CS241046B2 - Process for the preparation of new 1,1,2-triphenylpropane and 1,1,2-triphenylpropene derivatives - Google Patents

Abstract

The invention relates to a process for the production of new derivatives of 1,1,2-triphenylpropane and 1,1,2-triphenylpropene of the general formula I

Description

(54) Process for the production of new derivatives of 1,1,2-triphenylpropane and 1,1,2-triphenylpropene ^{1 2}

The invention relates to a process for the production of new derivatives of 1,1,2-triphenylpropane and 1,1,2-triphenylpropene of the general formula I

in which A, B, X and Y have the meanings given in the description. The derivatives of the general formula I are prepared by reacting a compound of the general formula III with a R1-halide or R1-sulfonate, wherein R1 has the meanings given in the description, in the presence of an acid-binding agent, and the resulting mixture of stereoisomers is optionally separated into the individual stereoisomers and the basic compound of the general formula I is optionally converted into an acid addition salt or liberated from an acid addition salt.

The new compounds produced by the method according to the invention have an endocrine effect and excellently inhibit the growth of breast tumors induced by 7,12-dimethylbenz/a/anthracene.

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The invention relates to a process for the production of new derivatives of 1,1,2-triphenylpropane and 1,1,2-trifertylpropene.

'It is known that some triphenylalkene derivatives have estrogenic properties [J. Grundy: Chem. Rev, 57, 281 (1957); P. R. Parter et al.: J. Chem. Soc. 1948, 150; N. P. Buu-Hoí et al.: Chim. Ther. 1969, 327; W. J. Middleton et al.: J. Med. Chem. 14, 1193 (1971);

[US Patent No. 3,712,929].

Analogous derivatives containing 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 important representatives of this group of compounds are clomiphene [1-(4-(2-diethylaminoethoxy)phenyl)-1,2-diphenyl-2-chloroethylene] and tamoxifen [{Z )-1-(4-(2-dimethylaminoethoxy)phenyl)-1,2-diphenyl-1-butene], see F. P. Palopoli et al.: J. Med. Chem. 10, 84 (1966), or G. R. Bedford et al.: Nature 212, 733 (1966). Although both of the above derivatives have anti-estrogenic (estrogen antagonizing and weakly agonistic) properties, the former compound is used to induce ovulation [M. Murray et al.: J. Obstet. Gynaec. Br. Commonw. 78, 1108 (1971)] and oligospermia [J. F. Potts:

J. Am. Med. Ass. 231, 907 (1975)]; in contrast, tamoxifen is used primarily in the treatment of breast tumors [M. P. Cole, et al.: Brit.

J. Cancer 1971, 270], Undesirable side effects, namely visual impairment, were observed with long-term application of both compounds [H. J. Silverman: Am. J. Optom. 49, 335 (1972);

L. M. Roch et al.: Arch. Ophthalm. 77, 14 (1967); M. J; Kaiser-Kupfer et al.: Cancer. Treatment Rep. 62, 315 (1978)], liver damage (Martindale: The Extra Pharmacopoeia XXVII. 1392 (1977), The Pharmaceutical

Press, London] and the induction of thrombosis [K. Nevasaari et al.: Lancet 946 (1978)].

The object of the invention is to produce new compounds which would have more advantageous properties than the previously known derivatives and which would have a more satisfactory effect and few side effects which are undesirable.

The novel compounds produced by the method of the invention have diverse endocrine effects to varying degrees and excellently inhibit the growth of experimental breast tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA).

The subject of the invention is a method for producing new derivatives of 1,1,2-triphenylpropane and 1,1,2-triphenylpropene of the general formula I· ' ř ? z=\ ^0Rl

X Y (I) in which

A and B individually represent a hydrogen atom or together form a valence bond,

X and Y are the same or different substituents and represent a phenyl group optionally substituted in the para position by a halogen atom and

R1 represents a C _b4 alkyl, C _b4 epoxyalkyl, methoxymethyl group or a group of general formula II

R2 / ' , — CH2—CH2— N (II) \

R3 in which

R2 and R5 are the same substituents and represent a _C1-4 alkyl group or form a morpholino, pyrrolidine, N-methylpiperazine or heptamethyleneimine group with the adjacent nitrogen atom, with the proviso that in the case of

a) when A and B together form a valence bond and X and Y represent phenyl, R1 has a meaning other than methyl or ethyl,

b) when A and B together form a valence bond and X and Y represent phenyl, R1 in the case of (Z)-isomers has a meaning other than dimethylaminoethyl, diethylaminoethyl or morpholinoethyl and c) when A and B together form a valence bond and X represents p-fluorophenyl and Y represents phenyl, R1 has a meaning other than methyl, and their stereoisomers, their mixtures and addition salts of basic compounds of the general formula with acids.

The essence of the invention lies in the fact that the compound of general formula III is ? /=\ ' z y.

(111/.

' in which

A, B, X and Y have the above-mentioned meaning, are reacted with a Ri-halide or Ri-sulfonate, wherein Ri has the above-mentioned meaning, in the presence of an acid-binding agent, and the resulting mixture of stereoisomers is optionally separated into the individual stereoisomers and the basic compound of the general formula I is optionally converted into an acid addition salt or liberated from the acid addition salt.

The term "halogen atom" used in the specification includes all four halogens, i.e. fluorine, chlorine, bromine and iodine.

A preferred subgroup of general formula I consists of those derivatives in which A and B together form a valence bond.

Particularly preferred representatives of the compounds produced by the process according to the invention are ^the following derivatives of general formula I:

threo-1-[4-(2,3-epoxypropoxy)phenyl]-1,2-diphenyl-3,3,3-trifluoropropane, (E)-1,2-diphenyl-3,3,3-trifluoro-1-[4-(2-(4-methylpiperazino)ethoxy)phenyl]propene and their pharmaceutically acceptable acid addition salts.

The basic compounds of the general formula I form addition salts with acids. The usual inorganic acids (for example hydrochloric, hydrobromic, sulfuric, phosphoric, etc.) and organic acids (for example maleic, fumaric, lactic, methanesulfonic, p-toluenesulfonic, citric, etc.) can be used to form the salts.

Compounds of formula I can be prepared in the form of various stereoisomers (such as (Zj-isomers, (Ej-isomers, threoisomers and erythroisomers] and mixtures thereof. The invention includes all stereoisomers and mixtures thereof.

As acid-binding agents, for example, alkali metal hydroxides and alkali metal carbonates, preferably their salts, in a solvent or diluent, such as benzene, alcohol, etc., can be used. They are added in a mixture with a Ri-halide or Ri-sulfonate.

The resulting mixture of stereoisomers can be separated into individual stereoisomers by conventional methods (for example, fractional crystallization).

The basic compounds of the general formula I can be converted into their acid addition salts in a manner known per se by treatment with the corresponding acid in an inert solvent. It is expedient to prepare pharmaceutically acceptable acid addition salts of these basic compounds. The bases can be liberated from their acid addition salts by treatment with a strong base.

The starting materials of general formula III are, with the exception of (Z)-1,2-diphenyl-3,3,3-trifluoro-1-(4-fluorophenyl)propene, (Z)-[2-diphenyl-3,3,3-trifluoro-1-(hydroxyphenyl)propene and (E)-2-phenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propene (U.S. Patent No. 3,712,929) new compounds, the preparation of which is given in the examples.

The endocrinological and tumor inhibitory effects of the novel compounds produced by the process of the invention were demonstrated by the following tests. The following compounds were tested:

1,= threo-1.-[ 4-(2,3-epoxypropoxy (phenyl-.-1,2-trihexyl ^; 3;3,3-trifluoropropane, = 1-(4-(2,3-epoxypropoxy)phenyl)]-1,2-diphenyl-3,3 ₍ 3-trifluoropropene, = (E)-1,2-difluoropropane) enyl-3,3;3-tEifluoro-1-[i'4-( 2' -/4-methylpiperazino/eyloxy(phenyl)-propene, = 1-[4-(2-dimethylaminoethoxy:)phenyl]2-phenyl-3,3,3-trifluoro-1-('4-methQX3^phenyl)-.,· propene, = (E)rl,2,diphenyl-3,3,3-trifluoro-24<4-(2T rpyrrolidinoethoxy) phenyl [propene, = (E)-1,2-diphenyl-3,3,3-trifluoro-1-(4-(2-morpholinoethoxy (phenyl]propene, = (E)-1-(4-(2-diethylaminoethoxy (phenyl)-1,2-diphenyl-3,3,3-trifluoropropene, = 1-pheny 1-2-(4-methoxyphenyl)-1-( 4-(2-Dimethylaminoethoxy)phenyl-3,3,3-trifluoropropene.

The antiestrogenic effect was determined by the method of M. J. K. Harper et al.: [J. Reprod. Fert. 13, 101 (1967) J. Immature, 24-day-old female rats were premedicated with 5 μ% estradiol subcutaneously once daily for 3 days. The test substance was also dosed orally once daily for 3 days. On the fourth day, the animals were sacrificed and the weight of the uterus after cleaning was determined.

Table I shows the antiestrogenic effect (i.e. inhibition of the uterotropic effect of estradiol) of some representatives of the compounds of general formula I. '

.....7

Table I

Determination of antiestrogenic effect in immature female rats

Test compound Dose, mg/kg per day 0.1 0.3 1.0 3.0 10.0-

Clomiphene, Tamoxifen J —37.1 —45.6+6.85 —55.2+2.5 I.·-·· 2 - · —29 —24 4 —65.2+3.93 5 —52.8+4.2 —52.2+6.12

—67.7 —73.3 —60.9+4.04 —70.9+4.52 —68.6+4.83 —3.0 —39 —38 —78 —66 —71.9+1.81 —71.8+5.0 -72.2+5.5 -60.8+2.13 -68.2+3.32 —63.0+3.68

Note: -· _

The antiestrogenic effect (i.e., uterine weight-reducing effect) of the tested compounds is given in percentage. Each group consisted of 5 to 10 animals.

The antiestrogenic effect of some of the compounds listed in Table I reaches a value corresponding to the effect of clomiphene or tamoxifen, used as comparison compounds. At a dose of 1 mg/kg per os, compound No. 1 causes only insignificant inhibition; when this compound is used in an oral dose of even 10 mg/kg, the inhibition is only 39%.

The estrogenic (uterotropic) effect was determined by the method of R. J. Dorfman [Endocrinology 55, 65 (1954)]. Female rats (24 days old) were treated with the test compound once daily orally. On the fourth day the animals were sacrificed and the weight of the uterus after cleaning was determined. Table II shows the estrogenic (uterotropic) effect of some compounds of the general formula Ϊ at various doses. The table also contains the corresponding values of the very active ethinylestradiol and of tamoxifen and clomiphene used as reference substances; the two last-mentioned compounds are known antiestrogenic agents.

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The compounds mentioned have weak estrogenic properties as a whole or their effect is somewhat less than the corresponding effect of tamoxifen in a certain dose range (0.1 to 1.0 mg/kg). The curve showing the effect as a function of dose is different for compound no. 1 from the previous compounds, namely it is somewhat steeper. In the dose range used (0.01 to 0.3 mg/kg p.o.) the estrogenic effect is even less than the weak agonistic effect of antiestrogenic agents, while the maximum achievable increase in uterine weight exceeds the maximum effect achievable with the use of antiestrogenic agents. In the latter compounds, the antiestrogenic effect is already dominant at higher doses and suppresses the weak agonistic effect.

The stimulatory effect on the release of luteinizing hormone is determined as follows:

Immature female rats are treated subcutaneously with the test compound at the age of 24 to 25 days. Two hours after the second administration, the animals are sacrificed and the level of luteinizing hormone (LH) is measured in plasma by radioimmunoassay. At a dose of 1 mg/kg s.c., the test compounds significantly increase the level of LH in the plasma of female rats. The results are summarized in Table III.

Table of lilies

Effect of increasing plasma LH levels in immature female rats

Tested Compound Change in LH Level in % compared to Control

Tamoxifen 117

96 ' 106 9 53

Note:

each group consisted of 4 to 5 animals. Dose: 2X1 mg/kg s.c. ,

The effect of the compounds produced by the method according to the invention on hormone-dependent tumors is determined by the method of P. Griswold et al. [Cancer Research 26, 2169 (1966)] on breast carcinomas induced by 7,12-dimethylbenz(a yantracene (DMBA). Administration begins at a tumor weight of 500 milligrams and is carried out for one month three times a week at an oral dose of 20 mg/kg. The size of the resulting tumor is measured by the method of the above-mentioned authors and by the method of V. C. Jordan et al. [Europ. J. Cancer. 12, 419 (1976)) using a caliper. The tumor volume is determined by the method of Griswold. Measurement of tumors and observation of the animals continued for 2 months after the end of the administration period.

To evaluate the effect, a relative effectiveness index is introduced:

This value is determined based on the number of animals cured completely or temporarily, or showing permanent or short-term remission. The evaluation is carried out based on the following table:

complete cure 10 points temporary cure 8 points. permanent remission 6 points short remission or unchanged state ' 4 points

The change in average tumor count during treatment is determined as follows:

the initial number of tumors was not higher in any animal 8 points the average number of tumors doubled 6 points a greater increase in the average number of tumors was observed 0 points.

The sum of the points determined in duplicate is expressed for each animal as a % of the number of points of maximum effect producing complete cure. These values are considered as relative efficacy. The results are given in Table IV.

Table IV

Effect on DMB-induced mammary carcinomas in rats Tested Effect Relative

compound Healed Remission (3) (4) Without effect effect. (1) (2) Untreated control —- — — — 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) — completely, (2) = temporarily, (3) = permanent, (4) = short

Pharmaceutical preparations with the active ingredient produced according to the invention may contain one or more compounds of general formula I, their stereoisomers, mixtures thereof or acid addition salts of basic compounds of general formula I and suitable, inert, solid or liquid pharmaceutical carriers.

Pharmaceutical preparations can be applied both in human therapy and in the treatment of animals to influence the endocrine system. Many compounds of the general formula I strongly inhibit the growth of experimental tumors that have been induced. Pharmaceutical preparations can be prepared advantageously in the form of preparations suitable for oral administration (for example tablets, capsules, powder mixtures, solutions, suspensions, emulsions, elixirs, etc.) or as parenteral preparations (for example solutions and suspensions). The preparations contain conventional inert, solid or liquid carriers (for example starch, lactose, magnesium stearate, silicon dioxide, magnesium carbonate, polyvinylpyrrolidone, water, etc.). The content of active substance in the preparation is usually 0.05 to 98 %. The preparations may contain other conventional excipients (for example emulsifying, dispersing, wetting and disintegrating agents, buffers, etc.) used in the pharmaceutical industry.

The production of these pharmaceutical preparations is carried out using procedures that are known and common in the pharmaceutical industry.

The daily dose of the compounds of the general formula I depends on many factors (for example, the condition of the patient, the degree of the disease, the activity of the active substance used, etc.). Usually, the daily oral dose is about 0.01 to 10 mg/kg of body weight.

The values given are for informational purposes only and in a given case the doses may be less or more than the given range.

The invention is explained in more detail on the basis of the following examples of specific embodiments.

Example

Production of threo-1,2-diphenyl-3,3,3-trifluoro-1-(4-(methoxymethoxy]phenyl]propane)

10.26 g (30 mmol) of threo-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propane (preparation 1] is dissolved in 40 ml of benzene and the solution is mixed with 2 g (50 mmol) of sodium hydroxide and 4 g (50 mmol) of chloromethyl ether and heated to boiling for one hour. The reaction mixture is diluted with 100 ml of benzene, washed with 20% ammonium chloride solution and dried. The solution is evaporated and the residue is crystallized from isopropyl alcohol. 7.45 g (64.2%) of the title compound are obtained. M.p. 100-103 degrees Celsius.

Analysis for C23H21F3O2: calculated:

C 71.49%, H 5.48%, F 14.75%, found:

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

Example 1 and 2

Production of threo-1-[4-(2,3-epoxypropoxy)phenyl]-1,2-diphenyl-3,3,3-trifluoropropane

3.42 g (10 mmol) of threo-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propane (preparation 1) are dissolved in 40 ml of ethanol and the solution is mixed with 0.48 g (12 mmol) of sodium hydroxide and 9.2 g (100 mmol) of 1,2-epoxy-3-chloropropane. The reaction mixture is heated to boiling for one hour, evaporated and the t-butyl alcohol is removed from it. The residue is diluted with 30 ml of dichloromethane, washed with water and dried. The solution is concentrated by evaporation and the residue is crystallized from methanol. 2.85 g of the title compound are obtained. Yield 71.6%. M.p. 113-116 °C.

Analysis for C24H21F3O2:

calculated:

C 72.35%, H 5.31%, F 14.31%, found:

.C 72.26%, H 5.14%, F 14.47%.

Example 1 3

Production of erythro-1-{ 4-(2,3-epoxypropoxy)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-hydroxyphenyl)propane (Preparation 1) was reacted with 1,2-epoxy-3-chloropropane as described in Example 2 in the presence of sodium hydroxide. The product obtained was recrystallized twice from methanol. 2.18 g (44%) of the title compound were obtained. M.p. 115-118 °C. Analysis for C24H21F3O2:

calculated:

C 72.35%, H 5.31%, F 14.31%, found: .

C 72.18%, H 5.46%, F 14.37%.

Example 4

Production of (E j -1- [4-(2,3-epoxypropoxy)phenyl] -1,2-diphenyl-3,3,3-trifluoropropene

3.40 g (10 mmol) of (E)-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propene were dissolved in 30 ml of anhydrous benzene and the solution was stirred with 0.29 g (12 mmol) of sodium hydride for half an hour. After adding 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 residue was crystallized from methanol. 2.46 g (.62%) of the title compound were obtained. M.p. 73.5-76 °C.

Analysis for C24H19F3O: calculated:

C 72.72%, H 4.83%, F 14.38%, ώλΙρτρππ’

C 72.89%, H 4.88%, F 14.61%. (E)-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propene used as starting material is prepared as follows:

' .15.4 g (45 mmol) of 1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propane (preparation 1) in 75 ml of ethanol is heated in the presence of 2.2 g (55 mmol) of sodium hydroxide with 6.9 g (55 mmol) of benzyl chloride for one hour to boiling. The reaction mixture is diluted with 300 ml of water, neutralized with 1 N hydrochloric acid and extracted with 200 ml of chloroform. The organic layer is washed with water, dried and concentrated. The residue is crystallized from ethanol. 17 g (86.6% of the product is obtained. M.p. 94-118 '-C.

Analysis for C28H23F3O: 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 were heated with 17.25 g (76 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 80 ml of benzene for 2 hours to boiling and worked up as described in recipe 2. The (E)-1-(4-benzyloxyphenyl)-1,2-diphenyl-3,3,3-trifluoropropene obtained melts at 128-129 °C (after recrystallization from ethanol). Yield 6.21 g (38%).

Analysis for C28H21F3O: calculated:

C 78.13%, H 4.92%, F 13.24%, found:

C 78.34%, H 5.10%, F 13.24 °/o.

The structure of the above compound was proven by NMR spectrum.

6.02 g (14 mmol) of the above compound were hydrogenated in a mixture of methanol and tetrahydrofuran (1:1) in the presence of a palladium catalyst supported on carbon. 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 were obtained. M.p. 113-120 °C.

Analysis for C21H15F3O:

calculated:

C 74.11%, H 4.45%, F 16.75%, found:

C 74.17%, H 4.85%, F 16.53%. Example 5

Production of 1-[4-(2,3-epoxypropoxy)phenyl]-1-phenyl-3,3,3-irifluoro-2-(4-chlorophenyl)propane

6.03 g (16 mmol) of 1-phenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)-2-(4-chlorophenyl)propane are dissolved in 60 ml of methanol, the solution is mixed with 0.8 g (20 mmol) of sodium hydroxide and 14.8 g (160 mmol) of 1,2-epoxy-3-chloropropane and heated to boiling for 2 hours. The reaction mixture is worked up as described in Example 3. After crystallization from methanol, 4.44 g (64%) of the title compound are obtained. M.p. 141-144 °C.

Analysis for C24H20CIF3O2: 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%.

The starting material 1-phenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)-2-(4-chlorophenyl)propane is produced by the method according to Regulation 1 as follows:

4'-Chloro-2,2,2-trifluoroacetophenone [R. Fuchs: J. Org. Chem. 22, 993—994 (1957)] is reacted in ethanol in the presence of sodium ethylate with benzyltriphenylphosphonium chloride; 1-Phenyl-3,3,3-trifluoro-2-(4-chlorophenyl)propene is obtained with a yield of 68%. M.p. 63 to 66 degrees Celsius (after crystallization from hexane).

Analysis for C15H10CIF3:

• calculated:

C 63.73%, H 3.57%, Cl 12.54%, F 20.16%, ηl1Ρ7ΡΠa*

C 63.91%, H 3.81%, Cl 12.37%, F 20.03%.

The product obtained is hydrogenated in acetic acid in the presence of 10% palladium-on-carbon catalyst; 1-Phenyl-3,3,3-trifluoro-2-(4-chlorophenyl)propane is obtained in a yield of 86%. Boiling point: 118-120°C/53.33 Pa, n _D ²⁰ = 1.5230.

1S

Analysis for CisH^ClFs:

calculated:

C 63.28%, H 4.25%, Cl 12.45%,

F 20.02%, found:

C 63.51%, H 4.40%, Cl 12.38%,

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 degrees Celsius. Yield 45.3%.

Analysis for CisHnBrClFu calculated:

C 49.55%, H 3.05%, Br 11.98%,

Cl 9.75 «/o, F 15.63 %, found:

C 49.63 O/o, 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 isopropyl alcohol, the obtained 1-phenyl-3,3,3-trifluoro-2-(4-chlorophenyl)-1-(4-methoxyphenyl)propane melts at 164-171 °C. Yield '66%.

Analysis for C22H18CIF3O:

calculated:

C 67.61 «/o, H 4.64%, Cl 9.07%, ''

F 14.58%, found:

C 67.76%, H 4.70%, Cl 9.01%,

F 14.45%.

The product is reacted with pyridine hydrochloride. The 1-phenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)-2-(4-chlorophenyl)propane obtained is further processed without further purification.

Example 6

Production of threo-1-[4-(2-dimethylaminoethoxy)phenyl j-1,2-dlphenyl-3,3,3-trifluoropropane hydrochloride

6.84 g (20 mmol) of threo-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propane (preparation 1) were stirred for half an hour in 60 ml of anhydrous xylene with 0.6 g (24 mmol) of sodium hydride. The 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 was mixed with 10 ml of 9.36% methanol in hydrochloric acid and evaporated again. The product was crystallized from isopropyl alcohol.

5.76% (64%) of the title compound is obtained. M.p. 219-231°C.

Analysis for C23H27CIF3NO:

calculated:

C 66.74%, H 6.05%, Cl 7.88%,

F 12.67%, N'3.11%, found:

C 66.47%, H 6.03%, Cl 7.96%,

F 12.86%, N 3.00%.

Example 1 and 7

Production of threo-1,2-diphenyl-3,3,3-trifluoro-1-(4-(2-morpholnoethoxy jphenyl)propane

3.42 g (10 mmol) of threo-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propane (preparation 1) was reacted according to the procedure given in Example 6 first with sodium hydride and then with 2-(chloroethyl)morpholine in xylene. After crystallization from hexane, 3.12 g (68.5%) of the title compound were obtained. M.p. 87-89 ^° C.

Analysis for C27H2JF3NO2:

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

Production of (E)-1,2-diphenyl-3,3,3-trifluoro-1-[4-(2-pyrrolidinoethoxy)phenyl]propene

2.72 g (8 mmol) of (E)-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propene (Example 4) was reacted as in Example 4 first with sodium hydride and then with 2-(chloroethyl)pyrrolidine in xylene. After crystallization from hexane, 2.15 g (61.4 percent) of the title compound was obtained. M.p. 84.5-86 °C.

Analysis for C27H23F3NO:

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

Production of threo-1,2-diphenyl-3,3,3-trifluoro-1-(4-propoxyphenyl j propane

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

Analysis for C24H23F3O:

calculated:

C 74.98%, H 6.03%, F 14.83%,' found:

C 75.01%, H 6.20%, F 14.95%.

Example 10

Production of threo-1-[4-(3,4-epoxy)-2-hydroxy/butoxyphenyl]-1,2-diphenyl-3,3,3-trifluoropropane

3.42 g (10 mmol) of threo-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propane (preparation 1) are heated with 17 ml of DL-diepoxybutane for half an hour at 100 °C. The reaction mixture is evaporated, the residue is diluted with 300 ml of ether, washed with water and dried. The solution is concentrated and the residue is crystallized from isopropyl alcohol. 3.22 g (75.2%) of the title compound are obtained. M.p. 121-126 °C. The product obtained is chromatographed in a mixture of hexane and acetone (3:2). Chromatographically uniform threo-1-[4-(/ (3,4-epoxy) -2-hydroxy/butoxy)phenyl] -1,2-diphenyl-3,3,3-trifluoropropane is crystallized from isopropyl alcohol. Yield 1.90 g (44.4%). M.p. 130-133°C.

Analysis for C25H23F3O3:

calculated:

C 70.08%, H 5.41%, F 13.30%, ' found:

C 70.30%, H 5.74%, F 13.09%.

They applied

Preparation of (E)-1,2-diphenyl-3,3,3-trifluoro-1,4-(2-(4-methylpiperazino)ethoxy)phenylpropene, a 100 ml solution of 3.40 g (10 mmol) of (E)-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propene (Example 4) in anhydrous benzene is stirred for half an hour with 0.29 g (12 mmol) of sodium hydride, then combined with 5 ml of a solution of 2.44 grams (15 mmol) of 1-methyl-4-(2-chloroethyl)piperazine in anhydrous benzene [Cymerman-Craig: Austral. J. Chem. 9, 89 (1956)] and heated for 5 hours. The reaction mixture is diluted with 100 ml of benzene, washed with water, dried over magnesium sulfate, filtered and evaporated. The product crystallizes from hexane. Yield 3.03 g (65%). M.p. 94-96°C.

Analysis for C28H29F3N2O:

calculated:

C 72.08%, H 6.27%, F 12.22%,

N 6.00%, found:

C 72.14%, H 6.30%, F 12.20%, N 6.11%.

Example 12 ·

Preparation of (E)-1,2-diphenyl-3,3(3-trifluoro-1,4-(2-(heptamethyleneimino)ethoxy]phenylpropene A solution of 1.70 g (5 mmol) of (E)-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl]propene (Example 4) in anhydrous benzene was stirred for half an hour with 0.15 g (6 mmol) of sodium hydride, then combined with 2 ml of a solution of 1.06 g (6 mmol) of N-(2-chloroethyl)heptamethyleneimine [Blicke and Doorenbos: J. Am. Chem. Soc. 75, 2317 (1954)] in anhydrous benzene and the procedure was continued as described in Example 11. The product was recrystallized from hexane. Analysis for C30H32F3NO:

calculated:

C 75.13%, H 6.73%, F11.88%,

N 2.92%, found:

C 74.93%, H 6.70%, F 11.70%,

N 2.98%. - - ’

Example 1 3 '

Production of threo-1-(4-(2-(dimethylamino)ethoxy]phenyl-1,2-diphenyl-3,3,3-trifluoropropane) hydrochloride

17. A solution of 3.42 g (10 mmol) of threo-1,2-diphenyl-3,3,3-trifluoro ^: 1-(4-hydroxyphenyl)propane (preparation 1) in benzene (17 ml) was heated for three hours with 0.67 g (12 mmol) of ground potassium hydroxide and 1.84 g (12 mmol) of N,N-dimethyl-urea (James, J. Pract. Chem. 31, 416). The reaction mixture was diluted with 50 ml of benzene, washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in methanol and the pH of the solution was adjusted to 3 with methanol containing hydrochloric acid. The product was filtered off. Yield 2.7.4 g (61%). M.p. 228 to 230 degrees Celsius.

Analysis for C2H27C1F2NO:· calculated:

C 66.74%, H 6.05%, Cl 7.88%,

F 12.67%, N 3.11%, found:

C 66.53%, H 6.09%, Cl 7.95%,

F 12.74%, N 3.03%.

Regulation 1

Production of er/thro-α-threo-1,2-diphenyl-3,3,3-trifluoro-1- [ 4-(2-morpholinoethoxy j phenyl J propane

1.20 g (2.67 mmol) of erythro-1-[4-(2-bromomethoxy)phenyl]-1,2-diphenyl-3,3,3-trifluoropropane are heated to boiling with 4.80 g of morpholine. The cooled reaction mixture is diluted with 50 ml of ether and washed with water until neutral. The ether solution is filtered, concentrated to dryness and the residue is crystallized from hexane. 1.02 g (83.6%) of erythro-1,2-diphenyl-3,3,3-trifluoro-1-(4-(2-morpholinoethoxy]phenyl]propane are obtained. Melting point 112-115 °C.

Analysis for C27H28F3NO2:

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-bromoethoxy)phenyl]-1,2-diphenyl-3,3,3-trifluoropropane are heated to boiling with 14 g of morpholine. The reaction mixture is worked up as described above.

The obtained threo-1,2-diphenyl-3,3,3-trifluoro-1-(4-(1-morpholinoethoxy)phenyl)propane is recrystallized from hexane. Yield 2.85 g (78.3 percent). Melting point 88-91 °C.

Analysis for CžzHzsFsNOz:

calculated:

C 71.19%, H 6.20%, F 12.51%,

3.08%, ' found:

- C 71.24%, H 6.44%, F 12.45%,

N 3.03%.

The starting material erythro- and threo-1-[4-(2-bromoethoxy)phenyl]-1,2-diphenyl-3,3,3-trifluoropropane can be produced as follows:

To a solution of 27 g (1.17 gatom) of sodium and 500 ml of anhydrous ethanol at 0 to 2 °C is added a solution of 4 ^C S g (1.18 mol) of benzyltriphenylphosphonium chloride [G. Witting: Chem. Ber. 87, 1318 (1954)) and 1,500 ml of anhydrous ethyl alcohol, after which the mixture is mixed with a solution of 204 g (1.17 mol) of 2,2,2-trifluoroacetophenone and 100 ml of anhydrous ethyl alcohol. The mixture is left to stand overnight, then evaporated, the residue is mixed with 800 ml of petroleum ether, filtered and washed. The filtrate is evaporated and the residue is distilled under reduced pressure. 268 g (92.5%) of 1,2 diphenyl-3,3,3-trifluoro20 propene are obtained. Boiling point 107 to 109 °C at 26.7 Pa; Melting point 58 to 61 °C.

Analysis for C1SH11F3: 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 above product are hydrogenated in the presence of a 10% palladium-on-carbon catalyst in 4,000 ml of acetic acid at 20 C for 6 to 8 hours. The solution is evaporated and the residue is distilled off under reduced pressure. 252 g (93.3%) of 1,2-diphenyl-3,3,3-trifluoropropane are obtained. Boiling point 94 to 96 ^C C/13.3 Pa; n _o ²⁰ = 1.5100.

Analysis for C15H13F3:

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 above product are dissolved in 2,500 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 mol) of bromine in 500 ml of carbon tetrachloride over 30 minutes at 50 °C. The reaction mixture is heated to boiling for 2 hours, then cooled, washed with sodium sulfate solution, sodium bicarbonate solution and water, dried and concentrated. The residue is crystallized from 1,260 ml of ethanol. 140 g of erythro-1-bromo-1,2-diphenyl-3,3,3-trifluoropropane are obtained. Yield 42.6%. Melting point 164-165 °C. Analysis for CisHizBrFs:

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 is evaporated to one third of the original volume. The precipitated product is filtered off. 130 g (39.5%) of threo-1-bromo-1,2-diphenyl-3,3,3-trifluoropropane are obtained. Melting point 91-94°C.

Analysis for Ci5Hi2BrF3:

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 compound was confirmed by NMR spectrum.

270 g (0.82 mol) of the above mixture of erythro- and threo-isomers are dissolved in 2500 ml of anisole. 110 g (0.83 mol) of anhydrous aluminum chloride are added to the solution with stirring at 6°C and the mixture is left to stand overnight at room temperature. The reaction mixture is then mixed with a mixture of 4 kg of ice and 600 ml of 36% hydrochloric acid and extracted with 3 liters of chloroform. The organic layer is washed with sodium bicarbonate and water, dried and the solution is concentrated. The residue is crystallized from 750 ml of isopropyl alcohol. The product obtained (162 g, 55%, m.p. 121-126°C) is recrystallized from 1500 ml of isopropyl alcohol. 109 g (37%) of threo-1,2-diphenyl-3,3,3-trifluoro-1-(4-methoxyphenyl)propane are obtained. Melting point 129-131°C.

Analysis for C22H19F3O: “· calculated: ’ '

C 74.14%, H 5.37 θ/o, F 16.00%, found:

C 74.08%, H 5.47%, F 15.75%.

Spectral data: u _C h 3 050, 3 025, 2 995, 2 950,

925, 2900, 2830; in _c =c 1605, 1580, 1508; y ^Ar 808, 786, 758, 702; β _CH(A r ] ₂ =4.60 (d), 1H; δ chicf 3 | =4.23 (m), 1H;

_OHCH3 = 3.60 (s), 1H; á _Ar = 6.7-7.3 (m), 14H.

The mother liquor from the first crystallization was evaporated to dryness and the residue was mixed with 300 ml of hexane and filtered. The crude product obtained (96 g, 27%, mp 89-101 °C) was ^{recrystallized} several times from 960 ml of isopropyl alcohol. 41.4 g (14%) of erythro-1,2-diphenyl-3,3,3-trifluoro-1-(4-methoxyphenyl)-propane were obtained. Melting point 108-111 °C.

and

Analysis for C22H19F3O: calculated:

C 74.14%, H 5.37%, F 16.00%, found: . . '

C 74.23%, H 5.18%, F 16.17%.

Spectral data: at _CH 3 090, 3 060, 3 025,

010, 2960, 2940, 2915, 2840; in _C -c 1658, 1 612, 1 590, 1 513, 1500; y _Ar 808, 790, 762, 708, 702; <S _CH( Ar| ₂ = 4.60 (d), 1H; S _O ch ₃ =· = 3.60 (s), 3H; á _CH(CF3) = 4.23 (mj, 1H, č _Ar = = 6.4-7.6 (m), 14H.

100 g (0.28 mol) of threo-1,2-diphenyl-3,3,3-trifluoro-1-(4-methoxyphenyl)propane are 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 is filtered, evaporated and the residue is crystallized from a mixture of chloroform and hexane (1:2). 85.7 g (90%) of threo-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propane are obtained. Melting point 123-135 °C.

Analysis for C21H17F3O:

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. in the manner described in the previous paragraph. The obtained erythro-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propane is crystallized from a mixture of chloroform and hexane (1:2). 32.5 g (84.5%) of the above product is obtained. Melting point 114-117 °C. Analysis for C21H17F3O:

calculated:

C 73.67%, H 5.01%, F 16.65%, found:

C 73.52%, H 4.97%, F 16.71%. A 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-dibromoethane and 18.5 g (0.33 mol) of powdered potassium hydroxide is heated to boiling with stirring. The reaction mixture is diluted with 1.5 liters of dichloromethane, washed with 10% hydrochloric acid and water and dried. The solvent and excess 1,2-dibromomethane are removed under reduced pressure and the residue is crystallized from benzene. 97.7 g (87%) of threo-1-[4-(2-bromoethoxy)phenyl]-1,2-diphenyl-3,3,3-trifluoropropane are obtained. Melting point 144 to 151 °C.

Analysis for C23H2oBrF30:

calculated:

C, 61.48 Ή 4.49%, Br 17.78%,

F 12.68%, found:

C 61.55%, H 4.57%, Br 17.63%,

F 12.71%, g (87.6 mol) of erythro-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propane is reacted with 1,2-dibromoethane in the manner described in the previous paragraph. The obtained erythro-1-(4-(2-bromoethoxy)phenyl)-1,2-diphenyl-3,3,3-trifluoropropane is crystallized from benzene. Yield: 27.9 g (71%). Melting point 130 to 133 °C.

rite

Analysis for C23H2oBrF30:

C 61.48%, H 4.49%, Br 17.78%,

F 12.68%, calculated:

C 61.60%, H 4.63%, Br 17.60%,

F 12.77%.

Regulation 2

Production of (E)-1-(4-(2-azidoethoxy)phenyl j -1,2-diphenyl-3,3,3-trifluoropropene

9.83 g (22 mmol) of (E)-1-[4-(2-bromomethoxy)phenyl]-1,2-diphenyl-3,3,3-trifluoropropene are dissolved in 100 ml of 2-methoxyethanol and the solution is mixed with a solution of 2.86 g (44 micromol) of sodium azide and 10 ml of water. The reaction mixture is heated to boiling for one hour and worked up as described in recipe 3. After recrystallization from ethanol twice, 7.40 g (82%) of the title compound are obtained. Melting point 73-75 °C.

Analysis for C23H18F3N3Q.' calculated:

C 67.47 «/ο, Η 4.43%, F 13.92%,

Ν 10.27 «/ο, ' η q 1 ω·7 η ·

C 67.61%, H 4.45%, F 13.77

N 10.11 o/o.

(Ε)-1-[4-(2-bromoethoxy)phenyl]-1,2-diphenyl-3,3,3-trifluoropropene, used as starting material, is prepared as follows:

A solution of 44.7 g (0.1 mol) of threo-1-[4-(2-bromoethoxy)phenyl]-1,2-diphenyl-3,3,3-trifluoropropene (Example 1) in 225 ml of benzene is heated to boiling with stirring for 30 hours with 45.4 g (2.2 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone [D. Walker et al.: J. Org. Chem. 30, 3240 (1965)]. The reaction mixture is cooled and the precipitated 2,3-dichloro-5,6-dicyano-1,4-hydroquinone is filtered off. The residue is mixed with 100 ml of chloroform and the precipitated 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is filtered off. The residue is diluted with 400 ml of chloroform, washed with 10% sodium bicarbonate solution and water and dried. The solution is evaporated and the residue is crystallized from 220 ml of ethanol. The crude product obtained (E : Z = = 4:1, 34.4 g, 77%, 1.1. 110-118 °C) is recrystallized from 200 ml of ethanol. 29.5 g (66%) of isomer (E) is obtained. Melting point 118-120 °C.

Analysis for CzjHisBrFsO calculated:

C 61.67%, H 4.06%, B, 17.87%,

F 12.74%, found*

C 61.80%, H 4.15%, Br 17.59%,

F 12.90%.

The mother liquor of the above product was evaporated and the residue was recrystallized several times from ethanol. 2.14 g (4.8%) of [Zj-1-(4-(2-bromoethoxy}phenyl]-1,2-diphenyl-3,3,3-trifluoropropene were obtained. Melting point 135-138 °C. Spectral data:

Isomer (E): uch = 3060, 3020, 2920, 2900, 2850; u _c „ _c = 1590, 1495; / _Al .= 815, 822, 758, 705; $ CGH5 — 4.08 (t), 2H; <S _erCH2 =3.46 (ie, 2H; ó' _Ar = 6.4-7.4 (m), 14H.

' Isomer (Z): at _CH = 3080, 3060, 3030, 2.935, 2870; u _c „ _c = 1610, 1510; y _Ar = 832, 770, 760, 715; «Soch? = 4.28 (t), 2H; δ βγοη ₂ = 3.59 (t), 2H; <5 _Ar = 6.8-7.4 (m), 14H.

Regulation 3

Production of ethyl-1,2-diphenyl-3,3,3-trifluoro-1-[4-(2-(bis-2-hydroxyethyl)aminoethoxyphenyl]propane hydrochloride

8.98 g (20 mmol) of erythro-1-[4-(2-bromoethoxy)phenyl]-1,2-diphenyl-3,3,3-trifluoropropane (prepared according to Example 1) were dissolved in 42 g (400 mmol) of diethanolamine and heated for half an hour at 100-120 °C. The reaction mixture was worked up and the residue was crystallized from a mixture of isopropyl alcohol acidified with hydrochloric acid and ether (1:2). 5.98 g (58.7%) of the title compound were obtained. Melting point 190-195 °C. Analysis for C27H31CIF3NO3:

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%.

Example of use:

Production of pharmaceutical preparations

a) Tablets

Tablets containing 10 mg of active ingredient, having the following composition and suitable for oral administration, can be manufactured by methods known in the pharmaceutical industry:

Claims (6)

SUBJECT 1. Production method. The novel derivatives of 1,1,2-triphenylpropane and 1,1,2-triphenylpropene of the general formula in which: A and B are each hydrogen or form a valence bond, -X and Y are the same or different substituents and represent a phenyl group optionally substituted in the para position by a halogen atom and R1 is C1. ₄ alkyl. Whose. _{4 is an} epoxyalkyl, methoxymethyl or o-group of the general formula II R2 / —CH2 — CH2 —N (II) R3 in which R 2 - and R 3 are the same substituents and are C _1-6 . ₄ alkyl radical or forms with the adjacent nitrogen atom a morpholino group, pyrrolidino, N-methylpiperazino or heptamethyleniminovou, with the proviso that if (a) when A and B together form a valence bond and X and Y are phenyl, R 1 is other than methyl or ethyl, 128 compositions are produced by the known methods of the pharmaceutical industry: Component Quantity (mg) threo-1- [4- (2,3-epoxypropoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropane. 10.0 Maize starch 84,0 Magnesium stearate 1.0 Colloidal silicon dioxide 5,0 total 100 (0 mg VYNAEBZ.U (b) when A and B together form a valence bond and X and Y are phenyl, R1 in the case of the (Z) -isomers is other than dimethylaminoethyl, diethylaminoethyl or morpholinoethyl, and c) when A and B together form a valence bond and X is p-fluorophenyl and Y is phenyl, R 1 is other than methyl, and their stereoisomers, mixtures thereof and acid addition salts of basic compounds of formula I, characterized in that the compound of formula III. in which A, B, X and Y are as defined above in reaction with R 1 -halide- or R 1 -sulfonate, wherein R 1 is as defined above, in the presence of a composition which binds. an acid, and the resulting mixture of stereoisomers is optionally separated into individual stereoisomers and the basic compounds of formula I are optionally converted into an acid addition salt, or is converted into an acid addition salt. z. addition: salt-with acid released. 2. A process according to claim 1, wherein the compounds of formula III are used as starting materials in which A and B together form a valence bond, X.-and Y are respectively phenyl and R1 is dimethylaminoethyl, diethylaminoethyl, heptamethyleniminaethyl, morpholinoethyl or N-methylpiperazinoethyl. 3. The process according to claim 1, wherein the starting material is a compound of the formula III in the form of chloride, bromide, mesylate or p-tosylate. 4. The process according to claim 1, wherein the acid binding agent is an alkali metal hydroxide or an alkali metal carbonate. / 5. The process of claims 1 to 4, wherein the reaction is carried out in an inert organic solvent. ^r 6. A process according to claim 1, wherein benzene or ethanol is used as the solvent.