -CONH(C ⁇ -C 4 )alkyl, -NH 2 , C ⁇ -C 4 alkylamino, di-(Ci-C alkyl)amino, - NHSO 2 (C ⁇ -C 4 )alkyl, -NHCO(C ⁇ -C 4 )alkyl
• -NH-, -N(C ⁇ -C 4 alkyl)-, -N ( in which case the ring can be bonded via the nitrogen), and -S(O) m -, wherein m is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from hydroxyl, halo, -C4 alkyl, trihalomethyl, C1-C 4 alkoxy, trihalomethoxy, -C4 acyloxy, -C4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, hydroxy(C ⁇ -C 4 )alkyl, -CO 2 H, -CN, -CONHR,, -NH 2 , ( - C4)alkylamino, di-(C ⁇ -C4alkyl)amino, -NHSO 2 R ⁇ , -NHCORi, -NO 2 and phenyl optionally substituted with
• the more preferred formulations and methods of treatment of this invention are those having or utilizing, along with one or more pharmaceutical carriers or excipients: a) one or more estrogens; and b) one or more compounds selected from the general structures I or II, above, wherein: R ⁇ is selected from H, OH or the C1-C4 esters or alkyl ethers thereof, halogen;
• R 2 , R 3 , R 4 , R 5 , and R ⁇ $ are independently selected from H, OH or the C 1 -C4 esters or alkyl ethers thereof, halogen, cyano, -C6 alkyl, or trifluoromethyl, with the proviso that, when Ri is H, R 2 is not OH;
• X is selected from H, Ci-C ⁇ alkyl, cyano, nitro, trifluoromethyl, halogen;
• Y is the moiety
• R 7 and R 8 are selected independently from H, Ci-C ⁇ 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 hydroxyl, halo, C 1 -C4 alkyl, trihalomethyl, C ⁇ -C4alkoxy, trihalomethoxy, C ⁇ -C4alkylthio, C 1 -C4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, hydroxy(C ⁇ -C 4 ) alkyl, -CO 2 H, -CN, -CONH(C ⁇ - C 4 ), -NH 2 , C ⁇ -C 4 alkylamino, C ⁇ -C 4 dialkyla
• the rings formed by a concatenated R7 and Rs, mentioned above, may include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, or hexamethyleneamine rings.
• the ring so formed is optionally substituted with 1-3 substituents selected from a group containing -C3 alkyl, trifluoromethyl, halogen, hydrogen, phenyl, nitro, -CN.
• the compounds of Formulas (I) and (II) are partial estrogen agonists and display high affinity for the estrogen receptor. Unlike many estrogens, however, these compounds do not cause increases in uterine wet weight. These compounds are antiestrogenic in the uterus and can completely antagonize the trophic effects of estrogen agonists in uterine tissue. These compounds are useful in treating or preventing mammal disease states or syndromes which are caused or associated with an estrogen deficiency. This tissue selectivity allows their use for desirable estrogenic activity in certain tissues, such as bone, while limiting that activity in others, such as uterine tissue.
• 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.
• 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 (ffl) listed herein.
• conjugated estrogenic hormones such as those in Wyeth-Ayerst Laboratories' Premarin ® products, with one or more compounds of Formulas (I) or (ffl) listed herein.
• Esterified estrogens such as those sold by Solvay Pharmaceuticals, Inc. under the Estratab® tradename, may also be used with the present formulations.
• the salts of the applicable estrogens most preferably the sodium salts.
• Examples of these preferred salts are Sodium estrone sulfate, Sodium equilin sulfate, Sodium 17alpha-dihydroequilin sulfate, Sodium 17alpha-estradiol sulfate, Sodium Delta8,9- dehydroestrone sulfate, Sodium equilenin sulfate, Sodium 17beta-dihydroequilin sulfate, Sodium 17alpha- dihydroequilenin sulfate, Sodium 17beta-estradiol sulfate, Sodium 17beta- dihydroequilenin sulfate, Estrone 3-sodium sulfate, Equilin 3-sodium sulfate, 17alpha- Dihydroequilin 3-sodium sulfate, 3beta-Hydroxy-estra-5(10),7-dien-17-one 3-sodium sulf
• the present compounds of Formulas (I) and (II) are tissue selective compounds having the ability to behave like estrogen agonists, such as by lowering cholesterol and preventing bone loss, or like estrogen antagonists. Therefore, these compounds in the present formulations are useful for treating many maladies including osteoporosis, prostatic hypertrophy, infertility, breast cancer, endometrial hyperplasia, endometrial cancer, endometriosis, cystic glandular hyperplasia, uterine hyperplasia, cervical hyperplasia, benign prostatic hyperplasia, cardiovascular disease, contraception, Alzheimer's disease and melanoma.
• maladies including osteoporosis, prostatic hypertrophy, infertility, breast cancer, endometrial hyperplasia, endometrial cancer, endometriosis, cystic glandular hyperplasia, uterine hyperplasia, cervical hyperplasia, benign prostatic hyperplasia, cardiovascular disease, contraception, Alzheimer's disease and melanoma.
• the formulations of this invention may also be used to treat bone loss resulting from secondary osteoporosis, including that categorized as endocrine in nature, including that resulting from glucocorticoid excess, hyperparathyroidism, hyperthyroidism, hypogonadism, hyperprolactinemia, and diabetes mellitus.
• the bone loss may also be the drug-induced, such as that resulting from heparin treatments, alcohol consumption, or the use of tobacco, barbiturates or corticosteroids.
• the drug-induced loss of bone may also stem from treatment with gonadotropin releasing hormone (GnRH or LHRH) or synthetic GnRH antagonists or agonists, such as the leuprolide acetate injectable sold by TAP Pharmaceuticals Inc.
• Such bone loss may also result from immobilization of the individual, chronic renal failure, malabsorption syndrome, hepatic disease, chronic obstructive lung disease, rheumatoid arthritis, or sarcoidosis.
• these formulations can be used for hormone replacement therapy in post-menopausal women or in other estrogen deficiency states where estrogen supplementation would be beneficial.
• the symbiotic activity of the compounds and estrogen(s) of the present methods of treatment are particularly of interest in overcoming the unwanted consequences of estrogen therapy, such as breakthrough bleeding and/or excessive endometrial stimulation, which may lead to endometrial hyperplasia or endometriosis.
• These formulations therefore, may be used in methods of treating or preventing excessive estrogenic uterine stimulation in a mammal.
• the primary target tissues for estrogens include the reproductive tract (ovary; uterus; vagina), mammary tissue, skeleton, cardiovascular system and the central nervous system (CNS).
• the reduction in circulating estrogens results in a number of changes.
• a change in lipid profile occurs with increases in Low Density Lipoprotein (LDL) and decreases in High Density Lipoprotein (HDL) commonly measured and an associated increased risk of a cardiovascular event (heart attack, stroke).
• LDL Low Density Lipoprotein
• HDL High Density Lipoprotein
• Changes in the central nervous system include an increase in vasomotor symptoms (hot flush) and potentially changes in cognition and memory.
• Estrogen replacement therapy normalizes some of these changes, particularly those associated with the cardiovascular system (reduced LDL, increased HDL, reduced risk of heart attack), the skeleton (maintenance of bone mass, reduced fracture risk), and central nervous system (reduction in frequency and severity of the hot flush). While the reproductive tract responds, it is not all positive. On the positive side, vaginal dryness is alleviated. However , negative uterine responses include hypertrophy and hyperplasia, along with some menstrual-like bleeding. The breast is also affected and there are data correlating exogenous estrogen therapy with an increased risk of breast cancer.
• TSE tissue selective estrogen
• the tissue selective estrogen (TSE) compounds of this invention provide positive skeletal and cardiovascular affects similar to estrogens, without the negative effects associated with the uterus and breast.
• the combinations of TSEs and estrogens derive the positive effects of estrogens on the CNS, bone and cardiovascular, with the combination providing complimentary or additive effects on the bone and cardiovascular systems.
• the major variable is the TSEs ability to block estrogenic influence on the uterus and breast, which are the two major negative effects of unopposed estrogens.
• the formulations 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 reso ⁇ tion 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 hysterectorny/oophorectomy, 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 formulations in individuals with bone fractures, defective bone structures, and those receiving bone-related surgeries and/or the implantation of prosthesis.
• these formulations can be used in treatments for osteoarthritis, Paget's disease, osteomalacia, osteohalisteresis, endometrial cancer, 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 Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, in conjunction with a therapeutically desirable amount of an estrogen.
• 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 of Formulas (I) and (II) will vary according to the malady and the individual being treated and will be subjected to the judgment of the medical practitioner involved. It is preferred that the administration of one or more of the compounds herein begins at a low dose and be increased until the desired effects are achieved. Similarly, it will be understood that the dosage(s) of the estrogen(s) utilized in the present formulations will be selected according to conventional methods. It is most preferred that the dosage will be monitored to achieve the desired result with the minimum of estrogen(s) necessary.
• Effective administration of these compounds of Formulas (I) and (II) may be given at a dose of from about 0.01 mg/day to about 1,000 mg/day. Preferably, administration will be from about 1 mg/day to about 600 mg/day in a single dose or in two or more divided doses. Most preferably a daily dose of between about 1 mg/day and about 150 mg day will be administered. Such doses may be administered in any manner useful in directing the active compounds herein to the recipient, including orally, parenterally (including intravenous, intraperitoneal and subcutaneous injections, implants, etc.), intravaginally 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 Formulas (I) and (II) 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 abso ⁇ tion 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 estrogen of this invention will be administered in the dosages of conventional regimens, according to the recipient's tolerance and the particular treatment or maintenance schedule intended.
• the compounds of Formulas (I) and (II) herein will be administered in an amount necessary to agonize or antagonize the estrogen(s) of the formulation's activity to the level desired.
• conjugated estrogens USP
• it is preferred that the daily doseage is from 0.1 mg to 5.0 mg, more preferably between about 0.3 mg and about 2.5 mg, most preferably between about 0.3 and about 1.25 mg/day.
• a daily dosage may be from about 1 ⁇ g to about 0.15 mg/day and a dosage of from about 1 ⁇ g to about 0.3 mg/day may be used for ethynyl estradiol, preferably between about 2 ⁇ g to about .15 mg/day of ethynyl estradiol.
• the compounds of this invention can be formulated neat or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice.
• the pharmaceutical carrier may be solid or liquid.
• a solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
• the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
• the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient.
• Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
• Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
• the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
• the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
• suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g.
• cellulose derivatives preferably sodium carboxymethyl cellulose solution
• alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, lethicins, and oils (e.g. fractionated coconut oil and arachis oil).
• the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
• Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
• the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
• Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
• the compounds of this invention can also be administered orally either in liquid or solid composition form.
• the compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository, creams, gels, etc.
• the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
• the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic abso ⁇ tion into the blood stream via the skin.
• the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
• the creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type.
• Pastes comprised of abso ⁇ tive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
• a variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
• the dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached; precise dosages for oral, parenteral, transdermal, rectal or vaginal suppositories, nasal, or intrabronchial and other administrations will be determined by the administering physician based on experience with the individual subject treated.
• the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
• the composition is subdivided 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 compound(s) of Formulas (I) and (II) and the estrogen(s) 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 compounds of Formulas (I) and (II) and the estrogens of these formulations have been determined, it may preferable to inco ⁇ orate both into a single formulation for ease of administration.
• the formulations herein may or may not include other pharmaceutically active components.
• the process for preparing a compound of formula I or II comprises one of the following: a) reacting a compound of formula
• Rl-R6 and X are as defined above with an acrylamide of formula
• the initial indole synthesis of Scheme 2 may be accomplished by heating an appropriately substituted aniline (1) with an appropriately substituted alpha- bromophenylalkyl-phenone (2) in a suitably high boiling solvent such as DMF. The product is then alkylated with 4-iodobenzyl bromide to give the substituted indole (3). At this point, deprotection of phenols (if present) is done. Normally, the phenols are protected as benzyl ethers and can conveniently be cleaved with TMSI. The propargylamines can then be coupled to the phenyl iodide.
• the propargylamines are typically prepared from an alkynyl bromide or alkynyl tosylate by substitution with the appropriate amine.
• the substitution reaction is done in situ, without isolating the propargylamine.
• Compounds substituted at the 3-position with groups other then alkyl may be prepared by first preparing the indole substituted at the 3- position with -H. The indole can then be electrophilically halogenated, formylated, etc., to give other 3- substituted compounds.
• the title compounds of Examples 21-23 were produced using a solution containing a 10 fold molar excess of a secondary amine in DMF cooled to 0°C and treated with propargyl bromide (3 eq, 80% solution in toluene). After 1 h at 0°C, the reactions were allowed to rt for 1 h. The indole iodide (4a, 1 eq) was added followed by Cu(I)I (0.1 eq) and Pd(PPh 3 ) 2 Cl 2 (0.035 eq). The reaction mixture was then stirred 16-48 h and worked up by pouring into water and extracting into EtOAc. The EtOAc is concentrated and chromatographed on silica gel using EtOAc/hexane as eluting system.
• CHO cells overexpressing the estrogen receptor were grown in 150 mm" dishes in DMEM + 10% dextran coated charcoal, stripped fetal bovine serum. The plates were washed twice with PBS and once with lOmM Tris-HCl, pH 7.4, lmM EDTA. Cells were harvested by scraping the surface and then the cell suspension was placed on ice. Cells were disrupted with a hand-held motorized tissue grinder using two, 10-second bursts. The crude preparation was centrifuged at 12,000g for 20 minutes followed by a 60 minute spin at 100,000g to produce a ribosome free cytosol. The cytosol was then frozen and stored at -80°C. Protein concentration of the cytosol was estimated using the BCA assay with reference standard protein.
• the competition assay was performed in a 96-well plate (polystyrene*) which binds ⁇ 2.0% of the total input [ H]-17 ⁇ -estradiol and each data point was gathered in triplicate. IOOUG/IOOUL of the receptor preparation was aliquoted per well. A saturating dose of 2.5 nM [ H]17 ⁇ -estradiol + competitor (or buffer) in a 50 uL volume was added in the preliminary competition when lOOx and 500x competitor were evaluated, only 0.8 nM [ H] 17 ⁇ -estradiol was used. The plate was incubated at room temperature for 2.5 h.
• CPM Counts per minute
• DPM disintegrated per minute
• IC 50 For the generation of IC 50 curves, % binding is plotted vs compound. IC 50 's are generated for compounds that show >30% competition at 500x competitor concentration. For a description of these methods, see Hulme, E.C., ed. 1992.
• Ishikawa cells were maintained in DMEM/F12 (50%:50%) containing phenol red + 10% fetal bovine serum and the medium was supplemented with 2 mM Glutamax, 1% Pen/Strap and 1 mM sodium pyruvate. Five days prior to the beginning of each experiment (treatment of cells) the medium was changed to phenol red-free DMEM/F12 + 10% dextran coated charcoal stripped serum. On the day before treatment, cells were harvested using 0.5% trypsin/EDTA and plated at a density of 5 X 10 cells/well in 96-well tissue culture plates.
• Test compounds were dosed at 10 "6 , 10 "7 and 10 “8 M in addition to 10 "6 M (compound) + 10 "9 M 17 ⁇ - estradiol to evaluate the ability of the compounds to function as antiestrogens.
• Cells were treated for 48 h prior to assay.
• lysis buffer 0.1 M Tris-HCl, pH 9.8, 0.2% Triton X-100
• pNPP para-nitrophenylphosphate
• CHO Chinese Hamster Ovary cells (CHO) which had been stably transfected with the human estrogen receptor were maintained in DMEM + 10% fetal bovine serum (FBS).
• FBS fetal bovine serum
• Reporter DNA Promega plasmid pGL2 containing two tandem copies of the vitellogenin ERE in front of the minimal thymidine kinase promoter driving the luciferase gene
• B-galactosidase expression plasmid pCHHO Pharmacia
• carrier DNA pTZl 8U
• the luciferase data was generated as relative light units (RLUs) accumulated during a 10 second measurement and automatically transferred to a JMP (SAS Inc) file where background RLUs were subtracted.
• the B-galactosidase values were automatically imported into the file and these values were divided into the RLUs to normalize the data.
• the estrogenic and antiestrogenic properties of the compounds were determined in an immature rat uterotrophic assay (4 day) that (as described previously by L.J.Black and R.L.Goode, Life Sciences, 26, 1453 (1980)).
• Immature Sprague-Dawley rats female, 18 days old were tested in groups of six. The animals were treated by daily ip injection with 10 uG compound, 100 uG compound, (100 uG compound + 1 uG 17 ⁇ -estradiol) to check antiestrogenicity, and 1 uG 17 ⁇ -estradiol, with 50% DMSO/50% saline as the injection vehicle.

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