Fispemifene

1 Vote

Fispemifene, HM 101
Fispemifene; UNII-3VZ2833V08;
cas 341524-89-8

Molecular Formula:	C26H27ClO3
Molecular Weight:	422.94378 g/mol

2-[2-[4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenoxy]ethoxy]ethanol
Treatment of Hypogonadism
Androgen Decline in the Aging Male (Andropause) in phase 2
Fispemifene is the Z-isomer of the compound of formula (I)

WO 01/36360 describes a group of SERMs, which are tissue-specific estrogens and which can be used in women in the treatment of climacteric symptoms, osteoporosis, Alzheimer’s disease and/or cardiovascular diseases without the carcinogenic risk. Certain compounds can be given to men to protect them against osteoporosis, cardiovascular diseases and Alzheimer’s disease without estrogenic adverse events (gynecomastia, decreased libido etc.). Of the compounds described in said patent publication, the compound (Z)-2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol (also known under the generic name fispemifene) has shown a very interesting hormonal profile suggesting that it will be especially valuable for treating disorders in men. WO 2004/108645 and WO 2006/024689 suggest the use of fispemifene for treatment or prevention of age-related symptoms in men, such as lower urinary tract symptoms and diseases or disorders related to androgen deficiency in men.
Quatrx had been conducting phase II clinical development for the treatment of androgen decline in the aging male. Unlike testosterone replacement therapies that are typically topical or injection therapies, fispemifene is an oral treatment and is not a formulation of testosterone. Fispemifene utilizes the body’s normal feedback mechanism to increase testosterone levels. Originally developed at Hormos, QuatRx gained rights to the drug candidate following a merger of the companies pursuant to which Hormos became a wholly-owned subsidiary of QuatRx.
Known methods for the syntheses of compounds like ospemifene and fispemifene include rather many steps. WO 02/090305 describes a method for the preparation of fispemifene, where, in a first step, a triphenylbutane compound with a dihydroxysubstituted butane chain is obtained. This compound is in a second step converted to a triphenylbutene where the chain is 4-chlorosubstituted. Then the desired Z-isomer is crystallized. Finally, the protecting group is removed to release the ethanol-ethoxy chain of the molecule.
Fispemifene is a selective estrogen receptor modulator (SERM) studied in phase II clinical trials at Forendo Pharma for the treatment low testosterone in men. The compound is also in phase II clinical studies at Apricus for the treatment of men with secondary hypogonadism.
In 2013, Forendo Pharma acquired the drug from Hormos Medical for the treatment of male low testosterone.
In 2014, Apricus Biosciences acquired U.S. rights for development and commercialization
PATENT
https://www.google.com/patents/US7504530
EXAMPLE 2 2-{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethoxy}-ethanol (Compound I)
{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethoxy}-acetic acid ethyl ester was dissolved in tetrahydrofuran at room temperature under nitrogen atmosphere. Lithium aluminium hydride was added to the solution in small portions until the reduction reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride solution. The product was extracted into toluene, which was dried and evaporated in vacuo. The residue was purified with flash chromatography with toluene/triethyl amine (9.5:0.5) as eluent. Yield 68%.
¹H NMR (200 MHz, CDCl₃):
2.92 (t, 2H, ═CH ₂CH₂Cl),
3.42 (t, 2H, ═CH₂ CH₂ Cl),
3.59-3.64 (m, 2H, OCH₂CH₂O CH₂CH ₂OH),
3.69-3.80 (m, 4H, OCH₂ CH ₂OCH ₂ CH₂OH),
3.97-4.02 (m, 2H, OCH₂CH₂OCH₂CH₂OH),
6.57 (d, 2H, aromatic proton ortho to oxygen),
6.78 (d, 2H, aromatic proton meta to oxygen),
7.1-7.43 (m, 10H, aromatic protons).
………….
PATENT
WO 2001036360
https://www.google.com/patents/WO2001036360A1?cl=en
……………
PATENT
WO 2002090305
 http://www.google.co.in/patents/WO2002090305A1?cl=en
EXAMPLE
a) [2-(2-chloroethoxy)ethoxymethyl]benzene
is prepared from benzyl bromide and 2-(2-chloroethoxy)ethanol by the method described in literature (Bessodes, 1996).
b) {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl}phenylmethanone

The mixture of 4-hydroxybenzophenone (16.7 g, 84.7 mmol) and 48 % aqueous sodium hydroxide solution (170 ml) is heated to 80 °C. Tetrabutylammonium bromide (TBABr) (1.6 g, 5.1 mmol) is added and the mixture is heated to 90 °C. [2-(2-Chloroethoxy)ethoxymethyl]benzene (18. g, 84.7 mmol) is added to the mixture during 15 min and the stirring is continued for additional 3.5 h at 115-120 °C. Then the mixture is cooled to 70 °C and 170 ml of water and 170 ml of toluene are added to the reaction mixture and stirring is continued for 5 min. The layers are separated and the aqueous phase is extracted twice with 50 ml of toluene. The organic phases are combined and washed with water, dried with sodium sulphate and evaporated to dryness. Yield 31.2 g.
Another method to prepare {4-[2-(2-benzyloxyethoxy)ethoxy]phenyl}phenyl- methanone is the reaction of 2-(2-benzyloxyethoxy)ethyl mesylate with 4- hydroxybenzophenone in PTC-conditions.
Η NMR (CDCI3): 3.64-3.69 (m, 2H), 3.74-3.79 (m, 2H), 3.90 (dist.t, 2H), 4.22 (dist.t, 2H), 4.58 (s, 2H), 6.98 (d, 2H), 7.28-7.62 (m, 8H), 7.75 (td, 2H), 7.81 (d, 2H).


c) 1- {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl} – 1 ,2-diphenyl -butane- 1 ,4-diol
R = BENZYL
Lithium aluminum hydride (1.08 g, 28.6 mmol) is added into dry tetrahydrofuran (60 ml) under nitrogen atmosphere. Cinnamaldehyde (6.65 g, 50 mmol) in dry tetrahydrofuran (16 ml) is added at 24-28 °C. The reaction mixture is stirred at ambient temperature for 1 h. {4-[2-(2- Benzyloxyethoxy)ethoxy]phenyl}-phenyl-methanone (14.0 g, 37 mmol) in dry tetrahydrofuran (16 ml) is added at 50-55 °C. The reaction mixture is stirred at 60 °C for 3 h. Most of tetrahydrofuran is evaporated. Toluene (70 ml) and 2 M aqueous hydrogen chloride (50 ml) are added. The mixture is stirred for 5 min and the aqueous layer is separated and extracted with toluene (30 ml). The toluene layers are combined and washed with 2M HC1 and water, dried and evaporated. The product is crystallized from isopropanol as a mixture of stereoisomers (8.8 g, 50 %).
Η NMR (CDCI3 ): 1.75-2.10 (m, 2H), 3.20-4.16 (m, 1 OH), 4.52 and 4.55 (2s, together 2H), 6.61 and 6.88 (2d, together 2H), 6.95-7.39 (m, 15H), 7.49 and 7.57 (2d, together 2H).

d) Z- 1 – {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl} -4-chloro- 1 ,2-diphenyl-but- 1-ene
R = BENZYL
1 – {4- [2-(2-Benzyloxy-ethoxy)ethoxy]phenyl} – 1 ,2-diphenyl -butane- 1 ,4-diol (10.0 g, 19.5 mmol) is dissolved in toluene (50 ml). Triethylamine (2.17 g, 21.4 mmol) is added to the solution and the mixture is cooled to -10 °C. Thionyl chloride (6.9 g, 58.5 mmol) is added to the mixture at -10 – ±0 °C. The mixture is stirred for 1 hour at 0-5 °C, warmed up to 70 °C and stirred at this temperature for 4 hours. Solvent is evaporated, the residue is dissolved to toluene, washed three times with 1M HC1 solution and twice with water. The Z-isomer of the product is crystallized from isopropanol-ethyl acetate. Yield 3.0 g. The filtrate is purified by flash chromatography to give E-isomer.
Z-isomer: Η NMR (CDCI3): 2.91 (t, 2H), 3.41 (t, 2H), 3.55-3.85 (m, 6H), 3.99 (dist.t, 2H), 4.54 (s, 2H), 6.40 (s, 1H), 6.56 (d, 2H), 6.77 (d, 2H), 7.10- 7.50 (m, 15H)
E-isomer: 1H NMR (CDCI3): 2.97 (t, 2H), 3.43 (t, 2H), 3.65-3.82 (m, 4H), 3.88 (dist.t, 2H), 4.15 (dist.t, 2H), 4.58 (s, 2H), 6.86 -7.45 (m, 19H)
FINAL STEP
e) 2- {2-[4-(4-Chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethoxy } ethanol:
Z- 1 – {4-[2-(2-Benzyloxy-ethoxy)ethoxy]phenyl} -4-chloro- 1 ,2-diphenyl -but- 1-ene (3.8 g, 7.4 mmol) is dissolved in ethyl acetate under nitrogen atmosphere , Zn powder (0.12 g, 1.85 mmol) and acetyl chloride (1.27 g, 16.3 mmol) are added and the mixture is stirred at 50 °C for 3 h (Bhar, 1995). The reaction mixture is cooled to room temperature, water (10 ml) is added and stirring is continued for additional 10 min. The aqueous layer is separated and the organic phase is washed with 1 M aqueous hydrogen chloride solution and with water. Ethyl acetate is evaporated and the residue is dissolved in methanol (16 ml) and water (4 ml). The acetate ester of the product is hydrolysed by making the mixture alkaline with sodium hydroxide (1 g) and stirring the mixture at room temperature for 1 h. Methanol is evaporated, water is added and the residue is extracted in ethyl acetate and washed with 1 M hydrogen chloride solution and with water. Ethyl acetate is evaporated and the residue is dissolved in toluene (25 ml), silica gel (0.25 g) is added and mixture is stirred for 15 min. Toluene is filtered and evaporated to dryness. The residue is crystallised from heptane-ethyl acetate (2:1). The yield is 71 %.
Z-isomer: 1H NMR (CDCI3): 2.92 (t, 2H), 3.41 (t, 2H), 3.58-3.63 (m, 2H), 3.69-3.80 (m, 4H), 3.96-4.01 (m, 2H), 6.56 (d, 2H), 6.78 (d, 2H), 7.10-7.40 (m, 10H).
Z ISOMER IE FISPEMIFENE
E-2- {2- [4-(4-Chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethoxy} ethanol is prepared analogously starting from E-l-{4-[2-(2-benzyloxy- ethoxy)ethoxy]phenyl} -4-chloro- 1,2-diphenyl-but-l-ene. The product is purified by flash chromatography with toluene-methanol (10:0.5) as eluent.
E-isomer: 1H NMR (CDCI3): 2.97 (t, 2H), 3.43 (t, 2H), 3.65-3.79 (m, 4H), 3.85-3.90 (m, 2H), 4.13-4.17 (m, 2H), 6.85-7.25 (m, 2H).
Debenzylation of 1 – {4-[2-(2-benzyloxy-ethoxy)ethoxy]phenyl} -4-chloro- 1 ,2- diphenyl-but- 1-ene is also carried out by hydrogenation with Pd on carbon as a catalyst in ethyl acetate-ethanol solution at room temperature.
………….
PATENT
http://www.google.com/patents/US5491173

Patent	Submitted	Granted
Method for the preparation of 2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol and its isomers [US6891070]	2004-06-17	2005-05-10
Formulations of fispemifene [US2007104743]	2007-05-10
METHODS FOR THE PREPARATION OF FISPEMIFENE FROM OSPEMIFENE [US7504530]	2008-09-04	2009-03-17
METHOD FOR THE PREPARATION OF THERAPEUTICALLY VALUABLE TRIPHENYLBUTENE DERIVATIVES [US2011015448]	2011-01-20
METHOD FOR THE PREPARATION OF THERAPEUTICALLY VALUABLE TRIPHENYLBUTENE DERIVATIVES [US7812197]	2008-08-28	2010-10-12

WO2001036360A1	1 Nov 2000	25 May 2001	Pirkko Haerkoenen	Triphenylalkene derivatives and their use as selective estrogen receptor modulators
EP0095875A2	20 May 1983	7 Dec 1983	Farmos Group Ltd.	Novel tri-phenyl alkane and alkene derivatives and their preparation and use

Citing Patent	Filing date	Publication date	Applicant	Title
WO2008099059A1 *	13 Feb 2008	21 Aug 2008	Hormos Medical Ltd	Method for the preparation of therapeutically valuable triphenylbutene derivatives
WO2008099060A2 *	13 Feb 2008	21 Aug 2008	Hormos Medical Ltd	Methods for the preparation of fispemifene from ospemifene
CN101636372B	13 Feb 2008	27 Mar 2013	霍尔莫斯医疗有限公司	Method for the preparation of therapeutically valuable triphenylbutene derivatives
EP1636159A1 *	5 May 2004	22 Mar 2006	Hormos Medical Ltd.	Method for the treatment or prevention of lower urinary tract symptoms
EP2518039A1	13 Feb 2008	31 Oct 2012	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
EP2821385A2	13 Feb 2008	7 Jan 2015	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
US7504530	13 Feb 2008	17 Mar 2009	Hormos Medical Ltd.	Methods for the preparation of fispemifene from ospemifene
US7812197	13 Feb 2008	12 Oct 2010	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
US8293947	16 Sep 2010	23 Oct 2012	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
US8962693	19 Aug 2013	24 Feb 2015	Hormos Medical Ltd.	Method for the treatment or prevention of lower urinary tract symptoms

WO2002090305A1	Mar 21, 2002	Nov 14, 2002	Hormos Medical Corp	A new method for the preparation of 2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol and its isomers
WO2004108645A1	May 5, 2004	Dec 16, 2004	Hormos Medical Corp	Method for the treatment or prevention of lower urinary tract symptoms
WO2006024689A1 *	Jul 20, 2005	Mar 9, 2006	Taru Blom	Use of a selective estrogen receptor modulator for the manufacture of a pharmaceutical preparation for use in a method for the treatment or prevention of androgen deficiency
WO2007099410A2 *	Nov 9, 2006	Sep 7, 2007	Hormos Medical Ltd	Formulations of fispemifene
WO2014060640A1	Oct 17, 2013	Apr 24, 2014	Fermion Oy	A process for the preparation of ospemifene
CN100526277C	May 5, 2004	Aug 12, 2009	霍尔莫斯医疗有限公司	Method for the treatment or prevention of lower urinary tract symptoms
CN102532073A *	Dec 30, 2011	Jul 4, 2012	北京赛林泰医药技术有限公司	Ethylene derivative serving as selective estrogen receptor modulators (SERMs)
EP1786408A1 *	Jul 20, 2005	May 23, 2007	Hormos Medical Ltd.	Use of a selective estrogen receptor modulator for the manufacture of a pharmaceutical preparation for use in a method for the treatment or prevention of androgen deficiency
EP1951250A2 *	Nov 22, 2006	Aug 6, 2008	SmithKline Beecham Corporation	Chemical compounds
EP2258360A2	May 5, 2004	Dec 8, 2010	Hormos Medical Ltd.	Method for the treatment or prevention of lower urinary tract symptoms
EP2518039A1	Feb 13, 2008	Oct 31, 2012	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
EP2821385A2	Feb 13, 2008	Jan 7, 2015	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
US6891070	Mar 21, 2002	May 10, 2005	Hormos Medical Corporation	Method for the preparation of 2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol and its isomers
US7504530	Feb 13, 2008	Mar 17, 2009	Hormos Medical Ltd.	Methods for the preparation of fispemifene from ospemifene
US7560589	Jul 27, 2004	Jul 14, 2009	Smithkline Beecham Corporation	Cycloalkylidene compounds as modulators of estrogen receptor
US7569601	May 14, 2007	Aug 4, 2009	Smithkline Beecham Corporation	Cycloalkylidene compounds as modulators of estrogen receptor
US7799828	Jun 8, 2009	Sep 21, 2010	Glaxosmithkline Llc	Cycloalkylidene compounds as modulators of estrogen receptor
US7812197	Feb 13, 2008	Oct 12, 2010	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
US7825107	May 22, 2007	Nov 2, 2010	Hormos Medical Ltd.	Method of treating men suffering from chronic nonbacterial prostatitis with SERM compounds or aromatase inhibitors
US8293947	Sep 16, 2010	Oct 23, 2012	Hormos Medical Ltd.	Method for the preparation of therapeutically valuable triphenylbutene derivatives
US8299112	Sep 15, 2011	Oct 30, 2012	Aragon Pharmaceuticals, Inc.	Estrogen receptor modulators and uses thereof
US8455534	Sep 13, 2012	Jun 4, 2013	Aragon Pharmaceuticals, Inc.	Estrogen receptor modulators and uses thereof
US8962693	Aug 19, 2013	Feb 24, 2015	Hormos Medical Ltd.	Method for the treatment or prevention of lower urinary tract symptoms

WO1996007402A1 *	Sep 6, 1995	Mar 14, 1996	Michael Degregorio	Triphenylethylenes for the prevention and treatment of osteoporosis
WO1996035417A1 *	May 10, 1996	Nov 14, 1996	Cancer Res Campaign Tech	Combinations of anti-oestrogen compounds and pkc modulators and their use in cancer therapy
WO1997032574A1 *	Mar 4, 1997	Sep 12, 1997	Degregorio Michael	Serum cholesterol lowering agent
WO1999042427A1 *	Feb 19, 1999	Aug 26, 1999	Kalapudas Arja	E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol and pharmaceutical compositions thereof
WO1999063974A2 *	Jun 10, 1999	Dec 16, 1999	Endorecherche Inc	Selective estrogen receptor modulator in combination with denydroepiandrosterone (dhea) or analogues
EP0095875A2 *	May 20, 1983	Dec 7, 1983	Farmos Group Ltd.	Novel tri-phenyl alkane and alkene derivatives and their preparation and use

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