NO864343L - SUBSTITUTED 1,1,2-TRIFENYLBUT-1-ENER. - Google Patents

Description

In J. Med. Chem. 25, 1070 (1982), acetoxy-substituted 1,1,2-triphenylbut-1-enes are described as mammary tumor suppressors.

The subject matter of the invention is defined in the patent claims.

The compounds produced according to the invention have an affinity for the estrogen receptor and show a markedly improved tumor-inhibiting effect, for example on hormone-dependent MXT mammary tumors in mice. The compounds according to the invention, especially those containing a carbomoyloxy group, multiply enriched in the mammary carcinoma cells and therefore lead to an increased estrogen-antagonizing effect and an increased inhibition of the growth of the hormone-dependent mammary carcinoma.

The compounds according to the invention also have an antiandrogenic effect (for example in male mice (cultivation NMRI), the growth of the seminal vesicles and prostate respectively is clearly inhibited in untreated mice). This effect is comparable to the effect of the estrogen diethylstillboestrol used as a medicine,

which, for example, finds application in the therapy of prostate cancer.

Furthermore, such compounds of formula I, which for example contain a carbamoyloxy group substituted with 3-chloroethyl- or B-bromomethyl, a C^-Cg-alkenoyloxy group or an S-chloro- respectively 3-bromopropanoyloxy group (-0-CO-CH2-CH2Cl , -0-CO-CH2-CH2Br), in addition cytotoxically active and are therefore estrogen receptor-affinity cytostatics,

they are therefore, for example, both effective on hormone-independent as well as hormone-dependent tumors, for example on mammary carcinoma (for example, hormone-independent human MDA mammary carcinoma cell line, hormone-dependent human MCF-7 mammary carcinoma cell line, hormone-dependent MXT mammary tumor/mouse). With these compounds, an enrichment of the cytotoxic action groups (for example C1-CH2-CH2, Br-CH2-CH2) takes place in the tumor cell with high specificity, which also reduces the systemic toxicity

of the cytostatic drug. Since such compounds have two different points of attack, i.e. next to an estrogen-antagonizing action component, a cytotoxic action component is also present, the use of such an estrogen receptor-affinous cytostatic agent is above all advantageous when in the hormonal therapy of human breast carcinoma a lower receptor status respectively appearance of resistance

- can make the therapy result questionable.

In particular, the compounds; according to the above invention, the previously known compounds show a surprisingly better effect in long-term peroral use. . Furthermore, the compounds according to the invention are distinguished by good resorption, especially in the gastrointestinal tract, and good tolerability.

If R. denotes a C 2 -C 8 alkanoyl group, which contains

a carboxy group, such a carboxy group is particularly located in the $ or w position of the alkanoyl residue, the latter preferably containing 3 to 5 carbon atoms. Examples of such groups are: -carboxypropionyl (-CO-CH2-CH2-CO2H). If R4 is a C2-C6-alkanoyl group, which contains a halogen atom (preferably chlorine or bromine), this is preferably in the -position of the alkanoyl residue, examples of this are: -C0-CH2-CH2C1,

-CO-CH2-CH2Br.

If one of the radicals R 1 , R 2 or R 2 is a C 2 -C 8 -alkanoyloxy group, it is preferably a C 2 -C 4 -alkanoyloxy group, especially the acetoxy group. As a C₁-Cg-alkenoyloxy group (i.e. R4=C₁-Cg-alkenoyl) the group -O-CO-CH=CH2 can be mentioned, for example. The substituents R 1 , R 2 and R 2 are preferably present

in the 4-position of the relevant phenyl rings. R 1 - is preferably an ethyl group.

In particular, the active substances according to the invention concern the following compounds:

a) Compounds of formula I, wherein

R^, R 2 and R^ are the same or different and mean one

carbamoyloxy group or a C-^-Cg-alkenoyloxy group (preferably -OCO-CH=CH2) or a C3-C6-alkanoyloxy group, containing a chlorine or bromine atom in the bi-position (preferably chlorine or bromopropionoxy), wherein one or two of the residues , R2 and R^ can also

be hydrogen (in particular R^ is hydrogen). The residues R 1 , R 2 and R 2 are thereby preferably in the 4-position of the phenyl rings. R 1 is preferably the ethyl group. Depending on the position and number of the substituents R-^, R2 and R^, there are estrogens, partial or true antiestrogens. The compounds are, for example, effective on breast and prostate cancer. Importantly, these compounds are estrogen receptor affine, although no free hydroxy groups are present.

b) Compounds of formula I, wherein

R^ is carbamoyloxy group, optionally containing a

or two g-chloroethyl or 3-bromomethyl residues, R^ means hydroxy, the group -O-PO(OH)2, a carbamoyloxy group, a 2-dimethylaminoethyloxy group, a C2-Cg-alkenoyloxy group or a C2~Cg-alkanoyloxy group, which optionally contains in the 3-position a carboxy group or a halogen atom and R^ is hydrogen or has the same meanings as R-^, since in the latter case R^ can also be hydrogen or in which R-^ is a carbamoyloxy group, which optionally contains one or two 3 -chloroethyl or 3-bromomethyl residues, R2 denotes hydroxy, the group -0-PO(OH)2, a carbamoyloxy group, a 2-dimethylethylaminoethyloxy group, a C^-Cg alkenoyloxy group or a C2-C6 alkanoyloxy group, as optionally in 3 -position contains a carboxy group or a halogen atom and R^ is hydrogen or has the same meanings as R2, since in the latter

in the case also R 2 can be hydrogen. The substituents R 1 , R 2 , R 3 are thereby preferably in the 4-position of the phenyl rings.

R 1 - is preferably ethyl.

c) Compounds of formula I, wherein"

R 2 means a 2-(Di-C 1 -C 4 -alkylamino)-ethyloxy group

(for example dimethylamino-ethyloxy group), preferably in the 4-position), R^ is a carbamoyloxy group (preferably in the 4-position), which may optionally also contain one or two B-chloro or 3-bromomethyl residues,

and R 1 means hydrogen.

R 1 is preferably ethyl.

The introduction of the residue R^ by acylation takes place with the aid of an acid of the formula R-OH, where R means an aminocarbonyl group, an aminocarbonyl group containing one or two 3-chloroethyl residues or the 3-bromomethyl residue at the N-atom, the group -PO(OH )2, a C 1 -C 8 -alkenoyl group, a C 2 -C 8 -alkanoyl group or a C 2 -C 8 -alkanoyl group, containing an additional carboxy group or a halogen atom (especially chlorine or bromine and namely in the 3-position), and such acid is preferably activated. If such an activated acid is used for the acylation, it is preferably compounds of the formula R-X, in which R has the above meaning and X means a halogen atom, a group of the formula -OR<1>, -SR<1> or a group with formula -OS03H or -OCO-R", and R' means a C-^-C^-alkyl radical or in the case of -OR' respectively -SR'

also a phenyl residue, a phenyl residue substituted by nitro groups, C-^-C^-alkyl groups, C-^-C^-alkyl groups or halogen atoms (chlorine, fluorine, bromine), a cyanomethyl residue or a carboxymethyl residue and R" means a linear or branched C-L-C,--alkyl radical or C2-C5-alkenyl radical a C-^-C^-alkyl radical with an extra carboxy group or an extra halogen atom, where R can also be the group P0C12 or the cyano group, if X is halogen and in these

cases, a saponification with the aid of a mineral acid (sulfuric acid, hydrochloric acid) is also followed, or where R can also be the group -C0C1, if X is halogen, and in this case the reaction product formed is also reacted with ammonia or 3-chloroethylamine, 3- bromomethylamine, bis-3-chloroethylamine or bis-3-bromomethylamine. If necessary, an acid-binding substance is added here (e.g. tertiary aliphatic amines, pyridine).

The saponification with mineral acids takes place, for example, in an aqueous medium at temperatures between 50 and 100°C. The reaction with ammonia or the previously indicated 6-chloroethyl or 3-bromomethylamines takes place in inert solvents, which are used for the acylation, the temperature range being, for example, between 0 and 25°C.

If X means a halogen atom, it preferably revolves

whether chlorine, bromine or iodine, if R' and R" respectively mean alkyl residues or alkoxy acid residues, these are preferably low molecular weight and consist of 1 to 4 carbon atoms.

The acylation is carried out, for example, in a common solvent or suspending agent such as water, possibly with the addition of a solubilizing agent (for example, lower aliphatic alcohols, lower aliphatic ketones, dimethylformamide) or indifferent agents. As a solvent or suspension agent, for example,

take into account: lower aliphatic alcohols with 1-6 C atoms (eg n-butanol, tert-butanol), low molecular weight aliphatic ethers (eg 4-10 C atoms), low molecular weight aliphatic ketones (eg 3-6 C atoms ), saturated cyclic ethers, such as tetrahydrofuran, dioxane, low molecular saturated chloro or fluorohydrocarbons with 1-5 C atoms, the individual C atoms may be substituted one or more times (2 to 3 times) with chlorine and/or fluorine, such as chloroform, methylene chloride, possibly by chlorine or bromine substituted aroma-

tical hydrocarbons such as benzene, toluene, xylene, chlorobenzene, dimethylformam-d, dimethylsulfoxy, tetramethylurea, pyridine, N-methylpyrrolidone. Mixtures of these mentioned solvents can of course also be used.

The process is carried out at temperatures between 0 and 200°C, preferably 15 and 150°C.

Often, especially when X means a halogen atom or the group -COR", the presence of an acid-binding substance such as alkali hydroxides, alkali carbonates, alkali hydrogen carbonates, alkali acetates, alkaline earth carbonates, trialkylamines, dialkylamines, pyridine and the like is appropriate. Thereby, the acid-binding agent can also used at the same time alone or in a mixture with other common agents as a solvent (for example pyridine).

During the acylation, one can also proceed in such a way that one first prepares an alkali compound from the compound to be reacted, by reacting it in an inert solvent such as dioxane, dimethylformamide, benzene or toluene with an alkali metal, alkali hydride or alkali amides (especially sodium or sodium compounds) at temperatures between 0 and 150°C and, for example, then the acylating substance (compound R-X, X = halogen) is added.

If the free acid R-OH is used, its activation is necessary in the presence of condensing agents such as dicyclohexylcarbodiimide, tetraethylpyrophosphite, 5-(3'-sulfophenyl)-ethylisoxazole, sulfuric acid bis-alkylamides (for example SO/N(CH^) 2_/2),N,N'-carbonyldiimidazole and so on (Organic Reactions, vol. 12, 1962, pages 205 and 239).

During the acylation (introduction of R, respectively a C2-C8 alkanoyl group) one can also proceed selectively, i.e.

one acylates, for example, only one or two of the free hydroxy groups of the starting substance II, that is achieved

for example by corresponding acylation of a starting substance II, in which R- is hydrogen and the residues R^ and R2 are hydroxy groups (preferably in the same positions of the phenol ring) with only one mole of the acylating agent per 1 mol of compound II.

In the compound thus obtained, the free hydroxy group mentioned above can also be acylated by another acyl residue R .

Another possibility for selective acylation consists in starting from a starting compound of formula II, in which one or two of the residues R-^, R2 or R^ are etherified (i.e. forming a C-^-C8-alkoxy group), the others means hydroxy or hydrogen (one of the residues R-^, R 2 or R^, however, means at least one hydroxy group) and acylates the free hydroxy groups present in the indicated manner and then the alkoxy groups present are cleaved off in a known manner. Also

here, the free hydroxy groups thus formed can then be additionally acylated by an acyl residue R^ in the manner indicated.

The removal of ether groups takes place, for example, without solvents or in an inert solvent with boron tribromide, boron trifluoride, aluminum chloride, silicon tetrachloride, aluminum tribromide, sodium methylthiolate, (CH3)3SiCl+NaJ at temperatures between -70°C and 200°C.

Solvents for this ether cleavage include, for example: aliphatic halogen hydrocarbons such as methylene chloride, aromatic hydrocarbons such as benzene, toluene, xylene, halogenated aromatic hydrocarbons such as chlorobenzene, dichlorobenzenes, dimethylformamide, acetonitrile.

Furthermore, this ether cleavage can also take place with the aid of concentrated hydroiodic acid, pyridine hydrochloride, hydrobromic acid, methylmagnesium iodide with or without solvent at temperatures between 20°C and 250°C.

As a solvent for the latter cleavage, for example: aliphatic ethers come into consideration

alkyl residues of 1 to 6 C atoms.

The acyl groups in the compounds of formula I can again be cleaved off solvolytically, whereby the corresponding free hydroxy compounds of formula I are obtained. This solvolytic cleaving takes place, for example, by saponification with dilute acids or with the help of basic substances (pot ash, soda ash, aqueous alkali solutions, alcoholic alkali solutions, NH^) at temperatures between 10 and 150°C, especially 20 to 1C6°C.

Selective cleavage is also possible, as only one acyl residue (R^) is cleaved off.

Compounds of formula I, in which one or more of the residues R1'R2 °^ R3 ^is a C^-C^-alkenoyloxy group, can also be obtained from corresponding compounds I, where one or more of the residues means a C^-C8-alkanoyloxy group , which in the 8-position contains a chlorine or bromine atom, with the aid of a base (for example a tertiary amine, such as triethylamine, tripropylamine, N-methylpyrrolidine and pyridine) splitting off the halogen atom while forming an a-g-positioned double bond . This reaction takes place, for example, at temperatures between 100 and 150°C in an inert solvent (aromatic hydrocarbons, such as toluene, xylene and chlorobenzene or hydrogen halides such as methylene chloride or chloroform).

When the two left-hand phenyl residues in formula I are different, the compounds according to the invention with formula I are usually obtained in the form of mixtures of the corresponding cis-

and trans isomers. Thereby, the cis-form means a compound I, where the phenyl ring with the substituent R^

is in the cis position to the phenyl ring with the substituent R^. Is the phenyl ring with the substituent R2 in the trans position

to the phenyl ring with the substituent R-j, then there is a trans-form! .

The division of the cis- and trans-isomers can be carried out by means of desirable methods known to those skilled in the art for splitting cis- and trans-isomers, for example by fractional crystallization of the mixed isomers or their salts from an organic solvent or mixture of solvents, for example methanol , acetone or petroleum ether or a mixture thereof or by chromatographic separation of the mixed isomers or salts thereof.

Particularly effective in this case is the presence of isomers

of the cis forms.

Of course, the compounds according to the invention with formula I can also be used in the form of their cis-trans mixtures.

If the compounds of formula I contain a carboxy group, such compounds can also exist in the form of corresponding salts with physiologically tolerable inorganic or organic cations. Examples of inorganic cations include: NH^+/ cations of alkali metals (Na, K), the alkaline earth metals (Ca, Mg), bismuth, aluminum or iron.

Examples of organic cations include: Cations of primary, secondary and tertiary C-^-Cg-alkyl amines, which may also contain another amino group (such as cations of trimethylamine, of trimethylamine or of ethylenediamine), of cyclic amines (piperidine, morpholine, piperazine) or of C^-Cg cycloalkylamines (for example cyclohexylamine).

The starting materials are known or can be prepared respectively, starting from corresponding 1-methoxyphenyl-2-phenyl-ethanones or from 1-methoxyphenyl-2-methoxyphenyl-ethanones (i.e. the methoxy groups can sit in different places on the phenyl ring) according to the respective analogue that of Dodds, Roe. Roy. Soc. B 127, 148 (1939) referred to the procedure (compare to this also example 1).

The corresponding 1,2-diphenylethanone is available, for example, by Friedel-Crafts acylation of anisole with phenylacetyl chloride optionally substituted with a methoxy group. This is followed by the ethylation of 1,2-diphenylbutan-1-one. After the Grignard addition with methoxyphenylmagnesium bromide and subsequent water elimination using a H2SO4/glacial acetic acid mixture, the methoxy-substituted 1,1,2-triphenylbut-1-ene is obtained.

Synthesis of N,N-bis-6-chloroethyl-chloroformamide: 21.0 g of bis-3-• chloroethylamine hydrochloride (1.2 mol) are dissolved in a little water and alkalized with cold Na-pCO^ solution. The separated base is taken up in ice-cold ether, it is shaken twice more with ice-cold ether. The ether phases are dried while cooling over Na2SO4. The ether is removed at 5°C on a rotary evaporator and the thus isolated Nor-Lost base is taken up in 400 ml of dry benzene. During ice-cooling, this solution is mixed drop by drop

a solution of 7.3 g (0.07 mol) of phosgene in dry toluene. It is allowed to stand for a few hours, the separated bis-B-chloroethylamine hydrochloride is filtered and the solvent is removed on a rotary evaporator. The yellow oily residue is distilled under high vacuum at 1 .5 torr and 125°C.

The corresponding N,N-bis-B-bromomethyl-chloroformamide can be prepared analogously to this.

The compounds produced according to the invention show a good effect on hormone-dependent MXT-M 3.2 mammary tumors in mice. The action of the 3-halocarboxylic acid ester is particularly predominant. For example, after subcutaneous implantation of MXT 3.2 mammary tumor in BDF 1 mice at a dose of 1.2 mg/kg body weight/mouse, a %T/C value of 1% is achieved. The letter T means "treated animal group", C means "untreated control group". A %T/C value of 1% then means that the tumor weight of the treated group is only 1% of the tumor weight of the non-treated control group.

The lowest, already effective dose in the above-mentioned animal experiments is, for example

6 mg/kg orally

2 mg/kg subcutaneously

2 mg/kg intravenously

As a general dose range for the effect (animal experiments as above), examples include:

6 - 30 mg/kg orally, especially 15 mg

2-10 mg/kg subcutaneously, especially 6 mg 2-10 mg/kg intravenously, especially 6 mg

The direction of action of the compounds according to the invention

is comparable to the effect of the well-known drug Tamoxifen, however there are particularly the following differences:

The compounds prepared according to the invention also work

on hormone-independent mammary tumor cells.

Indications for the compounds produced according to the invention may come into consideration: hormone-dependent tumors such as endometrial, ovarian, prostate, cervix and mammary carcinoma.

Contraindication: none

The pharmaceutical preparations usually contain

between 10 to 200, preferably 10 to 40 mg of the active components according to the invention.

The administration can, for example, take place in the form of tablets, capsules, pills, dragees, drops, ointments, gels, creams or in liquid form. As a liquid form of application, examples include: oily or alcoholic or aqueous solutions as well as suspensions and emulsions^....

Preferred application forms are tablets containing between 10 and 40 mg or solutions containing between 0.01 to 1% of active substance.

The individual doses of the active components according to the invention can, for example, be a) for oral drug forms between 10 and 40 mg, preferably 15 mg, b) for parenteral drug forms (for example intravenously, intramuscularly) between 2-10 mg, preferably

6mg,

c) in pharmaceutical forms for rectal or vaginal application between 10 and 40 mg, preferably 15 mg, d) in pharmaceutical forms for local application to the skin and mucous membranes (for example in the form of solutions,

lotions, emulsions, ointments, etc.) between 2 and 10 mg, preferably 6 mg.

(The doses are respectively referred to free base.)

For example, it can be recommended 3 times a day 1 to 4

tablets with a content of 10 to 40 mg of active substance or, for example, by intravenous injection 1 to 4 times a day an ampoule of 10 to 25 ml content with 2 to 10

mg substance. For oral administration, the minimum daily dose is, for example, 10, the maximum daily dose for oral administration should not exceed 200.

The acute toxicity of the compounds produced according to the invention on mice (expressed as LD mg/kg, method according to Miller and Tainter, Proe. Soc. Exper. Biol. a. Med. 57 (1944) 261) lies, for example, with oral application between 1000 and 1500 mg/kg (respectively over 1000 mg/kg.

Example_el_l

1,1-bis-(4-carbamoyloxy-phenyl)-2-phenyl-but-1-ene

To a solution of 25 g (25 mmol) phosgene in anhydrous

toluene, a suspension of 10 mmol of 1,1-bis-(4-hydroxy-phenyl)-2-phenyl-but-1-ene and 2.5 g (20 mmol) of dimethylaniline in anhydrous toluene is placed under stirring and cooling. The reaction suspension is stirred for a further 12 hours at room temperature and is then washed with dilute HCl, saturated NaHCO 3 solution and f 2 O, and then dried over Na 2 SO 3 .

Into the toluene solution NH 2 • 1,1-bis-(4-carbamoyl-oxy-phenyl)-2-phenyl-but-1-ene precipitates out.

Melting point 2 02°C.

Yield: 65% of the theoretical.

The starting materials can, for example, be obtained as follows:

To a solution of 15.5 g (0.1 mol) phenylacetyl chloride

21.6 g (0.2 mol) of anisole are added in portions to 80 ml of dichloroethane and then, with stirring and ice-cooling, also 24.0 g (0.2 mol) AlCl^-It is heated for 5 hours under reflux and stirred for a further 2 hours at room temperature . The mixture is poured with stirring into 500 ml of ice water and the dichloroethane phase is separated. The aqueous phase is extracted twice with CHCl^. The combined organic phases are washed twice with 10% caustic soda and three times with water, dried over CaCl2. The solvent is removed on a rotary evaporator. The 1-(4-methoxy-phenyl)-2-phenyl-ethanone thus formed melts at 77°C.

A still warm solution of 2.3 g (0.1 gram atom) of sodium in 44 ml of absolute ethanol is added dropwise with stirring to a mixture of 22.6 g (0.1 mol) of 1-(4-methoxy-phenyl)-2- phenylethanone and 15.6 g (0.1 mol) ethyl iodide. After completion of the vigorous reaction, heat under reflux for 15 minutes. A solution of 1.2 g (0.05 gram atoms) of sodium in 22 ml of absolute ethanol and 7.8 g (0.05 mol) of ethyl iodide is added twice more at intervals of 30 minutes and heated for 4 hours under reflux. Ethanol and excess ethyl iodide are removed on a rotary evaporator. After addition of 1^0 to the residue, shake out twice with ether. The organic phases are washed with Na 2 S 2 O 2 solution and t 2 O. The solvent is removed after drying over CaCl2 and the 1-(4-methoxy-phenyl)-2-phenyl-butan-1-one formed is recrystallized. Melting point 45°C.

7.3 g (0.3 gram atoms) of magnesium is poured over with 10 ml of absolute ether. A solution of 56.1 g (0.3 mol) of 4-bromoanisole in 200 ml of ether is added dropwise. After completion of the reaction, heating is continued for another 30 minutes under reflux. 0.1 mol = 25.4 g (0.1 mol) of 1-(4-methoxy-phenyl)-2-phenyl-butan-1-one in 60 ml of absolute ether is now added dropwise to the Grignard solution. After completion of the dropwise addition, it is heated for 2 hours under reflux. After hydrolysis with ice water/3N f^SO^, the aqueous phase is shaken with ether. The ether layers are washed with saturated NaHCO 3 solution and f 2 O, dried over CaCl 2 and extracted with ether. To the crude product of the Gridnard reaction is added 50 ml of an I^SG^/glacial vinegar mixture (volume ratio 2:8). It is then heated for 20 minutes at 70°C in a water bath. After cooling and adding water, extract twice with ether. The ether phase is washed with NaOH and r2O and dried over CaCl2. The ether is removed and the crude product is recrystallized. The 1,1-bis-(4-methoxy-phenyl)-2-phenyl-but-1-ene thus formed melts at 115°C.

A solution of 3.5 g of 1,1-bis(4-methoxy-phenyl)-2-phenyl-but-1-ene (0.01 mol) in 150 ml of absolute CH 2 Cl 2 is cooled under nitrogen to -60°C. While stirring, 7.5 g of BBr^ are added

(0.03 mol). After 15 minutes, the cooling bath is removed and stirred for a further 3 hours at room temperature. Finally, while cooling, 10 ml of methanol is also added and allowed to stir for 30 minutes. The solvent is removed at 25°C in vacuo. The raw product is mixed with 2N NaOH and stirred at room temperature until everything is dissolved. After acidification with 3N I^SO^, 1,1-bis(4-hydroxy-phenyl)-2-phenyl-but-1-ene precipitates. It is recrystallized from methanol.

Melting point 200 C, yield: 90% of the theoretical.

Example_el_2

1,1-bis(4-6-chloro-propionoxy-phenyl)-2-phenyl-but-1-ene

5 mmol = 1.6 g of 1,1-bis-(4-hydroxyphenyl)-2-phenyl-but-1-ene is suspended in 50 mmol (= 6.4 g) of 3-Cl-propionic acid chloride. After 2 hours of stirring at 120°C, the excess acid chloride is removed in vacuo. The oily residue is purified over a silica gel column (eluent: CHCl^/acetic acid 10:1)

and the product is recrystallized from ethanol.

Yield: 81%

Melting point 82°C.

Example_el_3

1,1-bis(4-3-bromo-propionoxy-phenyl)-2-phenyl-but-1-ene

Production takes place analogously to example 2, in that only

instead of 3-chloro-propionic acid chloride, 8.6 g of 3-bromo-propionic acid chloride are now used.

Yield: 72%

Melting point 94°C.

Exemgel_4a

1-(4-N,N-bis-3-chloroethylcarbamoyloxy)-phenyl7~1-(4-hydroxy-phenyl)-2-phenyl-but-1-ene

3.8 g (0.02 mol) chloroformate-bis-3-chloroethylamide and let the mixture stir for 4 days at room temperature.

The precipitated pyridine hydrochloride is filtered off, pyridine is distilled off. The product is isolated on a silica gel column (eluent CHCl3/acetic acid ethyl ester 10:1) and the isomers (cis-trans isomers) are separated using fractional crystallization from ethanol.

The isomer of the above formula (the carbamoyl residue is cis-positioned to the unsubstituted phenyl group) melts at 135°C. Yield: 32%.

The second isomer (the carbamoyl residue is trans-placed to the unsubstituted phenyl group) was isolated only as a mixture with the cis compound of melting point 128-129°C.

Example_4b

1-(4-N,N-bis-B-bromomethylcarbamoyloxy)-phenyl7-1-(4-hydroxy-phenyl)-2-phenyl-but-1-ene.

The preparation takes place analogously to example 4a using chloroformic acid bis-bromomethylamide. Colorless crystals, melting point 125°C, yield: 28%.

Example_5

1-(4-(N,N-bis-S-chloroethylcarbamoyloxy-phenyl)-1,2-bis-(4-hydroxy-phenyl)-but-1-ene

3.6 g (0.01 mol) of 1,2-bis-(4-methoxy-phenyl)-1-(4-hydroxy-phenyl-but-1-ene) are dissolved with 7.7 g (0.04 mol) chloroformic acid-bis-3-chloroethylamine in pyridine and stirred for 4 days at room temperature. The pyridine is derotated and the product is isolated by means of column chromatography (silica gel, CHCl^/acetic acid ethyl ester 10:1) and recrystallized in ethanol. The formed l-/4- N,N-bis-B-chloroethylcarbamoyloxy)-phenyl7~1, 2-bis-(4-methoxy-phenyl)-but-1-ene melts at 73°C (Yield: 42%

of the theoretical).

A solution of 5.3 g (0.01 mol) of this substance in 150 ml of absolute CH 2 Cl is cooled under nitrogen to -60°C.

While stirring, a similarly cooled solution of 7.5 g (0.03 mol) boron tribromide in 50 ml of absolute CH 2 Cl 2 is slowly added dropwise. After 15 minutes, the cooling bath is removed, it is allowed to stir for 3 hours at room temperature and then 10 ml of methanol is added while cooling. After stirring for half an hour, the mixture is washed with saturated NaHCO^ solution, the CH2Cl2 phase is dried over NaSO^, the solvent is distilled off and the product is isolated by means of column chromatography (silica gel, eluent CHCl-j/ethyl acetate 2:1). The demethylated compound thus formed melts at 138°C. (Cis-trans mixture). Yield: 35% of the theoretical.

Preparation of the starting material:

7.3 g (0.3 gram atom) of magnesium is poured over with 10 ml of absolute tetrahydrofuran. A solution of 77.2 g (0.3 mol) of 4-bromo-phenyl-tetrahydropyranyl ether in 200 ml of absolute tetrahydrofuran is added dropwise. After completion of the reaction, heating is continued for 30 minutes under reflux. 28.4 g (0.1 mol) of 1,2-bis-(4-methoxy-phenyl)- butan-l-one in 60 ml of absolute tetrahydrofuran to the Grignard solution. After completion of the instillation, heat under reflux for 2 hours. The mixture is poured into 500 ml of ice water/

3N H2S04 and the aqueous phase is shaken with ether. The ether phases are washed with saturated NaHCO 3 solution and H 2 O, dried over Na 2 SO 4 and the ether is removed.

70 ml are now added to the crude product of the Grignard reaction

of a methanol/3N HCl mixture (volume 1:1) and allowed to stir overnight at room temperature. The methanol is distilled off, the residue is taken up in water and shaken out with ether. The ether phases are washed with NaHCO 3 solution and water.

The product is isolated using column chromatography (silica gel, eluent: CHCl^/ethyl acetate 10:1)

and brought to crystallization in ethanol. The 1,2-bis(4-methoxy-phenyl)-1-(4-hydroxy-phenyl)-but-1-ene thus formed melts at 82°C.

Eczema<pe>l_6

1-(4-(N,N-bis-8-chloroethylcarbamoyloxy)-phenyl7-1-(4-hydroxyphenyl)-2-(3-hydroxyphenyl)-but-1-ene

The synthesis takes place analogously to example 5. One only starts from 1-(4-hydroxy-phenyl-1-(4-methoxyphenyl)-2-(3-methoxy-phenyl)-but-1-ene instead of 1,2- bis(4-methoxyphenyl)-1-(4-hydroxy-phenyl-buten-1-ene).

Yield: 4 3%

Melting point 92-94°C (cis-trans mixture)

The production of the starting material appears analogously to example 5.

Example_el_7

1-(N,N-bis-g-chloroethylcarbamoyloxy)-phenyl7~1,2-bis-(4-acetoxyphenyl)-but-1-ene

0.5 g (=1 mmol of 1-(4-(N,N-bis-B-chloroethylcarbamoyloxy)-phenyl)-1,2-bis-(4-hydroxyphenyl)-but-1-ene is stirred with 1.5 g 6 mmol) of acetic anhydride in 4 ml of pyridine for 1 hour at 80°C. The pyridine is distilled off and the oily residue is purified using column chromatography (silica gel:

CHCl^/acetic acid ethyl ester 10:1).

The product crystallizes from ethanol.

Yield: 5 3.0%

Melting point 108°C.

Example_el_8

1,1-bis-(4-acroyloxy-phenyl)-2-phenyl-but-1-ene

2.5 mmol (- 1.3 g) 1,1-bis-(4-g-chloro-propionoxy-phenyl)-2-phenyl-but-1-ene, 8 mmol (= 0.8 g) triethylamine and 10 ml of p-hydroquinone are dissolved in 50 ml of dry toluene and heated for 20 hours under reflux. The toluene is distilled off, the oily residue is purified over a silica gel column (eluent: CHCl3/acetic ester 10:1) and the product is recrystallized from ethanol.

Yield: 52.8%.

Melting point 7 9°C.

Example_el_9

1,1-bis-[4-(N,N-bis-6-chloroethylcarbamoyloxy)-phenyl]-2-phenyl-but-1-ene

A solution of 3.2 g (0.01 mol) 1,1-bis-(4-hydroxyphenyl)-2-phenyl-but- l in 50 ml of pyridine and the mixture is allowed to stand for 4 days at room temperature.

The precipitated pyridine hydrochloride is filtered off, the pyridine is distilled off in a vacuum. The residue is purified over a silica gel column (eluent: CHCl3/acetic ester 10:1) and recrystallized in ethanol.

Colorless crystals, melting point 83°C, yield: 64%.

Eczema gel_10

1-(4-(N,N-bis-B-chloroethylcarbamoyloxy)-phenyl7-1-(4-acetoxy-phenyl)-2-phenyl-but-1-ene

The preparation takes place from 1-(N,N-bis-B-chloroethyl-carbamoyloxy)-phenyl7~1-(4-hydroxy-phenyl)-2-phenyl-but-1-ene and acetic anhydride analogously to example 7.

Melting point 5 8°C, yield: 85%.

Example_el_ll

1-(4-(N,N-bis-8-chloroethylcarbamoyloxy)-phenyl7-1-(4-acetoxyphenyl)-2-(3-acetoxyphenyl)-but-1-ene

The preparation takes place from 1-(,N-bis-B-chloroethylcarbamoyl-oxy)-phenyl7-1-(4-hydroxyphenyl)-2-(3-hydroxyphenyl)-but-1-ene and acetic anhydride analogously to example 7.

As the substance has no melting point, it is characterized by the nuclear magnetic resonance spectrum "^H-NMR.

Analysis values:

<C>31<H>31C12N06(584.5)

"'"H-NMR recording in deuterated chloroform at 90 megahertz

= 1.00 (t,J=8Hz, 3H,CH3), 2.40 (t,6H,COCH3), 2.50

(q,j=8Hz,2H,CH2), 3.85 (d,8H,N(CH2CH2C1)2),

7.00-7.44 (m,12H, aromatic.H).

Example_el_12

1,1-bis(4-monochloroacetoxyphenyl)-2-phenyl-but-1-ene

1.6 g (5 mmol) of 1,1-bis-(4-hydroxyphenyl)-2-phenyl-but-1-ene are suspended in 5.7 g (50 mmol) of chloroacetyl chloride and stirred for 1 hour at 120°C . Excess chloroacetyl chloride is distilled off and the crude product is purified over a silica gel column (eluent: CHCl3/acetic ester 10:1). The oily product crystallizes in ethanol.

Colorless crystals, melting point 115°C, yield: 68%.

Example_13

1,1-bis-(4-monobromoacetoxyphenyl)-2-phenyl-but-1-ene

Preparation takes place analogously to example 12 using 50 mmol of bromoacetyl chloride.

Colorless crystals, melting point 85°C, yield: 64%.

Examples of pharmaceutical preparations. 5§El^E_i2_m2_YiElS§2mt_§t2£^ 10 g of active substance according to example 1 is micronised, passed with 106.7 g of calcium hydrogen phosphate through a sieve (1 mm mesh size) and homogenized. This mixture is moistened with a solution of 2.3 g of gelatin and 1.0 g of polyoxyethylene (20)-sorbitan monooleate in 20.7 g of water, granulated through a sieve of mesh size 2 mm and dried at 40°C. The dry granules and 20 g of maize starch are passed through a 0.8 mm sieve and homogenised. This mass is filled on a suitable capsule machine to 140 mg in hard gelatin capsules of size 3. 1 capsule contains 10 mg of active substance.

Tablets_10_m2_active_stoff

10 g of active substance according to example 3 (micronized) and

107.6 g of calcium hydrogen phosphate are mixed and moistened with a solution of 2.3 g of gelatin and 0.1 g of polyoxyethylene (20)-sorbitan monooleate in 20.6 g of water. This mass is granulated through a 2 mm sieve and dried at 40°C. This granule, 35 g of corn starch and 5 g of talc is then put through a sieve (0.8 mm mesh size) and homogenised.

In the usual way, this mass is pressed on a suitable machine

to tablets of 160 mg weight and a diameter of 7 mm.

1 tablet contains 10 mg of active ingredient.

I22§k§ 222 §oppl increase

5 g of active substance according to example 6 are dissolved while stirring and heating to approx. 40°C in 1.8 liters of groundnut oil for injection purposes and filled to 2 liters. Under aseptic conditions, this injection solution is sterilized by filtration over a germ-proof filter (0.2 µm pore size).

Finally, under aseptic conditions and under nitrogen gassing, 1.1 ml (nominal volume 1 ml) is filled into sterile 2 ml ampoules. 1 ampoule contains 2.5 mg of active substance.

Claims (1)

Process for the preparation of substituted 1,1,2-triphenylbut-l-enes with the general formula in which the radicals R-^, R2 and R^ are the same or different and mean hydrogen or the group OR^, and R4 means a C-^-C8-alkenoyl group, a carbamoyl group, a carbamoyl group containing one or two 8-chloroethyl residues or 6-bromomethyl residues, or a C2-C8 alkanoyl group containing a halogen atom, and R^ means a C-^-C8 alkyl group, wherein at least one of the residues R-^, R2 or R^ is not a hydrogen atom and in which one or two of the residues R-^ . one or two of these residues means the carbamoyloxy group or a carbamoyloxy group containing one or two B-chloroethyl residues or (3-bromomethyl residues and their salts with therapeutically stable cations, characterized in that in a compound of formula in which Rj. has the stated meaning and the radicals R'^, R'2 and R'2 mean hydroxy groups or one or two of the radicals R'1'R,2'R<l>3°9S^ can be hydrogen or a C-^-Cg - ■ alkoxy group, the residue R^ is introduced by acylation of the hydroxy group or groups, with R^ having the indicated meaning in addition to hydrogen, then optionally present C-^-Cg alkoxy groups are removed, R^ is optionally introduced into the hydroxy groups thus formed, optionally it is removed from a C2-C8 alkanoyl group containing a halogen atom, halogen hydrogen and formed compounds with a carboxy group are optionally transferred to their salts.