IE56152B1 - New 1,1,2-triphenyl-but-1-ene-derivatives,as well as processes for their preparation and their use as medicaments - Google Patents

Abstract

1. 1,1,2-triphenyl-but-1-en-derivatives represented by general formula (1), the configuration of which corresponds to E form see diagramm : EP0107208,P11,F2 in which R in position 3' or 4' is a methyl group, methoxy group, hydroxy group or a halogen atom and R**1 is an alkyl group with 1 to 4 C atoms, and the therapeutically acceptable salts thereof.

Description

This invention relates to new 1,1,2-triphenyl-but-l-ene derivatives which possess valuable therapeutically-applicable properties.

From British Patent Specification 1 013 907 it emerges that 1,1,2triphenyl-alkene derivatives can possess anti-oestrogenic properties and therefore they come into consideration for treatment of hormonedependent tumors. One of them, (ZJ-l-^'-iZ-dimethylaminoethoxyJphenyl] -1,2-diphenyl-but-l-ene (Tamoxifen, INN rec.) has already proved good in the therapy of hormone-dependent mammary tumors.

In German Offenlegungsschrift (DE-OS) 2 807 599 it has been established that a metabolite of Tamoxifen? (Z)-l-C4*-dimethylaminoethoxy)phenyl]-l-(4lhydroxyphenyl)-2-phenyl-but-l-ene displays similar strong anti-oestrogenic activity. This holds true also for a number of {Z)-l-[4l-2-d1methy1am1noethoxy)-phenyl]-l-(4l-hydrojiyphenyl)*2-phenyl-but-l-ene derivatives as & described in European Application 0 002 097. From German Offenlegungs- * schrift (DE-OS) 3 046 719 it emerges that (E)-l-C4l"(2-alkylaminoethoxy) phenyl] -l-(3'hydroxyphenyl)-2-phenyl-but-l-enes also possesses marked * anti-oestrogenic properties.

In a highly specific test procedure it has been ascertained that a number of new 1,1,2-triphenyl-but-l-ene derivatives are clearly superior to Tamoxifen in their anti-oestrogenic effect. As shown below, compounds of the general formula (1) inhibit the growth of mammary tumor cells much more strongly than Tamoxifen. This is in keeping with their stronger binding affinity to oestrogen receptors.

The invention concerns 1,1,2-triphepyl-but-l-ene derivatives of the general formula (1), whose configuration corresponds to the E-form: E-Form in which R in position 3* or 4' represents a methyl group» methoxy group» hydroxy group or a halogen atom and represents an alkyl group with 1 to 4 cations» and the therapeutically acceptable salts thereof.

In this specification, the terms E-Form and Z-Form (E = entgegen" meaning "across}, Z = Hzusanwnrt meaning "together1*) refer to the position of the 3'-hydroxyphenyl group (priority 1 on the C-atora 1) relative to the position of the substituted phenyl group (priority 1 on C-atom 2) on the double bond in the butene chain [Nomenclature rule: R.T. Morrison, R.N. Boyd, Lehrbuch der Organischen Chemie, Verlag Chemie» page 167 (1974)].

The E- and Z-forms are clearly distinguished in their proton resonance signals of the dialkylamino group and the O-CH? group in the -O-CHZCH2H(CM3)2 side chain. The signals of the E-form in the claimed compounds are shifted to higher values compared to the Z-form. [p.J. Collins, J.J. Hobbs and CX Enters, J. Med. Chem. 14,952 (1971)].

The invention also concerns a process for production of compounds of general formula (1) characterised in that carbinols of the general formula (2) in which R in position 31 or 4* can be a methyl group, methoxy group, a protecting group which can easily be converted to a hydroxy group, preferably the acetoxy or tetrahydropyranyloxy group or a halogen atom, 2 R can be a lower alkyl group, and R represents an easily-hydrolysable protective group, are dehydrated in a manner known per se by the action of mineral acid, while removing the protecting groups, the E-form is isolated from the resulting pair of isomers and optionally it is converted to a therapeutically acceptable salt. γήθ easily-hydrolysable protective group is preferably the tetrahydropyranyloxy residue in the case of R or the tetrahydropyranyl residue in p the case of R , The elimination of the protective group or groups and the dehydration 1s achieved successfully with mineral acid in an alcoholic medium, preferably in ethanolic hydrochloric acid solution. The 15 separation of the pair of isomers can be carried out by crystallisation or by chromotographic methods. According to solubility, the free bases or acid-addition salts are used for separation.

The starting materials needed for synthesis of the compounds according to the invention can be produced by the following process, for example: By reaction of potassium phenylate with 2-chlorethyl-N,N-dialkylammonium chloride at elevated temperature in ethanolic caustic potash solution and conversion of the reaction product into the hydrochloride, compound (3) is obtained: (R1)2NCH2CH20 -o x HC1 (3) in which R has the same meaning as in Formula (2) (4) In a Friedel-Crafts Reaction of compound (3) with substituted phenylacetyl chlorides of the general formula (4) ci-coch2 in which R in position 3' or 4' can be a methyl group, methoxy group, 5 acetoxy group or a halogen atom, ethanones of general formula (5) are obtained (RbgHCH^O (5) in which R has the same meaning meaning as in formula (2). as in formula (4) and R has the same Compounds of the general formula (5) are converted with ethyl bromide in dimethyl formamide in the presence of sodium hydride to substituted butanones of the general formula (6) in which R has the same meaning as in formula (4) and has the same meaning as in formula (2).

Compounds of general formula (6) react in anhydrous tetrahydrofuran with 3*-(2-tetrahydropyranyloxy)-phenyl magnesium bromide to diastereomeric carbinols of the general formula (7) in which R has the same meaning as in formula meaning as in formula (2). (4) and R1 has the same Compounds of general formula (7) cleave off the tetrahydropyranyl 5 residue in the presence of mineral acid even at room temperature in alcoholic solution and are converted by heat, with dehydration and optionally with elimination of a further protective group, to a pair of isomers, from which the E-isomer in its salt form or its base form can be isolated, so that compounds of general formula (1) in accord10 ance with claim 1 can be obtained.

The following compounds support the claims Table 1 No. (1) Melting Point °C (1) 1 -ch3 3'-CH3 169 (a) 2 -ch3 4'-CH3 168 (a) 3 -ch3 4'-OCH3 133 to 134 (a) 4 -ch3 3'-OH 186 (h) 5 -ch3 4'-Cl 161 to 162 (a) 6 -ch3 4*-Br 169 to 170 (a) 7C2H5 4* -OCH3 128 to 130 (0 (1) Crystallised from : (a) acetone (b) ether/petroleum ether (c) acetonitrile I he superiority of the claimed compounds is substantiated clearly in highly specific test procedures. a) Binding affinity to oestradiol receptors The measurement of binding affinity to oestradiol receptors is carried out according to the method of W* Devleeschouwer, G. Leclercq, A. Danguy and J.C. Heuson tEurop. J. Cancer, 14, 821 - 723 (1978)].

The uterus cytosol of female prepubertal white 2 kg heavy rabbits (to Zealand type) was incubated for 18 hours at 4°C with 2.5 x 10’$ Μ£3Η> oestradiol as well as with addition of unlabelled oestradiol (control) or test substances at various concentrations. The binding affinity to the oestradiol receptor is expressed as the concentration of unlabelled oestradiol (control) or test substance added to the uterus cytosol which achieved a 50 percent displacement of the cHj- oestradiol bound to the oestradiol receptor.

Table 2 BlM1.h9.Affl J V the tesjt substances Compound R2 R Oestradiol (Control) 1.8 x 109 Tamoxifen H H 2.5 x 107 1 OH 3--CH3 3.5 x IO’8 2 OH 4'-CH3 7.3 x 10‘8 3 OH 4'-OCH3 2.8 x 10-8 5 OH 4*-Cl 8.5 X IO'8 * Molar concentration of the substance which displaces 50% C^Hjoestradiol from the oestradiol receptor.

The affinity of the claimed compounds for the oestradiol receptor is 3 to 9 times higher than with Tamoxifen. b) Inhibition of RHA synthesis in isolated human breast tumor cells Some years ago, it became possible to isolate oestrogen receptor positive [ER breast tumor cells from patients and to grow them continuously lb in vitro. These so-called Cell Lines contain almost all the morphological characteristics and metabolic activities observed in vivo. Therefore they represent an ideal model for testing anfi-oestrogens, as direct statements can be made about the influence on the cell types to be treated in vivo.

Io tost P Cancer Research 36 e 4595 - 4601 (1976)] .

ZR-75-1 cells were incubated with Tamoxifen or with one of the claimed com pounds for 48 hours in concentrations of 4 x lO6Gflto 1 x lO’7]^]» then mixed with labelled uridine or tEiymidine and after one hour the incorpororation rate of the labelled material into the cells was determined.

Table 3 shows the percentage inhibition of the cellular RftA-synthesis by the claimed compounds in comparison to Tamoxifen.

To imitate conditions in vivo the potency of the anti-oestrogenic effect lb of the claimed compounds was tested in the presence of an oestrogen.

ZR-75-1 cells were mixed simultaneously with one of the claimed compounds in a concentration of Ί x 10"^CM]and with 17-a-oestradiol (1 x after incubation for 48 hours labelled uridine or thymidine was added and after one hour the rate of incorporation of the labelled material into the cells was determined (Table 4).

Table 3 Percentage inhibition of RHA°synthesis in ZR-75-1 cells, in comparison with Tamoxifen.

Concentrations of Substance 4 x IO-6 [MJ J 1 x 106 CMJ i x io’7D«3 Compound Ho. Percent age I n h 1 b i t i ο n 1 100 74 47 Tamoxifen 100 44 29 2 100 . 62 42 Tamoxifen 100 39 16 3 100 68 36 Tamoxifen 99 43 13 4 100 73 33 Tamoxifen 100 44 29 5 100 61 41 Tamoxifen 100 39 16 6 100 70 47 Tamoxifen 100 59 43 7 91 37 4 Tamoxifen 93 46 2 As appears from Table 3P the claimed compounds inhibit RHA-synthesis in ZR-75-1 cells much more strongly from a dilution of 1 x IO6 tMj than Tamoxifen which has been taken as the comparative substance in each of the tests concerned.

Table 4 Percentage inhibition of RNA-synthesis in ZR-75-1 cells Concentrations of Substance Compound 1 x IO'6 CMj Compound + 17-e-oestradiol 1x10'6CmJ 1 it 10'8 E M3 Compound No. Perce ntage Inhibition 1 74 74 2 62 58 3 68 65 4 73 79 6 70 74 7 37 41 As appears from Table 4, the claimed compounds inhibit the RNA -synthesis in ZR-75-1 cells unhindered also in the presence of a relatively high concentration of 17-e-oestradiol.

The compounds according to the invention therefore represent a valuable enrichment of the stock of medicines and can be used for treatment of malign breast tumors.

The invention also concerns medicines which contain a compound of general formula (1) as active ingredient as well as conventional pharmaceutical carriers and adjuvants.

The claimed compounds are preferably administered orally. Usually the 5 oral dose amounts to 0.01 to 0.2 g, preferably 0.02 to 0.1 g. Nevertheless it can under certain circumstances be necessary to deviate from the above doses, depending upon the Individual behaviour with respect to the medicament or the kind of formulation and the point of time or the interval at which the administration takes place. Thus it <0 can be sufficient in some cases to manage with less than the above minimum amount, while in other cases the above-mentioned upper limit must be exceeded. In the case of application of larger amounts, it can be advisable to divide these into several individual doses through the day. The active Ingredient can be made up in conventional form for lb oral administration e.g. in capsules, as tablets or as dragees. The release of the claimed compounds can be accelerated or delayed according to pharmaceutical adaptation.

By mixing with solid powdery carriers such as micronised cellulose» potato starch or maize starch9 with additives such as sodium citrate or calcium carbonate and binders such as polyvinyl pyrrol1donegelatine or cellulose derivatives^ optionally with addition of lubricants such as magnesium stearate» sodium lauryl sulphate or polyethylene glycolsR they can be worked up into tablets or to dragee cores. Obviously with the oral administration forms, flavour adjusting agents 2b can be added.

Two-part capsules, e.g. of hard gelatine^ as well as closed soft gelatine capsules with a softener such as e.g. glycerine are suitable as other forms of administration. The push-together capsules contain the active ingredient preferably as a granulate e.g. mixed with fillers such as lactose» saccharose, mannite, starches such as e.g. potato starch or amylopectin, celluose derivatives or highly dispersed silicates. In soft gelatine capsules the active ingredient is dissolved or suspended in suitable fluids, e.g. in plant oils or in fluid polyethylene glycols. Π ic ρι ίμΙικ 11 mi of ♦ hr* strtrtlhq mnl.rrinls Is Production of the starting materials. a) NgN-dimethyl-2-phenoxyethy1 anwonlian chloride. 117 g (1*8 Hoi) potassium hydroxide and 94.1 g (1.0 Hoi) phenol were dissolved in 500 ml ethanol, mixed with a suspension of 144 g (1.0 Hoi) 2-chloroethyl-N,N-dimethy1 ammonium chloride in 500 ml ethanol and heated with vigorous stirring for 1 hour under reflux. After cooling the product is drawn off from the precipitated potassium chloride, post-washed with ethanol and the filtrate is concentrated under vacuum to dryness. The residue is taken up with ether, washed several times with 10 percent caustic soda solution, and then with water, and dried over sodium sulphate. By introduction of dry hydrogen chloride N,N-dimethyl-2phenoxyethyl ammonium chloride is obtained, which can be recrystallised from isopropanol. Colourless crystals of melting point 163°C.

Yield 104.7 g. b) 1-C4l°2-din@thy1ami noethoxy) phenylj -2°(subst. pheqy1)-ethan-1-one. .1 g (0.1 Hoi) NpN-d1methyl"2-phenoxyethyl ammonium chloride and 0.12 Hoi of a corresponding substituted phenyl acetyl chloride in 1 1 di chloromethane are mixed in portions with 24.7 g (0.18 Hoi) anhydrous aluminium chloride at room temperature with vigorous stirring, then warmed slowly and heated for 2 hours under reflux. After cooling the mixture is poured onto ice, 100 ml concentrated hydrochloric acid is added thereto, separation is effected and the organic phase is agitated twice more with 10 percent hydrochloric acid. The united aqueous solutions are made alkaline and extracted three times with 200 ml ethyl acetate each time. After washing mth water and drying over sodium sulphate the solvent is distilled off under vacuum and the resulting 1- £4*-(2-dimethylaminoethoxy) phenyl] -2«($ubst. phenyl)-ethan-1-one is re-crystallised out of petroleum ether. c) 1- C42-(2-dimethylaminoethoxy)phenyl3 -2-(subst.phenyl)-butan-l-one The preparation is carried out by reaction of a corresponding 1- [4*2-diraethylam1noethoxy)phenyl] -2-(subst. phenyl)-ethan-l-one with ethyl bromide and sodium hydride in anhydrous dimethyl formamide as described in detail in German Patent Specification (DE-PS) 3 046 719 (Example -lb). d) 1 - [41 - (2-dimethy 1 ami noethoxy) Phenyl ] -2- (subst, phenyl 1- C3*-(2-tetrahydropyranyloxy)phenyl3-butan-1-o1 (Diasterecmers) The preparation is carried out by reaction of the 1- [4'-(2-dimethylam1noethoxyjphenyl] -2-(subst. phenyl)butan-l-one with 3'-(2-tetrahydropyranyloxy)phenyl magnesium bromide in anyhydrous tetrahydrofuran, as described in detail in German Patent Specification (DE-PS) 3 046 719 (Example le).

The claimed process is described in more detail below by way of production Examples.

Example 1 Production according to the invention of (E)-l- [4,-(2-dimethylam1noethoxy)phenyl] -l-O'hydrojiyphenyl)^(4'-methoxyphenyl )-but-1-ene (Compound Ho. 3). 51.9 g (0.1 Mol) of the diastereomer mixture of 1- t4,-(2-dimethylaminocthoxyjphenyl] -2-(4*-methoxyphenyl )-1- [ 3l-(2-tetrahydropyranyloxy) phenyl] -butan-l-ol in 1.5 1 ethanol are mixed with 60 ml concentrated hydrochloric acid and heated for 2 hours under reflux. Then the solvent is removed under vacuum^ and the residue is suspended in 200 ml dilute ammonia solution and agitated twice with 250 ml ethyl acetate each time. The organic phase is washed to a neutral state with water and after drying over sodium sulphate the solvent is removed under vacuum. The residue is crystallised out of acetone. Colourless crystals of melting point 133 134°C; Rf 0.35 CHC13/CH3OH (7/3) ; yield 8.34 g (20%).

C27M31MO3 (W·5) Calculated Found C 77.66 H 7.48 N 3.36 C 77.45 H 7.52 N 3.31 Molecular Height 417 (determined by mass spectrometry) IR-Spectrura (KBr) γ(Ο-Η) 3650 to 2600 an -Spectrum * (COC13) 0.90 «. (3) CH^ Cj=7.oJ 2.33 s (6) 2.43 to 2.87 m (4) CHL, and Cty« 3.63 to 4.10 •3 1* (5) CH^O and 0^0 i ind 3.80 s 5.23 wide s (1) OH interchangeable with Ο?θ] 6.33 to 7.47 m (12) Aroma tics-H * Taken at 60 MHz; the chemical shifts are given In ppm against TMS (=0.0), the relative intensities are enclosed in brackets, s = singlet; d = doublet; t = triplet; m « multiplef; J = coupling constant in Hz. 6 = 0.0.

Example 2 Production according to the invention of (E)-l- L4,-(2-dimethylaiainoethoxy)phepyl] -l^-bis-p'-hydroxy-phenyl)but-l-ene (Compound Ho. 4) 58.9 g (0.1 Mol) of the diasterecmer mixture of l-C4’-(2-dimethylaminoethoxy)phenyl] -1,2-bis- C3'-2(tetrahydropyranyloxy)-phenyl] -butan-l-ol In 1 1 95 percent ethanol 1s mixed with 30 ml concentrated hydrochloric acid» then heated for 2 hours under reflux and worked up as in Example 1. Colourless light-sensitive crystals of melting point 186°C £ ether/ petroleum ether 1/1)] ; R? 0.20LCHC13/CH3OH (7/3)] ; yield 24.2 g (60%). c26H29N°3 (403.5) Calculated Found C 77.39 C 77.53 H 7.24 H 7.39 N 3.47 N 3.44 Molecular Height 403 (defend ned by mass spectrometry) IR-Spectrum (KBr)Y(0H) 3600 fo 2300 -1 an ^H-NMR-Spectrum (d6-DMS0) : 0.83 t (3) (¾ E J"7.o] 2.17 s (6) (CH3),N 2.33 to 2.73 m (4) OL and CH-N 3.90 t (2) CHJ) [J.6.0] 6.40 to 7.43 nt (12) Aromatics-H 9.33 wide s (2) OH ^interchangeable with D20 Example 3 Production according to the invention of (E)-2-(4'-bromophenyl)-l-E4*-(2-diraethylaminoethoxy)phenyl] -1 (3'-hydroxyphenyl)-but-l-ene (Compound No. 6). 56.8 g (0.1 Mol) of the diastereomer mixture of 2-(4,-bromophepyl)-l* C 4'-(2-dimethylaminoethoxy)phenyl] -1E3'-(2-tetrahydropyranyloxy)phenyl] -butan-l-ol in 500 ml ethanol are mixed with 25 ml concentrated hydrochloric acid, then heated for 2 hours under reflux and worked up 20 as in Example 1, Colourless crystals of melting point 169 to 170°C C acetone3 ; Rf 0.30CCHCl3/CH30H (7/3)] ; yield 30.3 g (65%). (..ι(Η.ιηΙ1γΝΙ>ζ (46(.,1) Molecular Height 465 * IR-Spectrum (KBr) CrtlcuIdled Found C 66.96 II 6.(16 N I.(HI C 66.71 H 5.88 N 3.02 (determined by mass spectrometry) γ(Ο-Η) 3600 to 2400 cm’1 ^-NMR-Spectrum (dg-OMSO) : 0.83 2.23 2.30 to 2.73 3.93 6.50 to 7.60 9.43 * Molecular weight with Bromisotope 79. (3, % [j=7.0] (6) (CH3)2N (4) CH^ and O^N [□-6.0J (2) CHgO (12) Aromatics-H (1) OH {^interchangeable with D^oj Example 4 Medicament containing (Ε,-1-C 4’-dimethylaminoethoxyJphenylj 1-(3'-hydroxyphenyl ,-215 (3' -methylphenyl J-but-l-ene-hydrochloride. 21.82 g powdered (E)-l-C4(-(2-dimethylaminoethoxy)phenyll -l-(3'hydroxyphenyl)-2-(3,-methylpheny1)-but-l-ene- hydrochloride are blended with 40 g lactose and 140 g starch, then mixed with 33 g talc and 13 g calcium stearate, and after careful thorough mixing, the mixture is filled into two thousand hard gelatine capsules of suitable size so that each capsule contains 10 mg active ingredient (calculated as free base).

Example 5 Medicament containing (E)-l- [4*(2-dimethylaminoethoxy)phenyl] -l-(3'-hydroxyphenyl)-2(4'-methoxyphenyl)-but-l-ene. .0 g finely powdered (E)-l- C4’-(2-dimethylarainoethoxy)phenyl] -1(3'-hydroxyphenyl)-2-(4*-methoxyphenyl)-but-l-ene, after blending with Illg mannite, 15 g maize starch and 6 g alginic acid, is granulated and the dried granulate after careful blending with 0.75 g methyl cellulose and 1.5 g magnesium stearate is compressed into one thousand tablets, so that each tablet contains 20 mg active ingredient.

Example 6 Production according to the invention of (E)-l-C4*-(2-diethylaminoethoxy) phenyl] -l-(3'-hydroxyphenyl)-2(4*-methoxyphenyl)-but-l-ene For preparation of the NpN’diethyl-2-phenoxyethyl arcmonium chloride, 117 g (1-8 Mol) potassium hydroxide and 94.1 g (1 Mol) phenol in 1 1 ethanol are reacted vrith 172 g (1.0 Mol) 2-chloroethyl-MtlN"diethylaiEmonium chloride, as described above under a). Colourless crystals with a melting point of 136 - 137¾ are obtained from isopropanol in a yield of 79 g.

In an analogous manner to that described in b) above or in DE-PS 46 719, the l-C4'-(2-d1ettiylaminoethoxy)phenyl]-2-(4lmetho3typhenyl)1- £3*-(2-tetrahydropyranyloxy)phenylJ -butan-l-ol is prepared therefrom. 54.7 g (0.1 Mol) of the diastereomeric mixture of 1-C4*-{2-diethy1aminoethoxy)phenyl] -2-{4tmethoxypheny1)-l- C3,-(2-tetrahydropyranyloxy)-phenyl] -butan-l-ol in 1 1 ethanol are reacted with 30 ml cone, hydrochloric acid, then heated for 2 hours under reflux and worked up as described in Example 1. Colourless light-sensitive crystals of melting point 128° - 130°C (acetonitrile); Rf 0.46 fbenzene, triethylamine (94/6)]; yield 7.6 g (20%).

C29H35NO3 <445·6> Molecular weight 445 1H-ftHR-$pectrum (COC13) (determined by mass spectrometry) 0.70 to 1.23 RI (9) 3¾ 2.23 to 2.97 m (8) 3CH^ and OCCHg 3.67 to 4.03 t and 3.73 s (5) CH^O and CKjO 6.27 to 7.30 m (12) Aroma tics-H 7.8 s (1) OH (^interchangeable with D^O

Claims (6)

1. 1,1,2-triphenyl-but-l-ene derivatives represented by general formula (I), the configuration of which corresponds to E form in which R in position 3' or 4 1 is a methyl group, methoxy group, hydroxy group or a halogen atom and R^ is an alkyl group with 1 to 4 carbon atoms, and the therapeutically acceptable salts thereof.

2. A process of producing 1,1,2-triphenyl-but-l-ene derivatives as claimed in claim 1, wherein carbinols represented by general formula (2) (2) ft 20, in which R In position 3‘ or 4* may be a methyl group» methoxy group» a protecting group which can easily be converted to a hydroxy group» preferably the acetoxy or tetrahydropyranyloxy group or a halogen atom» and i 5 R may be a lower alkyl group p and R represents an easily hydrolysable 5 protecting group p are dehydrated In a manner known per se by the action of mineral acid while removing the protecting groups» the E form Is isolated from the resulting pair of Isomers and optionally is converted to a therapeutically acceptable salt.

3. A drug containing a compound according to claim 1 as active ingredient» 10 as well as canon carrier and auxiliary substances.

4. A process for producing l P b2“triphenyl-but-l-ene derivatives substantially as described herein with reference to Exanples 1 D 2 0 3 and G.

5. 1,l p 2-tr1phenyl-but-bene derivatives whenever prepared by a process as claimed In claim 2 or claim 4. 15

6. A drug containing Iph2-tr1phenyl-but“l-ene derivatives of formula (1) as defined In claim 1 substantially as described herein with reference to Examples 4 and 5.