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Fispemifene for hypogonadism

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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)

 

Figure US07504530-20090317-C00004

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 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

Figure imgf000013_0002R = 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

Figure imgf000013_0003R = 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).

Figure imgf000003_0001Z 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

 

 

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।

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09b37-misc2b027LIONEL MY SON
He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy
सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
औकात बस इतनी देना,
कि औरों का भला हो जाये।

 

 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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