JP2010520218A - Bazedoxifene bisphosphate - Google Patents

Abstract

  Disclosed are bazedoxifene bisphosphorates, pharmaceutical compositions containing bazedoxifene bisphospholates, preparations thereof, and therapeutic uses thereof.

Description

(Cross-reference of related applications)
This application claims priority from US Provisional Application No. 60 / 892,044, filed Feb. 28, 2007, which is incorporated herein by reference in its entirety.

  The present disclosure relates to selective estrogen receptor modulators 1- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indole-5-ol. The present invention relates to a bisphosphate ester of (bazedoxifene), its composition, its preparation and its intended use.

を有する、バゼドキシフェン（１−［４−（２−アゼパン１−イル−エトキシ）−ベンジル］−２−（４−ヒドロキシ−フェニル）−３−メチル−１Ｈ−インドール−５−オル、またはバゼドキシフェン遊離塩基）は、典型的には、選択的エストロゲン受容体モジュレータ（ＳＥＲＭｓ）と称される薬物のクラスに属する。その分類と一致して、バゼドキシフェンおよびその塩は、エストロゲン受容体（ＥＲ）に対する親和性を示すが、組織選択的エストロゲン様作用を示す。例えば、酢酸バゼドキシフェンは、子宮刺激作用の前臨床モデルにおいて、ほとんど、または全く子宮反応の刺激作用を示さない。逆に、酢酸バゼドキシフェンは、卵巣が摘出された骨減少症のラットモデルにおいて、骨喪失の阻害およびコレステロールの低下においてエストロゲンアゴニスト様作用を示す。ＭＣＦ−７細胞株（ヒト乳癌細胞株）において、酢酸バゼドキシフェンは、エストロゲンアンタゴニストとして機能する。これらのデータは、バゼドキシフェンが、骨および心血管系脂質パラメータにおいてエストロゲン性であり、および子宮および乳房組織において抗エストロゲン性であり、したがって、エストロゲン受容体が関与する、数々の異なる疾患および疾患様状態を治療する可能性があることを明示している。 The following chemical formula:

Bazedoxifene (1- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indole-5-ol, or bazedoxifene free base ) Typically belong to a class of drugs called selective estrogen receptor modulators (SERMs). Consistent with its classification, bazedoxifene and its salts show affinity for the estrogen receptor (ER) but show a tissue-selective estrogenic effect. For example, bazedoxifene acetate exhibits little or no stimulation of uterine responses in preclinical models of uterine stimulation. Conversely, bazedoxifene acetate exhibits an estrogen agonist-like effect in inhibiting bone loss and lowering cholesterol in a rat model of osteopenia with ovariectomy. In the MCF-7 cell line (human breast cancer cell line), bazedoxifene acetate functions as an estrogen antagonist. These data indicate that bazedoxifene is estrogenic in bone and cardiovascular lipid parameters and antiestrogenic in uterus and breast tissue, and thus a number of different diseases and disease-like conditions involving the estrogen receptor It is clear that there is a possibility of treating.

  US Pat. Nos. 5,998,402 and 6,479,535 report the preparation of bazedoxifene and its salts. Synthetic preparations of bazedoxifene and its salts are also described in the general literature. For example, Miller et al. , J .; Med. Chem. 2001, 44, 1654-1657. A detailed description of the biochemical activity of drugs is also described in the general literature (eg Miller et al., Drugs of the Future, 2002, 27 (2), 117-121). Further, US Patent Publication No. 2005/0227964 reports bazedoxifene ascorbate, a composition containing bazedoxifene ascorbate, dispersions thereof, preparations thereof, and uses thereof. Each of the above references is incorporated herein by reference in its entirety.

US Pat. No. 5,998,402 US Pat. No. 6,479,535 US Patent Publication No. 2005/0227964

Miller et al. , J .; Med. Chem. 2001, 44, 1654-1657. Miller et al. , Drugs of the Future, 2002, 27 (2), 117-121.

  Since drug formulation, for example, improved solubility and bioavailability, is always sought, there is a continuing need for new forms of existing drug molecules. The bisphosphates of bazedoxifene (bazedoxifene bisphosphate) described herein and compositions containing them meet these and other needs.

  The present disclosure provides a bisphosphate of bazedoxifene (bazedoxifene bisphosphate) and a pharmaceutical composition containing the same.

  Certain embodiments provide a method of preparing bazedoxifene bisphosphate.

  Another embodiment provides a method of treating a disease, symptom, or disorder associated with an estrogen deficiency or an excess of estrogen in a mammal in need of treatment, wherein an effective amount of bazedoxifene bisphosphate, Or administering a pharmaceutically acceptable salt or hydrate thereof.

  Some embodiments provide a method of treating a disease or disorder associated with endometrial tissue growth or abnormal development in a mammal in need of treatment, bazedoxifene bisphosphate, or a medicament thereof Administering an effective amount of a pharmaceutically acceptable salt or hydrate.

  Some embodiments provide a method of contraception and administer an effective amount of bazedoxifene bisphosphate, or a pharmaceutically acceptable salt or hydrate thereof, in a mammal in need of contraception Includes steps.

  Some embodiments provide a method of lowering cholesterol in a mammal in need of cholesterol reduction, and an effective amount of bazedoxifene bisphosphate, or a pharmaceutically acceptable salt or hydrate thereof Administering a product.

  Some embodiments provide a method of treating one or more vasomotor disorders in a mammal in need of treatment for vasomotor disorders, wherein an effective amount of bazedoxifene bisphosphate, or a pharmaceutical thereof Administering an acceptable salt or hydrate.

  Some embodiments provide a method for inhibiting or delaying bone demineralization or treating or inhibiting osteoporosis in postmenopausal or estrogen deficient women in need of treatment, and an effective amount of bazed Administering xifene bisphosphate, or a pharmaceutically acceptable salt or hydrate thereof, and conjugated estrogens.

  Some embodiments provide a method of treating or inhibiting menopause or postmenopausal disorders in postmenopausal or estrogen deficient women in need of treatment, wherein an effective amount of bazedoxifene bisphosphate, Or administering a pharmaceutically acceptable salt or hydrate thereof and conjugated estrogens.

  Some embodiments provide a method of inhibiting bone loss in a mammal in need of inhibition of bone loss, wherein an effective amount of bazedoxifene bisphosphate, or a pharmaceutically acceptable salt thereof, or Administering a hydrate.

  Some embodiments provide a method of treating breast cancer in a mammal in need of treatment for breast cancer, wherein an effective amount of bazedoxifene bisphosphate, or a pharmaceutically acceptable salt or hydrate thereof Administering a product.

Ｉ
の構造を有するバゼドキシフェンのビスリン酸エステル（バゼドキシフェンビスリン酸塩）の化合物、またはその医薬的に容認可能な塩を提供し、式中、 Some embodiments have formula I:

I
A compound of a bisphosphate of bazedoxifene (bazedoxifene bisphosphate) having the structure: or a pharmaceutically acceptable salt thereof, wherein:

R ¹³ and R ¹⁴ are each independently selected from —P (═O) (OR ¹ ) (OR ² ) and —P (═O) (OR ³ ) (OR ⁴ );

R ¹ , R ² , R ³ and R ⁴ are each independently H, protecting group, C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, Selected from cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein 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 heterocycloalkylalkyl each are optionally 1, 2, 3, 4 or 5 R ⁵ Is replaced by

Each R ⁵ is independently halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (═O) ^{R b, C (= O)} NR c R d, C (= O) OR a, OC (= O) R b, OC (= O) NR c R d, NR c R d, NR c C (= O ) R ^b , NR ^c C (═O) OR ^a , NR ^c S (═O) ₂ R ^b , S (═O) R ^b , S (═O) NR ^c R ^d , S (═O) ₂ R ^b , and S (═O) ₂ NR ^c R ^d ,

Each R ^a is independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, hetero Selected from arylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclo Each of alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally OH, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl Substituted by arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl,

Each R ^b is independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, Selected from heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, hetero Each of cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally OH, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl Substituted by R, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl,

R ^c and R ^d are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl , Arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, Each of cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally OH, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, halo, C _{1 -6} alkyl, _{C 1 6} haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, substituted by cycloalkyl or heterocycloalkyl,

Alternatively, R ^c and R ^d together with the N atom to which it is attached form a 4, 5, 6 or 7 membered heterocycloalkyl group.

In some embodiments, R ¹ , R ² , R ³ and R ⁴ are each independently H, 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 said _C1-10 alkyl, _C1-10 haloalkyl, C Each of _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is independently halo, C _{1- 4} alkyl, C _1-4 Haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, _{heterocycloalkylalkyl, CN, NO 2, OH,} C 1-4 _{alkoxy, C 1- 4} haloalkoxy, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, _{amino, C 1-4 alkylamino, C 2-8} dialkylamino, SH, -S- _{(C 1-4} alkyl), C (= O) H, C ( = O) - (C 1-4 alkyl), C (= O) - ( aryl), C (= O) - ( _{arylalkyl), C (= O) NH} 2, C ₍₌ O) NH _{(C 1-4 alkyl), C (= O) N} (C 1-4 _{alkyl) 2, C (= O)} OH _{C (= O) O- (C} 1-4 alkyl), C (= O) O- ( arylalkyl), OC (= O) H , OC (= O) - (C 1-4 alkyl), OC ( = O) - (aryl), OC (= O) - ( _{arylalkyl), OC (= O) NH} 2, OC (= O) NH (C 1-4 alkyl), OC (= O) NH- ( aryl _{alkyl), OC (= O) N} (C 1-4 _{alkyl) 2, NHC (= O)} - (C 1-4 alkyl), NHC (= O) - ( aryl), NHC (= O) - ( aryl alkyl), _{N (C 1-4 alkyl) C (= O) - (} C 1-4 alkyl), _{N (C 1-4} alkyl) C (= O) - (aryl), _{N (C 1-4} alkyl ) C (= O) - (arylalkyl), NHC (= O) O- ( arylalkyl), NHC (= O) O- (C 1- Alkyl), NHC (= O) O- ( arylalkyl), NHC (= O) NH (C 1-4 alkyl), NHC (= O) NH- ( aryl), NHC (= O) NH- ( arylalkyl ), NHC (═O) NH (C _1-4 alkyl) ₂ , N (C _1-4 alkyl) C (═O) NH (C _1-4 alkyl), N (C _1-4 alkyl) C (= O) NH- (aryl), N ( _C1-4alkyl ) C (= O) NH- (arylalkyl), N ( _C1-4alkyl ) C (= O) NH ( _C1-4alkyl ) _{2 , NHS (= O) 2 -} (C 1-4 _{alkyl), NHS (= O) 2} - ( _{aryl), NHS (= O) 2} - ( _{arylalkyl), S (= O) 2} - (C 1- _4- alkyl), S (= O) _2- (aryl), S (= O) _2- (arylalkyl) ), S (═O) ₂ NH (C _1-4 alkyl), S (═O) ₂ NH (aryl), and S (═O) ₂ NH (arylalkyl), 1, 2, 3 Optionally substituted with 4 or 5 substituents.

In some embodiments, R ¹ , R ² , R ³ and R ⁴ are each independently H, 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 said _C1-10 alkyl, _C1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl are each independently halo, C _{1 -4} alkyl, C _{1 -4} haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, _{heterocycloalkylalkyl, CN, NO 2, OH,} C 1-4 alkoxy, C Optionally substituted with 1, 2 or 3 substituents selected from _1-4 haloalkoxy, amino, C _1-4 alkylamino and C _2-8 dialkylamino.

In some embodiments, R ¹ , R ² , R ³ and R ⁴ are each independently H, 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.

In some embodiments, R ¹ , R ² , R ^3, and R ⁴ are each independently selected from H, a protecting group, C _1-10 alkyl, and C _1-10 haloalkyl. In some embodiments, R ¹ , R ² , R ³ , and ⁴ are each independently selected from H, a protecting group, C _1-6 alkyl, and C _1-6 haloalkyl.

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 C _1-4 alkyl. In some embodiments, 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.

Ｉａ
の構造を有するか、または、その医薬的に容認可能な塩である。 In some embodiments, a compound of the present disclosure has formula Ia:

Ia
Or a pharmaceutically acceptable salt thereof.

ＩＩ
の構造を有するか、または、その医薬的に容認可能な塩である。
定義 In some embodiments, a compound of the present disclosure has formula II:

II
Or a pharmaceutically acceptable salt thereof.
Definition

As used herein, the term “optionally substituted” means that the substitution is optional and thus the substitution of the specified atom or moiety is possible. Where substitution is desired, such substitutions do not exceed the normal valence of the specified atom or moiety, and any number on the specified atom or moiety provided that the substitution results in the appropriate compound. Is replaced with a group selected from the indicated groups. For example, if a methyl group (ie, CH ₃ ) is optionally substituted, one to a maximum of three hydrogens on the carbon atom can be substituted. Examples of suitable substituents are _{halogen, CN, NH 2, OH,} SO, SO 2, COOH, OC 16 _{alkyl, CH 2 OH, SO 2 H} , C 16 alkyl, _{OC 16} alkyl, C (= O) C ₁₆ alkyl, C (═O) O—C ₁₆ alkyl, C (═O) NH ₂ , C (═O) NHC ₁₆ alkyl, C (═O) N (C ₁₆ alkyl) 2, SO ₂ C ₁₆ alkyl , SO ₂ NH—C ₁₆ alkyl, SO ₂ N (C ₁₆ alkyl) ₂ , NH (C ₁₆ alkyl), N (C ₁₆ alkyl) ₂ , NHC (═O) C ₁₆ alkyl, NC (═O) (C ₁₆ alkyl) ₂ , aryl, O-aryl, C (═O) -aryl, C (═O) O-aryl, C (═O) NH-aryl, C (═O) N (aryl) ₂ , SO ₂ - aryl, _SO 2 NH - aryl, _SO 2 N _(aryl) 2, NH (aryl), N _(aryl) 2, NC (= O) aryl, NC (= O) _{(aryl) 2,} heterocyclyl, O- heterocyclyl, C (= O) -Heterocyclyl, C (= O) O-heterocyclyl, C (= O) NH-heterocyclyl, C (= O) N (heterocyclyl) ₂ , SO ₂ -heterocyclyl, SO ₂ NH-heterocyclyl, SO ₂ N (heterocyclyl) ₂ , NH (heterocyclyl), N (heterocyclyl) ₂ , NC (═O) -heterocyclyl, and NC (═O) (heterocyclyl) ₂ .

As used herein, “alkyl”, “alkylenyl”, or “alkylene”, used alone or as a suffix or prefix, has 1 to 12 carbon atoms, branched and straight chain It is intended to include both saturated aliphatic hydrocarbons, or where a specific number of carbon atoms is provided, that specific number is intended. For example, “C ₁₆ alkyl” represents an alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, npropyl, ipropyl, nbutyl, ibutyl, secbutyl, tbutyl, pentyl, and hexyl, or any subset thereof. As used herein, “C ₁₃ alkyl”, whether or not a terminal substituent or alkylene (or alkylenyl) group linking two substituents, specifically includes branched and It is understood to include both straight chain methyl, ethyl, and propyl.

  As used herein, “alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds. Exemplary alkenyl groups include ethenyl, propenyl, and cyclohexenyl. The term “alkenylenyl” refers to a divalent linked alkenyl group.

  As used herein, “alkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds. Exemplary alkynyl groups include ethynyl and propynyl. The term “alkynylenyl” refers to a divalent linking alkynyl group.

As used herein, “aromatic” refers to one or more polyvalent ones having aromatic character (eg, 4n + 2 delocalized electrons) and having up to about 20 ring-forming atoms. A group having an unsaturated ring.

As used herein, the term “aryl” refers to an aromatic ring structure composed of 5 to 14 carbon atoms. A ring structure containing 5, 6, 7 and 8 carbon atoms will be a monocyclic aromatic group, for example phenyl. Ring structures containing 8, 9, 10, 11, 12, 13, or 14 carbon atoms are those in which at least one carbon has any two adjacent rings therein, for example, naphthyl. (Eg, the ring is a “fused ring”) will be a polycyclic moiety. The term “aryl” also includes polycyclic systems having two or more adjacent rings in which two or more carbons are common (the ring is a “fused ring”), wherein at least one of the rings is , Aromatic (eg, the other ring can be cycloalkyl, cycloalkenyl or cycloalkynyl). The terms ortho, meta, and para correspond to 1,2,1,3, and 1,4 disubstituted benzenes, respectively. For example, the terms 1,2 dimethylbenzene and ortho-dimethylbenzene are synonymous.

  As used herein, “cycloalkyl” refers to cyclized alkyl, alkenyl, and / or having the specified number of carbon atoms (the ring structure has from 3 to 20 ring-forming carbon atoms). A non-aromatic cyclic hydrocarbon containing an alkynyl group. Cycloalkyl groups can include single or polycyclic (eg, having 2, 3, or 4 fused or bridged rings) groups. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, clopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and adamantyl. A moiety having one or more aromatic rings (ie, having a bond in common) fused to a cycloalkyl ring, eg, a benzo derivative of cyclopentane (ie, indanyl), cyclopentene, and cyclohexane are also Included in the definition.

  As used herein, the term “heterocyclyl” or “heterocyclo” or “heterocycle”, as part of a ring structure, is independently selected from one or more heterocycles selected from N, O, and S. It means monovalent and divalent structures including rings having atoms and having 3 to 29 ring-forming atoms, for example, constituting 3 to 7 membered rings. A heterocycle group may be saturated or partially saturated or unsaturated, containing one or more double bonds, and the heterocycle group may contain one or more rings, as in the case of polycyclic systems. Where specifically shown, the nitrogen in the heterocyclyl can optionally be quaternized. It should be understood that when the total number of S and O in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to one another.

  Examples of heterocycles include 1H indazole, 2pyrrolidonyl, 2H, 6H1, 5,2 dithiazinyl, 2H pyrrolyl, 3H indolyl, 4 piperidonyl, 4aH carbazole, 4H quinolizinyl, 6H1, 2,5 thiadiazinyl, acridinyl, azabicyclo, azetidine, azepan , Aziridine, azosinyl, benzimidazolyl, benzodioxole, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazo Ril, benzimidazolonyl, carbazolyl, 4aH carbazolyl, b carbolinyl, chromanyl, chromenyl, cinnolinyl, diazepane, decahydroquinolinyl, 2H, 6H1,5,2 Thiazinyl, dioxolane, furyl, 2,3 dihydrofuran, 2,5 dihydrofuran, dihydrofuro [2,3b] tetrahydrofuran, furanyl, furazanyl, homopiperidinyl, imidazolidine, imidazolidinyl, imidazolinyl, imidazolyl, 1H indolyl, indolenyl, indolinyl, indolizinyl, indolyl , Isobenzofuranyl, isochromanyl, isoindazolyl, soindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3 oxadiazolyl, 1,2,4 oxadiazolyl, 1,2 , 5 oxadiazolyl, 1,3,4 oxadiazolyl, oxazolidinyl, oxazolyl, oxyra Oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenasadinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4piperidonyl, purinyl, pyranyl, Pyrrolidinyl, pyrroline, pyrrolidine, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, N-oxide pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyldione, pyrrolinyl, pyrrolyl Pyridine, quinazolinyl, quinolinyl, 4H quinolidinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, teto Lamethylpiperidinyl, tetrahydroquinoline, tetrahydroisoquinolinyl, thiophane, thiotetrahydroquinolinyl, 6H1,2,5thiadiazinyl, 1,2,3thiadiazolyl, 1,2,4thiadiazolyl, 1,2,5thiadiazolyl 1,3,4 thiadiazolyl, thiantenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, thiirane, triazinyl, 1,2,3 triazolyl, 1,2,4 triazolyl, 1,2,5 These include, but are not limited to, triazolyl, 1,3,4 triazolyl, and xanthenyl, or a subset thereof.

  As used herein, “heteroaryl” refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen (the ring structure has up to about 20 ring-forming atoms) Point to. Heteroaryl groups include monocyclic and polycyclic (eg, having 2, 3, or 4 fused rings) systems. Examples of heteroaryl groups include pyridyl (ie, pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (ie, furanyl), quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyryl, oxazolyl, benzofuryl, benzothienyl , Benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4 thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, and indolinyl. In some embodiments, the heteroaryl group has 1 to about 20 ring-forming atoms, and in further embodiments 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 or 2 heteroatoms. In some embodiments, the heteroaryl group has 1 heteroatom.

  As used herein, “heterocycloalkyl” refers to cyclized alkyl, alkenyl, and alkynyl groups in which one or more ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. Including non-aromatic heterocycles (such ring structures have from about 3 to about 20 ring-forming atoms). Heterocycloalkyl groups can be single or polycyclic (eg, 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 heterocycloalkyl groups can be optionally substituted with oxo or sulfide. The definition of heterocycloalkyl also includes moieties having one or more aromatic rings that are fused to non-aromatic heterocycle rings, for example, phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indolene and isoindolene groups. In some embodiments, the heterocycloalkyl group has about 3 to about 20 ring-forming atoms. In some embodiments, 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 or 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” as used herein refers to an alkyl group, as defined above, with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, npropoxy, isopropoxy, nbutoxy, isobutoxy, tbutoxy, npentoxy, isopentoxy, cyclopropylmethoxy, allyloxy, and propargyloxy. Similarly, “alkylthio” or “thioalkyl” represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulfur bridge.

“Amino” as used herein refers to NH ₂ .

  “Alkylamino” as used herein refers to an amino group substituted by an alkyl group.

  “Dialkylamino” as used herein refers to an amino group substituted by two alkyl groups.

  As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, and iodo.

As used herein, “haloalkyl” refers to an alkyl group having one or more halogen substituents. Examples of haloalkyl groups include CF ₃ , C ₂ F ₅ , CH ₂ CF ₃ , CHF ₂ , CCl ₃ , CHCl ₂ , and C ₂ Cl ₅ . The term “perhaloalkyl” is intended to represent an alkyl group in which all hydrogen atoms are replaced with halogen atoms. Examples of perhaloalkyl groups include CCl ₃ and CF ₃ . The term “perfluoroalkyl” is intended to represent an alkyl group in which all hydrogen atoms are replaced with fluorine atoms. An example of perfluoroalkyl is CF ₃ (ie, trifluoromethyl).

As used herein, “haloalkoxy” refers to an —O-haloalkyl group. An example of a haloalkoxy is OCF _3.

  As used herein, “aryloxy” refers to an —O-aryl group. An example of an aryloxy group is phenoxy.

  As used herein, “heteroaryloxy” refers to an —O-heteroaryl group. An example of a heteroaryloxy group is pyridin-2-yloxy [i.e., -O- (pyridin-2-yl)].

"Arylalkyl" as used herein refers to C _1-10 alkyl substituted by aryl and "cycloalkylalkyl" refers to a C _1-10 alkyl substituted by cycloalkyl. An example of an arylalkyl group is benzyl.

"Heteroarylalkyl" as used herein refers to C _1-10 alkyl substituted by a heteroaryl, "heterocycloalkylalkyl" refers to a C _1-10 alkyl substituted by heterocycloalkyl.

  As used herein, “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.

を指すことを意図し、式中、ｐは、１、２、３、４、５、６または７（すなわち、Ｃ_３９シクロアルキル）であり、Ｃ_３９シクロアルキルは、Ｒ^ｄにより置換され、「Ｃ（＝Ｏ）−Ｃ_３９シクロアルキルＲ^ｄ」の結合点は、式の左側にある、カルボニル基の炭素原子を介する。 As used herein, some substituents are described as a combination of two or more groups. For example, the formula “C (═O) —C ₃₉ cycloalkyl R ^d ” has the structure:

Wherein p is 1, 2, 3, 4, 5, 6 or 7 (ie, C ₃₉ cycloalkyl), wherein C ₃₉ cycloalkyl is substituted by R ^d and “ The point of attachment of “C (═O) —C ₃₉ cycloalkyl R ^d ” is through the carbon atom of the carbonyl group on the left side of the formula.

The compounds of the present disclosure can be derivatized in a variety of ways. As used herein, a “derivative” of a compound refers to a salt (eg, a pharmaceutically acceptable salt), any complex (eg, an inclusion body or clathrate with a compound such as cyclodextrin, or Mn ²⁺ And coordination complexes with metal ions such as Zn ²⁺ ), esters such as in vivo hydrolysable esters, polymorphic forms of compounds, solvents (eg hydrates) or lipids, and coupling partners and protecting groups ( A compound having an amino and / or hydroxyl protecting group).

As used herein, the term “protecting group” means a temporary substituent that protects a potentially reactive functional group from unwanted chemical transformation. Such protecting groups include, but are not limited to, esters of phosphoric acid, esters of carboxylic acid, silyl ethers of alcohol, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (e.g., incorporated in its entirety herein by reference, Greene, T.W.and Wuts, P.G.M.Protective Groups in Organic Synthesis, 3 rd Ed .; Wiley & Sons, 1999), protecting groups are well known to those skilled in the art.

  The compounds of the present disclosure are intended to be stable compounds (compounds having a stable structure). As used herein, “stable compound” and “stable structure” are isolated from the reaction mixture to a useful degree of purity and stable and strong enough to be formulated into an effective therapeutic agent. It is meant to indicate a compound.

  Various compounds of the present disclosure may exist in particular stereoisomeric forms. The present disclosure includes cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D) -isomers, (L) -isomers, racemic mixtures thereof, as encompassed within the scope of this disclosure And all such compounds, including, and other mixtures. Additional asymmetric carbon atoms can be present in substituents such as alkyl groups. As with all such isomers, mixtures thereof are intended to be included in this disclosure. The compounds described herein can have asymmetric centers. Compounds of the present disclosure that contain asymmetric substituent atoms can optionally be isolated in active or racemic form. Methods for preparing optically active forms are well known in the art, such as by resolution of racemic forms or by synthesis from optically active starting materials. If necessary, separation of the racemic material can be achieved by methods well known in the art. Many stereoisomers of olefins, C═N double bonds, and the like can also exist in the compounds described herein, and all such stable isomers are contemplated in this disclosure. The cis and trans isomers of the compounds of the present disclosure are described and can be separated as a mixture of isomers or as separated isomer forms. If a specific stereochemical or isomeric form is not specifically indicated, when the compound contains a chiral center, all individual optical forms of structures such as enantiomers, epimers, and diastereomers as well as the compound A racemic mixture of is intended.

  Compounds can exist in numerous tautomeric forms, and references herein to compounds include all such forms. For the avoidance of doubt, compounds may exist in one of several tautomers, and when only one tautomer is specifically described or shown, all others are still within the scope of this disclosure. Is included. As used herein, “tautomerism” refers to other structural isomers that exist in equilibrium resulting from a rearrangement of hydrogen atoms. For example, keto-enol tautomerism is that the resulting compound has the properties of both a ketone and an unsaturated alcohol.

The present disclosure further includes isotopically labeled compounds of the present disclosure. “Isotope” or “radiolabeled” compounds are those in which one or more atoms have an atomic mass or a mass number different from the atomic mass, or typically a naturally occurring (ie, naturally occurring) mass. A compound that is exchanged or substituted by a number of atoms. Suitable radionuclides for incorporation into the compounds of the present disclosure include ² H (also described as deuterium D), ³ H (also described as tritium T)), ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I, or Any subset of, but not limited to. In some embodiments, the radionuclide is selected from the group consisting of ³ H, ¹⁴ C, ¹²⁵ I, ³⁵ S, and ⁸² Br. The radionuclide incorporated into the radiolabeled compound will depend on the specific application of the radiolabeled compound. For example, for in vitro receptor labeling and competition assays, compounds incorporating ³ H, ¹⁴ C, ⁸² Br, ¹²⁵ I, ¹³¹ I, or ³⁵ S will generally be most useful. For radioactive imaging applications, ¹¹ C, ¹⁸ F, ¹²⁵ I, ¹²³ I, ¹²⁴ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br or ⁷⁷ Br will generally be most useful.

  In certain embodiments, the salt of the compound is physiologically most acceptable and non-toxic. Many examples of salts are well known to those skilled in the art. All such salts are within the scope of various embodiments, and reference to a compound includes the salt form of the compound.

  Compounds having acidic groups such as carboxylic acid, phosphoric acid, sulfuric acid, sulfonic acid group are alkali or alkaline earth metals such as Na, K, Mg and Ca, and organic amines such as triethylamine and tris (2hydroxyethyl) amine. Can form salts with other species. Salts, for example, compounds having a basic group of amines, an inorganic acid such as hydrochloric acid, phosphoric acid, or sulfuric acid, or an organic acid such as acetic acid, citric acid, benzoic acid, fumaric acid, or tartaric acid Can be formed from A compound having both an acid group and a basic group can form an inner salt.

  Acid addition salts can be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts are hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methane Including salts formed with sulfonic acid, ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propanoic acid, butyric acid, malonic acid, glucuronic acid, and lactobionic acid.

If the compound has a functional group that can be anionic or anionic (eg, COOH can be COO ⁻ and PO ₃ H ₂ can be PO ₃ H ⁻ ), the salt can be used as a counter ion. Can form with cations. Examples of cations include 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⁺ and ammonium ions (ie NH ₄ ⁺ ), And substituted ammonium ions (eg, NH ₃ R ⁺ , NH ₂ R ₂ ⁺ , NHR ₃ ⁺ , NR ₄ ⁺ ), but are not limited thereto. Examples of substituted ammonium ions include ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, and amino acids such as lysine and arginine. Non-limiting examples include those derived. An example of a common quaternary ammonium ion is N (CH ₃ ) ₄ ⁺ .

  When the compound contains an amine function, a quaternary ammonium salt can be formed, for example, by reaction with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of this disclosure.

  When the compound contains an amine function, acid addition salts can also be formed using a wide variety of acids, both inorganic and organic acids. Examples of acid addition salts include hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, Examples thereof include salts formed using methanesulfonic acid, ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propanoic acid, butyric acid, malonic acid, glucuronic acid, and lactobionic acid. In such cases, the counter ion is from the acid used (eg, when hydrochloric acid is used, the counter ion will be a chloride ion).

“Counterion” includes chlorine ion (Cl), bromine ion (Br), hydroxide ion (OH), acetate ion (CH ₃ COO), sulfate ion (SO ₄ ² ), tosylate ion (CH ₃ phenyl SO _3). ), Benzenesulfonate ion (phenyl SO ₃ ), sodium ion (Na ⁺ ), potassium ion (K ⁺ ), and ammonium ion (NH ₄ ⁺ ), to represent small, negative or positively charged species.

  As used herein, “pharmaceutically acceptable” refers to humans within normal medical judgment and without causing transient toxicity, irritation, allergic reactions, or other problems or complications. And a compound, substance, composition and / or dosage form suitable for use in contact with animal tissue and in proportion to a reasonable effect / risk ratio.

  As used herein, “pharmaceutically acceptable salt” is disclosed herein, wherein the parent compound is modified by producing its acid or basic salt (ie, including a counter ion). Refers to a derivative of the compound. Examples of pharmaceutically acceptable salts include, but are not limited to, organic acid salts of minerals or basic residues such as amines and alkali or acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include existing non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such existing non-toxic salts include salts derived from inorganic acids such as hydrochloric acid and phosphoric acid, and salts prepared from organic acids such as lactic acid, maleic acid, citric acid, benzoic acid, and methanesulfonic acid. Is mentioned.

  Pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by existing chemical methods. In general, such salts react the free acid or the base form 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. Can be prepared. Instead of water or an organic solvent, or a mixture of the two, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile can be used.

Compounds containing amine functional groups can also form N-oxides. References herein to compounds containing an amine function also include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Particular examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (eg, peroxycarboxylic acid), see, eg, March, J. et al. Advanced Organic ^Chemistry, 4 th Ed. , Wiley & Sons, 1999. More specifically, N-oxides are described in Deady, L. et al. W. Syn. Comm. , 1977, 7, 509514, and the amine compound reacts with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

Esters can be formed between the hydroxyl or carboxylic acid groups present in the compound and the appropriate carboxylic acid or alcohol reaction partner using techniques well known in the art. Examples of esters are compounds containing C (═O) OR, where R is an ester such as a C _1-7 alkyl group, a C _3-20 heterocyclyl group, or a C _5-20 aryl group, for example. It is a substituent. Particular examples of ester groups _{include C (= O) OCH 3,} C (= O) OCH 2 CH 3, C (= O) OC (CH 3) 3, and -C (= O) OPh However, it is not limited to these. An example of an acyloxy (reverse ester) group is represented by OC (= O) R, wherein R is, for example, a C _1-7 alkyl group, a C _3-20 heterocyclyl group, or a C _5-20 aryl group. Acyloxy substituents such as Specific examples of acyloxy groups include OC (═O) CH ₃ (acetoxy), OC (═O) CH ₂ CH ₃ , OC (═O) C (CH ₃ ) ₃ , OC (═O) Ph, and OC (= O) but _CH 2 Ph and the like, without limitation.

  A derivative that is a prodrug of a compound can be converted in vivo or in vitro to one of the parent compounds. Usually, at least one of the biochemical activities of a compound can be activated by conversion of the prodrug to reduce it in the prodrug form of the compound and release the compound or its metabolite. Some prodrugs are esters of the active compound (eg, a physiologically acceptable metabolically labile ester). During metabolism, the active group is obtained by cleaving the ester group. Such esters may, for example, pre-protect any other reactive groups present in the parent compound, if appropriate, to esterify any carboxylic acid group (C (═O) OH) of the parent compound, Thereafter, it can be formed by deprotection as necessary.

Such metabolically unstable esters include, but are not limited to, those of the formula: — (═O) OR, where R is, for example, C _1-7 alkyl (eg, , Me, Et, nPr, iPr, nBu, sBu, iBu, tBu), C _1-7 aminoalkyl (eg aminoethyl, 2 (N, N diethylamino) ethyl, 2 (4 morpholino) ethyl), or acyloxy C _{1 -7} alkyl (for example, acyloxymethyl, acyloxyethyl, pivaloyloxymethyl, acetoxymethyl, 1acetoxyethyl, 1 (1methoxy1methyl) ethylcarbonyloxyethyl, 1 (benzoyloxy) ethyl, isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl, cyclohexylcarbonyloxymethyl 1-cyclohexylcarbonyloxyethyl, cyclohexyloxycarbonyloxymethyl, 1 cyclohexyloxycarbonyloxyethyl, (4 tetrahydropyranyloxy) carbonyloxymethyl, 1 (4 tetrahydropyranyloxy) carbonyloxyethyl, (4 tetrahydropyranyl) carbonyl Oxymethyl, or 1- (4-tetrahydropyranyl) carbonyloxyethyl).

  Some prodrugs are enzymatically activated and in active compounds, or in further chemical reactions, active compounds (eg, antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), And a ligand-directed enzyme prodrug therapy (LIDEPT)) is obtained. For example, the prodrug can be a sugar derivative or other glycoside conjugate, or can be an amino acid ester derivative.

  Other derivatives include a coupling partner of a compound in which the compound is linked to a coupling partner, for example by chemically binding to or physically linking to the compound. Examples of coupling partners include labels or reporter molecules, support substrates, carriers or transfer molecules, and agonists, drugs, antibodies or inhibitors. A coupling partner can be covalently linked to a compound of the present disclosure via a suitable functional group on the compound such as a hydroxyl group, a carboxyl group, or an amino group. Other derivatives include the formulation of compounds using liposomes.

As used herein, the term “leaving group” means a moiety that can be substituted by another moiety during a chemical reaction, such as by nucleophilic attack. Leaving groups are well known in the art and include, for example, halogen, hydroxy, alkoxy, —O (C═O) R a , —OSO 2 —R b , and —OSi (R c ) 3 where R a is C 1-8 alkyl, C 3-7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, R b is C 1-8 alkyl, aryl (optionally one or more halo, cyano , Nitro, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or substituted by C 1-4 haloalkoxy), or heteroaryl (optionally one or more halo, cyano, nitro, C 1-4 alkyl, C 1-4 haloalkyl, substituted C 1 -C 4 alkoxy, or C 1-4 haloalkoxy), and R c, C 1-8 alkyl It is. Exemplary leaving groups include chloro, bromo, iodo, 4-nitrophenyl carbonate, methylate, tosylate, and trimethylsilyl.

Composition

  The compounds described herein can be prepared by a variety of means well known to those skilled in the art of organic synthesis. The compounds can be synthesized using the methods described below, as well as organic chemistry well known in the art, or variations thereof, as understood by those skilled in the art.

  The compounds can be prepared from readily available starting materials using the following general methods and procedures. When providing typical or exemplary process conditions (ie, reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other appropriate process conditions are also applied by routine procedures unless otherwise stated. Can be used as judged by the vendor.

The process described herein can be monitored according to any suitable method known in the art. For example, product formation may be performed by spectroscopic means such as nuclear magnetic resonance spectroscopy (eg, ¹ H or ¹³ C NMR), infrared spectroscopy (IR), spectrometry (eg, UV-visible), or mass spectrometry. Or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

The preparation of the compounds can include 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 chemical properties of protecting groups are described, for example, in Greene, T .; W. and Wuts, P.A. G. M.M. ^{Protective Groups in Organic Synthesis, 2 nd} Ed. Wiley & Sons, 1991, which is incorporated herein in its entirety by reference.

  The reactions of the procedures described herein can be performed in a suitable solvent that can be readily selected by one skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, ie, in the temperature range from the freezing point of the solvent to the boiling point of the solvent. Any reaction can be carried out in one solvent or a mixture of one or more solvents. Depending on the particular reaction step, an appropriate solvent for the particular reaction step can be selected.

  The compounds can be prepared, for example, using the reaction pathways and techniques described below.

As shown in Scheme 1, a series of novel bazedoxifene diphosphates (compounds of formulas 1-4 and 1-5) are represented by 1- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2. Synthesized starting from-(4-hydroxy-phenyl) -3-methyl-1H-indole-5-ol (bazedoxifene free base, compound 1-1). Compound 1-1 is reacted with two or more molar equivalents of phosphoramidite 1-2, wherein:
R ¹ and R ² are each independently a protecting group, C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclo alkyl, arylalkyl, heteroarylalkyl, selected from cycloalkylalkyl and _{heterocycloalkylalkyl, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10} alkynyl, aryl, cycloalkyl, Each of 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, C _1-6 alkyl, C _1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (═O ) R ^b , C (═O) NR ^c R ^d , C (═O) OR ^a , OC (═O) R ^b , OC (═O) NR ^c R ^d , NR ^c R ^d , NR ^c C (= ^{O) R b, NR c C} (= O) OR a, NR c S (= O) 2 R b, S (= O) R b, S (= O) NR c R d, S (= O) 2 R ^b , or S (═O) ₂ NR ^c R ^d ,
R ⁶ and R ⁷ are each independently C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C, each optionally substituted with 1, 2, 3, 4 or 5R ^5. Selected from _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, or
R ⁶ and R ⁷ together with the bonding N atom form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3, 4 or 5R ⁵ ;
Each R ^a is independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl is selected from cycloalkylalkyl and heterocycloalkylalkyl, said _{C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6} alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl Each of cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally OH, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl Substituted by R, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl,
Each R ^b is independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, Selected from heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, hetero Each of cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally OH, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl Substituted by R, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl,
R ^c and R ^d are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl , Arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, Each of cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally OH, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, halo, C _{1 -6} alkyl, _{C 1 6} haloalkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, substituted by cycloalkyl or heterocycloalkyl, or
R ^c and R ^d together with the bonding N atom form a 4, 5, 6 or 7-membered heterocycloalkyl group and in the presence of a base (eg tetrazole) bis (phosphite triester) intermediate 1 -3. In certain embodiments, R ¹ and R ² are each independently selected from protecting groups, C _1-10 alkyl and cycloalkyl. In some embodiments, 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 attached, for example To form a heterocyclylalkyl, optionally substituted with one or more C _1-6 alkyl substituents, such as methyl or ethyl, or C _1-6 alkoxy substituents. Suitable protecting groups include protecting groups for hydroxyl groups, examples of which are described, for example, in Greene, T., et al., Which is hereby incorporated by reference in its entirety. W. and Wuts, P.A. G. M.M. ^{Protective Groups in Organic Synthesis, 2 nd} Ed. Wiley & Sons, 1991;

The bis (phosphite triester) intermediate 1-3 is oxidized to the corresponding bis (phosphate triester) 1-4 with an oxidizing reagent (eg, hydrogen peroxide). In some embodiments, excess oxidizing reagent provides both phosphorus atoms in intermediate 1-3 that are oxidized to form P═O bonds in bis (phosphate triester) 1-4. Use to do. Excess oxidizing reagent is removed by any suitable method, such as using a reducing reagent (eg, sodium metabisulfite) during the work procedure (eg, when isolating and / or purifying the product). Bis (phosphate triester) 1-4 is hydrolyzed (partially) under appropriate conditions, such as in acid conditions (eg, in the presence of an inorganic acid such as HCl) to give bis (phosphate monoester). Ester) 1-5 is obtained.
Scheme 1

Alternatively, as shown in Scheme 2, 1- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indole-5-ol ( Bazedoxifene free base; compound 2-1) is reacted with phosphoramidite 2-2a and phosphoramidite 2-2b in the presence of a base such as a tertiary amine (eg, tetrazole) simultaneously or sequentially to produce mixed bis (phosphite) Acid triester) intermediate 2-3 (phosphoramidite 2-2a is the same or different from phosphoramidite 2-2b and R ¹ , R ² , R ³ and R ⁴ are each independently R ¹ and R ² , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently defined in R ⁶ and R ⁷ of Scheme 1. ) Bis (phosphite triester) intermediate 2-3 (R ¹¹ and R ¹² are each independently selected from —P (OR ³ ) (OR ⁴ ) and —P (OR ¹ ) (OR ² )) Is the corresponding bis (phosphate triester) 2-4 (R ¹³ and R ¹⁴ are each independently -P (= O) (OR ³ ) (OR ⁴ ) and -P (= O) (selected from OR ¹ ) (OR ² )), and bis (phosphate monoester) 2-5 undergo transformations similar to those described in Scheme 1 above.
Scheme 2

Alternatively, as shown in Scheme 3, bazedoxifene diphosphate 3-5 is 1- [4- (2-azepane-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl)- Synthesized starting from 3-methyl-1H-indole-5-ol (bazedoxifene free base, compound 3-1). Compound 3-1 is a suitable organic base (such as pyridine) and a suitable inorganic base (such as an alkali metal carbonate such as Na ₂ CO ₃ ) to form a mixed ester-halide intermediate 3-3. In the presence, it is reacted with two or more molar equivalents of phosphite oxytrihalide 3-2 (each X ¹ is independently halo such as chloro or bromo). In some embodiments, the oxyphosphite oxytrihalide 3-2 (having the formula: (═O) (X ¹ ) ₃ ) is P (═O) Cl ₃ . In some embodiments, the amount of phosphite oxytrihalide 3-2 used is about 2 to about 4, about 2 to about 3, about 2.0 to about 2. of that of compound 3-1. 5, or about 2.5 to about 3.0 molar equivalents. In some embodiments, the organic base is a trialkylamine (eg, triethylamine (“TEA”), diisopropylethylamine (“DIPEA”), a cyclic amine (eg, 1,4-diazabicyclo [2.2.2] octane). ("DABCO"), diaza (1,3) bicyclo [5.4.0] undecane ("DBU")), aromatic amines (eg, triphenylamine), dimethylaminopyridine (DMAP), and heteroaromatics Selected from tertiary amines such as amines (eg, pyridine and lutidine) In some embodiments, the organic base comprises pyridine, hi some embodiments, the amount of organic base used is compound 3- A molar equivalent of greater than about 4, about 5, about 7, about 9, about 11, or about 13. In some embodiments, The amount of organic base to be is a value between about 9 and 13 molar equivalents, or between about 10 and about 12 molar equivalents of that of compound 3-1. A metal carbonate, such as sodium carbonate, or potassium carbonate, or cesium carbonate, hi some embodiments, the amount of inorganic base used is about 4, about 5, about 6, about 3 of compound 3-1. Greater than 7, about 8, or about 9 molar equivalents In some embodiments, the amount of inorganic base used is between about 4 and about 6 molar equivalents of that of compound 3-1, or from about 4 to about Values between 5 molar equivalents In some embodiments, the amount of inorganic base used is about 4 molar equivalents of compound 3-1, although not wishing to be bound by any particular theory, The presence of both organic and inorganic bases can cause intermediate 3- Of the improvement in yield is thought to be advantageous.

  The reaction to form intermediate 3-3 is carried out in a suitable organic solvent system comprising one or more organic solvents. A wide variety of organic solvents can be used in the solvent system, including polar aprotic organic solvents, etc., ie polar organic solvents that are not readily deprotonated in the presence of strongly basic reactants or reagents. Suitable aprotic solvents are, for example, ethers, halogenated hydrocarbons (eg chlorinated hydrocarbons such as methylene chloride, and chloroform), propyl nitrile, ethyl formate, ethyl acetate, hexachloroacetone, acetone, ethyl methyl ketone. , Ethyl acetate, sulfolane, nitromethane, and nitrobenzene, but are not limited thereto. Esters, alkyl nitrites (such as acetonitrile), and dimethoxymethane, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, tetrahydrofuran, diisopropyl ether, dibutyl ether, ethylene Many ether solvents include, but are not limited to, glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, and t-butyl methyl ether. included. In some embodiments, the solvent system comprises a halogenated hydrocarbon (eg, methylene chloride). In some embodiments, the solvent system comprises an ether (eg, THF).

  The mixed ester halide intermediate 3-3 is hydrolyzed under suitable base conditions (eg, in the presence of an inorganic base in an aqueous solution of NaOH, such as an alkali metal hydroxide, etc.) to give bis (phosphate monophosphate). Ester) salt 3-4 (sodium salt when NaOH is used). In some embodiments, an aqueous solution of NaOH (e.g., to promote hydrolysis by adjusting the pH of the reaction mixture to a value greater than 7, such as by adjusting the pH from about 8 to about 9). 3N solution). In some embodiments, the pH of the reaction mixture is adjusted to a value of about 8 to about 9 by adding a base (water soluble NaOH) followed by an inorganic acid (such as a water soluble HCl solution).

The aqueous layer of the reaction mixture (containing salt 3-4) is separated from the organic layer (containing organic solvent), for example, by using a separatory funnel. The bis (phosphate monoester) 3-5 is then adjusted to the salt 3-4 (eg, the water-soluble pH to about 2 or about 1 using a suitable inorganic acid such as a water-soluble HCl solution. ) Is acidified and thus isolated / separated by precipitating bis (phosphate monoester) 3-5. The precipitate is isolated, for example, by filtration. In some embodiments, further purification of bis (phosphate monoester) 3-5 is achieved, for example, by preparative high performance liquid chromatography (HPLC). In some embodiments, the entire process of bis (phosphate monoester) 3-5 from compound 3-1 (as shown in Scheme 3) is carried out in one reactor (one pot process).
Scheme 3

In scheme described herein, should functional (response) groups, when present on a substituent such as R ^1, R ^2, if appropriate and / or desired, be noted that can be carried out further modifications is there. For example, the CN group can be hydrolyzed to obtain an amide group, the carboxylic acid can be converted to an amide, the carboxylic acid can be converted to an ester, which can in turn be reduced to an alcohol, which in turn can be further modified. In another example, the OH group can be converted to a better leaving group such as mesylate, which in turn is suitable for nucleophilic substitution with CN or the like. Those skilled in the art will recognize such additional modifications. Thus, a compound of formula I having a substituent containing a functional group (such as compounds 1-4 of Scheme 1) can be converted to another compound of formula I having a different substituent.
Method

Bazedoxifene and its salts are selective estrogen agonists with affinity for estrogen receptors, as described in US Pat. No. 5,998,402, which is incorporated herein by reference in its entirety. Unlike other types of estrogen agonists, bazedoxifene and its salts are antiestrogenic in the uterus and can antagonize the trophic effects of estrogen agonists in uterine tissue. Bazedoxifene phosphate (phosphate ester) can act as a prodrug of bazedoxifene (see Example 5 below). During metabolism (eg, in the presence of alkaline phosphatase), the P-OR bond of a compound having the formula: P (═O) (OH) ₂ OR is cleaved to yield the active drug (HOR). Accordingly, the bazedoxifene bisphosphates described herein and compositions comprising bazedoxifene bisphosphate treat or prevent diseases, symptoms, or disorders associated with estrogen deficiency or estrogen excess. You can find many uses related to doing. They can also be used in methods of treating diseases, symptoms or disorders resulting from proliferation or abnormal development, action or growth of endometrium or endometrial-like tissue.

  The bazedoxifene bisphosphate bazedoxifene of the present disclosure, and compositions thereof, for example, improved properties associated with solubility and bioavailability. For example, bazedoxifene bisphosphate of formula II was determined to have other forms of bazedoxifene (eg, bazedoxifene ascorbate has a solubility of 1.66 mg / mL. For example, US Patent Publication No. 2005/0227964. Compared to the above), it exhibits improved solubility and can lead to increased bioavailability and decreased dose.

  The bazedoxifene bisphosphates described herein have the ability to function like estrogen agonists by preventing cholesterol loss and bone loss. Therefore, bazedoxifene bisphosphate is osteoporosis, prostatic hypertrophy, androgenetic alopecia, vaginal and skin atrophy, acne, malformed uterine bleeding, endometrial polyps, benign breast disease, uterine fibroids, adenomyosis, Ovarian cancer, infertility, breast cancer, endometriosis, endometrial cancer, polycystic ovary syndrome, cardiovascular disease, contraception, Alzheimer's disease, cognitive decline and CNS disorders and melanoma, prostate cancer, colon cancer, CNS cancer Are useful for treating a number of diseases, symptoms, or disorders resulting from estrogenic effects and estrogen excess or deficiency. In addition, bazedoxifene bisphosphate can be used for contraception in premenopausal women and hormone replacement therapies in postmenopausal women (eg, treatments for vasomotor disorders such as hot flashes), or It can be used as a hormone replacement therapy in estrogen deficiency symptoms where estrogen replacement is useful. They can also be used in diseases where amenorrhea is useful, such as leukemia, endometrial resection, chronic kidney disease or liver disease, or blood clotting disease or disorder.

  Bazedoxifene bisphosphate can be used in methods of treating and preventing bone loss that can result from individual formation of new bone tissue and imbalance of old tissue resorption leading to net loss of bone. Such bone deficits range from individuals, especially postmenopausal women, bilateral ovariectomized women, those who have received corticosteroid therapy or who have received corticosteroid therapy for a long time, experienced genital dysgenesis Occurs in those who suffer from Cushing's syndrome. A special need for bone replacement, including teeth and oral bone, is the use of bazedoxifene bisphosphate in fractures, individuals who have lost bone structure, and those who have undergone bone-related surgery and / or prosthetic transplants. Can also be used. In addition to the above-mentioned problems, bazedoxifene bisphosphate is effective in osteoarthritis, hypocalcemia, hypercalcemia, Paget's disease, osteomalacia, osteocalcinosis, multiple myeloma, and bone tissue. Can be used to treat other forms of cancer that have adverse effects.

  Methods for treating the diseases, symptoms, and disorders listed herein may be bazedoxifene bisphosphate, or a salt or solvent (eg, hydrate) form thereof, or equivalent, as described herein. It should be understood to include administering to a person in need of such treatment a therapeutically effective amount of a solid dispersion or composition comprising the product. In some embodiments, bazedoxifene bisphosphate is administered in the form of a solid dispersion. As used herein, the term “treatment” referring to a disease includes prevention, inhibition and / or amelioration of the disease.

  As used herein, synonymously “individual” or “patient” refers to a mammal such as a mouse, rat, other rodent, rabbit, dog, cat, cow, sheep, horse, primate, or human. Refers to any animal, including

As used herein, a “therapeutically effective amount” is a biological to tissue, system, animal, or human that includes one or more of the following as required by a researcher, veterinarian, physician, or other clinician: Alternatively, it refers to the amount of active compound or pharmaceutical agent that elicits a pharmaceutical response.
(1) prevention of disease; for example prevention of disease, symptom or disorder in an individual who may predispose to the disease, symptom or disorder but has not yet experienced or developed a disease pathology or symptom;
(2) Inhibition of disease; for example, inhibition of disease, symptom, or disorder (ie, further development of lesion and / or symptom in an individual experiencing or developing a disease, symptom, or disorder lesion or symptom) And (3) amelioration of the disease; for example, improvement of the disease, symptom, or disorder (ie, lesion and / or in an individual experiencing or developing a disease, symptom, or disorder lesion or symptom) Symptom reversal).
Dosage and formulation

  The bazedoxifene bisphosphate described herein can be formulated for administration to a patient in any of a variety of ways. In some embodiments, bazedoxifene bisphosphate is administered alone, ie, without the addition of excipients or other additives. For example, as described herein, a solid dosage form or dispersion comprising more than about 95 wt%, more than about 98 wt%, or more than about 99 wt% bazedoxifene bisphosphate (e.g., a tablet or Capsule) is administered directly to the patient.

  In some embodiments, a medicament for administering bazedoxifene bisphosphate described herein in combination with one or more pharmaceutically acceptable carriers (excipients) to a patient. Form a composition. The composition can contain a therapeutically effective amount of any bazedoxifene bisphosphate. In some embodiments, the composition comprises about 1% to about 99% by weight bazedoxifene bisphosphate. In a further embodiment, the composition comprises from about 1% to about 50% by weight bazedoxifene bisphosphate. In yet a further embodiment, the composition comprises about 1% to about 30% by weight bazedoxifene bisphosphate. In yet a further embodiment, the composition comprises about 1% to about 20% by weight bazedoxifene bisphosphate. In still further embodiments, the composition comprises about 1 wt% to about 10 wt% bazedoxifene bisphosphate.

  Formulations containing bazedoxifene bisphosphate can be administered to a person in need at daily doses ranging from about 0.1 mg to about 1000 mg of bazedoxifene bisphosphate. Exemplary dose ranges include about 10 mg / day to about 600 mg / day, or about 10 mg / day to about 60 mg / day. The dose may be either once daily or in divided doses of 2 or more times. Such doses can be administered in any manner that facilitates the influx of the compound into the bloodstream, including orally, via implants, parenterally, vaginally, rectally, and transdermally.

  Transdermal administration includes administration of all lining layers of the body's pathway, including the entire body surface and epithelial and mucosal tissues. Such administration can be, for example, in the form of a lotion, cream, colloid, foam, patch, or suspension.

  Oral formulations comprising bazedoxifene bisphosphate described herein include, but are not limited to, tablets, capsules, oral tablets, troches, lozenges, oral liquids, and suspensions. Includes all oral forms already used. In certain embodiments, an oral formulation comprising bazedoxifene bisphosphate described herein comprises an active compound and / or a pharmaceutically acceptable starch (eg, corn, potato, or tapioca starch), sugar , Artificial sweeteners, powdered cellulose such as crystalline or microcrystalline cellulose, flour, gelatin, and mixtures of inert fillers and diluents such as gums.

  Tablets can be formulated by existing compression method, wet granulation method, or dry granulation method. Magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethyl cellulose calcium, polyvinylpyrrolidone, gelatin Alginate, acacia gum, xanthan gum, sodium citrate, complex silicate, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium silicate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dried starch And pharmaceutically acceptable diluents (fillers), binders, lubricants, disintegrants, suspending agents, or stabilizers, including but not limited to powdered sugar. Oral formulations used herein may use standard slow or sustained release formulations or spansul. Rectal suppositories can be made from traditional materials, including cocoa butter, and glycerin, with or without the addition of waxes to alter the suppository's melting point. Water-soluble suppository bases such as polyethylene glycol of various molecular weights can also be used.

  Film coatings useful with the formulations of the present invention are well known in the art and generally consist of a polymer (usually a cellulose polymer), a colorant, and a plasticizer. Additional materials such as wetting agents, sugars, flavors, oils and lubricants can be included in the film coating formulation. The compositions and formulations herein are also combined and processed as a solid and then made into a capsule form, such as a gelatin capsule.

  The filler or diluent can be any material well known in the art useful for preparing solid oral formulations. Examples of pharmaceutically acceptable fillers include, but are not limited to, lactose, microcrystalline cellulose, sucrose, mannitol, calcium phosphate, calcium carbonate, powdered cellulose, maltodextrin, sorbitol, starch, and xylitol.

  The formulations of the present invention can also include a degrading agent. These degrading agents can be selected from those well known in the art, including pregelatinized starch and sodium starch glycolate. Examples of useful degrading agents include croscarmellose sodium, crospovidone, starch, alginic acid, sodium alginate, clay (eg, bee gum or xanthan gum), cottony cellulose, ion exchange resins, or food acids (citric acid, tartaric acid) Such as those using malic acid, fumaric acid, lactic acid, adipic acid, ascorbic acid, aspartic acid, erythorbic acid, glutamic acid, and succinic acid), effervescent systems, and alkaline carbonate components (sodium bicarbonate, calcium carbonate, Magnesium carbonate, potassium carbonate, ammonium carbonate and the like), but is not limited thereto. In certain embodiments, a degrading agent useful herein can comprise from about 4% to about 40% by weight of the composition, such as from about 15% to about 35%, such as from about 20% to about 35%. .

  Some components can have multiple functions in the formulation. Certain components can act as both fillers and decomposers, for example. The function of the components of a particular formulation can be single, even if its nature allows multiple functions.

  The pharmaceutical formulations and excipient systems herein can comprise an antioxidant or a mixture of antioxidants such as ascorbic acid. Other antioxidants used include sodium ascorbate and ascorbyl palmitate, optionally in combination with small amounts of ascorbic acid. Exemplary ranges for the amount of antioxidant in the formulation are from about 0.05% to about 15%, from about 0.5% to about 15%, or from about 0.5% to about 5% by weight of the formulation. %. In some embodiments, the pharmaceutical formulation is substantially free of antioxidants.

  Pharmaceutical compositions comprising bazedoxifene bisphosphate described herein can also be formulated with steroidal estrogens, such as conjugated estrogens, USPs and the like. The amount of bazedoxifene bisphosphate of the present invention used in the formulation can be adjusted according to the particular formulation used, the amount and type of steroidal estrogens in the formulation, and the specific therapeutic instructions to be considered. In some embodiments, the bazedoxifene bisphosphate described herein is used in an amount sufficient to antagonize the action of a particular estrogen to a desired level. The dose range of conjugated estrogens can be from about 0.3 mg to about 2.5 mg, from about 0.3 mg to about 1.25 mg, or from about 0.3 mg to about 0.625 mg. In the combination formulation, an exemplary range for the amount of bazedoxifene bisphosphate described herein is from about 10 mg to about 40 mg. In the steroidal estrogen mestranol, the daily dose can be from about 1 μG to about 150 μG, and in ethinyl estradiol, the daily dose can be from about 1 μG to 300 μG. In some embodiments, the daily dose is between about 2 μG and about 150 μG.

Examples of oral formulations include bazedoxifene bisphosphate as described herein and the following excipient system:
a) a filler that forms between about 1% to about 99% by weight of the total formulation, eg, between about 20% to about 85% of the formulation from about 4% to about 45% by weight of the total formulation; Decomposing agent is a decomposing agent,
b) Lubricants that form from about 0.2% to about 15% by weight of the composition. In some embodiments, the lubricant is magnesium stearate or another metallic stearic acid (eg, calcium stearate or zinc stearate), fatty acid ester (eg, sodium stearyl fumarate), fatty acid (eg, stearic acid). ), Fatty alcohol, glyceryl behenate, mineral oil, paraffin, hydrogenated salad oil, leucine, polyethylene glycol, metallic lauryl sulfate or sodium chloride.

  The percentages listed above for fillers, disintegrants, lubricants and antioxidants in exemplary formulations are based on the final pharmaceutical composition. The remainder of the final pharmaceutical composition consists of bazedoxifene bisphosphate and a pharmaceutically acceptable surface coating such as, for example, an additional active compound and / or a coating or capsule as described herein Consists of. In some embodiments, the bazedoxifene bisphosphate comprises about 1% to about 99%, about 10 to about 95%, or about 20% to about 90% by weight of the final composition. A coating or capsule consists of up to 8% by weight of the formulation.

Suitable additional excipients and dosage forms for use with bazedoxifene bisphosphate are well known in the art and are described, for example, in Remington, J. et al. P. ^{, Remington's Pharmaceutical Sciences, 17 th} Ed. Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.

The following examples are presented for illustrative purposes and are not limiting. Those skilled in the art will readily recognize a variety of parameters that can be changed and modified to achieve similar or similar results.
Examples Example 1: Preparation of bazedoxifene bisphosphates 4-2 and 4-3

実施例２：バゼドキシフェンビスリン酸塩４−２の特性評価
プロトンおよび炭素核磁器共鳴（^１Ｈ−ＮＭＲおよび^１３Ｃ−ＮＭＲ） As shown in Scheme 4, bazedoxifene free base (Compound 4-1, 941 mg, 2 mmol) and tetrazole (840 mg, 12 mmol) were dissolved in 50 mL of a 1: 1 mixture of dry tetrahydrofuran and methylene chloride. Stirred under nitrogen, di-tert-butyldiisopropyl-phosphoramidite (3.3 g, 12 mmol) was added and the reaction mixture was stirred at room temperature overnight. Then 30% hydrogen peroxide (1.2 mL) was added and the reaction mixture was stirred for 1 hour. The excess hydrogen peroxide was then reduced with 25 mL of saturated sodium disulfite aqueous solution for 30 minutes in an ice bath. The reaction mixture was extracted with 50 mL of ethyl acetate and washed with 2 × 50 mL of trisulfite name trim. The organic layer was dried over anhydrous sodium sulfate and the organic solvent was removed by rotavap. An oil (3 g) was obtained by preparative HPLC (Luna C18 column, 50 × 250 mm, flow rate = 100 mL / min, using 75% acetonitrile (ACN) and 25% 20 mM ammonium acetate buffer pH = 4.5). Bazedoxifene bis-phosphate _{4-2 (C 46 H 68 N 2} O 9 P 2) retention time is 10 minutes. Acetonitrile was first removed from the collected fractions by rotary evaporation and then extracted with CH ₂ Cl ₂ . The organic solvent was removed by rotary evaporation. About 3 mL of yellow oil (bazedoxifene bisphosphate 4-2) is obtained (exact mass measured [M + H] ⁺ 855.45; calculated 855.44), then 4 mL ethanol and 1 mL Of 36% HCl. The reaction mixture was stirred at room temperature for 3 hours, and then the pH of the mixture was adjusted to about 5 to 7 with ammonium hydroxide. Pure end product (bazedoxifene bisphosphate 4-3) was prepared by preparative HPLC (identical Luna column, flow rate = 100 mL / min, A = 0.1% trifluoroacetic acid (TFA) / H ₂ O , B = 100% ACN; 0-2 min 15% B, 2-25 min, 15% B to 40% B). The product was collected at the main peak at 15 minutes and lyophilized. A total of 237 mg of white solid was obtained. The structural characteristics of bazedoxifene bisphosphate 4-3 (ie, bazedoxifene bisphosphate of formula II) were determined by high resolution mass spectrometry (HRMS) (exact mass measured [M + H ] ⁺ 631.20; calcd 631.19).
Scheme 4

Example 2: Characteristics of bazedoxifene bis-phosphate 4-2 rating proton and carbon nuclear magnetic resonance ⁽¹ H-NMR and ¹³ C-NMR)

バゼドキシフェンビスリン酸塩４−２

実施例３：バゼドキシフェンビスリン酸塩４−３の特性評価
プロトンおよび炭素核磁器共鳴（^１Ｈ−ＮＭＲおよび^１３Ｃ−ＮＭＲ） The proton and carbon NMR spectrum of bazedoxifene bisphosphate 4-2 prepared according to Example 1 in deuterated dimethyl sulfoxide (DMSO-d ₆ ) was consistent with its structure. DMSO-d ₆ was used as an internal reference for both protons (δ = 2.50 ppm) and carbon (δ = 39.5 ppm). Table 1 summarizes the chemical shift assignments for bazedoxifene bisphosphate 4-2.

Bazedoxifene bisphosphate 4-2

Example 3 Characterization of Bazedoxifene Bisphosphate 4-3 Proton and Carbon Nuclear Resonance ( ¹ H-NMR and ¹³ C-NMR)

バゼドキシフェンビスリン酸塩４−３

実施例４：３７℃でのバゼドキシフェンビスリン酸塩４−３の溶解度 The proton and carbon NMR spectra of bazedoxifene bisphosphate 4-3 prepared according to Example 1 in deuterated dimethyl sulfoxide (DMSO-d ₆ ) were consistent with its structure. DMSO-d ₆ was used as an internal reference for both protons (δ = 2.50 ppm) and carbon (δ = 39.5 ppm). Table 2 summarizes the chemical shift assignments for bazedoxifene bisphosphate 4-3.

Bazedoxifene bisphosphate 4-3

Example 4: Solubility of bazedoxifene bisphosphate 4-3 at 37 ° C

A sample of bazedoxifene bisphosphate 4-3 of Example 1 (ca. 20 mg each) was placed in a vial to which 1 mL of water was added. The mixture was shaken by hand for 10 seconds and then placed in a 37 ° C. water bath at 50 rpm for 18 hours. The sample was then filtered through a syringe disc filter (13 mm 0.2 μm nylon (Whatman)). The filtrate was analyzed by HPLC. The solubility of bazedoxifene bisphosphate 4-3 was determined to be 4 mg / mL.
Example 5: Conversion of bazedoxifene bisphosphate 4-3 to bazedoxifene

実施例６：３日間未成熟ラット子宮アッセイ Conversion of bazedoxifene bisphosphate 4-3 (5 μg / mL in 20 mM Tris buffer, pH 7.4) to bazedoxifene was observed in vitro using alkaline phosphatase. The concentration of alkaline phosphatase is about 7 units. Table 3 summarizes the in vitro conversion profile of bazedoxifene bisphosphate 4-3 to bazedoxifene in the presence of alkaline phosphatase.

Example 6: Three-day immature rat uterus assay

実施例７：バゼドキシフェンビスリン酸塩５−５の調製 The in vivo effects of bazedoxifene bisphosphate 4-3 on uterine weight were observed as shown in Table 4. Immature Sprague-Dawley rats were treated once daily for 3 days (see, eg, Komm et al. Endocrinology, 2005, 146 (9), 3999-4008, incorporated herein by reference in its entirety. To do). Each group (N = 6) includes ethynylestradiol (EE), EE + 1- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H- Indole-5-ol (bazedoxifene / BZA) or EE + 4-3 was administered orally. The vehicle was 2% Tween 80 / 0.5% methylcellulose. Approximately 24 hours after the last dose, the animals were euthanized, the uterus was removed, the accompanying fat was removed, and any internal fluid was squeezed out and weighed.

Example 7: Preparation of bazedoxifene bisphosphate 5-5

As shown in Scheme 5, 1- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indole-5-ol (bazedoxifene free base Compound 5-1, 3.88 g, 8.08 mmol) and pyridine (7.0 mL, 86.4 mmol, 11 molar equivalents) were dissolved in dichloromethane (70 mL). To this solution was added sodium carbonate (3.4 g) and phosphorus oxychloride (Compound 5-2, 2.00 mL, 21.8 mmol, 2.7 equiv) with stirring. Stirring was continued under nitrogen and the reaction was monitored by mass spectrometry. When phosphorylation (compound of compound 5-3) was complete, cold NaOH solution (3N, 20 mL) and water (300 mL) were added. The pH of the aqueous portion of the mixture was then adjusted to 8-9 by adding an appropriate amount of aqueous HCl solution. Dichloromethane (100 mL) was then added. After thorough mixing of the mixture, the aqueous layer was separated and acidified by the addition of a concentrated aqueous HCl solution (the pH value of the aqueous layer was adjusted to about 1). The solid precipitate was then collected by filtration and an off-white solid (compound 5-5, 3.10 g, mono- [1- [4- (2-azepan-1-yl-ethoxy) -benzyl] phosphate) -3-methyl-2- (4-phosphonooxy-phenyl) -1H-indol-5-yl] ester). Solid 5-5 was further purified using preparative HPLC.
Scheme 5

  Various modifications of the present disclosure in addition to those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

Claims (56)

Formula I:

I
Or a pharmaceutically acceptable salt thereof,
Where
R ¹³ and R ¹⁴ are each independently selected from P (═O) (OR ¹ ) (OR ² ) and P (═O) (OR ³ ) (OR ⁴ );
R ¹ , R ² , R ³ and R ⁴ are each independently H, protecting group, C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, Selected from cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, said C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C ₂ Each of ₋₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally 1, 2, 3, 4 or 5 R ⁵ Is replaced by
Each R ⁵ is independently halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (═O ) R ^b , C (═O) NR ^c R ^d , C (═O) OR ^a , OC (═O) R ^b , OC (═O) NR ^c R ^d , NR ^c R ^d , NR ^c C (= ^{O) R b, NR c C} (= O) OR a, NR c S (= O) 2 R b, S (= O) R b, S (= O) NR c R d, S (= O) 2 Selected from R ^b and S (═O) ₂ NR ^c R ^d ,
Each R ^a is independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, Selected from heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, hetero Each of cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally OH, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl Substituted by R, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl,
Each R ^b is independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, Selected from heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, hetero Each of cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally OH, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl Substituted by R, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl,
R ^c and R ^d are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl , arylalkyl, heteroarylalkyl, selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein the _{C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6} alkynyl, aryl, heteroaryl, Each of cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally OH, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, halo, C _{1 -6} alkyl, _{C 1 6} haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or substituted by cycloalkyl or heterocycloalkyl,
Or a compound, or a pharmaceutically acceptable salt thereof, wherein R ^c and R ^d together with the attached N atom form a 4, 5, 6 or 7 membered heterocycloalkyl group. R ¹ , R ² , R ³ and R ⁴ are each independently H, protecting group, C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, Selected from cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, said C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _{2 -10} alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, each of the cycloalkylalkyl and heterocycloalkylalkyl, independently, _{halo, C 1-4 alkyl, C 1- 4-} Haloalkyl, Ally Le, cycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, _{heterocycloalkylalkyl,} CN, NO 2, _{OH, C 1-4 alkoxy, C 1-4} halo alkoxy, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, _{amino, C 1-4 alkylamino, C 2-8} dialkylamino, SH, -S- _{(C 1-4} alkyl), C (= O) H, C (= O ) - (C 1-4 alkyl), C (= O) - ( aryl), C (= O) - ( _{arylalkyl), C (= O) NH} 2, C (= O) NH _{(C 1-4 alkyl), C (= O) N} (C 1-4 _{alkyl) 2, C (= O)} OH, C (= O) O- (C _-4 alkyl), C (= O) O- ( arylalkyl), OC (= O) H , OC (= O) - (C 1-4 alkyl), OC (= O) - ( aryl), OC ( = O) - _{(arylalkyl), OC (= O) NH} 2, OC (= O) NH (C 1-4 alkyl), OC (= O) NH- ( arylalkyl), OC (= O) N ( C _1-4 alkyl) ₂ , NHC (═O)-(C _1-4 alkyl), NHC (═O)-(aryl), NHC (═O)-(arylalkyl), N (C _1-4 alkyl) ) C (= O)-( _C1-4alkyl ), N ( _C1-4alkyl ) C (= O)-(aryl), N ( _C1-4alkyl ) C (= O)-(arylalkyl) ), NHC (= O) O- ( arylalkyl), NHC (= O) O- (C 1-4 alkyl), NHC = O) O- (arylalkyl), NHC (= O) NH (C 1-4 alkyl), NHC (= O) NH- ( aryl), NHC (= O) NH- ( arylalkyl), NHC (= O) NH _{(C 1-4 alkyl)} 2, _{N (C 1-4 alkyl) C (= O) NH (} C 1-4 alkyl), _{N (C 1-4} alkyl) C (= O) NH- ( Aryl), N (C _1-4 alkyl) C (═O) NH— (arylalkyl), N (C _1-4 alkyl) C (═O) NH (C _1-4 alkyl) ₂ , NHS (═O ) _2- (C _1-4 alkyl), NHS (═O) _2- (aryl), NHS (═O) _2- (arylalkyl), S (═O) _2- (C _1-4 alkyl), S (= _{O) 2} - _{(aryl), S (= O) 2} - ( _{arylalkyl), S (= O) 2} N _{(C 1-4 alkyl), S (= O) 2} NH ( aryl), and S _{(= O)} is selected from 2 NH (arylalkyl), optionally 1, 2, 3, 4 or 5 substituents The compound of claim 1, which is substituted with R ¹ , R ² , R ³ , and R ⁴ are each independently H, 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 said C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C Each of _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is independently halo, C _1-4 alkyl, C _{1 -4} haloalkyl, A Lumpur, cycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, _{heterocycloalkylalkyl,} CN, NO 2, _{OH, C 1-4 alkoxy, C 1-4} 3. A compound according to claim 1 or claim 2, optionally substituted with 1, 2 or 3 substituents selected from haloalkoxy, amino, _C1-4 alkylamino and _C2-8 dialkylamino. R ¹ , R ² , R ³ , and R ⁴ are each independently H, protecting group, C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl 4. A compound according to any one of claims 1 to 3, selected from: cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl. R ¹ , R ² , R ³ , and R ⁴ are each independently selected from H, protecting group, C _1-10 alkyl and C _1-10 haloalkyl. The compound according to item. 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. The compound according to item. The compound according to any one of claims 1 to 6, wherein R ¹ , R ² , R ³ , and R ⁴ are each independently selected from H, a protecting group, and C _1-6 alkyl. . The compound according to any one of claims 1 to 7, wherein R ¹ , R ² , R ³ , and R ⁴ are each independently selected from H, a protecting group, and C _1-4 alkyl. . 9. A compound according to any one of claims 1 to 8, wherein R < ¹ >, R < ² >, R < ³ > and R < ⁴ > are each independently selected from H and tert-butyl. The compound according to any one of claims 1 to 9, wherein R ¹ , R ² , R ³ , and R ⁴ are each C _1-6 alkyl. 11. The compound according to claim ¹ , wherein R ¹ , R ² , R ³ , and R ⁴ are each tert-butyl. Formula Ia:

Ia
A compound according to any one of the preceding claims, having the structure: or a pharmaceutically acceptable salt thereof. Formula II:

II
The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or hydrate thereof.   The pharmaceutical composition according to claim 14, further comprising a pharmaceutically acceptable carrier.   14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or hydrate thereof, and one or more steroidal estrogens.   The pharmaceutical composition according to claim 16, wherein the steroidal estrogen component comprises conjugated estrogens.   A method of treating a disease, symptom, or disorder associated with estrogen deficiency or excess estrogen in an animal in need of treatment, comprising a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof. Administering a possible salt or hydrate.   A method of treating a disease or disorder associated with endometrial tissue growth or abnormal development in an animal in need of treatment, comprising a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof. Administering an acceptable salt or hydrate.   A method of treating contraception in a premenopausal woman in need of contraceptive treatment, comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or hydrate thereof. A method comprising the steps of:   A method for lowering cholesterol in a mammal in need of cholesterol reduction, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or hydrate thereof. Including.   A method of treating one or more vasomotor disorders in a postmenopausal woman in need of treatment of a vasomotor disorder, comprising a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof. Administering a salt or hydrate. 24. The method of claim 22, wherein the vasomotor disorder is hot flashes.   A method of inhibiting or delaying bone demineralization or treating or inhibiting osteoporosis in postmenopausal or estrogen deficient women in need of treatment, comprising a therapeutically effective amount of the compound of claim 1, Or administering a pharmaceutically acceptable salt or hydrate thereof and conjugated estrogens.   A method of treating or inhibiting a menopausal or postmenopausal disorder in a postmenopausal or estrogen deficient woman in need of treatment for a menopausal or postmenopausal disorder, comprising a therapeutically effective amount of claim 1. Administering a compound, or a pharmaceutically acceptable salt or hydrate thereof, and conjugated estrogens.   A method of inhibiting bone loss in a mammal in need of treatment for bone loss, comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or hydrate thereof. A method comprising steps.   A method of treating breast cancer in a mammal in need of treatment for breast cancer, comprising the step of administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof. Including.   In mammals in need of the following compounds, 1- [4- (2-azepane-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indole-5-ol A method of delivering (bazedoxifene) comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof.   30. The method of claim 28, wherein the mammal is a woman.   The woman has a disease, symptom or disorder associated with estrogen deficiency or excess estrogen, proliferation or abnormal development of endometrial tissue in postmenopausal women, contraception, high cholesterol, disease associated with one or more vasomotor disorders Or suffering from one or more of a disorder, postmenopausal or postmenopausal disorders in postmenopausal or estrogen deficient women, bone demineralization or osteoporosis, bone loss, and breast cancer in postmenopausal or estrogen deficient women Item 30. The method according to Item 29.   14. A compound according to any one of claims 1 to 13 for use in therapy.   14. A compound according to any one of claims 1 to 13 for treating a disease, condition or disorder associated with estrogen deficiency or excess estrogen in a mammal.   14. Use of a compound according to any one of claims 1 to 13 as a drug.   14. Use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for treating a disease, condition or disorder associated with estrogen deficiency or excess estrogen in a mammal. Formula II:

II
Or a pharmaceutically acceptable salt thereof, comprising:
Forming a compound of formula I according to claim 1, or a salt thereof;
Hydrolyzing a compound of formula I to form a compound of formula II;
A synthesis method comprising: ^{R 1, R 2, R 3} , and ^{R 4} _are each _{C 1-6} alkyl, The method of synthesis according to claim 35. ^{R 1, R 2, R 3} , and ^{R 4} are each tert- butyl, synthetic methods claimed in claim 35.   38. A method of synthesis according to any one of claims 35 to 37, wherein the step of hydrolyzing the compound of formula I comprises reacting the compound of formula I with an inorganic acid in the presence of water.   The synthesis method according to claim 38, wherein the inorganic acid is HCI. (I) Bazedoxifene (1- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indole-5 in the presence of a base Ol) in formula (a) or formula (b):

(A) (b)
Is reacted with a compound having the formula:

(C)
Forming a compound of:
(Ii) reacting said compound of formula (c) with an oxidizing reagent to form a compound of formula I;
Further including
here,
R ¹¹ and R ¹² are each independently selected from P (OR ¹ ) (OR ² ) and —P (OR ³ ) (OR ⁴ );
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are each independently C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cyclo Selected from alkyl, 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 attached N atom form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3, 4 or 5 R ⁵ ,
And / or R ⁸ and R ⁹ together with the N atom attached form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3, 4 or 5 R ⁵ The synthesis method according to claim 35. The compound of step (i) is a compound having the formula (a),
R ¹¹ and R ¹² are each P (OR ¹ ) (OR ² );
41. The synthesis method according to claim 40, wherein R ¹³ and R ¹⁴ are each P (═O) (OR ¹ ) (OR ² ). Formula I:

I
A synthetic method for preparing a compound of
(I) Bazedoxifene (1- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indole-5 in the presence of a base Ol) in formula (a) or formula (b):

Is reacted with a compound having the formula:

(C)
Forming a step;
(Ii) reacting said compound of formula (c) with an oxidizing reagent to form a compound of formula I;
Including
here,
R ¹¹ and R ¹² are each independently selected from —P (OR ¹ ) (OR ² ) and —P (OR ³ ) (OR ⁴ );
R ¹³ and R ¹⁴ are each independently selected from —P (═O) (OR ¹ ) (OR ² ) and —P (═O) (OR ³ ) (OR ⁴ );
R ¹ , R ² , R ³ , and R ⁴ are each independently a protecting group, C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cyclo Selected from alkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, said _C1-10 alkyl, _C1-10 haloalkyl, _C2-10 alkenyl, _C2- Each of ₁₀ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally represented by 1, 2, 3, 4 or 5 R ^5. Replaced by
Each R ⁵ is independently halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (═O ) R ^b , C (═O) NR ^c R ^d , C (═O) OR ^a , OC (═O) R ^b , OC (═O) NR ^c R ^d , NR ^c R ^d , NR ^c C (= ^{O) R b, NR c C} (= O) OR a, NR c S (= O) 2 R b, S (= O) R b, S (= O) NR c R d, S (= O) 2 Selected from R ^b , and S (═O) ₂ NR ^c R ^d ;
R ⁶ , R ⁷ , R ⁸ , and R ⁹ are each independently C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cyclo Selected from alkyl, 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 bonding N atom form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3, 4 or 5 R ⁵ ,
And / or R ⁸ and R ⁹ together with the N atom attached form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2, 3, 4 or 5 R ⁵ And
Each R ^a is independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, Selected from heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, hetero Each of cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally OH, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl Substituted by R, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl,
Each R ^b is independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, Selected from heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, hetero Each of cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally OH, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl Substituted by R, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl,
R ^c and R ^d are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl , arylalkyl, heteroarylalkyl, selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein the _{C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6} alkynyl, aryl, heteroaryl, Each of cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally OH, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, halo, C _{1 -6} alkyl, _{C 1 6} haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, substituted by cycloalkyl or heterocycloalkyl,
Alternatively, R ^c and R ^d together with the N atom to form a 4, 5, 6 or 7 membered heterocycloalkyl group. R ¹ and ^{R 2} are each independently a protecting _group, it is selected from _{C 1-10} alkyl, and cycloalkyl, the method of synthesis according to claim 42. 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 attached N atom form a heterocycloalkyl group, optionally substituted by one or more C _1-6 alkyl or C _1-6 alkoxy. Or the synthesis method according to 43. The compound of step (i) is a compound having the formula (a),
R ¹¹ and R ¹² are each —P (OR ¹ ) (OR ² );
R ¹³ and ^{R 14} are ^{each, -P (= O) (OR} 1) a (OR ^2), The method as claimed in any one of claims 42 44. R ¹ and R ² are each C _1-10 alkyl;
R ⁶ and R ⁷ are each C _1-10 alkyl;
The base of step (i) is tetrazole;
The synthesis method according to claim 45, wherein the oxidizing reagent in step (ii) is hydrogen peroxide. Formula II:

II
A synthetic method for preparing a compound of
(I) Bazedoxifene (1- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H- in the presence of organic and inorganic bases Indol-5-ol) is reacted with a compound having the formula P (═O) (X ¹ ) ₃ , wherein each X ¹ is independently halo, and the formula (d1):

(D1)
Forming a compound of:
(Ii) hydrolyzing the compound of formula (d1) in the presence of a base to form a salt of the compound of formula II;
(Iii) optionally isolating the compound of formula II, or a salt thereof;
A synthesis method comprising: The formula of step (i): P (= O ) wherein the compound having a ^(X _{1) 3} is, P (= O) Cl is _3, the method of synthesis according to claim 47. 48. The amount of the compound having the formula: P (═O) (X ¹ ) ₃ is between about 2 and about 3 molar equivalents relative to the amount of bazedoxifene in step (i). 48. The synthesis method according to 48.   50. The synthesis method according to any one of claims 47 to 49, wherein the organic base of step (i) is pyridine and the inorganic base of step (i) is sodium carbonate.   The amount of pyridine is between about 9 and 13 molar equivalents relative to the amount of bazedoxifene, and the amount of sodium carbonate is between about 4 and about 6 molar equivalents relative to the amount of bazedoxifene. The synthesis method according to claim 50.   52. The synthesis method according to any one of claims 47 to 51, wherein the reaction of step (i) is carried out in a solvent system containing a polar aprotic organic solvent.   53. The synthesis method according to any one of claims 47 to 52, wherein the base used for hydrolysis of the compound of formula (d1) in step (ii) is an alkali metal hydroxide.   54. A synthetic method according to any one of claims 47 to 53, wherein the method comprises isolating a compound of formula II or the salt thereof.   55. A synthesis method according to any one of claims 47 to 54, wherein step (iii) comprises precipitating the compound of formula II from an aqueous solution. Step (iii)
Acidifying the aqueous solution formed in step (ii) containing a salt of said compound of formula II;
Precipitating the compound of formula II from the acidified aqueous solution;
The synthesis method according to any one of claims 47 to 55, comprising: