128607-22-7

Usage

Uses

Used in Pharmaceutical Industry:
2-(4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy)ethanol is used as a therapeutic agent for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) caused by menopause. It addresses the needs of an estimated 150 million postmenopausal women worldwide, with 40–70% suffering from VVA. The treatment with ospemifene increases the thickness of vaginal tissue, reducing its fragility and the potential for pain during sexual intercourse.
Additionally, ospemifene has been studied for its potential use in treating osteoporosis and vasomotor symptoms, further expanding its applications in the pharmaceutical industry for addressing postmenopausal health concerns.

Originator

Tess Diagnostics and Pharmaceuticals/Hormos Medical/QuatRx (Finland)

Clinical Use

Ospemifene is a SERM that is currently in Phase II/III clinical trials for the treatment of postmenopausal osteoporosis and urogenital atrophy. It is a known metabolite of toremifene, a triphenylethylene derivative used to treat breast cancer.Ospemifene has been shown to have beneficial effects on the bone without significant estrogen-related side effects. The beneficial effect observed on bone stems from this agent's ability to increase osteoblast proliferation and, as a result, to enhance bone mineralization as well as bone formation. Unlike tamoxifen, ospemifene does not induce osteocyte apoptosis.

Synthesis

The drug can be synthesized succinctly in two steps. First, alkylation of commercially available 4-hydroxybenzophenone (130) with ethylene carbonate and catalytic sodium iodide in refluxing toluene provided benzophenone 131 in 94% yield. This was followed by a McMurry coupling involving benzophenone 131 with chloropropiophenone 132 in the presence of zinc powder and titanium tetrachloride in 2-methyltetrahydrofuran. This reaction gave rise to a mixture of triphenylethylenes directly as a 5.5:1 ratio of Z to E isomers which could be separated by crystallization in aqueous methanol to give a mixture of olefins, 98% of which was comprised of the desired Z-isomer corresponding to ospemifene (XVII). The product purity was further improved by recrystallization to give 99.9% of the Z-isomer in 46% yield from 131. Thus, ospemifene was synthesized in two steps and 43% overall yield.

InChI:InChI=1/C24H23ClO2/c25-16-15-23(19-7-3-1-4-8-19)24(20-9-5-2-6-10-20)21-11-13-22(14-12-21)27-18-17-26/h1-14,26H,15-18H2/b24-23-

Upstream product

• 1137-42-4 4-Hydroxybenzophenone 
• 98-88-4 benzoyl chloride 
• 936-59-4 3-chloropropiophenone 
• 1602487-46-6 2-(4-benzoylphenoxy)ethyl benzoate 
• 451-40-1 phenyl benzyl ketone 
• 89777-91-3 4-[(tetrahydropyran-2-yl)oxy]-1,2-diphenylbutan-1-one 
• 1601484-78-9 2-(4-(2-phenylacetyl)phenoxy)ethyl pivalate 
• 122-99-6 2-Phenoxyethanol 
• 1601484-79-0 2-(4-(1-phenylcyclopropanecarbonyl)phenoxy)ethyl pivalate 
• 1601484-80-3 (Z)-2-(4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy)ethyl pivalate 
• 58214-99-6 2-phenoxyethyl pivalate 
• 65-85-0 benzoic acid 
• 1602487-45-5 2-(4-benzoylphenoxy)ethyl pivalate 
• 14814-17-6 (4-(2-hydroxyethoxy)phenyl)(phenyl)methanone 

Downstream Products

• 1046827-45-5 (Z)-{2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethoxy}-acetic acid ethyl ester 

Relevant academic research and scientific papers

Design, synthesis, anti-proliferative evaluation and docking studies of 1: H -1,2,3-triazole tethered ospemifene-isatin conjugates as selective estrogen receptor modulators

A library of 1H-1,2,3-triazole-tethered ospemifene-isatin and ospemifene-spiroisatin conjugates have been synthesized and evaluated for their anti-proliferative activities against MCF-7 and MDA-MB-231 cell lines. The evaluation studies revealed that compound 11j was the most potent with an IC50 value of 1.56 μM against the MCF-7 cell line. Compounds 11k and 11l also displayed a similar trend, with several-fold lower effective concentrations in ER+ cells than in ER- cells. SAR studies revealed that conjugates having a bromo-substituent at the C-5 and C-7 positions of the isatin ring with ethyl/propyl as the spacer were observed to be active with the most potent compound being ～30 times more potent than Tamoxifen against the MCF-7 cell line. The evaluation results were further supported by docking studies and the stronger binding affinity of the synthesized conjugates was attributed to their greater structural bulk and greater occupation of the ERα active site.

Triarylethylene-indolin-2,3-dione molecular conjugates: Design, synthesis, docking studies and anti-proliferation evaluation

A series of 1H-1,2,3-triazole-linked ospemifene-isatin and O-methylated ospemifene-isatin conjugates were synthesized and assayed for their anti-proliferative activities against estrogen-responsive as well as estrogen-non-responsive cells. The non-cytotoxic conjugate 14e, with an optimal combination of bromo substituents at the C-5/C-7 positions of isatin, proved to be a promising hit with an IC50 value of 31.62 μM against MCF-7 and 19.23 μM against MDA-MB-231. The observed anti-proliferative activities of active conjugates were further corroborated via docking studies carried out on estrogen receptor subtypes α and β.

Polymorphic forms of the formulations (by machine translation)

The present invention provides formulations, the chemical name (Z)- 2 - [4 - (4 - chloro - 1, 2 - diphenyl - d - 1 - enyl) phenoxy] ethanol polymorphic forms, it has excellent stability, and can be a reproduction of the crystal structure. In addition, the present invention also provides formulations polymorph forms of preparation method. (by machine translation)

METHOD FOR PRODUCING TRIPHENYLBUTENE DERIVATIVE

We provide a novel and useful process for preparing triphenyl-butene derivative. A process for the preparation of a compound represented by Formula (IV): wherein R1 is hydrogen or substituted or unsubstituted alkyl, characterized by reacting a compound represented by Formula (V): with a compound represented by Formula (VI): wherein R1 has the same meaning as defined above, in the presence of 1) a polyvalent metal chloride, 2) a reducing agent and 3) an alkali metal salt and/or a substituted or unsubstituted phenol.

PROCESS FOR THE PREPARATION OF OSPEMIFENE AND FISPEMIFENE

Disclosed is a process for the synthesis of the active ingredients ospemifene and fispemifene which comprises reacting phenol 4 with an alkylating agent X- CH2CH2-Y of formula 7, wherein X is a leaving group and Y is the -(OCH2CH2)nOH group wherein n is zero or 1; or X and Y, taken together, represent an oxygen atom; to give ospemifene or fispemifene of formula 8.

PROCESS FOR PREPARATION OF OSPEMIFENE

The present invention relates to a process for the preparation of ospemifene and pharmaceutically acceptable salts thereof which comprises the step of recycling the undesired E-4-(4-hydroxy-1,2-diphenylbut-1-enyl)phenol to generate an isomeric mixture of Z,E-4-(4-hydroxy-1,2-diphenylbut-1-enyl)phenol.

METHODS FOR IMMUNOMODULATION OF CANCER AND INFECTIOUS DISEASE THERAPY

The present invention provides methods for modulating the immune response of a subject to a therapeutic agent, the method comprising administering an effective amount of a triphenyl ethylene (TRIP) compound with an effective amount of the therapeutic agent. In particular embodiments, the TRIP compound enhances the immune response of the subject to the therapeutic agent. In some embodiments, the TRIP compound is administered in different dosing schedules to provide a biphasic immunomodulation effect.

A PROCESS FOR THE PREPARATION OF OSPEMIFENE

The present invention is related to the process for the preparation ospemifene or (Z)-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol (I) and to intermediate compounds used in the process.

A PROCESS FOR THE PREPARATION OF OSPEMIFENE

The present invention is related to the process for the preparation ospemifene or (Z)-2-[4-(4-chloro-l,2-diphenyl-but-l-enyl)phenoxy]ethanol (I) and to intermediate compounds used in the process.

NEW PROCESSES FOR PRODUCING BENZOPHENONE DERIVATIVES

There is provided a process for the preparation of a compound of formula (I): wherein X, R1, R2a, R2b, R2c, R2d, R2e, R3a, R3b, R3c, R3d and R3e are as described in the description. Such compounds may, for example, be useful medicament (or intermediates for medicaments).