SI8311239A8 - Process for obtaining new derivatives of 1,1,2-triphenyl-propan and 1,1,2-triphenyl propene - Google Patents

Description

Process for the preparation of new 1,1,2-triphenyl-propane and 1,1,2-triphenylpropene derivatives

1. FIELD OF THE INVENTION

The present invention is in the field of chemistry.

2. Technical problem defined

The present invention relates to a process for the preparation of new 1,1-triphenylpropane and 1,1,2-triphenyl-propene derivatives.

3. State of the art

Some triphenyl-alkene derivatives are known to have astrogenically estrogenic properties. [J. Grundy: Chem. Rev. 57, 281 (1957); P.R. Carter et al .: J. Chem. Soc. 1948, 150; Н.П. Buu-Hoi et al: Chim. Ther. 1969, 327; W.J. Middleton et al .: J. Med. Chem. 14,1193 (1971); U.S. Pat. 3 1712 929], analog derivatives, which have basic substituents on the aromatic ring, act primarily as antiestrogenic agents [D.J. Collins et al .: J. Med. Chem. 14, 952 (1971)]. The two most prominent representatives of these compounds are clomiphene [1- (4- [2-diethylamino-ethoxy] -phenyl) -1,2-diphenyl-2-chloro-ethylene] and tamoxifen [(Z) -1- (4- [2-dimethylamino] -Ethoxy] -phenyl) -1,2-diphenyl-butene] - FP Palopoli et al., J. Med. Chem. 10, 84 (1966) and G.R. Bedford et al: Nature 212, 733 (1966). Although both of the aforementioned derivatives have antiestrogenic (estrogen antagonizing and poorly agonistic) properties, the first compound is administered to induce ovulation [M. Murray et al .: J. Obstet. Gynaec. Nr. Commonw. 78, 1108 (1971)] and in oligospermia [J. F. Potts: J. Am. Med. Ass. 231, 907 (1975)]; versus thorne tamoxifen is primarily used in the treatment of mammalian tumors [M.P. Cole et al: Brit. J. Cancer. 1971, 270]. Long-term administration of both of these compounds has shown adverse side effects, which are harmful to the eyes [H.J. Silverman: Am. J. Optom. 49, 335 (1972): L.M. Roch et al .: Arch. Ophtalm. 77.14 (1967); M.J. Kaiser-Kupfer et al .; Cancer Treatment Rep. 62, 315 (1978)], liver [Martindale: The Ectra Pharmacopoeia XXVII, 1392 (1977). The Pharmaceutical Press, London], effects that cause thrombosis [K. Nevasaari et al .: Lancet 946 (1978)].

4. Description of a solution to a technical problem with examples of execution

It is an object of the present invention to provide a process for the preparation of novel compounds which in their action are stronger than known compounds, in addition exhibiting more specific action and to a lesser extent exhibiting undesirable side effects.

The present invention is a process for the preparation of novel 1,1,2-triphenylpropane and 1,1,2-triphenyl-propene derivatives of general formula I

CF

OR (I) in which they denote

A and B independently of one another, a hydrogen atom or together forming a valence bond, X and Y same or different, unsubstituted phenyl group or phenyl group optionally substituted in the p-position by a halogen atom or a C _1-6 alkoxy group i

R 1 is a C 1 -C 6 alkyl-, epoxyalkyl-, methoxyalkyl- or benzyl group or a group of general formula II

- ch ₂ - ch ₂ - n

(II) in which ^R 2 ^iR 3 Independent One of drugog označavaju C ^ -alkyl-smaller group or together with the neighboring nitrogen atom obrazuju maximum osmočlani heterocyclic ring or a maximum šestočlani heterocyclic ring, koji in datom case contain a more heteroatoms and koji u datom case substituted by a lower alkyl group, with the heading da

a. when A and B together form a valence bond and X and Y denote a phenyl group, then R _{1 is} different from methyl and ethyl;

b. when A and B together form a valence bond and X and Y denote a phenyl group, then in the case of the (Z) -isomer, R _; other than dimethylaminoethyl-, diethylaminoethyl-, morpholinoethyl- or piperidinoethyl- groups, and

c. when A and B together form a valence bond and X stands for phenyl group and Y stands for p-methoxy-phenyl group, then R _{3 is} different from methyl or pyrrolidino-ethyl group,

d. when A and B together form a valence bond and X stands for p-methoxyphenyl, ρ-fluorophenyl-, or p-ethoxy-phenyl-group and Y stands for phenyl group, then R _{1 is} different from methyl group.

e. when A and B together form a valence bond and X and Y denote the p-methoxy-phenyl group, then R _{3 is} different from the methyl group, and their stereoisomers, mixtures of stereoisomers and their acid addition salts.

By the term alkyl group, as used herein, either alone or in combination with another term, such as e.g. terms, alkoxy or epoxyalkyl groups, means non-linear or branched saturated aliphatic hydrocarbon groups of 1-6, preferably 1-4 C atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl , etc., primarily methyl or ethyl). The term halogen atom encompasses all four halogens (i.e., fluorine, chlorine, bromine and iodine). If R ₂ and R ₃ together with the nitrogen atom form a heterocyclic group, which is optionally substituted by an alkyl group, pyrrolidino-, piperidino-, heptamethylenimino-, morpholino-, piperazino- and N-methyl- piperazino groups.

A suitable subgroup of compounds of general formula (I) are those derivatives, in which A and B together form a valence bond.

A further suitable subgroup of the compounds of general formula (I) are those derivatives in which A and B together form a valence bond or independently represent a hydrogen atom, X and Y are the same or different and denote a phenyl group and R ₃ denotes C ^ - C epoksialkil-group or a smaller group of the general formula (II), u kojoj R ₂ and R ₃ Independent One of drugog označavaju C ^ C / alkyl-smaller group or together with the nitrogen atom obrazuju - u datom case of C _M-alkyl substituted by grupom - a piperazino-, pyrrolidino-, piperidino- or morpholino-group.

Particularly suitable representatives of the compounds obtained according to the process of the present invention are the following derivatives of general formula (I): threo-1- [4- (2,3-epoxy-propoxy) phenyl] -1,2-diphenyl-3,3,3- trifluoro-propane, (E) -1,2-diphenyl-3,3,3-trifluoro-1- [4- (2- [4-methyl-piperazino] -ethoxy) -phenyl] -propene, and their pharmaceutically acceptable acid addition salts.

The base compounds of general formula (I) form acid addition salts. For the formation of salts, conventional inorganic acids (eg, hydrochloric, hydrobromic, sulfuric, phosphoric acid, etc.) and organic acids (eg, maleic, fumaric, lactic, methanesulfonic, p-toluenesulfonic, citric acid, etc.) may be used.

The compounds of general formula (I) may be in the form of various stereoisomers [such as (Z) - or (E) -isomers, threo- and erythro-isomers] and mixtures thereof. The present invention includes the preparation of all stereoisomers and mixtures thereof as well as the preparation of their pharmaceutically acceptable acid addition salts.

The invention provides a process wherein the compound of general formula (III) ^{CT is} 5- <l ·

X

OH (m) in which A, B, X and Y have the meanings given above, is reacted with Rj-halide or Rj-sulfonate (wherein Rj has the meaning given above) in the presence of an acid-binding agent, and what if If desired, the resulting mixture of stereoisomers is decomposed into individual stereoisomers and, if desired, the resulting base compound of general formula I is converted into its acid addition salt or liberated from the resulting acid addition salt.

As acid binders, e.g. alkaline metal hydroxides, alkaline metal carbonates - preferably alkaline metal salts - in a solvent or diluent, e.g. benzene, alcohol, etc., with R ^ halide or R ^ sulfonate.

The resulting mixture of stereoisomers can be decomposed into individual stereoisomers using conventional methods (eg by means of fractional crystallization).

The base compounds of general formula (I) can be conveniently converted by reaction with the appropriate acid in an inert solvent into their acid addition salts. It is advantageous to produce pharmaceutically acceptable acid addition salts of these compounds of basic character. Bases can be released from their acid addition salts by treatment with a strong base.

The starting materials of the general formula (III) - with the exception of (Z) -1,2-diphenyl-3,3,3-trifluoro-1- (4fluoro-phenyl) -propene, (Z) -1,2-diphenyl-3, 3,3-Trifluoro-1- (4-hydroxy-phenyl) -propene and (E) -2-phenyl-3,3,3-trifluoro-1- (4-hydroxy-phenyl) -1- (4-methoxyphenyl) ) -propene (see U.S. Patent No. 3,712,929) - represent novel compounds whose preparation is illustrated in the Examples.

The endocrinological and tumor-preventing effects of the invention have been demonstrated by the following experimental tests by the invention of these novel compounds. The following test compounds were used in the case:

= threo-1- [4- (2,3-epoxy-propoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoro-propane, = 1- [4- (2,3-epoxy- propoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoro-propene, = (E) -1,2-diphenyl-3,3,3-trifluoro-1- [4- (2- [ 4-Methyl-piperazino] -ethoxy) phenyl-propane, = 1- [4- (2-dimethylamino-ethoxy) -phenyl] -2-phenyl-3,3,3-trifluoro-1- (4-methoxyphenyl) - propene, = (E) -1,2-diphenyl-3,3,3-trifluoro-2- [4- (2-pyrrolidino-ethoxy) -phenyl] -propene, = (E) -1,2-diphenyl- 3,3,3-Trifluoro-1- [4- (2-morpholino-ethoxy) -phenyl] -propene,

- (E) -1- [4- (2-Diethylamino-ethoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoro-propene, = 1-phenyl-2- (4-methoxy-phenyl) ) -1- [4- (2-Dimethylamino-ethoxy) -phenyl] -3,3,3trifluoro-propene.

The anti-estrogenic fact has been proven by the method of M.J.K. Harper et al [J. Reprod. Fert. 13, 101 (1967)]. Young 24 day old female rats were treated for 3 days with 5 ptg of estradiol s.c. once a day. The test substance was also administered within 3 days p.o. once a day. On the fourth day, the animals were killed and the weight of the uterus measured after cleaning.

Table 1 illustrates the antiestrogenic action (i.e., preventing the uterotropic effect of estradiol) of some representatives of the compounds of general formula (I).

TABLE 1: Determination of anti-estrogenic effect in infant rats in females at mg / kg / day

examined compound 0.1 0.3 1.0 3.0 10,0 clomifen -37.1 -67.7 -73.3 tamoxifen -45.6 ± 6.85 -55.2 ± 2.5 -60.9 + 4.04 -70.9 + 4.52 -68.6 ± 4.83 1 -3.0 -39 2 -29 -24 -38 -78 -66 4 -65.2 + 3.93 -71.9 + 1.81 -71.8 ± 5.0 -72.2 + 5.5 5 -52.8 ± 4.2 -52.2 ± 6.12 -60.8 ± 2.13 -68.2 ± 3.32 -63.0 ± 3.68

Note:

The anti-estrogenic effect (i.e., the uterine weight reduction effect) of the test compounds was given in%. Each group consisted of 5-10 animals.

The anti-estrogenic action of the individual compounds of general formula (I) listed in Table 1 achieves the corresponding effect of clomifene and tamoxifen, which were used as reference compounds. At a dose of 1 mg / kg p.o. compound no. 1 causes almost insignificant prevention if this compound is administered at an oral dose of as much as 10 mg / kg, the prevention is only 39%.

The estrogenic (uterotropic) effect was determined according to the method of R.J. Dorfman [Endocrinology 55, 65 (1954)]. Female rats (24 days old) were treated once daily orally. On the fourth day, the animals were killed and, after cleansing, the weight of the uterus measured. Table 2 gives the estrogenic (uterotropic) effect of some compounds of general formula (I) given at different doses. The table also contains the corresponding values of the very active ethinylestradiol and tamoxifen and clomifene which are given as reference compounds (the latter two compounds being known antiestrogen agents).

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These compounds generally have poor estrogenic properties, or their effect in some particular dose ranges (0.1-1.0 mg / kg) is slightly less than the corresponding tamoxifen effect. Dose-effect curve of compound no. 1 is different from the same curve of the earlier compound, namely it is a bit steeper. In the applied dose range (0.01-0.3 mg / kg p.o.) the estrogenic effect is even less than the weak agonistic effect of the antiestrogens, whereby the maximum uterine weight gain achieved exceeds the maximum effect that can be achieved with the use of antiestrogens. With the latter compounds at higher doses, the antiestrogenic action is dominant and suppresses the weak agonist effects.

The action, which stimulates the release of lutenizing hormone, is determined as follows.

Female rats (24 to 25 days old) were treated subcutaneously with the compound tested. Two hours after the second treatment, the animals were gutted and the concentration (level) of luteinizing hormone (LH) was measured from the plasma using a radioimmune method. At a dose of 1 mg / kg s.c. the compounds tested significantly increase the plasma luteinizing hormone concentration in female rats. The results obtained are given in Table 3.

TABLE 3: Plasma concentration of luteinizing hormone increases the concentration of luteinizing hormone in% compound compared to the tamoxifen control assay in rats of females.

106

The remark each group consisted of 4-5 animals. dose 2x1 mg / kg s.c.

The effect of finding compounds on hormone-dependent tumors was determined according to the method of P. Griswold et al. [Cancer Research 26, 2169 (1966)] on mammalian carcinoma 11 induced by 7,1-dimethyl-benz (a) anthracene (DMBA). Treatment was started at a tumor weight of 500 mg and performed once a month three times a week with an oral dose of 20 mg / kg. The size of the tumors formed was measured according to the method of the above authors and according to the method of V.C. Jordan et al. (Europ. J. Cancer 12, 419 (1976)] using a Schubler. Tumor volume was determined according to the Griswold method. Tumor measurement and observation of animals continued for two months after the end of the treatment period.

To evaluate the effect, a relative effectiveness index was introduced: this value was determined based on the number of animals that were finally cured or temporarily cured, or showed permanent or short remission. The calculation was performed based on the following table:

final healing 10 points temporary healing 8 points permanent remission 6 points short remission or unchanged balance 4 points

The change in the average number of tumors that occurred during the treatment was evaluated as follows:

the initial number of tumors was not increased in any animal 8 points the average number of tumors was doubled 6 points a large increase in the average number of tumors 0 points.

The sum of points determined in two ways for each animal is given as% of the maximum effect points that cause final healing. These values were considered as values of relative effectiveness. The results obtained are given in Table 4.

TABLE 4: Effect on cancer (mammalian type) rats induced by DMBA test compound healthy (1) remission (2) (3) (4) relative efficacy

nedelo- % in fact

untreated control

rehearsal - - - - 25/25 0 tamoxifen 2/5 1/5 - 1/5 1/5 70 1 4/5 1/5 - - - 96 4 - - 3/4 1/4 60 10 4/5 - - - 1/5 90 11 1/5 - 3/5 - 1/5 72 15 2/5 - 2/5 - 1/5 70

(1) = final healing (2) = temporary healing (3) = permanent remission (4) = short remission.

The subject of the present invention are further pharmaceutical preparations containing as one active substance one or more compounds of general formula (I), their stereoisomers, mixtures of stereoisomers or their acid addition salts in combination with suitable inert, solid or liquid pharmaceutically acceptable carriers. Pharmaceutical preparations can be used in both human and animal (veterinary) therapy to act on the endocrine system. Several representatives of the compounds of general formula (I) strongly inhibit the growth of experimentally induced tumors. The inventive pharmaceutical compositions can be conveniently prepared in the form of agents suitable for oral administration (e.g., tablets, capsules, powders, solutions, suspensions, emulsions, elixirs, etc.) or for parenteral administration (e.g., solutions, suspensions). These preparations contain the usual inert, solid or liquid carriers (eg starches, milk sugar, magnesium stearate, silica, magnesium carbonate, polyvinylpyrrolidone, water, etc.). The active substance content of these preparations is generally 0.05-98%. These preparations may also contain other excipients that are common in the pharmaceutical industry (eg emulsifying, dispersing, wetting and decomposing agents, buffers, etc.).

The preparation of the present pharmaceutical compositions is accomplished by the use of known and commonly used methods used in the pharmaceutical industry.

The daily dosage of finding new compounds of general formula (I) depends on many factors (eg, patient's condition, severity of disease, activity of the active substance used, etc.). The daily oral dose is generally about 0.1-10 mg / kg body weight.

The above values are for informational purposes only and the dose applied in each case may be above or below the dose of the given limit values.

The present invention will be further explained by the following examples.

Example 1

Preparation of threo-1,2-diphenyl-3,3,3-trifluoro-1- [4- (methoxy-methoxy) -phenyl] propane

10.26 g (30 mmol) of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxy-phenyl) -propane (regulation 1) was dissolved in 40 ml of benzene and the solution was mixed with 2 g (50 mmol) of sodium hydroxide and 4 g (50 mmol) of chloromethylether and then refluxed for one hour. The reaction mixture was diluted with 100 ml of benzene, washed with 20% ammonium chloride solution and dried. The solution was evaporated, the residue crystallized from isopropanol. 7.45 g (64.2%) of the title compound are obtained. T.t. 100-103 ° C.

Analysis (based on formula C ₂₃ H ₂₁ F ₃ O ₂ ):

calculated: C 71.49%, H 5.48%, F 14.75%.

found: C 71.72%, H 5.71%, F 14.91%.

Example 2

Preparation of threo-1- [4- (2,3-epoxy-propoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropane

3.42 g (10 mmol) of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxy-phenyl) -propane (regulation 1) was dissolved in 40 ml of ethanol and the solution was mixed with 0 , 48 g (12 mmol) of sodium hydroxide and 9.2 g (100 mmol) of 1,2-epoxy-3-chloro-propane. The reaction mixture was heated to reflux for 1 hour, evaporated and the solvent was removed by removing the added n-butyl alcohol. The residue was diluted with 30 ml of dichloromethane, washed with water and dried. The solution was evaporated and the residue was crystallized from methanol. 2.85 g of the title compound are obtained. The yield is 71.6%. T.t. 113-116 ° C.

Analysis (with reference to formula C ₂₄ H ₂₁ F ₃ O ₂ ):

calculated: C 72.35%, H 5.31%, F 14.31%, found: C 72.26%, H 5.14%, F 14.47%.

Example 3

Preparation of erythro-1- [4- (2,3-epoxy-propoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropane

4.28 g (12.5 mmol) of erythro-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxy-phenyl) -propane (regulation 1) is reacted with 1,2-epoxy- 3-chloropropane as described in Example 24 in the presence of sodium hydroxide. The product obtained was recrystallized twice from methanol. This gives 2.18 g (44%) of the title compound. T.t. 115-116 ° C.

Analysis (with reference to formula C ₂₄ H ₂₁ F ₃ O ₂ ):

calculated: C 72.35%, H 5.31%, F 14.31%, found: C 72.18%, H 5.46%, F 14.37%.

Example 4

Preparation of (E) -1- [4- (2,3-epoxy-propoxy) -phenyl-1,2-diphenyl-3,3,3-trifluoropropene

3.40 g (10 mmol) (E) -1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxy-phenyl) -propene was dissolved in 30 ml of anhydrous benzene and the resulting solution stirred for half an hour with 0.29 g (12 mmol) of sodium hydride. After the addition of 1.39 g (15 mmol) of 1,2-epoxy-3-chloropropane, the reaction mixture was heated for 5 hours, diluted with 70 ml of benzene, washed with water and dried. The solution was concentrated and the resulting residue was recrystallized from methanol. 2.46 g (63%) of the title compound are obtained. T.t. 73.5-76 ° C.

Analysis (with reference to formula C ₂₄ H ₁₉ F ₃ O):

calculated: C 72.72%, H 4.83%, F 14.38%, found: C 72.89%, H 4.88%, F14.61%.

(E) -1,2-Diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) -propene, which was used as starting material, was obtained as follows:

15.4 g (45 mmol) of 1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) -propane (regulation 1) was heated in 75 ml of ethanol in the presence of 2.2 g (55 mmol) ) of sodium hydroxide with 6.9 g (55 mmol) of benzyl chloride over a period of 1 hour (reflux). The reaction mixture was diluted with 300 ml of water, neutralized with 1 N hydrochloric acid and extracted with 200 ml of chloroform. The organic phase is washed with water, dried and concentrated. The residue was crystallized from ethanol. This gives 17 g (86.6%) of the product. T.t. 94-118 ° C.

Analysis (with reference to formula C ₂₈ H ₂₃ F ₃ O):

calculated: C 77.76%, H 5.36%, F 13.18%, found: C 77.95%, H 5.44%, F 13.42%.

16.42 g (38 mmol) of the above compound was heated with 17.25 g (76 mmol) of 2,3-dichloro-5,6 dicyano-1,4-benzoquinone in 80 ml of benzene for two hours with reflux and then process as described in regulation 2. The (E) -1- (4-benzyloxyphenyl) -1,2-diphenyl-3,3,3-trifluoro-propene obtained is dissolved at 128-129 ° C (after crystallization from ethanol). Yield 6.21 g (38%).

Analysis (with respect to the formula C ^ H ^ FgO):

calculated: C 78.13%, H 4.92%, F 13.24%, found: C 78.34%, H 5.10%, F 13.24%.

The structure of the above compound was demonstrated using the NMR spectrum.

6.02 g (14 mmol) of the above compound was hydrogenated in a mixture of methanol and tetrahydrofuran (1: 1) in the presence of a coal palladium catalyst. The catalyst was filtered off, the filtrate was evaporated and the residue was crystallized from a mixture of chloroform and hexane (1: 2). 3.50 g (73.5%) of (E) -1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) -propene are obtained. Mp 113120 ° C. Analysis (with reference to formula C ₂₁ H ₁₅ F ₃ O):

calculated: C 74.11%, H 4.45%, F 16.75%, found: C 74.17%, H 4.85%, F 16.53%.

Example 5

Preparation of 1- [4- (2,3-epoxy-propoxy) -phenyl] -1-phenyl-3,3,3-trifluoro-2- (4-chlorophenyl) -propane

6.03 g (16 mmol) of 1-phenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) -2- (4-chlorophenyl) -propane was dissolved in 60 ml of methanol, the solution was mixed with 0.8 g (20 mmol) of sodium hydroxide and 14.8 g (160 mmol) of 1,2-epoxy-3-chloropropane and refluxed for 2 hours. The reaction mixture was treated as described in Example 3. After crystallization from methanol, 4.44 g (64%) of the title compound was obtained. T.t. Mp 141-144 ° C.

Analysis (with reference to the formula C ₂₄ H ₂₀ ClF ₃ O ₂ ):

calculated: C 66.59%, H 4.66%, Cl 8.19%, F 13.17%, found: C 66.71%, H 5.05%, Cl 8.35%, F 13.29 %.

1-Phenyl-3,3,3-trifluoro-1- (4-hydroxy-phenyl) -2- (4-chlorophenyl) -propane, used as starting material, is prepared as described below and in regulation 1 :

4′-chloro-2,2,2-trifluoro-acetophenone [R.Fuchs: J. Org. Chem. 22, 993-994 (1957)] in ethanol is reacted with benzyl-triphenylphosphonium chloride in the presence of sodium ethylate. 1-Phenyl-3,3,3-trifluoro-2- (4-chlorophenyl) -propene was obtained in 68% yield. T.t. 63-66 ° C (after crystallization from hexane).

Analysis (in relation to formulu C ₁₅ H _1O C1F _3):

calculated: C 63.73%, H 3.57%, Cl12.54%, F 20.16%, found: C 63.91%, H 3.81%, Cl12.37%, F 20.03%.

The resulting product is hydrogenated in acetic acid in the presence of a 10% palladium catalyst on coal. 1-Phenyl-3,3,3-trifluoro-2- (4-chlorophenyl) -propane was obtained in 86% yield. Boiling point 118-120 ° C / 0.4 mm Hg, n ²⁰ D = 1.5230.

Analysis (with reference to formula C ₁₅ H ₁₂ C1F ₃ ):

calculated: C 63.28%, H 4.25%, C112.45%, F 20.02%, found: C 63.51%, H 4.40%, C112.38%, F 19.93%.

The above product is brominated in carbon tetrachloride. After crystallization from hexane, the obtained 1-bromo-1-phenyl-3,3,3-trifluoro-2- (4-chlorophenyl) -propane melts at 143-146 ° C. Yield 45.3%.

Analysis (with respect to formula C ₁₅ H _n BrClF ₃ ):

calculated: C 49.55%, H 3.05%, Br 21.98%, Cl 9.75%, F 15.68%, found: C 49.68%, H 3.15%, Br 22.03 %, Cl 9.71%, F 15.53%.

The product obtained is reacted with anisole in the presence of aluminum chloride. After crystallization from isopropanol, the obtained 1-phenyl-3,3,3-trifluoro-2- (4-chlorophenyl) -1- (4methoxyphenyl) -propane melts at 164-171 ° C. Yield 66%.

Analysis (with reference to the formula C ₂₂ H _lg ClF ₃ O):

calculated: C 67.61%, H 4.64%, Cl, 9.07%, F 14.58%, found: C 67.75%, H 4.70%, Cl 9.01%, F 14, 45%.

The above product is reacted with pyridine hydrochloride.

The resulting 1-phenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) -2- (4-chlorophenyl) -propane was further processed without purification.

Example 6

Preparation of threo-1- [4- (2-dimethylaminoethoxy) -phenyl-1,2-diphenyl-3,3,3-trifluoropropane hydrochloride

6.84 g (20 mmol) of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) -propane (regulation 1) was stirred in 60 ml of anhydrous xylene with 0.6 g ( 24 mmol) of sodium hydride over a half hour period. This mixture was mixed with a 4.16 M solution of 2-dimethylaminoethyl chloride in xylene (7.2 ml, 30 mmol). The reaction mixture was heated for 2 hours, then evaporated, the residue mixed with 10 ml, 9.36% solution of hydrogen chloride in methanol and evaporated again. The product was crystallized from isopropanol. 5.76 g (64%) of the title compound are thus obtained. T.t. 229-231 ° C.

Analysis (with respect to formula C ₂₅ H _2? C1F ₃ NO):

calculated: C 66.74%, H 6.05%, CI 7.88%, F 12.67%, N 3.11%, found: C 66.47%, H 6.03%, CI 7.96 %, F 12.86%, N 3.00%.

Example 7

Preparation of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4- (2-morpholino-ethoxy) -phenylpropane)

3.42 g (10 mmol) of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) -propane (regulation 1) is reacted first with sodium hydride and then with 2- ( chloroethyl) -morpholine in xylene as solvent (according to the procedure described in Example 6). Crystallization from hexane gave 3.12 g (68.5%) of the title compound. T.t. 87-89 ° C.

Analysis (with reference to formula C ₂₇ H _2g F ₃ NO ₂ ):

calculated: C 71.19%, H 6.20%, F 12.51%, N 3.08%, found: C 71.41%, H 6.48%, F 12.35%, N 3.01 %.

Example 8

Preparation of (E) -1,2-Diphenyl-3,3 «3-trifluoro-1- [4- (2-pyrrolidinoethoxy) -phenyl] -propene

2.72 g (8 mmol) (E) -1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) -propene (Example 4) is reacted (as described in Example 4) first with sodium hydride followed by 2- (chloroethyl) -pyrrolidine in xylene. Crystallization from hexane gave 2.15 g (61.4%) of the title compound. T.t. 84.5-86 ° C.

Analysis (with reference to formula C ₂₇ H ₂₆ F ₃ NO):

calculated: C 74.12%, H 5.99%, F 13.03%, N 3.20%, found: C 74.40%, H 6.11%, F 13.15%, N 3.15 %.

Example 9

Preparation of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4-propoxyphenyl) -propane

A solution of 3.42 g (10 mmol) of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) propane (regulation 1) and 35 ml of anhydrous benzene was mixed with 0.8 g (20 mmol) of powdered sodium hydroxide and 6.8 g (40 mmol) of n-propyl iodide. The reaction mixture was refluxed for 4 hours, diluted with 50 ml of benzene, washed with neutral water and dried. The solution was concentrated and the residue was crystallized from isopropanol. 3.32 g (86.5%) of the title compound are obtained. T.t.t. 77-80 ° C.

Analysis (with reference to formula C ₂₄ H ₂₃ F ₃ O):

calculated: C 74.98%, H 6.03%, F 14.83%, found: C 75.01%, H 6.20%, F 14.95%.

Example 10

Preparation of threo-1- [4- (f (3,4-epoxy) -2-hydroxy] -butoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoro-propane

3.42 g (10 mmol) of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) -propane (regulation 1) is heated with 17 ml of DL-diepoxy-butane over a period of time. for half an hour at 100 ° C. The reaction mixture was evaporated, the residue was diluted with 300 ml of ether, washed with water and dried. The solution was evaporated and the residue was crystallized from isopropanol. This gives 3.22 g (75.2%) of the title compound. T.t. 121-126 ° C. The resulting product was chromatographed in a mixture of hexane and acetone (3: 2). Chromatographic uniform threo-1- [4 - ([(3,4-epoxy) -2-hydroxy] -butoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoro-propane was crystallized from isopropanol. The yield was 1.90 g (44.4%). T.t. 130-133 ° C.

Analysis (with reference to formula C ₂₅ H ₂₃ F ₃ O ₃ ):

calculated: C 70.08%, H 5.41%, F 13.30%, found: C 70.30%, H 5.74%, F 13.09%.

Regulation 1

Preparation of erythro- and threo-1,2-diphenyl-3,3,3-trifluoro-1- [4- (2-morpholinoethoxy) -phenyl] propane

1.20 g (2.67 mmol) of erythro-1- [4- (2-bromoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropane was heated with 4.80 g of morpholine under reflux. The cooled reaction mixture was washed with neutral water (after dilution with 50 ml ether). The ether solution was filtered, concentrated to dryness and the residue crystallized from hexane. 1.02 g (83.6%) of erythro-1,2-diphenyl-3,3,3-trifluoro-1- [4- (2-morpholino-ethoxy) -phenyl] -propane are obtained. T.t. 112115 ° C.

Analysis (with respect to the formula C ^ H ^ FjNOj):

calculated: C 71.19%, H 6.20%, F 12.51%, N 3.08%, found: C 71.07%, H 6.37%, F 12.71%, N 2.97 %.

3.60 g (8 mmol) of threo-1- [4- (2-bromoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropane was refluxed with 14 g of morpholine. The reaction mixture was treated as given above. The resulting threo-1,2-diphenyl-3,3,3-trifluoro-1- [4- (2-morpholinoethoxy) -phenyl] propane was crystallized from hexane. The yield was 2.85 g (78.3%). T.t. 88-91 ° C.

Analysis (with respect to the formula C ^ H ^ EjNOJ:

calculated: C 71.19%, H 6.20%, F 12.51%, N 3.08%, found: C 71.24%, H 6.44%, F 12.45%, N 3.03 %.

Erythro- and threo-1- [4- (2-bromoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropane used as starting material can be obtained as follows:

To a solution of 27 g (1.17 g atoms) of sodium and 500 ml of anhydrous ethanol at 0-2 ° C was added a solution of 456 g (1.17 mol) of benzyl-triphenyl-phosphonium chloride [G. Wittig: Chem. Ber. 87,1318 (1954)] and 1500 ml of anhydrous ethyl alcohol, after which this mixture was mixed with a solution of 204 g (1.17 mol) of 2,2,2-trifluoroacetophenone and 100 ml of anhydrous ethyl alcohol. The reaction mixture was allowed to stand overnight, then concentrated, the residue was mixed with 800 ml of light petroleum, filtered and washed. The filtrate was evaporated and the residue was distilled off in vacuo. 268 g (92.5%) of 1,2-diphenyl-3,3,3trifluoro-propene are obtained. The boiling point is 107-109 ° C / 26.7 Pa, m.p. 58-61 ° C.

Analysis (with respect to formula C ₁₅ H _n F ₃ ):

calculated: C 72.57%, H 4.47%, F 22.96%, found: C 72.49%, H 4.23%, F 23.20%.

268 g (1.08 mol) of the bump product is hydrogenated in the presence of a 10% palladium-on-coal catalyst in 4000 ml of acetic acid at a temperature of 20 ° C for 6-8 hours. The solution was evaporated and the residue distilled off under reduced pressure. 252 g (93.3%) of 1,2-diphenyl-3,3,3-trifluoropropane are obtained. The boiling point is 94-96 ° C / 13.3 Pa, n ²⁰ D = 1.5100.

Analysis (with reference to formula C ₁₅ H ₁₃ F ₃ );

calculated: C 71.98%, H 5.26%, F 22.75%, found: C 72.12%, H 5.44%, F 22.50%.

250 g (1 mol) of the bump product was dissolved in 2500 ml of carbon tetrachloride, followed by the addition of 5 g (0.02 mol) of benzoyl peroxide and then a solution of 176 g (1.1 gmol) of bromine in 500 ml of carbon tetrachloride over a period of 30 minutes at 50 ° C. The reaction mixture was heated at reflux for 2 hours, then cooled, washed with sodium thiosulphate solution, then with sodium bicarbonate solution and finally with water. It is then dried and concentrated. The residue was crystallized from 1260 ml of ethanol. 140 g of erythro-1-bromo-1,2-diphenyl-3,3,3-trifluoro-propane are obtained. The yield is 42.6%. T.t. Mp 164-165 ° C.

Analysis (with reference to formula C ₁₅ H ₁₂ BrF ₃ ):

calculated: C 54.73%, H 3.67%, Br 24.28%, F 17.32%, found: C 54.97%, H 3.93%, Br 23.98%, F 17.36 %.

The mother liquor was matched to one third of the volume that was in the beginning. The extracted product is filtered off. 130 g (39.5%) of threo-1-bromo-1,2-diphenyl-3,3,3-trifluoro-propane are obtained, m.p. 91-94 ° C.

Analysis (with reference to formula C ₁₅ H ₁₂ BrF ₃ ):

calculated: C 54.73%, H 3.67%, Br 24.28%, F 17.32%, found: C 54.86%, H 3.82%, Br 24.01%, F 17.27 %.

The structure of the above product was confirmed using the NMR spectrum. The structures of all the products obtained above were confirmed in the same way.

270 g (0.82 mol) of the above erythro- and threoisomeric mixtures were dissolved in 2500 ml of anisole. The solution was stirred at 6 ° C with 110 g (0.83 mol) of anhydrous aluminum chloride and the resulting mixture was allowed to stand overnight at room temperature. The reaction mixture was mixed with a mixture of 4 kg of ice and 600 ml of 36% hydrochloric acid and then extracted with chloroform (3 liters). The organic phase is washed with sodium bicarbonate solution and then with water. It is then dried and concentrated. The residue was crystallized from 750 ml of isopropanol. The crude product obtained (162 g, 55%, mp 121-126 ° C) was recrystallized once more from 1500 ml of isopropanol. 109 g (37%) of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4-methoxyphenyl) -propane are obtained. T.t. Mp 129-131 ° C.

Analysis (with reference to formula C ₂₂ H ₁₉ F ₃ O):

calculated: C 74.14%, H 5.37%, F 16.00%, found: C 74.08%, H 5.47%, F 15.75%.

Spectral data:

_7ch 3050, 3025, 2995, 2950, 2925, 2900, 2830, in _{c = c} 1605,1580,1508 _Ύαγ 808, 786, 758, 702

= 4.60 (d), 1H, = 4.23 (m), 1H = 3.60 (s), 1H = 6.7-7.3 (m), 14H

The mother liquor from the first crystallization was evaporated to dryness and the resulting residue was mixed with 300 ml of hexane and then filtered. The crude product obtained (96 g, 27%, mp 89-101 ° C) was crystallized repeatedly from 960 ml of isopropanol. 41.4 g (14%) of erythro-1,2-diphenyl23 are obtained

3,3,3-Trifluoro-1- (4-methoxyphenyl) propane. T.t. 108-111 ° C.

Analysis (relative to formula C ₂₂ H ₁₉ F ₃ O): calculated: C 74.14%, H 5.37%, F 16.00%, found: C 74.23%, H 5.18%, F 16.17%.

Spectral data:

in _CH 3090, 3060, 3025, 3010,2960,2940, 2915, 2840 in _{c = c} 1658,1612,1590,1513,1500 7 ^ 808,790, 762, 708,702 = 4.60 (d), 1H

= 3.60 (s), 3H = 4.23 (m), 1H = 6.4-7.6 (m), 14H

100 g (0.28 mol) of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4-methoxyphenyl) -propane was heated with 300 g of pyridine hydrochloride for 3 hours at 200-220 °. C, then cooled, diluted with 700 ml of chloroform and washed with water until neutral. The solution was filtered, evaporated, and the residue was crystallized from a mixture of chloroform and hexane (1: 2). 85.7 g (90%) of threol, 2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) -propane are obtained, m.p. 123-135 ° C.

Analysis (with reference to formula C ₂₁ H ₁₇ F ₃ O):

calculated: C 73.67%, H 5.01%, F 16.65%, found: C 73.56%, H 4.92%, F 16.78%.

g (0.11 mol) of erythro-1,2-diphenyl-3,3,3-trifluoro-1- (4-methoxyphenyl) -propane is reacted with 120 g of pyridine hydrochloride as described above. The resulting erythro-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) -propane was crystallized from a mixture of chloroform and hexane (1: 2). 32.5 g (84.5%) of the above product are obtained. T.t. 114-117 ° C.

Analysis (with respect to the formula C ₂₁ H _1? F ₃ O):

calculated: C 73.67%, H 5.01%, F 16.65%, found: C 73.52%, H 4.97%, F 16.71%.

Mixture of 85.6 g (0.25 mol) of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) -propane, 400 ml of 1,2-dibromethane and 18,5 g (0.33 mol) of powdered potassium hydroxide is heated with stirring and reflux. The reaction mixture was diluted with 1.5 l of dichloromethane, washed with% hydrochloric acid and then with water and then dried. The solvent and excess 1,2dibromethane were removed in vacuo and the residue was crystallized from benzene. 97.7 g (87%) of threo-1- [4- (2-bromoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropane are obtained. T.t. Mp 144-151 ° C.

Analysis (with reference to formula C ₂₃ H _2Q BrF ₃ O):

calculated: C 61.48%, H 4.49%, Br 17.78%, F 12.68%, found: C 61.55%, H 4.57%, Br 17.63%, F 12.71 %.

g (87.6 mmol) of erythro-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) -propane is reacted with 1,2-dibromethane as described in the previous paragraph. The resulting erythro-1- [4 (2-bromoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropane was crystallized from benzene. The yield was 27.9 g (71%). T.t. 130-133 ° C.

Analysis (with reference to formula C ₂₃ H ₂₀ BrF ₃ O):

calculated: C 61.48%, H 4.49%, Br 17.78%, F 12.68%, found: C 61.60%, H 4.63%, Br 17.60%, F 12.77 %.

Regulation 2

Preparation of (E) -1- (4- (2-azidoethoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropene

9.83 g (22 mmol) (E) -1- [4- (2-bromoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoro-propene was dissolved in 100 ml of 2-methoxyethanol and the solution was mixed with a solution of 2.86 g (44 mmol) of sodium azide and 10 ml of water. The reaction mixture was heated to boiling for 1 hour and treated as described in regulation 3. After double crystallization from ethanol, 7.40 g (82%) of the title compound was obtained. T.t. 73-75 ° C.

Analysis (with reference to the formula C ₂₃ H _lg F ₃ N ₃ O):

calculated: C 67.47%, H 4.43%, F 13.92%, N 10.27%, found: C 67.61%, H 4.45%, F 13.77%, N 10.11 %.

(E) -1- [4- (2-Bromoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropane, which was used as starting material, is obtained as follows:

A solution of 44.7 (0.1 mol) threo-1- [4- (2-bromoxy) -phenyl] -1,2-diphenyl-3,3,3trifluoropropane (Example 1) in 225 ml of benzene was heated with 45 , 4 (0.2 mol) 2,3-dichloro 5,6-dicyan-1,4-benzoquinones [D. Walker et al .: J. Org. Chem. 30, 3240 (1965)], stirring for 30 hours and refluxing. The reaction mixture was cooled and the separated 2,3-dichloro-5,6-dicyan-1,4-hydroquinone filtered off. The residue was mixed with 100 ml of chloroform and the separated 2,3-dichloro-5,6-dicyan-1,4-benzoquinone filtered off. The residue was diluted with 400 ml of chloroform, washed with 10% sodium bicarbonate solution and water and then dried. The solution was evaporated and the residue was crystallized from 220 ml of ethanol. The crude product obtained (E: Z = 4: 1, 34.4 g, 77%, mp 110-118 ° C) was recrystallized once more from ethanol. 29.5 g (66%) of the (E) -isomer are obtained. T.t.t. 118-120 ° C.

Analysis (with reference to the formula C ₂₃ H _lg BrF ₃ O):

calculated: C 61.67%, H 4.06%, Br 17.87%, F 12.74%, found: C 61.80%, H 4.15%, Br 17.59%, F 12.90 %.

The mother liquor of the obtained products was evaporated and the residue was recrystallized repeatedly from ethanol. 2.14 g (4.8%) of (Z) -1- [4- (2-bromoxy) -phenyl] -1,2-diphenyl-3,3,3trifluoropropene are obtained. T.t. Mp 135-138 ° C.

Spectral data:

isomer (Ε): n _CH = 3060, 3020, 2020, 2900, 2850, in _{c = c} = 1590,1495 _7αγ = 815,822, 758, 705 S _OCH2 = 4.08 (t), 2H ^ BrCH2 ^- 3.46 (θ '2H,

8 ^ = 6.4 - 7.4 (m), 14H isomer (Ζ): p _ch = 3080, 3060, 3030, 2935, 2870 p _{c = c} = 1610.1510, _7αγ = 832, 770, 760, 715 ^δ ΟΟΗ2 = ^{4 '28} (0. ^{2H δ} ΒΓθΗ2 ^{= 3} ' ⁵⁹ ω, 2Η S _Ar = 6.8 - 7.4 (m), 14H

Regulation 3

Erythro-1,2-diphenyl-3,3,3-trifluoro-1- [4- (2-ibis- (2-hydroxyethyl) -aminol-ethoxy) phenyl26 propane hydrochloride

8.98 g (20 mmol) of erythro-1- [4- (2-bromoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropane (obtained according to Example 1) was dissolved in 42 g (400 mmol) of diethanolamine and heated for half an hour at a temperature of 100-120 ° C. The reaction mixture was treated as described above and the residue was crystallized from a mixture of isopropanol (containing hydrogen chloride) and ether (1: 2). 5.98 g (58.7%) of the title compound are obtained. T.t.t. 190195 ° C.

Analysis (with reference to formula C ₂₇ H ₃₁ C1F ₃ NO ₃ ):

calculated: C 63.59%, H 6.13%, Cl 6.95%, F 11.18%, N 2.75%, found: C 63.41%, H 6.29%, Cl 7.08 %, F 10.98%, N 2.80%.

Application example

Preparation of pharmaceutical preparations

a. Pills

Tablets suitable for oral administration, containing 10 mg of active substance and having the following composition, have been prepared using methods known in the pharmaceutical industry:

component quantity (mg) (E) -1,2-diphenyl-3,3,3-trifluoro-1- [4- (2- [2-hydroxyethylamino] -ethoxy) -phenyl] -propene (given as base) 10.0 cornstarch 49.6 milk sugar 109.00 polyvinylpyrrolidone 5.4 magnesium stearate 1.0 colloidal silicon dioxide 5.0 total weight 180.0 mg

Claims (8)

Claims: 1. A process for the preparation of new 1,1,2-triphenyl-propane and 1,1,2-triphenylpropene derivatives of general formula (I) (I) wherein A and B independently of one another a hydrogen atom or together form a valence bond, X and Y may be the same or different and independently represent an unsubstituted phenyl group or a phenyl group optionally substituted in the p-position by a halogen atom or C ^ -alkoxy group, R _{1 is a} C 1-6 -alkyl-, epoxyalkyl-, methoxy-methyl or benzyl group or a group of general formula II / -CH ₂ -CH ₂ -N \ R. (Π) in which R ₂ and R ₃ independently of one another denote a C _1-6 alkyl group or together with the adjacent nitrogen atom form a maximum of eight-membered heterocyclic rings, or a maximum of six-membered heterocyclic ring, which in this case contains more heteroatoms and which is optionally substituted by a lower alkyl group , provided, yes a. when A and B together form a bond and X and Y denote a phenyl group, then R _{t is} different from methyl or ethyl, b. when A and B together form a bond and X and Y denote a phenyl group, then in the case of the (Z) -isomer, R is other than dimethylaminoethyl-, diethylaminoethyl-, morpholinoethyl- or piperidino-ethyl groups. c. when A and B together form a bond and X stands for phenyl group and Y stands for p-methoxyphenyl group, then Rj is different from methyl and pyrrolidinoethyl, d. when A and B together form a bond and X stands for p-methoxyphenyl group, p-fluorophenyl or p-ethoxyphenyl group, and Y stands for phenyl group, then Rj is different from methyl, and e. when A and B together form a bond and X and Y denote a p-methoxyphenyl group, then R _{1 is other} than methyl, their stereoisomers, mixtures of these isomers and their acid addition salts, wherein the compound of general formula III CP: -H-OOH (III) in which A, B, X and Y have the meanings given above, reacts with R1-halide or R1-sulfonate (wherein R1 has the meaning given above) in the presence of an acid-binding agent, and if it desires that the resulting mixture of stereoisomers be broken down into individual stereoisomers and if desired the resulting basic compound of general formula I is converted into an acid addition salt or liberated from its acid addition salt. 2. The process of claim 1, wherein the starting materials are compounds of general formula (III) in which A and B together form a bonding moiety, X and Y independently of one another denote a phenyl group and R denotes dimethylaminoethyl-. diethylaminoethyl-, heptamethyleneaminoethyl-, morpholinoethyl- or N-methylpiperazinoethyl group. 3. The process of claim 1, wherein compounds of general formula (III) are used as starting point, in which A and B together form a valence bond, X denotes a phenyl group, Y denotes a p-methoxyphenyl group and R1 denotes dimethylaminoethyl - or a diethylaminoethyl group. A process according to claim 1, characterized in that compounds of general formula (III) are used as starting point in which A and B together form a valence bond, X stands for p-methoxyphenyl group, Y stands for phenyl group and R _t stands for dimethylaminoethyl - or a diethylaminoethyl group. A process according to any one of claims 1-4, characterized in that chloride, bromide, mesylate or p-tosylate are used as starting material. A process according to any one of claims 1-5, characterized in that alkaline metal hydroxide or alkaline metal carbonate is used as the acid binding agent. A process according to any one of claims 1-6, characterized in that the reaction is carried out in an inert organic solvent. 8. The process of claim 7, wherein benzene or ethanol is used as the solvent.