EP2125719A1 - Bis-phosphorates de bazédoxifène - Google Patents

Bis-phosphorates de bazédoxifène

Info

Publication number
EP2125719A1
EP2125719A1 EP08730988A EP08730988A EP2125719A1 EP 2125719 A1 EP2125719 A1 EP 2125719A1 EP 08730988 A EP08730988 A EP 08730988A EP 08730988 A EP08730988 A EP 08730988A EP 2125719 A1 EP2125719 A1 EP 2125719A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
arylalkyl
aryl
heterocycloalkyl
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.)
Withdrawn
Application number
EP08730988A
Other languages
German (de)
English (en)
Inventor
Mahdi B. Fawzi
Tianmin Zhu
Weitao Pan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth LLC
Original Assignee
Wyeth LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wyeth LLC filed Critical Wyeth LLC
Publication of EP2125719A1 publication Critical patent/EP2125719A1/fr
Withdrawn legal-status Critical Current

Links

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
    • 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
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P5/30—Oestrogens
    • 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
    • A61P5/32—Antioestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • This disclosure relates to bis-phosphoric acid esters of the selective estrogen receptor modulator 1 -[4-(2-azepan-1 -yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1 H- indol-5-ol (bazedoxifene), as well as compositions thereof, preparations thereof and uses thereof.
  • Bazedoxifene (1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3- methyl-1 H-indol-5-ol; or apeldoxifene free base), having the chemical formula shown below:
  • SARMs selective estrogen receptor modulators
  • bazedoxifene and its salts demonstrate affinity for estrogen receptors (ER) but show tissue selective estrogenic effects.
  • ER estrogen receptors
  • bazedoxifene acetate demonstrates little or no stimulation of uterine response in preclinical models of uterine stimulation.
  • bazedoxifene acetate demonstrates an estrogen agonist-like effect in preventing bone loss and reducing cholesterol in an ovariectomized rat model of osteopenia.
  • MCF-7 cell line human breast cancer cell line
  • This disclosure provides bis-phosphoric acid esters of apeledoxifene (bazedoxifene bis-phosphorates) and pharmaceutical compositions containing the same. [0007] Certain embodiments provide methods of preparing apeledoxifene bis- phosphorates.
  • kits for treating a disease, condition or disorder associated with estrogen deficiency or excess of estrogen in a mammal in need thereof which comprise administering an effective dose of a doxifene bis-phosphorate, or a pharmaceutically acceptable salt or hydrate thereof.
  • Some embodiments provide methods of treating a disease or disorder associated with proliferation or abnormal development of endometrial tissues in a mammal in need thereof, which comprise administering an effective dose of a doxifene bis-phosphorate, or a pharmaceutically acceptable salt or hydrate thereof.
  • Some embodiments provide methods of contraception in a mammal in need thereof, which comprise administering an effective dose of a doxifene bis-phosphorate, or a pharmaceutically acceptable salt or hydrate thereof.
  • Some embodiments provide methods of lowering cholesterol in a mammal in need thereof, which comprise administering an effective dose of a boledoxifene bis- phosphorate, or a pharmaceutically acceptable salt or hydrate thereof. [0012] Some embodiments provide methods of treating one or more vasomotor disturbances in a mammal in need thereof, which comprise administering an effective dose of a doxifene bis-phosphorate, or a pharmaceutically acceptable salt or hydrate thereof.
  • Some embodiments provide methods of inhibiting or retarding bone demineralization or treating or inhibiting osteoporosis in a postmenopausal or estrogen deficient woman in need thereof, which comprise administering an effective dose of a apeledoxifene bis-phosphorate, or a pharmaceutically acceptable salt or hydrate thereof, and conjugated estrogens.
  • Some embodiments provide methods of treating or inhibiting menopausal or postmenopausal disorders in a postmenopausal or estrogen deficient woman in need thereof, which comprise administering an effective dose of a adoxifene bis-phosphorate, or a pharmaceutically acceptable salt or hydrate thereof, and conjugated estrogens. [0015] Some embodiments provide methods of inhibiting bone loss in a mammal in need thereof, which comprise administering an effective dose of a apeledoxifene bis-phosphorate, or a pharmaceutically acceptable salt or hydrate thereof.
  • Some embodiments provide methods of treating breast cancer in a mammal in need thereof, which comprise administering an effective dose of a doxifene bis- phosphorate, or a pharmaceutically acceptable salt or hydrate thereof.
  • Certain embodiments provide compounds which are bis-phosphoric acid esters of apeledoxifene (bazedoxifene bis-phosphorates) having the structure of Formula I:
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, a protecting group, Ci- io alkyl, Ci_i 0 haloalkyl, C 2 -io alkenyl, C 2- io alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of said Ci_i 0 alkyl, Ci_i 0 haloalkyl, C 2 -io alkenyl, C 2 _io alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by 1 , 2, 3, 4 or 5 R 5 ;
  • each R a is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 2-6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of said Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 2 . 6 alkenyl, C 2 .
  • 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by OH, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, amino, halo, Ci_e alkyl, Ci -6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
  • each R b is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 6 alkenyl, C 2 - 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of said Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 6 alkenyl, C 2 .
  • 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by OH, Ci_ 6 alkoxy, Ci -6 haloalkoxy, amino, halo, C 1-6 alkyl, Ci -6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; and
  • R c and R d are each, independently, selected from H, C 1-I0 alkyl, Ci -6 haloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of said C 1-I0 alkyl, Ci -6 haloalkyl, C 2 . 6 alkenyl, C 2 .
  • 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by OH, C 1-6 alkoxy, Ci -6 haloalkoxy, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
  • R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, a protecting group, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of said C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalky is optionally substituted by 1 , 2, 3, 4 or 5 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 2-10 alken
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, a protecting group, C 1 - 10 alkyl, C 1 - 10 haloalkyl, C 2 -io alkenyl, C 2 -io alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of said Ci_i 0 alkyl, C 1-10 haloalkyl, C 2 _ 10 alkenyl, d- 10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by 1 , 2 or 3 substituents independently selected from halo,
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, a protecting group, C 1 - I o alkyl, C 1- - I0 haloalkyl, C 2 . 10 alkenyl, C 2 . 10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, a protecting group, Ci-i 0 alkyl and Ci-i 0 haloalkyl. In some embodiments, R 1 , R 2 , R 3 , and R 4 are each independently selected from H, a protecting group, C 1-6 alkyl and C 1-6 haloalkyl. [0029] In some embodiments, R 1 , R 2 , R 3 and R 4 are each independently selected from H, a protecting group and C 1-6 alkyl. In some embodiments, R 1 , R 2 , R 3 , and R 4 are each independently selected from H, a protecting group, and d_ 4 alkyl.
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from H and tert-butyl. In some embodiments, R 1 , R 2 , R 3 , and R 4 are each C 1-6 alkyl. In some embodiments, R 1 , R 2 , R 3 , and R 4 are each tert-butyl.
  • the compounds of this disclosure have the structure of Formula Ia:
  • the compounds of this disclosure have the structure of
  • substitution means that substitution is optional and therefore it is possible for the designated atom or moiety to be unsubstituted. In the event a substitution is desired then such substitution means that any number of hydrogens on the designated atom or moiety is replaced with a selection from the indicated group, provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group (i.e., CH 3 ) is optionally substituted, then from 1 up to 3 hydrogens on the carbon atom can be replaced.
  • a methyl group i.e., CH 3
  • alkyl As used herein, “alkyl”, “alkylenyl” or “alkylene” used alone or as a suffix or prefix, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended.
  • “Ci -6 alkyl” denotes alkyl having 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl, or any subset thereof.
  • "Ci_ 3 alkyl” whether a terminal substituent or an alkylene (or alkylenyl) group linking two substituents, is understood to specifically include both branched and straight-chain methyl, ethyl, and propyl.
  • alkenyl refers to an alkyl group having one or more double carbon-carbon bonds.
  • exemplary alkenyl groups include ethenyl, propenyl, and cyclohexenyl.
  • alkenylenyl refers to a divalent linking alkenyl group.
  • alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds.
  • Exemplary alkynyl groups include ethynyl and propynyl.
  • alkynylenyl refers to a divalent linking alkynyl group.
  • aromatic refers to groups having one or more polyunsaturated rings having aromatic character (e.g., 4n + 2 delocalized electrons) and having up to about 20 ring-forming atoms.
  • aryl refers to an aromatic ring structure made up of from 5 to 14 carbon atoms. Ring structures containing 5, 6, 7 and 8 carbon atoms would be single-ring aromatic groups, for example, phenyl. Ring structures containing 8, 9, 10, 1 1 , 12, 13, or 14 would be a polycyclic moiety in which at least one carbon is common to any two adjoining rings therein (for example, the rings are "fused rings"), for example naphthyl.
  • aryl also includes polycyclic ring systems having two or more adjoining rings in which two or more carbons are common (the rings are "fused rings"), wherein at least one of the rings is aromatic (for example, the other ring(s) can be cycloalkyl, cycloalkenyl or cycloalkynyl).
  • ortho, meta and para apply to 1 ,2-, 1 ,3- and 1 ,4-disubstituted benzenes, respectively.
  • the names 1 ,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
  • cycloalkyl refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and/or alkynyl groups, having the specified number of carbon atoms (wherein the ring structure has 3 to 20 ring-forming carbon atoms). Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused or bridged rings) groups.
  • Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, and adamantyl.
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane (i.e., indanyl), cyclopentene, and cyclohexane.
  • heterocyclyl or “heterocyclic” or “heterocycle” refers to ring-containing monovalent and divalent structures having one or more heteroatoms, independently selected from N, O and S, as part of the ring structure and having from 3 to 20 ring-forming atoms, for example making up 3- to 7- membered rings.
  • Heterocyclic groups may be saturated or partially saturated or unsaturated, containing one or more double bonds, and heterocyclic groups may contain more than one ring as in the case of polycyclic systems. If specifically noted, nitrogen in the heterocyclyl may optionally be quatemized. It is understood that when the total number of S and O atoms in the heterocyclyl exceeds 1 , then these heteroatoms are not adjacent to one another.
  • heterocyclyls include, but are not limited to, 1 H-indazole, 2-pyrrolidonyl, 2H, 6H-1 , 5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1 , 2,5-thiadiazinyl, acridinyl, azabicyclo, azetidine, azepane, aziridine, azocinyl, benzimidazolyl, benzodioxol, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazoly
  • heteroaryl refers to an aromatic heterocycle (wherein the ring structure has up to about 20 ring-forming atoms) having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems.
  • heteroaryl groups include without limitation, pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (i.e., furanyl), quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1 ,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, and indolinyl.
  • pyridyl i.e., pyridinyl
  • pyrimidinyl pyrazinyl
  • the heteroaryl group has from 1 to about 20 ring-forming atoms, and in further embodiments from about 3 to about 20 ring-forming atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heteroaryl group has 1 heteroatom.
  • heterocycloalkyl refers to non-aromatic heterocycles (wherein the ring structure has about 3 to about 20 ring-forming atoms) including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom.
  • Heterocycloalkyl groups can be mono or polycyclic (e.g., fused-, bridged- and spiro- systems).
  • Suitable "heterocycloalkyl” groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3- dihydrobenzofuryl, 1 ,3-benzodioxole, benzo-1 ,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, and imidazolidinyl.
  • Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido.
  • Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non- aromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indolene and isoindolene groups.
  • the heterocycloalkyl group has from about 3 to about 20 ring-forming atoms.
  • the heterocycloalkyl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring- forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.
  • alkoxy or "alkyloxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy, cyclopropylmethoxy, allyloxy and propargyloxy.
  • alkylthio or “thioalkyl” represent an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
  • amino refers to NH 2 .
  • alkylamino refers to an amino group substituted by an alkyl group.
  • dialkylamino refers to an amino group substituted by two alkyl groups.
  • halo or halogen includes fluoro, chloro, bromo, and iodo.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • exemplary haloalkyl groups include CF 3 , C 2 F 5 , CH 2 CF 3 , CHF 2 , CCI 3 , CHCI 2 , and C 2 CI 5 .
  • perhaloalkyl is intended to denote an alkyl group in which all of the hydrogen atoms are replaced with halogen atoms.
  • perhaloalkyl groups include
  • perfluoroalkyl is intended to denote an alkyl group in which all of the hydrogen atoms are replaced with fluorine atoms.
  • perfluoroalkyl is CF 3
  • haloalkoxy refers to an -O-haloalkyl group.
  • An example of a haloalkoxy group is OCF 3 .
  • aryloxy refers to -O-aryl.
  • An example of an aryloxy group is phenoxy.
  • heteroaryloxy refers to -O-heteroaryl.
  • An example of a heteroaryloxy group is pyridine-2-yloxy [i.e., -O-(pyridine-2-yl)].
  • arylalkyl refers to Ci_io alkyl substituted by aryl
  • cycloalkylalkyl refers to Ci_ 10 alkyl substituted by cycloalkyl.
  • An example of an arylalkyl group is benzyl.
  • heteroarylalkyl refers to Ci_i 0 alkyl substituted by heteroaryl
  • heterocycloalkylalkyl refers to CM O alkyl substituted by heterocycloalkyl.
  • arylalkyloxy refers to -O-(arylalkyl) and "heteroarylalkyloxy” refers to -O-(heteroarylalkyl).
  • An example of an arylalkyloxy group is benzyloxy and an example of a heteroarylalkyloxy group is (pyridin-2-yl)-methoxy.
  • the compounds of the disclosure may be derivatised in various ways.
  • derivatives of the compounds include salts (e.g., pharmaceutically acceptable salts), any complexes (e.g., inclusion complexes or clathrates with compounds such as cyclodextrins, or coordination complexes with metal ions such as Mn 2+ and Zn 2+ ), esters such as in vivo hydrolysable esters, polymorphic forms of the compounds, solvates (e.g., hydrates), or lipids, and compounds having coupling partners and protecting groups (such as protecting groups for amino and/or hydroxyl groups).
  • salts e.g., pharmaceutically acceptable salts
  • any complexes e.g., inclusion complexes or clathrates with compounds such as cyclodextrins, or coordination complexes with metal ions such as Mn 2+ and Zn 2+
  • esters such as in vivo hydrolysable esters
  • polymorphic forms of the compounds solv
  • protecting group means a temporary substituent which protects a potentially reactive functional group from undesired chemical transformations.
  • Non-limiting examples of such protecting groups include esters of phosphoric acids, esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones respectively.
  • the field of protecting group chemistry has been reviewed (see, e.g., Greene, T. W. and Wuts, P. G. M. Protective Groups in Organic Synthesis, 3 rd Ed.; Wiley & Sons, 1999, which is incorporated herein by reference in its entirety), and protecting groups are well known to those skilled in the art.
  • the compounds of this disclosure are intended to be stable compounds (compounds with stable structure).
  • stable compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • a variety of compounds in this disclosure may exist in particular stereoisomeric forms. This disclosure takes into account all such compounds, including cis- and trans isomers, R- and S- enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this disclosure. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this disclosure. The compounds herein described may have asymmetric centers. Compounds of this disclosure containing an asymmetrically substituted atom may be isolated in optically active or racemic forms.
  • tautomer means other structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom. For example, keto-enol tautomerism where the resulting compound has the properties of both a ketone and an unsturated alcohol.
  • This disclosure further includes isotopically-labeled compounds of the disclosure.
  • radionuclides that may be incorporated in compounds of this disclosure include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 CI, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I, or any subset thereof.
  • the radionuclide is selected from the group consisting of 3 H, 14 C, 125 I , 35 S and 82 Br.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro receptor labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 I , 131 1, 35 S or will generally be most useful. For radio-imaging applications 11 C, 18 F, 125 1, 123 I, 124 I, 131 1, 75 Br, 76 Br or 77 Br will generally be most useful.
  • salts of the compounds are physiologically well tolerated and non toxic. Many examples of salts are known to those skilled in the art. All such salts are within the scope of various embodiments, and references to compounds include the salt forms of the compounds.
  • Compounds having acidic groups can form salts with alkaline or alkaline earth metals such as Na, K, Mg and Ca, and with organic amines such as triethylamine and Tris (2-hydroxyethyl)amine. Salts can be formed from compounds with basic groups, e.g. amines, with inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as acetic acid, citric acid, benzoic acid, fumaric acid, or tartaric acid. Compounds having both acidic and basic groups can form internal salts.
  • alkaline or alkaline earth metals such as Na, K, Mg and Ca
  • organic amines such as triethylamine and Tris (2-hydroxyethyl)amine.
  • Salts can be formed from compounds with basic groups, e.g. amines, with inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as acetic acid, citric acid
  • Acid addition salts may be formed with a wide variety of acids, both inorganic and organic.
  • Examples of acid addition salts include salts formed with hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic, toluenesulphonic, methanesulphonic, ethanesulphonic, naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids.
  • a salt may be formed with a cation as counterion.
  • cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ , as well as ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
  • Non-limiting examples of substituted ammonium ions include those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
  • the compounds may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of this disclosure.
  • acid addition salts may also be formed with a wide variety of acids, both inorganic and organic.
  • acid addition salts include salts formed with hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic, toluenesulphonic, methanesulphonic, ethanesulphonic, naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids.
  • Counterions are from the acids used (e.g., when hydrochloric acid is used, the counterion will be chloride).
  • Counterion is used to represent a small, negatively or positively charged species such as chloride (Cl ), bromide (Br ), hydroxide (OH ), acetate (CH 3 COO ) , sulfate (SO 4 2 ), tosylate (CH 3 -phenyl-SO 3 ), benezensulfonate (phenyl-SO 3 ), sodium ion (Na + ), potassium (K + ), and ammonium (NH 4 + ).
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof (i.e., also including counterions). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric and phosphoric; and the salts prepared from organic acids such as lactic, maleic, citric, benzoic, and methanesulfonic.
  • the pharmaceutically acceptable salts can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile can be used.
  • N-oxides Compounds containing an amine function may also form N-oxides.
  • a reference herein to a compound that contains an amine function also includes the N-oxide.
  • one or more than one nitrogen atom may be oxidised to form an N-oxide.
  • Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid); see, for example, March, J.
  • N-oxides can be made by the procedure of Deady, L. W. Syn. Comm., 1977, 7, 509-514 in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
  • MCPBA m-chloroperoxybenzoic acid
  • Esters can be formed between hydroxyl or carboxylic acid groups present in the compound and an appropriate carboxylic acid or alcohol reaction partner, using techniques well known in the art.
  • R is an acyloxy substituent, for example, a C 1-7 alkyl group, a C 3 . 2 o heterocyclyl group, or a C 5 - 20 aryl group.
  • Derivatives which are prodrugs of the compounds are convertible in vivo or in vitro into one of the parent compounds.
  • prodrug form of the compound typically, at least one of the biological activities of compound will be reduced in the prodrug form of the compound, and can be activated by conversion of the prodrug to release the compound or a metabolite of it.
  • Some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group is cleaved to yield the active drug.
  • R
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) and ligand-directed enzyme prodrug therapy (LIDEPT)).
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • Other derivatives include coupling partners of the compounds in which the compound is linked to a coupling partner, e.g., by being chemically coupled to the compound or physically associated with it.
  • coupling partners include a label or reporter molecule, a supporting substrate, a carrier or transport molecule, an effector, a drug, an antibody or an inhibitor.
  • Coupling partners can be covalently linked to compounds of this disclosure via an appropriate functional group on the compound such as a hydroxyl group, a carboxyl group or an amino group.
  • Other derivatives include formulating the compounds with liposomes.
  • R b is Ci -8 alkyl, aryl (optionally substituted by one or more halo, cyano, nitro, C 1 - 4 alkyl, Ci_ 4 haloalkyl, Ci_ 4 alkoxy, or Ci_ 4 haloalkoxy), or heteroaryl (optionally substituted by one or more halo, cyano, nitro, C 1 . 4 alkyl, Ci. 4 haloalkyl, C r C 4 alkoxy, or Ci. 4 haloalkoxy), and R c is Ci -8 alkyl.
  • Exemplary leaving groups include chloro, bromo, iodo, 4- nitrophenylcarbonate, mesylate, tosylate, and trimethylsilyl.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C NMR), infrared spectroscopy (IR), spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C NMR), infrared spectroscopy (IR), spectrophotometry (e.g., UV-visible), or mass spectrometry
  • chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • Preparation of compounds can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Greene, T. W. and Wuts, P. G. M. Protective Groups in Organic Synthesis, 2 nd Ed.; Wiley & Sons, 1991 , which is incorporated herein by reference in its entirety.
  • the reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • the compounds can be prepared, for example, using the reaction pathways and techniques as described below.
  • R 1 and R 2 are each independently selected from a protecting group, C 1-10 alkyl, C 1- - I0 haloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C 1 ⁇ 0 alkyl, C 1 ⁇ 0 haloalkyl, C 2 _i 0 alkenyl, C 2 _i 0 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by 1 , 2, 3, 4 or 5 R 5 ; each R 5 is independently halo, Ci -6 alky
  • R 6 and R 7 are each independently selected from C 1- - I0 alkyl, C 1-6 haloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, each optionally substituted by 1 , 2, 3, 4 or 5 R 5 ; or R 6 and R 7 together with the N atom to which they are attached form a A-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1 , 2, 3, 4 or 5 R 5 ; each R a is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2 .
  • each R b is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2 _e alkenyl, C 2 _e alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of
  • 6 alkenyl, C 2 . 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by OH, C- ⁇ -6 alkoxy, Ci -6 haloalkoxy, amino, halo, Ci- 6 alkyl, Ci_ 6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; and
  • R c and R d are each, independently, selected from H, Ci_io alkyl, Ci -6 haloalkyl, C 2 -e alkenyl, C 2 - ⁇ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of said d_i 0 alkyl, Ci -6 haloalkyl, C 2 - ⁇ alkenyl, C 2 -e alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by OH, Ci_ 6 alkoxy, Ci -6 haloalkoxy, amino, halo, Ci -6 alkyl, Ci -6
  • R 1 and R 2 are each independently selected from a protecting group, C- M0 alkyl and cycloalkyl.
  • R 6 and R 7 are each independently selected from C 1-10 alkyl and cycloalkyl, or R 6 and R 7 together with the N atom to which they are attached form a hetercycloalkyl optionally substituted by one or more Ci -6 alkyl substituents, e.g., methyl or ethyl, or Ci -6 alkoxy substituents.
  • Suitable protecting groups include those for hydroxyl groups, examples of which can be found, for example, in Greene, T. W. and Wuts, P. G. M.
  • the bis-(phosphorous acid tri-ester) intermediate 1-3 is oxidized to the corresponding bis-(phosphoric acid tri-ester) 1-4 by an oxidizing reagent (e.g., hydrogen peroxide).
  • an oxidizing reagent e.g., hydrogen peroxide
  • the excess oxidizing reagents are removed by suitable methods such as using a reducing reagent (e.g., sodium metabisulfate) during the work-up procedure (e.g., when isolating and/or purifying the product).
  • a reducing reagent e.g., sodium metabisulfate
  • the bis-(phosphoric acid tri- ester) 1-4 is (partially) hydrolyzed under appropriate conditions, such as under acidic conditions (e.g., in the presence of an inorganic acid such as HCI), to afford the bis- phosphoric acid mono-ester) 1-5.
  • the apeledoxifene di-phosphorate 3-5 is synthesized starting from 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3- methyl-1 H-indol-5-ol (bazedoxifene free base, compound 3-1 ).
  • Compound 3-1 is reacted with 2 or more molar equivalents of phosphorous oxytrihalide 3-2 (wherein each X 1 is independently halo, such as chloro or bromo) in the presence of a suitable organic base (such as pyridine) and a suitable inorganic base (such as alkali metal carbonate, e.g., Na 2 CO 3 ) to form a mixed ester-halide intermediate 3-3.
  • a suitable organic base such as pyridine
  • a suitable inorganic base such as alkali metal carbonate, e.g., Na 2 CO 3
  • the amount of phosphorous oxytrihalide 3-2 used is about 2 to about 4, about 2 to about 3, about 2.0 to about 2.5, or about 2.5 to about 3.0 molar equivalents to that of compound 3-1.
  • the organic base is selected from tertiary amines such as trialkylamines [e.g., triethylamine (“TEA”), diisopropylethylamine (“DIPEA”)], cyclic amines [e.g., 1 ,4-diazabicyclo[2.2.2]octane (“DABCO”), diaza(1 ,3)bicyclo[5.4.0]undecane (“DBU”)], aromatic amines (e.g., triphenylamine), dimethylaminopyridine (DMAP) and heteroaromatic amines (e.g., pyridine and lutidine).
  • TAA triethylamine
  • DIPEA diisopropylethylamine
  • cyclic amines e.
  • the organic base includes pyridine. In some embodiments, the amount of the organic base used is greater than about 4, about 5, about 7, about 9, about 1 1 , or about 13 molar equivalents to that of compound 3-1. In some embodiments, the amount of the organic base used is at a value of between about 9 and about 13 molar equivalents, or between about 10 and about 12 molar equivalents to that of compound 3-1.
  • the inorganic base includes alkali metal carbonate (e.g., sodium carbonate, or potassium carbonate, or cesium carbonate). In some embodiments, the amount of the inorganic base used is greater than about 4, about 5, about 6, about 7, about 8, or about 9 molar equivalents to that of compound 3-1.
  • the amount of the inorganic base (such as sodium carbonate) used is at a value of between about 4 and about 6 molar equivalents, or of between about 4 and about 5 molar equivalents to that of compound 3-1. In some embodiments, the amount of the inorganic base used is about 4 molar equivalents to that of compound 3-1. Although not wishing to be bound by any particular theory, it is believed that the presence of both the organic base and inorganic base is advantageous in improving the yield of the intermediate 3-3.
  • the reaction to form the intermediate 3-3 is carried out in a suitable organic solvent system which includes one or more organic solvents.
  • suitable organic solvents can be employed for the solvent system, including polar organic solvents, such as polar aprotic organic solvents - i.e., organic solvents that are not readily deprotonated in the presence of a strongly basic reactant or reagent.
  • Suitable aprotic solvents can include, by way of example and without limitation, ethers, halogenated hydrocarbons (e.g., a chlorinated hydrocarbon such as methylene chloride, and chloroform), propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, nitromethane, nitrobenzene, Also included within the term aprotic solvent are esters, alkylnitriles (such as acetonitrile), and many ether solvents including, without limitation, dimethoxymethane, tetrahydrofuran (THF), 2-methyl- tetrahydrofuran, 1 ,3-dioxane, 1 ,4-dioxane, furan, diethyl ether, tetrahydropyran, diisopropyl ether, di
  • the mixed ester-halide intermediate 3-3 is hydrolyzed under appropriate conditions, such as under basic conditions (e.g., in the presence of an inorganic base such as an alkali metal hydroxide, for example, an aqueous solution of NaOH), to afford the bis- phosphoric acid mono-ester) salt 3-4 (the sodium salt when NaOH is used).
  • an aqueous solution of NaOH for example, a 3N solution
  • an inorganic acid such as aqueous HCI solution
  • a base such as aqueous NaOH
  • the aqueous layer of the reaction mixture (containing salt 3-4) is separated from the organic layer (containing the organic solvent), for example, by using a separatory funnel.
  • the bis-(phosphoric acid mono-ester) 3-5 is isolated/separated by acidifying the aqueous solution of salt 3-4 (for example, adjusting the pH of the aqueous mixture to about 2 or about 1 ) using a suitable inorganic acid such as aqueous HCI solution, and thus precipitating the bis-(phosphoric acid mono-ester) 3-5.
  • the precipitate is isolated, e.g., by filtration.
  • further purification of the bis-(phosphoric acid mono-ester) 3-5 is achieved, for example, by preparative high-performance liquid chromatography (HPLC).
  • HPLC high-performance liquid chromatography
  • the entire process of making the bis-(phosphoric acid mono-ester) 3-5 from compound 3-1 (as shown in Scheme 3) is carried out in one reaction vessel (one-pot process).
  • a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to an amide; a carboxylic acid can be converted to a ester, which in turn can be reduced to an alcohol, which in turn can be further modified.
  • an OH group can be converted into a better leaving group such as mesylate, which in turn is suitable for nucleophilic substitution, such as by CN.
  • a compound of Formula I (such as compound 1-4 of Scheme 1 ) having a substituent which contains a functional group can be converted to another compound of Formula I having a different substituent group.
  • the apeledoxifene bis- phosphorates described herein, and compositions containing the same can find many uses related to treating or preventing a disease, condition or disorder associated with an estrogen deficiency or an excess of estrogen. They may also be used in methods of treatment for a disease, condition or disorder which results from proliferation or abnormal development, actions or growth of endometrial or endometrial-like tissues.
  • the bis-phosphoric acid esters of apeledoxifene of this disclosure, and compositions thereof have improved properties relating, for example, to solubility and bioavailability.
  • the apeledoxifene bis-phosphorate of Formula Il shows improved solubility (about 4.0 mg/mL; see Example 4 below) compared with other forms of apeledoxifene (for example, the solubility of apeledoxifene ascorbate was determined to be 1.66 mg/mL; see, e.g., U.S. Pat. Pub. No. 2005/0227964), which can result in increased bioavailability and lower dosages.
  • the apeledoxifene bis-phosphorates described herein have the ability to behave like estrogen agonists by lowering cholesterol and preventing bone loss. Accordingly, the apeledoxifene bis-phosphorates are useful for treating many diseases, conditions or disorders which result from estrogen effects and estrogen excess or deficiency including osteoporosis, prostatic hypertrophy, male pattern baldness, vaginal and skin atrophy, acne, dysfunctional uterine bleeding, endometrial polyps, benign breast disease, uterine leiomyomas, adenomyosis, ovarian cancer, infertility, breast cancer, endometriosis, endometrial cancer, polycystic ovary syndrome, 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.
  • the apeledoxifene bis-phosphorates can be used for contraception in premenopausal women, as well as hormone replacement therapy in post-menopausal women (such as for treating vasomotor disturbances such as hot flush) or in other estrogen deficiency states where estrogen supplementation would be beneficial. They can also be used in disease states where amenorrhea is advantageous, such as leukemia, endometrial ablations, chronic renal or hepatic disease or coagulation diseases or disorders. [0096]
  • the apeledoxifene bis-phosphorates can be used in methods of treatment for and prevention of bone loss, which can result from an imbalance in a individual's formation of new bone tissues and the resorption of older tissues, leading to a net loss of bone.
  • Such bone depletion results in a range of individuals, particularly in post-menopausal women, women who have undergone bilateral 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, including teeth and oral bone, replacement can also be addressed using the apeledoxifene bis-phosphorates in individuals with bone fractures, defective bone structures, and those receiving bone-related surgeries and/or the implantation of prosthesis.
  • the apeledoxifene bis-phosphorates 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 diseases, conditions and disorders listed herein are understood to involve administering to an individual in need of such treatment a therapeutically effective amount of a apeledoxifene bis-phosphorate as described herein or a salt or solvate (e.g., hydrate) form thereof, or a solid dispersion or composition containing the same.
  • the apeledoxifene bis-phosphorates are administered in the form of a solid dispersion.
  • the term "treating" in reference to a disease includes preventing, inhibiting and/or ameliorating the disease.
  • mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, or humans.
  • terapéuticaally effective amount refers to an amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following:
  • preventing the disease for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
  • inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting or slowing further development of the pathology and/or symptomatology); and
  • ameliorating the disease for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • the apeledoxifene bis-phosphorates described herein can be formulated for administration to a patient in any of a variety of ways.
  • the apeledoxifene bis-phosphorates are administered alone, i.e., without the addition of excipients or other additives.
  • solid dosage forms or dispersions e.g., tablets or capsules
  • containing greater than about 95%, greater than about 98%, or greater than about 99% (by weight) of a apeledoxifene bis-phosphorate described herein are directly administered to a patient.
  • a apeledoxifene bis-phosphorate described herein is combined with one or more pharmaceutically acceptable carriers (excipients) to form a pharmaceutical composition for administration to a patient.
  • the composition can contain any therapeutically effective amount of the apeledoxifene bis-phosphorate.
  • the composition contains about 1 to about 99% by weight of the apeledoxifene bis-phosphorate.
  • the composition contains about 1 to about 50% by weight of the apeledoxifene bis-phosphorate.
  • the composition contains about 1 to about 30% by weight of the apeledoxifene bis-phosphorate.
  • the composition contains about 1 to about 20% by weight of the apeledoxifene bis-phosphorate.
  • the composition contains about 1 to about 10% by weight of the apeledoxifene bis-phosphorate.
  • Formulations containing the apeledoxifene bis-phosphorates can be administered in daily doses ranging from about 0.1 mg to about 1000 mg of a the apeledoxifene bis- phosphorate to a person in need. Exemplary dose ranges include from about 10 mg/day to about 600 mg/day, or from about 10 mg/day to about 60 mg/day. The dosing can be either in a single dose or two or more divided doses per day. Such doses can be administered in any manner that facilitates the compound's entry into the bloodstream including orally, via implants, parenterally, vaginally, rectally, and transdermally.
  • Transdermal administrations include all administrations across the surface of the body and the inner linings of body passages including epithelial and mucosal tissues. Such administration may be, e.g., in the form of a lotion, cream, colloid, foam, patch, or suspension.
  • Oral formulations containing the apeledoxifene bis-phosphorates described herein include any conventionally used oral forms, including without limitation tablets, capsules, buccal forms, troches, lozenges, oral liquids, and suspensions.
  • oral forms containing the apeledoxifene bis-phosphorates described herein include mixtures of other active compounds and/or inert fillers and 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, and gums.
  • Tablet formulations can be made by conventional compression, wet granulation, or dry granulation methods and utilize pharmaceutically acceptable diluents (fillers), 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 phosphorate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar.
  • pharmaceutically acceptable diluents fillers
  • binding agents including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl
  • Oral formulations used herein may utilize standard delay or time release formulations or spansules.
  • Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppositories melting point, and glycerin.
  • Water soluble suppository bases such as polyethylene glycols of various molecular weights, may also be used.
  • Film coatings useful with the present formulations are known in the art and generally consist of a polymer (usually a cellulose polymer), a colorant and a plasticizer. Additional ingredients such as wetting agents, sugars, flavors, oils and lubricants can be included in film coating formulations.
  • 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 or diluent can be any substance known in the art that is useful for the preparation of solid oral formulations.
  • Non-limiting examples of pharmaceutically acceptable fillers are lactose, microcrystalline cellulose, sucrose, mannitol, calcium phosphorate, calcium carbonate, powdered cellulose, maltodextrin, sorbitol, starch, and xylitol.
  • the present formulations can also include disintegrant agents. These disintegrants can be selected from those known in the art, including pregelatinized starch and sodium starch glycolate.
  • disintegrant(s) useful herein can comprise from about 4% to about 40% of the composition by weight, e.g., from about 15% to about 35%, e.g., from about 20% to about 35%.
  • Some components can have multiple functions in the formulations; a component can act, for example, as both a filler and a disintegrant. Function of a component in a specific formulation may be singular even though its properties may allow multiple functionality.
  • the pharmaceutical formulations and excipient systems herein can also contain an antioxidant or a mixture of antioxidants, such as ascorbic acid.
  • Other antioxidants which can be used include sodium ascorbate and ascorbyl palmitate, optionally in conjunction with an amount of ascorbic acid.
  • An exemplary range for the amount of antioxidant(s) in the formulation is from about 0.05% to about 15% by weight, from about 0.5% to about 15% by weight, or from about 0.5% to about 5% by weight of the formulation.
  • the pharmaceutical formulations contain substantially no antioxidant.
  • Pharmaceutical compositions containing the apeledoxifene bis-phosphorates described herein can also be formulated with steroidal estrogens, such as conjugated estrogens, USP.
  • the amount of the present apeledoxifene bis-phosphorates used in the formulation can be adjusted according to the particular formulation used, the amount and type of steroidal estrogen in the formulation, as well as the particular therapeutic indication being considered.
  • the apeledoxifene bis-phosphorates described herein are used in an amount sufficient to antagonize the effect of the particular estrogen to the level desired.
  • the dose range of conjugated estrogens can be from about 0.3 mg to about 2.5 mg, about 0.3 mg to about 1.25 mg, or about 0.3 mg to about 0.625 mg.
  • An exemplary range for the amount of a apeledoxifene bis-phosphorate described herein in a combination formulation is about 10 mg to about 40 mg.
  • a daily dosage can be from about 1 ⁇ G to about 150 ⁇ G, and for ethinyl estradiol a daily dosage of from about 1 ⁇ G to 300 ⁇ G can be used. In some embodiments, the daily dose is between about 2 ⁇ G and about 150 ⁇ G.
  • An exemplary oral formulation contains a haledoxifene bis-phosphorate described herein and the following excipient systems: a) a filler and disintegrant together forming from about 1 % to about 99% by weight (wt) of the total formulation, for example between about 20% and about 85% of the formulation, of which from about 4% to about 45% by weight of the total formulation is the disintegrant; and b) a lubricant forming from about 0.2% to about 15% of the composition (wt).
  • the lubricant is magnesium stearate or another metallic stearate (e.g., calcium stearate or zinc stearate), a fatty acid ester (e.g., sodium stearyl fumarate), fatty acid (e.g., stearic acid), fatty alcohol, glyceryl behenate, mineral oil, paraffin, hydrogenated vegetable oil, leucine, polyethylene glycol, metallic lauryl sulfate or sodium chloride.
  • a metallic stearate e.g., calcium stearate or zinc stearate
  • a fatty acid ester e.g., sodium stearyl fumarate
  • fatty acid e.g., stearic acid
  • fatty alcohol e.g., glyceryl behenate, mineral oil, paraffin, hydrogenated vegetable oil, leucine, polyethylene glycol, metallic lauryl sulfate or sodium chloride.
  • the percentages listed above for the filler, disintegrant, lubricant and antioxidant in the exemplary formulation are based on final pharmaceutical composition.
  • the remainder of the final composition is made up of a apeledoxifene bis-phosphorate and, for example, additional active compounds and/or a pharmaceutically acceptable surface covering, such as a coating or capsule, as described herein.
  • the apeledoxifene bis- phosphorate comprises from about 1 % to about 99%, about 10 to about 95%, or about 20 to about 90% by weight, of the final composition; and a coating or capsule comprises up to about 8%, by weight, of the formulation.
  • Retention time of the bazedoxifene bis-phosphorate 4-2 (C 46 H 6S N 2 O 9 P 2 ) is 10 minutes.
  • the acetonitrile was first removed from the collected fraction by rotavap and then extracted by CH 2 CI 2 .
  • the organic solvent was removed by rotavap.
  • About 3 mL of the yellow oil material (the apeledoxifene bis-phosphorate 4-2) was obtained (measured accurate mass [M+H] + 855.45; calculated 855.44) and then it was dissolved into 4 mL of ethanol and 1 mL of 36% HCI.
  • the reaction mixture was stirred at room temp for 3 hours and then the pH of the mixture was adjusted by ammonium hydroxide to about 5-7.
  • the structure of the apeledoxifene bis-phosphorate 4-3 i.e., the apeledoxifene bis- phosphorate of Formula II
  • HRMS high-resolution mass spectrometry
  • Example 4 Solubility of Bazedoxifene Bis-phosphorate 4-3 at 37 0 C
  • Samples of apeledoxifene bis-phosphorate 4-3 of Example 1 (ca. 20 mg each) were placed in vials to which 1 ml_ of water was added. The mixture was shaken by hand for 10 seconds and then placed in a water bath of 37 0 C at 50 rotations/minute for 18 hours. The samples were then filtered through syringe disc filters (13 mm of 0.2 ⁇ m nylon (Whatman)). The filtrate was analyzed by HPLC. The solubility of apele bis- phosphorate 4-3 was determined to be 4 mg/mL.
  • Example 5 Conversion of Bazedoxifene Bis-phosphorate 4-3 to Bazedoxifene [0120] The conversion of apeledoxifene bis-phosphorate 4-3 (5 ⁇ g/mL in 20 mM Tris buffer, pH 7.4) to apeledoxifene was observed in vitro with alkaline phosphatase. Concentration of alkaline phosphatase was ⁇ 7 units. Table 3 summarizes the in vitro conversion profile of apeledoxifene bis-phosphorate 4-3 to chilie in the presence of alkaline phosphatase.
  • the vehicle was 2% Tween 80/ 0.5% methylcellulose.
  • the animals were euthanized and uteri were removed and weighed after trimming associated fat and expressing any internal fluid.
  • Example 7 Preparation of Bazedoxifene Bis-phosphorate 5-5 [0122] As shown in Scheme 5, 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy- phenyl)-3-methyl-1 H-indol-5-ol (bazedoxifene free base; compound 5-1 , 3.88 g, 8.08 mmol) and pyridine (7.0 ml_, 86.4 mmol, 1 1 molar equivalents) were dissolved in dichloromethane (70 ml_).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Diabetes (AREA)
  • Reproductive Health (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Hematology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Obesity (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des bis-phosphorates de bazédoxifène, des compositions pharmaceutiques contenant ceux-ci, des préparations de celles-ci et des utilisations thérapeutiques de celles-ci.
EP08730988A 2007-02-28 2008-02-28 Bis-phosphorates de bazédoxifène Withdrawn EP2125719A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US89204407P 2007-02-28 2007-02-28
PCT/US2008/055326 WO2008106600A1 (fr) 2007-02-28 2008-02-28 Bis-phosphorates de bazédoxifène

Publications (1)

Publication Number Publication Date
EP2125719A1 true EP2125719A1 (fr) 2009-12-02

Family

ID=39650528

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08730988A Withdrawn EP2125719A1 (fr) 2007-02-28 2008-02-28 Bis-phosphorates de bazédoxifène

Country Status (5)

Country Link
EP (1) EP2125719A1 (fr)
JP (1) JP2010520218A (fr)
CA (1) CA2678032A1 (fr)
MX (1) MX2009009178A (fr)
WO (1) WO2008106600A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2567959B1 (fr) 2011-09-12 2014-04-16 Sanofi Dérivés d'amide d'acide 6-(4-hydroxy-phényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
US11246874B1 (en) 2021-04-20 2022-02-15 Oxygen Biotech LLC Treatment of COVID-19

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6479517B1 (en) * 1995-02-28 2002-11-12 Eli Lilly And Company Phosphorous-containing benzothiophenes
US5998402A (en) * 1996-04-19 1999-12-07 American Home Products Corporation 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
US6479535B1 (en) * 1998-05-15 2002-11-12 Wyeth 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole and estrogen formulations
CN1370533A (zh) * 2001-02-27 2002-09-25 中国人民解放军军事医学科学院放射医学研究所 一类新的苯并噻吩类化合物在防治妇女绝经后综合症和其它与雌激素相关疾病中的用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008106600A1 *

Also Published As

Publication number Publication date
CA2678032A1 (fr) 2008-09-04
MX2009009178A (es) 2009-09-04
WO2008106600A1 (fr) 2008-09-04
JP2010520218A (ja) 2010-06-10

Similar Documents

Publication Publication Date Title
US7683051B2 (en) Crystalline polymorph of bazedoxifene acetate
US7683052B2 (en) Crystalline polymorph of bazedoxifene acetate
JP3545461B2 (ja) 二環式ヘテロ環含有スルホンアミド誘導体
EP1951680A1 (fr) Nouveaux derives de 2-aminopyrimidinone et leur utilisation
EP1951682A1 (fr) Novequx 2-aminopyrimidinone ou derives de 2-aminopyridinone et leur utilisation
EP0009445A1 (fr) Procédé de préparation d'hydroxy-9 ellipticine et de dérivés de celle-ci
WO2008106600A1 (fr) Bis-phosphorates de bazédoxifène
EP4143169A1 (fr) Procédé de préparation d'un inhibiteur de kinase
US20060030711A1 (en) Crystalline polymorph of pipindoxifene hydrochloride monohydrate
US20060030591A1 (en) Crystalline polymorph of pipindoxifene hydrochloride monohydrate
WO2021037198A1 (fr) Composés deutérés et leur utilisation dans le traitement du cancer
MXPA06011716A (en) Crystalline polymorph of a bazedoxifene acetate
WO2008100769A2 (fr) Procédé de sulfatation sélective de groupements hydroxyles aromatiques
MXPA06011717A (en) Crystalline polymorph of bazedoxifene acetate

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20090826

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: WYETH

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: WYETH LLC

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20110901