DE2452058A1 - PHENYL-BUTENONE AND BUTADIENE AND THE METHOD FOR THEIR MANUFACTURING - Google Patents

Description

j SUBMITTED

SANDOZ PATENT GMBIi
7850

P 24 52 058.9 Case 600-6577

Phenyl-butenones and -butadienes and processes for their

Manufacturing

The invention relates to new phenyl-butenones and -butadienes of formula I.

C = CH - A

wherein R is hydrogen, fluorine, chlorine or bromine, and R stand for an alkyl group with 1-3 carbon atoms,

O Z

! I 1

A groups of the formula -C-CH or -C = CH , in which Z is chlorine or bromine, and Y is either bromine, iodine, isobutyl, tert. Butyl, cyclohexyl, cyclohexenyl or a group of the formula II

609 8Ί9 / 128Α

- 2 - 600-6577

wherein R _{9 represents} hydrogen, fluorine, chlorine or bromine or an alkoxy group having 1-4 carbon atoms, or a group of the formula III

-N III,

denotes in which either R_ and R are identical or different and each represent an alkyl group with 1-3 carbon atoms, or R and R together represent the radical "(CH ₀ ) ~, in which η is 4 or 5, the radical -CH -CH-O-CH ^ -CH-, the radical -CH -CH = CH-CH - or the radical -CH ₂ -CH ₃ -N (R ₅ J-CK-CH ₂ -, where R _{5 is} hydrogen or represents an alkyl group having 1-3 carbon atoms, and processes for their preparation.

According to the invention, either

a) to compounds of the formula I by adding compounds of formula IV,

C-CH = C = CH ₂ IV, OH

0 9 B 1 9 / "i? R 1. ^ ^ÄD ORIGINAL

- 3 - 600-6577

where K ,. R and Y have the same meaning as above, with a treated with strong protonating agents, the Reaction in the presence of water takes place if compounds of the formula I in which A is a group of the formula

o. · '■■■' '■ ■ - ■ -. ■ .- ·

-C-CH ^ is to be produced, and .'the reaction in the presence of an acid of the formula HZ, in which Z has the above meaning, if compounds of the formula I are to be prepared, wherein A for

Z I is a group of the formula -C-CH, or

b) to compounds of the formula Ia,

R ₁ O ^Y ~ \,> -OCH-C-CH la,

ι
R.

wherein R, Y. and R _{1 have the} above meaning, by reaction of compounds of the formula V.

O Y - <> - C = CH-C-X V,

R Γι t \ 9, 1 Ώ / 1 ¹ P f:

- 4 - 600-6577

wherein R, R and Y have the above meaning and X is Is chlorine or bromine, 'with a methyl-introducing organometallic compound in an aprotic Medium, which is not detrimental to the reaction, reacts under anhydrous "conditions, and the reaction product then hydrolyzed.

The procedure specified under a) can be carried out as follows be carried out as described:

In the implementation according to the invention, protoni sizing agents mineral acids, for example hydrogen chloride acid, hydrobromic acid and sulfuric acid, aromatic or lower -'- aliphatic sulfonic acids, beir-pielsv-üi: -.:; p-Toluenesulfonic acid, can be used «The use of Lower carboxylic acids, such as acetic acid, are also possible, but in such a case it is convenient to use stronger ones To create conditions. The implementation takes place zv.'eckirJussigc: wisely in the presence of water-miscible polar organic " Solvents such as methanol or methanol. If pre-compounds of the formula I are produced

should, in which A represents a group of the formula -C-CJI, it is necessary that water is present in the reaction mixture. The implementation is expediently carried out at Temperatures from 10 to 100 ° C, preferably from 15 to 35 ° C.

BATH ORIGINAL

ß 0 ^c ! R 19 / ^; : Η L

- 5th - 600-6577

If acids of the formula HZ are used as protonating agents in the reaction according to the invention, this is in particular hydrochloric acid or hydrobromic acid. A mixture of compounds of the formula I in which A is a group of

O
Formula -C-CH-, and of compounds of the formula I in which

I.
represents a group of the formula -C-CH ₉ . Here, the 'connections can be separated with the aid of Trenrur.ethoöen known per se.

The procedure given under b). Can be described as follows carried out v / earth:

The reaction of compounds of the formula V with Kethylgruppan introductory organonstallischon compounds can be based on be carried out in a manner such as for the HGrK division of ketones by reacting acyl halides with orgaiiop.r? .allic compounds is known. The preferred organoF.etallic compounds are Grignard compounds, such as methyl magnesium halides, especially methyl magnesium bromide Suitable aprotic media are ethers such as tetrahydrofuran or diethyl ether, and the reaction is preferred at low temperatures, for example from -30 ° carried out down to 0 ° C. The subsequent hydrolysis of the reaction product can be carried out in a manner known per se, for example with the aid of a saturated aqueous ammonium chloride solution. If in the connections of the Formula V Y stands for an unsubstituted piperazine radical, should preferably have a further equivalent for the reaction of the organometallic reagent can be used.

609819 / 128A

BATH ORIGINAL

- 6 - 600-6577

The compounds of the formula I obtained can be isolated and purified in a manner known per se. If if desired, the free bases of the compounds of the formula I in which Y is a group of the formula III, be converted into their acid addition salts in a manner known per se and vice versa. For salt formation suitable acids are mineral acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as benzoic acid, acetic acid, maleic acid, p-toluenesulfonic acid and benzenesulfone ~ acid.

The compounds of formula I occur in the form of geometric Isomers and can be produced in pure cis or pure transform, but also in the form of isomer mixtures. The latter can, if desired, on known per se. Way separated into the individual isomers will. Using the procedure given under a) the compounds of the formula I are obtained exclusively or predominantly in the form of their trans isomers. The others Isomeric forms or mixtures can, if desired, on manner known per se, for example with the aid of a stereospecific synthesis or by reshaping the previously in particular compounds obtained in transform, for example by UV irradiation and subsequent Separation of the reaction mixture thus obtained. The procedure specified under b) provides the Compounds of the formula I in the same geometric form as the starting compounds

SAD ORIGINAL

.. _ii;) : r 7 - ■; 600-6577

are located". Although the compounds obtained according to the invention. fertilize. . . . . > Aussphliesslich or in the form transisomerer "in.-: are form of- mixtures, wherein the trans-form is predominant, for example in.einem extent of 60 - .95% .j, preferably 70 - 95% in particular from 80 _t ~ 95 %, it should be noted that the invention η i honors is limited-to-a-certain-form of the ..compounds, · - ^ - ■■■■■ .- ■ ". ■ ■ ^: ..: .-; . ■ ^:. ..-.-.- ·

The compounds .of the formal -IV. -Are either · known or _; ..- _; can be prepared in a manner known per se.

The compounds of the formula V can be obtained by bromination or. Chlorination of the free acids of formula VI.

R ₁ O ■ ■■■ .-: ■

^W'l!

^ V-Gf = CH-C-OH ■ VI,

wherein R, R and Y have obige.Bedeutung _r produced v / ground. -The reaction is carried out for example at temperatures from 30 to 120 ° C, wherein the chlorinating agent in particular Phof-trichloride, or preferably thionyl chloride ·, and as a particular P Bromieruhgsmittel ^{iosphortribroiriid:} verv7endet v / ground. The reaction is expediently carried out in an inert solvent, for example tetrahydrofuran * Instead of an inert solvent, however, an excess of the chlorinating or brominating agent can occur if these are liquid under the reaction conditions.

60 9 8 1 9/1? fU BAD ORiQj _WAL

- 8th - . 600-6577

The compounds of the formula V obtained can be isolated and purified in a manner known per se.

Compounds of the formula VI can be obtained by one compounds of the formula VII

FL O

- C = CH-C-OR ₀ VII,

where R ₁ Y and R have the above meaning, and R ~ is a straight-chain alkyl group with 1-6 carbon atoms, in particular for ethyl, is pre-soaped.

The saponification of compounds of the formula VII takes place zweeknvisε.1 gerweise by heating the connections of the Formula VII in an aqueous solution of an alkali metal " hydroxides, for example sodium hydroxide or potassium hydroxide, to temperatures of 70-120 ° C., The process is preferably carried out in the presence of another with water miscible solvent, for example an alkanol with 1-4 carbon atoms, such as ethanol or methanol, carried out,

The compounds of the formula VI obtained can be based on isolated and purified in a known manner.

The compounds of the formula VII are either known or can be prepared from known starting compounds in a manner known per se.

BATH ORIGINAL

609819/1284

- 9 - 600-6577

As already stated above, the compounds of formula 1 occur in the form of geometric isomers, and the geometric shape of the compounds of formula I obtained using process b) depends on the geometric shape of the output compounds of the formula V. Thus, for example, the compounds of the formula I using method b) can finally or predominantly obtained in transform if it is assumed that compounds of the formula V are exclusively or is predominantly in transformation. The compounds of formula V can be exclusive or predominant in Transform if you go to their Production of compounds of the formula VII starts out, which is exclusively or primarily in transform · "- .. The Compounds of the formula VII, which are exclusively odor predominantly in Trein form, can be produced wsrcori, by dehydration of compounds of the formula VIII,

OH O

Y - < ^y V- C-CH _? '-C ~ OR ₂ VIII

R ^R l

wherein R, R, R and Y obicje have a meaning.

The dehydrogenation of compounds of the formula VIII is conveniently carried out by heating compounds of the Formula VIII at temperatures of 80 - 200 ° C under vacuum, for example sv / ei He at a pressure of 0.01 - 0.5 mm Hg.

609819/1284

- 10 - 600-6577

The compounds obtained can be isolated and purified in a manner known per se.

Other isomeric forms of the compounds of the formula VII, from which the corresponding isomeric form-η of the end products of the formula I obtained can be obtained in a manner known per se, for example by stereocpecific synthesis from accessible Connections or by reshaping connections that are exclusively or predominantly obtained in transform, for example by UV irradiation, and then ™ send separation of the isomix mixtures on VJe.ise known per se can be obtained.

Obtained isomeric formulas of compound u π ge η of formula I can also be reshaped using the above cathodes and the isoiasric mixtures obtained per se known way to be separated.

The compounds of formula VIII are either known or can be made from accessible output connections on known way to be prepared * A preferred method for the preparation of compounds of formula VIII consists in that compounds of the formula IX

C - R
^{C R}

wherein R, R and Y have the above meaning, with compounds of formula X

BAD ORIGINAL 609819/1 284

- 11 - 600-6577

I! '
ZnBrCH ₂ COR ₂ X,

wherein R has the above meaning, reacts in an aprotic solvent under anhydrous conditions and the reaction product is then hydrolyzed.

For the implementation of compounds of the formula IX with compounds of the formula X is used, a particularly suitable solvent is ethers, such as tetrahydrofuran. The implementation is conveniently in the presence of trimethyl boron at 'performed. Suitable reaction temperature η be from 15 - 30 ° C. The subsequent hydrolysis can zv; eckitiässigerweise using water or a aqueous acid or base or an aqueous solution a salt, for example a concentrated aqueous ammonium hydroxide "or a dilute sulfuric acid, be performed. When using an aqueous base, it is advisable to add the hydrolysis device add glycerine.

The compounds of formula VIII obtained can be based on isolated and purified in a known manner.

The compounds of formula X can conveniently in situ by heating activated zinc, preferably in finely divided form, e.g. 20 mesh with

6 0 9 8 1 9/1 2 8 A

- 12 -. 600-6577

R -Bromoacetate in an aprotic solvent / at-, for example tetrahydrofuran. The reaction is conveniently carried out at temperatures of 15 - 30 ° C.

The compounds of the formula I are distinguished by a favorable pharmacodynamic effect. In particular the compounds of formula I have an anti-inflammatory effect, as the results of the known Carrageenan edema tests in rats can be obtained. The compounds of the formula I are indicated accordingly , for use as anti-inflammatory agents.

The daily dose of compounds of the Formula I for the above application should be from 70-1500 mg, preferably in smaller doses of 17.5-700 mg Administered 2-4 times a day or in sustained release form.

The compounds of the formula I can be used together with customary pharmaceutically acceptable diluents or Carriers and. optionally mixed with other additives and administered in the form of tablets or capsules.

The compounds of formula I can be in the form of the free Base or in the form of pharmaceutically acceptable acid addition salts are administered, the salts the have the same degree of effect as the free bases.

609819/128 L.

- 13 - 600-6577

The preferred compounds of formula I are those

Il

wherein A is the group -C-CH- and in particular those wherein Y is a radical of the formula II. The particularly preferred connection is that of the example la). As already stated above, the compounds are exclusively or predominantly in trans isomeric Shape.

19/1284

- 14 - 6C-0-6S77

Be isp iel '1: a) ^ - ^ g-

b) 2- (gi-Bighanyly].) ~ 4-chloro ~ 2_ _t 4-gsntadiene

2.5 ml of concentrated hydrochloric acid (12N) are slowly added to a solution of 1.5 g of 2- (p-biphenylyl) ~ 3,4-pentadien-2-ol in 50 ml of methanol. The resulting mixture is left to stand for 3 hours at room temperature and then a 10% aqueous solution of sodium acetate is added. The precipitate formed is filtered off, washed with water and dried over phosphorus pentoxide. This gives its pale yellow solid. The filtrate is concentrated to give more of the solid which is washed and dried as indicated above. The combined solids are purified using silica gel plates and methylene chloride as the eluant. Two fractions are obtained here; the first fraction consists of 2- (p-biphenylyl) -2-penten ~ 4 ~ one from the Snp. 130-133 ° C and the second fraction of 2- (p-biphenylyl) -4-chloro-2,4-pentadleη of melting point. 75 - 79 ° C.

To a solution of 10 g of 2- (p-biphenylyl) -3,4-pentadien-2 ~ ol 3 ml of concentrated hydrochloric acid (12N) are added in 200 ml of anhydrous methanol. The thus obtained Mixture is for 3 hours at room temperature

BATH ORIGINAL

609819/128 /,

- 15 - 600-6577

and then stirred in an ice bath for 2 hours » The precipitate formed in this way is filtered off and recrystallized from fentan, whereby the 2- (p ~ biphenylyl) -2-penten-4-one of m.p. 130-133 ° C receives.

The filtrate is evaporated to give an oil. that using silica gel plates and methylene chloride is purified as the eluent. This gives the 2 ~ (p ~ biphenylyl) -4 - chloro-2,4-pentadiene of melting point. 75 - 79 ° C,

Using those described in Examples 1 and 2 Process and suitable starting compounds in approximately equivalent proportions lead to the following compounds of formula I:

a) (i) 2 ~ (p-tert »Buty! phenyl) -2-penteiv ~ 4-one,

(ii) 2- (p "tert, Buty! phenyl) ~ 4-chloro-2,4" pentadiene,

b) (i) 2 ~ (p-bromophenyl) -2 "penten-4-one,

(ii) 2 ~ (p-bromophenyl) ~ 4-chloro-2,4-pentadiene,

c) (i) 2- (p-Cyclohexyl-m-chlorophenyl) "2-penten-4-one,

(ii) 2- (p-Cyclohexyl-m-chlorophenyl) -4-chloro-2,4 ~ pentadiene _r

d) (i) 2- (p-Isobutylphenyl) -2-penten ~ 4-one,

(ii) 2- (p-Isobutylphenyl) -4 ~ chloro-2,4-pentadiene,

- 16 - 600-6377

e) (i) 4- (p-Biphenylyl) -3-hepten ~ 2-one, '■ (ii) 4- (p-Biphenylyl) -2-chloro-1,3-heptadiene,

f) (i) 2- [p- (l ^l ~ cyclohexenyl) phenyl] ~ 2-penten-4-one,

(ii) 2- [p- (l'-Cyclohexenyl) phenyl] ~ 4-chloro-2,4 "pentadiene,

g) (i) 2- (p-Morpholinophenyl) -2- penten-4-one in the form

of its hydrochloride,

(ii) 2 ~ (p ~ Morpholinophenyl) -4-chloro ~ 2,4-pentadiene in the form of its hydrochloride _e

h) (i) 2- [p- (N ~ methylpipe.raKynyl) phenyl] -2 "penten-4-one in the form of its hydrochloride,

(ii) 2- [p- (N-Methylpiparazinyl) phenyl] ~ 4'-chloro - 2 _/ O pentadiene in the form of its hydrochloride,

i) (i) 2- [ρ- (3-pyrrolinyl) pheriyl] - 2-penten-4-one in the form its hydrochloride,

(ii) 2-tp ™ (3 "pyrrolinyl) phenyl] -4-chloro ™ 2,4-pentadiene in the form of its hydrochloride.

Example 4:

Using those described in Examples 1 and 2 Procedure, however, when the concentrated hydrochloric acid used there is replaced by 200 mg p-Toluenesulfonic acid hydrate in 10 ml of 90% aqueous Ethanol and leaving the reaction mixture at room temperature for 18 hours also leads to the 2 ~ (p-biphenylyl) -2-penten-4-one with a melting point of 130-133 ° C,

SAD

B Π 9 8 1 9/1 2 8 L

- 17 - 60C-6SV7

Be i spjLe I ₁ 5:

Using the procedure described in Example 4 and suitable starting compounds in approximately equivalent proportions lead to the compounds of Examples 3a) (i), b) (i), c) (i), d) (i), e) (i) and f) (i) and the p-toluenesulfonates of the compounds of Examples 3g) (i), 3h) (i) and 3i) (i).

At s ρ iel 6 j 2 ~ (pj ^ Bip ho πνΐχΐ ) ~ 3S E £ Si £ ü2l4 ~ 2 F ¹

6 _f 45 g of activated zinc metal (20 mash) are placed in a flask equipped with a magnetic stirrer and a separating funnel. The whole system is kept in a nitrogen atmosphere and on a water bath at a temperature of 25 ° C. A solution of 19.6 g of 4 "/ icetylbiphenyl in 75 ml of dry tetrahydrofuran and 75 ml of trimethyl borate (which has been distilled over calcium hydride) is added to the flask and the mixture is stirred. 11.1 ml of freshly distilled ethyl bromoacetate are poured into entered the flask and the mixture obtained was stirred for 12 hours at 25 ° C. A mixture of 25 ml of concentrated ammonium hydroxide and 75 ml of glycerine was added and the aqueous phase obtained was separated off. The aqueous phase was then treated 3 times with 25 ml of diethyl ether each time The combined organic extracts are extracted over anhydrous

19 / 128-6

- 18 - 60C-6577

Magnesium sulfate dried and the diethyl ether on a rotary evaporator removed. The residue is distilled in vacuo and that which passes over at 171-172 ° C./0.125 mm Hg Fraction collected., After unicrystallization from Petroleum ether gives the pure ethyl 3- (4-biphenylyl) -2-butenoate "

According to section a) 3- (4-biphenylyl) -2-butenoic acid ethyl ester obtained with 6 g of 85% potassium hydroxide mixed in 100 ml aqueous / ethanol and the obtained Mixture heated on a steam bath for 30 minutes. The mixture is then cooled and poured onto ice. The ice cream league mixture will. 3 times with 25 ml diethyl each - ether extracted. The aqueous phase is filtered off through Ce lit and the filtrate with 2N hydrochloric acid acidified to pH 4 and cooled. The precipitate formed is filtered off, washed with ether and filtered off with suction air-dried and finally in a high vacuum at 50 ° C gstrock.net. Here you get the pure 3- (4 ™ Biphenylyl) - ~ 2 ~ butenoic acid.

c) 3 ~ (4-biphenylyl) -2 ~ -bvitenoic acid chloride

The 3- (4-biphenylyl) ~ 2 ~ butenoic acid obtained in section b) is dissolved in 200 ml of dry tetrahydrofuran and the 4 ml of thionyl chloride are added to the solution. The resulting solution is heated in a nitrogen atmosphere for 3 hours and then the solvent and the excess of thionyl chloride are distilled off .. The residue obtained is

BATH

609819/1284

- 19 - 600-6577

rapidly distilled in a microdistillation apparatus,

with the 3- (4 ~ biphenylyl) -2-butenoic acid chloride

145 ~ 153 ° C and _{passes in a vacuum of 0 r} 075 nan Hg,

d) 2- (p _- "Biphenvlvl)" 2 - oanten ~ 4-qn

10 g of that obtained by the method of section c) crude 3 ~ - (4 - biphenylyl) -2-butenoic acid chloride in 200 ml dissolved dry tetrahydrofuran and the solution in a 500 ml round bottom flask equipped with a magnetic stirrer and a Separating funnel provided i & t, given * The whole system is kept in a nitrogen atmosphere. The solution will be cooled in a dry ice / isopropanol bath to -30 ° C and with 19.5 ml of a commercially available 2M methylmagnesium bromide solution in dry toluene is added dropwise over 30 minutes. After the addition is complete, the mixture is allowed to warm to room temperature and during Stirred for 1 hour. The reaction is started by adding 20 ml of a saturated aqueous Airnoniuiachlorid solution stopped and the organic layer separated. The aqueous layer is extracted twice with 20 ml of diethyl ether each time and the combined organic extracts are washed over dried anhydrous magnesium sulfate. Each evaporation of the solvent remains a residue which is recrystallized from petroleum ether. The thus obtained 2 ~ (p-biphenylyl) -2-penten ~ 4-one melts at 130 - 133 ° C,

bath

- 20 - € 00-6577

Eeispie1 7:

Using the procedure described in Example 6 and suitable starting compounds in approximately aquiva3.enten quantities one arrives at the connections of the Examples 3a) (i), b) (i), c) (i), d) (i), e) (i), f) (i), g) U) h) (i) and i) (i),

BATH ORIGINAL

6 0 9 8 19/128 /.

Claims (1)

- 21 - 600-657 7 P ate rit claims 1, Process for the production of new phenyl-butenones and -butadienes of formula I. wherein R is hydrogen, fluorine, chlorine or bromine, and R stand for an alkyl group with 1-3 carbon atoms, O Z I! 1 A groups of the formula -C-CH or -C = CH, in which Z is chlorine or bromine, means, and Y either bromine, iodine, isobutyl, tert-butyl, cyclohexyl, cyclonexenyl or a Group of. Form 1 II v; oi-in R "represents hydrogen, fluorine, chlorine or bromine or is an alkoxy group having 1-4 carbon atoms, or a group of formula III -N III, ^R 4 ^8AD 19/128 /. - 22 - COC-6577 means, in which either R and R are the same or different and each represent an alkyl group with 1-3 carbon atoms, or R_ and R together the radical - (CH) -, where η is 4 or 5, the radical -CH- CH ₂ -CH-CH-, the radical -CfI ₃ -CH = CH-CH - or the radical -CH -CH -N (R) -CH -CH-, where R _{r is} hydrogen or an alkyl group with 1-3 Carbon atoms, means characterized in that one either a) leads to compounds of the formula I by adding compounds dor formal IV R ₁ ^Y ~ - \ y ~ ^c " ^CH " ^c ~ ^CH 2 ' T "OH in which R, R ₁ and Y have the above meaning, treated with a strong protonating agent, the reaction taking place in the presence of water, if compounds of the formula I, in which A is a group of Il Formula -C-CH ₃ are to be prepared, and the reaction in the presence of an acid of the formula HZ, in which Z has the above meaning, takes place if compounds of the formula I are to be prepared in which A is a group of the formula -C = CH ₃ are to be produced, or BATH ORIGINAL 609819/1 ?? ^; . - 23 - 60C-6577 b) leads to compounds of the formula Ia, where R, Y and R have the above meaning, inceiu one Compounds of the form 1 V R. O y - <f \ - c-cii ' cx v, wherein R, R. and Y have the above meaning and X is Chlorine or brora, with a 3-iethyl introductory organo-metallic compound in an aprotic Medium, which is not disadvantageous for the reaction, reacted under anhydrous conditions, and the reaction product r then hydrolyzed. SAD 6098 19/1 28A - 24 - 600-6577 Germany New phenyl-butenones and -butadienes of the formula I. C = CH - A wherein R is hydrogen, fluorine, chlorine or bromine, and R stand for an alkyl group with 1-3 carbon atoms, 0 Z Il I A groups of the form 1 -C-CH or -C-CPI ₉ , in which Z is chlorine or bromine, and Y is either bromine, iodine, isobutyl, tert. Butyl, cyclohexyl, cyclohexenyl or a group of the formula II R, where R _? represents hydrogen, fluorine, chlorine or bromine or an alkoxy group having 1-4 carbon atoms, or a group of the formula III -N III, means in which either R and R are the same or different den and each represent an alkyl group having 1-3 carbon atoms stand, or R and R together the radical - (CHL) -, where η is 4 or 5, the radical -CH-CK-C- λ ι * jL aL 609819/128 A BAD original 600-6577 CH-CH-, the radical -CH -CH = CH-CH - or the res.t -CH -CH -N (R ₅ ) -CH -CH -, v / orin R for hydrogen or an alkyl group with 1-3 Carbon atoms means. 3. Therapeutic composition, characterized by the content of compounds of the formula I. 3700 / ST / SE SANDOZ-PATENT-GMBH 6 0 9 819/1 2 8 U