Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • 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
  • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/04—Ortho- or peri-condensed ring systems
  • C07D221/18—Ring systems of four or more rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/78—Ring systems having three or more relevant rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
  • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems

Definitions

• vasomotor symptoms i.e., hot flashes, night sweats, vaginal dryness, sleep disturbances, nausea and mood swings commonly affect women around menopause. In fact, a majority of postmenopausal women will experience vasomotor symptoms with a significant percentage of these women continuing to suffer symptoms for more than five years (Psychosom. Med. 1965, 27, 266; Med. Gynecol. Soc. 1969, 4, 268). Women who have undergone bilateral oophorectomy, radiotherapy or treatment with GnRH (gonadotropin releasing hormone) agonists are particularly prone to experiencing hot flashes (Br. J. Obstet. Gynaecol. 1977, 84, 769). Men have also been reported to experience vasomotor symptoms following treatment with a GnRH agonist (N. Engl. J. Med. 1981, 305, 663) or after orchidectomy (Urology 1980, 16, 620).
• GnRH gonadotropin releasing hormone
• HRT hormone replacement therapy
• Hot flashes are characterised by a warming sensation that begins in the chest and moves towards the neck and head, and are often accompanied by sweating, palpitations and cutaneous flashing. The episodes last from 30 seconds to 10 minutes.
• the hot flash event itself is thought to be centrally mediated resulting from a transient lowering of the thermoregulatory set point in the hypothalamus (for a review, see: Can. J. Physiol. Pharmacol. 1987, 65, 1312). Regulation of the thermoregulatory process may involve catecholamines, estrogen, testosterone, opioids and serotonin, among others (for a review, see: Mayo. Clin. Proc. 2002, 77, 1207).
• HRT is not recommended for women with a history of breast cancer, uterine cancer, ovarian cancer, or venous thromboembolism. Recent data also suggests HRT may not be suitable for women with coronary artery disease.
• Non-hormonal treatments generally are not fully efficacious (e.g. clonidine) and/or cause adverse effects (e.g., venlafaxine, gabapen tin).
• SERMs selective estrogen receptor modulators
• raloxifene was associated with a slight increased incidence of hot flash compared to placebo and tamoxifen is known to induce hot flashes in more than 50% of patients (Arch. Intern. Med. 1991, 151, 1842).
• vasomotor symptom therapies that overcome the liabilities of current treatments.
• a medication that possesses the positive attributes of previously disclosed SERMs such as raloxifene (i.e., positive effects on bone, uterus, breast and cardiovascular system) but also alleviates vasomotor symptoms.
• the present invention relates to a compound of formula I:
• n 0, 1 or 2;
• n 1, 2, 3 or 4;
• R is H or methyl provided that if m is 1 or 2, then R must be H and that if m is 0, then R must be methyl;
• R 1 is H, SO 2 (n-C 4 -C 6 alkyl) or COR 2 ;
• X is O or NR 3 .
• X 1 is O, CH 2 or C ⁇ O
• R 6 is H or F or R 6 combines with X 1 to form a moiety of the formula:
• R 2 is C 1 -C 6 alkyl; C 1 -C 6 alkoxy; NR 5 R 5a ; phenoxy; or phenyl optionally substituted with halo;
• R 3 and R 4 are independently H or C 1 -C 6 alkyl
• R 5 and R 5a are independently H, C 1 -C 6 alkyl or phenyl; or a pharmaceutical acid addition salt thereof.
• the present invention also relates to a pharmaceutical composition that comprises a compound of formula I, or a pharmaceutical acid addition salt thereof, and a pharmaceutical carrier.
• the pharmaceutical composition of the present invention may be adapted for use in treating one or more vasomotor symptoms.
• the present invention also relates to methods for treating one or more vasomotor symptoms employing a compound of formula I, or a pharmaceutical acid addition salt thereof.
• the present invention relates to a compound of formula I, or a pharmaceutical acid addition salt thereof, for use in treating one or more vasomotor symptoms.
• the present invention is further related to the use of a compound of formula I, or a pharmaceutical acid addition salt thereof, for the manufacture of a medicament for treating one or more vasomotor symptoms.
• the present invention also relates to a compound of formula II:
• R 1a is H, SO 2 CH 3 , SO 2 (n-C 4 -C 6 alkyl), COR 2 , C 1 -C 6 alkyl or benzyl;
• R 6 is H or F or R 6 combines with X 1 to form a moiety of the formula:
• X 2 is O or NR 7 ;
• the present invention also relates to a compound of formula III:
• X 2 is O or NR 7 ;
• R 8 is OH, O(C 1 -C 6 alkyl), S(C 1 -C 6 alkyl) or NR 4 (CO 2 (C 1 -C 6 alkyl))
• Z is C ⁇ O or CHOH
• R 7 is H, C 1 -C 6 alkyl or CO 2 (C 1 -C 6 alkyl); useful as an intermediate to a compound of formula I where R 6 combines with X 1 .
• the compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates; mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.
• halo refers to fluoro, chloro, bromo and iodo.
• C 1 -C 6 alkyl represents a straight, branched or cyclic hydrocarbon moiety having from one to six carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl and the like.
• Moieties such as a cyclobutylmethylenyl and cyclopropylmethyleneyl are also included within the scope of a C 1 -C 6 alkyl group.
• C 1 -C 4 alkyl refers specifically to methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclopropylmethyl and cyclobutyl.
• n-C 4 -C 6 alkyl refers specifically to n-butyl, n-pentyl and n-hexyl.
• a “C 1 -C 6 alkoxy” group is a C 1 -C 6 alkyl moiety connected through an oxy linkage.
• a pharmaceutical “acid addition salt” is a salt formed by reaction of the free base form of a compound of formula I with a pharmaceutical acid, such as described in the Encyclopedia of Pharmaceutical Technology, editors James Swarbrick and James C. Boylan, Vol 13, 1996 “Preservation of Pharmaceutical Products to Salt Forms of Drugs and Absorption”.
• Specific salt forms include, but are not limited to the: acetate, benzoate, benzenesulfonate, 4-chlorobenzenesulfonate; citrate; ethanesulfonate; fumarate; d-gluconate; d-glucuronate; glutarate; glycolate; hippurate; hydrochloride; 2-hydroxyethanesulfonate; dl-lactate; maleate; d-malate; 1-malate; malonate; d-mandelate; 1-mandelate; methanesulfonate; 1,5 napthalenedisulfonate; 2-naphthalenesulfonate; phosphate; salicylate; succinate; sulfate; d-tartrate; 1-tartrate; and p-toluenesulfonate.
• treating means alleviating, ameliorating, preventing, prohibiting, restraining, slowing, stopping, or reversing the progression or severity of a pathological condition, or sequela thereof, described herein.
• preventing means reducing the likelihood that the recipient of a compound of formula I will incur, further incur or develop any of the pathological conditions, or sequela thereof, described herein.
• a “vasomotor symptom” is a condition selected from the list of: hot flash, night sweats, vaginal dryness, sleep disturbances, nausea and mood swings; wherein said condition results from a decrease of circulating endogenous estrogen that occurs in a woman following cessation or reduction of menstration due to natural, surgical, or other processes.
• woman in need thereof is a woman either suffering from the claimed pathological condition, or is a woman at a recognized risk thereof, as determined by medical diagnosis, i.e., as determined by the attending physician.
• the term “effective amount” means an amount of a compound of formula I that is capable of treating the conditions described herein.
• Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column (see, e.g., J. Jacques, et al., “ Enantiomers, Racemates, and Resolutions” , John Wiley and Sons, Inc., 1981; E. L. Eliel and S. H. Wilen, “ Stereochemistry of Organic Compounds” , (Wiley-Interscience 1994), and European Patent Application No. EP-A-838448, published Apr. 29, 1998).
• the preferred enantiomer is that which possesses favorable activity in the biological assays disclosed herein.
• the preferred enantiomer typically possesses the slower retention time, i.e., elutes second.
• the activity of the individual isomers should be verified in the biological assays described herein.
• the compound of formula I is preferably employed in the treatment of hot flashes.
• the compound of formula I is preferably formulated in a dosage unit form, i.e.; in an individual delivery vehicle, for example, a tablet or capsule, prior to administration to the recipient woman.
• the compound of formula I is preferably administered orally.
• the compound of formula I may be prepared as described in the following Scheme (where R 8a is R 8 , H, or F), Preparations and Examples.
• the keto group may be reduced under standard conditions, e.g., employing borane to provide the corresponding benzyl alcohol.
• This reduced product may be cyclized under standard conditions, e.g., when R 8a is F, base catalyzation with potassium t-butoxide or when R 8a is other than F, acid catalyzation with HCl, to provide the corresponding compound of formula I or II.
• the keto group may be reduced under conditions that promote the cyclization reaction thus performing both steps in “one-pot” (see, e.g., Examples 96 and 108 below).
• R 1a is SO 2 CH 3 , C 1 -C 6 alkyl or benzyl (preferably methyl, benzyl or SO 2 CH 3 ) said hydroxy protecting groups may be removed under standard conditions (see, e.g., the procedures that follow or the latest edition of Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, N.Y.) to provide the compound of formula I where R 1 is H.
• X 2 is NR 7 and R 7 is CO 2 (C 1 -C 6 alkyl)
• said amino protecting group may also be removed as taught in the Greene.
• a formula I compound where R 1 is H may be further derivatized employing standard acylation or sulfonylation methodology to prepare a compound of formula I where R 1 is COR 2 or SO 2 (n-C 4 -C 6 alkyl).
• Compounds of formula IV may be prepared as shown below or by procedures analogous to those found in the art.
• Compounds of formula V are, in general, commercially available or can be prepared by procedures readily available to the ordinarily skilled synthetic organic chemist or as shown below.
• Conditions B 3:2 heptane/IPA w/0.2% DMEA, 8 ⁇ 30 cm, 365 nm, 350 ml/min.
• Conditions C 80/10/10 heptane/3A/MeOH w/0.2% DMEA, 8 ⁇ 34 cm, 260 nm, 375 ml/min.
• Conditions F 4:1 heptane/IPA w/0.2% DMEA, 8 ⁇ 30 cm, 350 nm, 350 ml/min.
• Conditions K 70/30 heptane/IPA w/0.2% DMEA, 8 ⁇ 34 cm, 320 nm, 350 ml/min.
• Conditions Q 70/30 heptane/IPA w/0.2% DMEA, 8 ⁇ 30 cm, 260 nm, 350 ml/min.
• Trifluoromethanesulfonic acid 6-benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester
• Trifluoromethanesulfonic acid 6-methanesulfonyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester
• Preparative HPLC's may be obtained, e.g., on a Mass Guided Waters Preparative System using a 20 ⁇ 100 mm C18 Symmetry column.
• the eluent is a binary system of bottle and bottle A (0.1% trifluoroacetic acid in water) B (0.1% trifluoroacetic acid in acetonitrile).
• the standard method is a gradient of 10-95% B.
• a compound of formula I contains a basic moiety (i.e., amino)
• said compound may be formulated as a pharmaceutical acid addition salt, e.g., as the hydrochloride salt or as a salt described in “Handbook of Pharmaceutical Salts: Properties, Selection and Use”, Weinheim, N.Y.: VHCA; Wiley-VCH, 2002.
• the active ingredient (a formula I compound) will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
• a carrier which may be in the form of a capsule, sachet, paper or other container.
• the carrier selves as a diluent, it may be a solid, semisolid or liquid material that acts as a vehicle, excipient or medium for the active ingredient.
• Suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral oil.
• the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
• Ishikawa Cell Proliferation Assay measures cell proliferation (using an alkaline phosphatase readout) in both an agonist mode in the presence of a compound of the present invention alone, and in an antagonist mode in which the ability of a compound of the present invention to block estradiol stimulation of growth is measured.
• Ishikawa human endometrial tumor cells are maintained in MEM (minimum essential medium, with Earle's salts and L-Glutamine, Gibco BRL, Gaithersburg, Md.), supplemented with 10% fetal bovine serum (FBS) (V/V), (Gibco BRL).
• MEM minimum essential medium, with Earle's salts and L-Glutamine, Gibco BRL, Gaithersburg, Md.
• FBS fetal bovine serum
• V/V fetal bovine serum
• DMEMRF-12 Dulbecco's Modified Eagle Medium: Nutrient Mixture F-12, 3:1 Mixture, phenol red-free, Gibco BRL
• DCC-FBS dextran coated charcoal stripped fetal bovine serum
• L-Glutamine 2 mM
• MEM sodium pyruvate 1 mM
• HEPES N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid] 2 mM
• Ishikawa cells are rinsed with Dulbecco's Phosphate Buffered Saline (1 ⁇ ) (D-PBS) without Ca +2 and Mg +2 (Gibco BRL), and trypsinized by a 3 minute incubation with 0:25% Trypsin/EDTA, phenol red-free (Gibco BRL).
• Cells are resuspended in assay medium and adjusted to 250,000 cells/mL. Approximately 25,000 cells in a 100 ul media are added to flat-bottom 96 wells microculture plates (Costar 3596) and incubated at 37° C. in a 5% CO 2 humidified incubator for 24 hours. The next day, serial dilutions of compounds are prepared in assay medium (at 6 times the final concentration in the assay). The assay is run in dual mode, agonist and antagonist modes.
• plates receive 25 ⁇ l/well of assay medium followed by 25 ⁇ l/well of a diluted compound of the present invention (at 6 ⁇ the final concentrations).
• plates receive 25 ⁇ l/well of 6 nM E 2 ( ⁇ -Estradiol, Sigma, St. Louis, Mo.) followed by 25 ⁇ l/well of a diluted compound of the present invention (at 6 ⁇ the final concentrations).
• media is aspirated from wells and 100 ⁇ l fresh assay medium is added to each microculture. Serial dilutions of compounds are prepared and added to the cells as described above. After an additional 72 hour incubation at 37° C.
• the assay is quenched by removing media and rinsing plates twice in Dulbecco's Phosphate Buffered Saline (1 ⁇ ) (D-PBS) (Gibco BRL). The plates are dried for 5 minutes and frozen at ⁇ 70° C. for at least 1 hour. The plates are then removed from the freezer and allowed to thaw at room temperature. To each well, 100 IA of 1-StepTM PNPP (Pierce Chemical Company, Rockford, Ill.) is added. After a 20-minute incubation, plates are read on a spectophotometer at 405 nm.
• the data is fitted to a linear interpolation to derive EC50 (for agonist mode) or IC50 (for antagonist mode) values.
• EC50 for agonist mode
• IC50 for antagonist mode
• a % efficacy for each compound is calculated versus E2 (1 nM) alone.
• a % efficacy for each compound is calculated versus the response to tamoxifen.
• This model for uterine antagonism utilizes immature (3 week old) female rats that are highly sensitive to estrogenic stimulation of the uterus given that their circulating estrogen levels are prepubertal.
• the uteri from immature rats are fully responsive to exogenous estrogen, yet are quiescent in the absence of exogenous estrogen.
• Administration of exogenous estrogen to immature rats produces a reliable elevation of uterine weight, which can be used to study uterine antagonist effects.
• the rats are treated with both estradiol and 4 different concentrations of a compound of the present invention for 3 days and then uterine wet weights are measured.
• E2 0.1 mg/kg, a maximal stimulatory estrogenic stimulus for reliably increasing uterine weight
• test compounds are dissolved in 20% ⁇ -hydroxycyclodextrin and administered by oral gavage in a volume of 0.2 mL daily (15 min. prior to the ethynyl estradiol gavage).
• a vehicle control, E2 alone and E2+raloxifene are also done as controls.
• the animals are fasted overnight following the final dose. On the following morning, the animals are weighed, then euthanized (by carbon dioxide asphyxiation) and the uteri rapidly collected (via a mid-line ventral incision) and weighed.
• Uterine weight/body weight ratios are calculated for each animal.
• ED 50 values are derived from a semi-log regression analysis of the linear aspect of the dose response curve. Both the UWR data and the percent inhibition data are statistically analyzed by one way analysis of variance (ANOVA) with post-hoc testing by Fisher's PLSD when indicated by a p ⁇ 0.05. Statistical analyses are performed using the Statview® 4.0 software package.
• Morphine withdrawal, rat hot flash model Simpkins et al. (1983) first published morphine withdrawal in the rat as a putative model for hot flashes, based on observations highlighting the similarity of symptoms of gonadal steroid withdrawal to those of opioid withdrawal. Although less severe, the signis and symptoms associated with clinical hot flashes, or estrogen deficiency, in the rat parallel those produced by naloxone-precipitated withdrawal in morphine dependent rats, including: 1) an increase in tail skin temperature, 2) a surge in luteinizing hormone and 3) an increase in heart rate. Each of these responses are associated with an increase in-sympathetic outflow, which is a current mechanistic hypothesis for hot flashes.
• morphine addicted humans show a withdrawal pattern suggesting increased sympathetic outflow and symptoms that include hot flashes.
• the morphine withdrawal hot flash model is responsive to agents typically used in the treatment of human hot flashes. This includes various forms of estrogen (Simpkins et al., 1983; LRL data), clonidine (LRL data), tibolone (LRL data), and medroxyprogesterone (LRL data).
• the model is sensitive to agents known to be associated with the induction of hot flashes in postmenopausal women.
• a modification of the original procedure of Simpkins et al. (1983) is used which employs ovariectomized Sprague-Dawley rats. Animals at 60 days of age (or 200-225 grams) are ovariectomized, and allowed a 14-day rest period to insure surgical recovery and clearance of endogenous ovarian hormones. Administration of a compound of the present invention (po or sc) is initiated on day 14 post-ovariectomy in a volume of 1 ml/kg. Once daily administration of test compound continues through the end of the experiment. On days 15 and 17 post-ovariectomy, the rats are lightly anesthetized with isoflurane and a single 75 mg morphine (free base) pellet is surgically implanted subcutaneously.
• ketamine 80 mg/kg; IM
• rats are then placed in individual plexiglass cages and temperature sensitive probes are applied to the dorsal side of the tail base. Temperature monitoring is initiated 30 minutes after administration of ketamine and is recorded every 15 seconds for a 1-hr period.
• naloxone is given subcutaneously 15 minutes after start of temperature monitoring sharp rise in tail skin temperature typically occurs within 5 minutes post-naloxone injection, and two quantitative endpoints are made: 1) tail skin temperature at 15 min post-naloxone, and 2) area under the temperature response curve for the 45-min post-naloxone measurement period. Following the 1-hour temperature collection period, the animals are sacrificed by decapitation and trunk blood is collected for assessment of serum LH levels (by ELISA). Uteri are also removed at this time, and wet weight recorded.
• Representative compounds of formula I were tested at or below 30 mg/kg PO and caused an attenuation of tail skin temperature increase, as measured by temperature change 15 minutes post naloxone injection OT AUC over 45 minutes post naloxone administration.
• the compound of formula I is useful in the treatment of vasomotor symptoms, particularly hot flashes, in a woman, particularly a post-menopausal woman.
• the compounds of the present invention are employed in a woman who has suffered at least one vasomotor symptom event.
• the compounds of the present invention are most typically employed to reduce the likelihood that the patient will further incur vasomotor symptoms.
• the specific dose administered is determined by the particular circumstances surrounding each situation. These circumstances include, the route of administration, the prior medical history of the recipient, the symptom being treated, the severity of the symptom being treated, and the age of the recipient. The recipient patient's attending physician should determine the therapeutic dose administered in light of the relevant circumstances.
• an effective minimum daily dose of a compound of formula I will exceed about 5 mg. Typically, an effective maximum daily dose will not exceed about 350 mg.
• the exact dose may be determined, in accordance with the standard practice in the medical arts of “dose titrating” the recipient; that is, initially administering a low dose of the compound, and gradually increasing the dose until the desired therapeutic effect is observed.

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