DE2505446A1 - NEW ORGANIC COMPOUNDS AND PROCEDURES FOR THEIR PRODUCTION - Google Patents

Description

SANDOZ - PATENT - GMBH Case 600-6658

New organic compounds and processes for their

Manufacturing

The invention relates to new biphenylylalkanoyl and alkenoyl acid derivatives. In particular, the invention relates Compounds of formula I,

where X is hydrogen or an alkyl or an alkoxy group each having 1-4 carbon atoms, B is hydrogen or an alkyl group with 1-4 carbon atoms and A for a group of the formulas II, III or IV,

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OH

-C-CH _n - -C-CH ₀ - or -C = CH-

I 2 Il ² I CH ₃ CH ₂ CH ₃

II III IV

stands, with the proviso that if X and B each represent

Are hydrogen, A is a group of the formula III.

According to the invention, either

a) to compounds of the formula Ia,

Il

Yes

wherein X and A have the above meanings by adding compounds of the formula Ib,

Ib

wherein X and A have the above meaning and B ^{1 is} a

Alkyl group with 1-4 carbon atoms, saponified, or

b) to compounds of the formula Ic,

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A'-C-OB

Ic

in which X and B have the above meanings, and A ^{1 represents} groups of the formulas III or IV by using compounds of the formula Id,

wherein X and B have the above meaning, subjecting them to dehydration, or

c) to compounds of the formula Ie,

Ie

wherein X and B ^{1 have the} above meaning by adding compounds of the formula V,

wherein X has the above meaning, with compounds of the formula VI,.

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■ ZnBxCHgC-QB 'VI

wherein B ^{1 has the} above meaning, is reacted in an aprotic solvent under anhydrous conditions and the reaction product is then hydrolyzed.

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

The inventive saponification of compounds of the formula Ib to give compounds of the formula Ia takes place on known manner, for example by hydrolysis with the aid of aqueous alkali metal hydroxide solutions, especially of aqueous sodium or potassium hydroxide solutions. The hydrolysis is expediently carried out at temperatures from 70-120 ° C and preferably in the presence of a water-miscible inert organic solvent, for example a lower alcohol, such as methanol or ethanol, carried out.

The method specified under b) above can be carried out as follows described, can be carried out:

The elimination of water from compounds of the formula Id takes place, for example, by heating them Connections conveniently in a vacuum. The compounds of the formula Id are preferably used in vacuo distilled at temperatures of, for example, 80-200 ° C. at a pressure of, for example, 0.01 to 0.5 mm Hg.

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This leads to a mixture of compounds of the formula Ic, in which A stands for a group of the formula III, and corresponding compounds of the formula Ic, wherein A is a group of the formula IV. The quantitative ratio of these compounds thus obtained depends in particular on the raw material used. Due to the well-known rule that hydrogen depends on the adjacent Carbon atom is split off, which is poorer in hydrogen, are in the mixture, however, compounds of Formula Ic, in which A is a radical of the formula IV, normally predominate. In any case, this can be obtained Mixture of compounds of the formula Ic is separated into the individual compounds of the formula Ic with the aid of separation processes known per se.

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

The reaction of compounds of the formula V with compounds of the formula VI is expediently carried out under the conditions customary for the Reformatski reaction, for example using aprotic solvents, for example ethers such as tetrahydrofuran, and temperatures of for example 15-70 ° C. The subsequent hydrolysis can be carried out in a manner known per se, for example by treating the reaction product obtained with water, an aqueous acid or base, or an aqueous solution of a salt, preferably with a concentrated ammonium hydroxide solution or dilute sulfuric acid.

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The compounds of the formula I obtained can be isolated and purified in a manner known per se. If if desired, the free acids of the formula I, wherein B stands for hydrogen, can be converted into their salts in a manner known per se, and vice versa.

The compounds of the formula I in which A is a radical of the formula IV can be in the form of geometric isomers occur and therefore in the form of pure isomers or in the form of isomer mixtures, which, if desired, can be separated into the individual isomers in a manner known per se. The one specified under b) Process leads to pure trans isomers or to mixtures in which the transform predominates. The cis forms can, if desired, with the help of other methods, in particular stereospecific methods, or by changing the configuration are obtained from compounds having a transform and by separating the obtained Mixture are isolated.

While the compounds of the formula I are usually in practically pure transform or in the form of an isomer mixture in which the transform predominates, for example to an extent of 60-95%, preferably 70-95%, in particular 80-95%, should be pointed out It will be appreciated that the invention is not intended to apply to any particular geometric form of connections of formula I limit.

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Those used as starting compounds in process c) above Compounds of the formula V are either known or can be based on available starting compounds known way.

The compounds of formula VI, which are also used as starting compounds in the process of section c), are conveniently obtained in situ by heating activated zinc, which is preferably finely divided (for example 20 mesh), with B'-bromoacetate to a temperature of for example 15-70 ° C in an aprotic solvent, for example an ether such as tetrahydrofuran. The process is preferably carried out in the presence of trimethyl borate. If the latter
in the in-situ preparation of compounds of the formula
VI is used, it is expedient to also use glycerol in the subsequent hydrolysis stage of process c)
to be added if an aqueous base is used for hydrolysis.

The compounds of the formula I have a favorable one
pharmacodynamic effect, in particular, stand out
the compounds of formula I by an anti-inflammatory effect from> as can be found in the known carrageenan-induced edema test in rats and the adjuvant arthritis test in rats, below
Use of Mycobacterium butyricum in Freund's adjuvant. The compounds of formula I are therefore indicated for use as anti-inflammatory agents.

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The daily dose of compounds of the formula I to be administered should be from 100 to 3000 mg, which is expedient administered in single doses of 25 to 1500 mg 2τ4 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 other additives, for example in the form of tablets, are administered.

The compounds of the formula I in which B is hydrogen can be used both in the form of the free acids and administered in the form of pharmaceutically acceptable salts. Suitable salts are, for example, alkali metal salts, such as sodium salts or triethyammonium salts.

The preferred compounds of formula I are those in which B is an alkyl group having 1-4 carbon atoms, but especially those in which A is a group of the formula IV. Also preferred compounds of Formula I are those in which X is hydrogen. The most preferred compound is that of the following Example 3a.

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Example 1; 3-hydroxy-3- (p-biphenylyl) -n-butyric acid-

ethy ester _;

6.45 g (0.1 mol) of activated finely divided (20 mesh) zinc metal are placed in a 500 ml beef flask fitted with an inlet tube and a magnetic stirrer is provided. The system is kept in a constant nitrogen atmosphere. The flask is placed in a water bath kept at 25 ° C. A solution of 19.6 g (0.1 mol) 4 ~ acetylbiphenyl in 75 ml dry tetrahydrofuran and 75 ml trimethyl borate (distilled over calcium hydride) is quickly admitted. The stirrer is turned on and 11.1 ml (0.1 mol) of freshly distilled bromoacetate are in added to a shot. The reaction mixture is during ' Stirred for 12 hours at 25 ° C, most of the Zinc is consumed. The reaction mixture is then concentrated by adding a solution of 25 ml Ammonium hydroxide and 75 ml glycerine, hydrolyzed. The organic phase is separated off. The aqueous phase is extracted 3 times with 25 ml of ether each time. the combined organic phases are dried over anhydrous magnesium sulfate. The desiccant is filtered off and the solvent in a rotary evaporator removed. This gives the title compound as a crude residue, which can be obtained by recrystallization from ether / Pentane (10:90) is purified. The 3-hydroxy-3- (p-biphenylyl) -n-butyric acid ether obtained in this way melts at 52-54 ° C.

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Example 2; 3-Hydroxy-3- (p-biphenylyl) -n-butyric acid ethyl ester

To a solution of 11 g of 4-acetylbiphenyl in 125 ml of absolute Tetrahydrofuran 10 g of ethyl bromoacetate are added. The solution obtained is made using molecular sieves dried.

In a flask fitted with a reflux condenser, a A dropping funnel and a gas inlet tube are provided, 6 g of an activated zinc powder are added. The container is dried by introducing dry nitrogen and the zinc powder from the dropping funnel with 30 ml of the above dried solution at room temperature. The mixture in the vessel is used until the start of the reaction heated to boiling. Then the external heat supply is turned off and the rest of the solution is dropped in drops added at a rate such that the system stuck to the boil. After the addition is complete (approx. 1 hour) the mixture is heated to boiling for a further hour. The mixture is then cooled and with 250 ml of anhydrous ether are added. The mixture is then on crushed ice, the 200 ml of a 2N sulfuric acid contains, poured. The layers formed are separated and the aqueous layer extracted twice with ether. The organic phases are then combined, dried over anhydrous magnesium sulfate and filtered off. The filtrate is evaporated to give the title compound as a residue. After recrystallization from ether / pentane (10:90) the 3-hydroxy-3- (pbiphenylyl) -n-butyric acid ethyl ester melts at 52-54 ° C.

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Example 3: a) 3 - ^ (g-BighenYlYl) _- 2-n-butenoic acid ethyl ester

and

That obtained using the procedure of Example 2 Crude 3-hydroxy-3- (p-biphenylyl) -n-butyric acid ethyl ester is distilled in vacuo (at 0.125 mm Hg) and the at 171-172 ° C passing fraction collected. The distillate, which solidifies on cooling, (mp. 46-50 ° C) is on silica gel plates chromatographed using pentane / ether (90:10) as eluent, two compounds, i.e. 3- (p-Biphenylyl) -2 ~ n-butenoic acid ethyl ester of m.p. 72-74 ° C and 3- (p-biphenylyl) -3-n-butenoic acid ethyl ester of Melting point 39-40 ° C. in a ratio of 3: 2.

Example 4: a) 3- ^ g-BighenYlYl) _- 2-n-butenoic acid ethyl ester

and

That obtained using the procedure of Example 1 crude 3-hydroxy-3- (p-biphenylyl) -n-butyric acid ethyl ester is subjected to vacuum distillation. The fraction passing over at 0.125 mm Hg and 171-172 ° C is collected and recrystallized from petroleum ether. This gives the 3- (p-biphenylyl) -2-n-butenoic acid ethyl ester of mp. 72-74 ° C. The ethyl 3- (p-biphenylyl) -3-n-butenoate obtained from the mother liquor by fractional recrystallization from ether / pentane. The connection melts at 39-40 ° C.

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Example 5; 3- (p-biphenylyl) -3-n-butenoic acid

15 g of 3- (p-biphenylyl) -3-n-butenoic acid ethyl ester are with 6 g of 85% potassium hydroxide in 100 ml of aqueous ethanol (95% ■) mixed and the resulting mixture for 30 Minutes in the steam bath. The mixture is then cooled, poured onto ice and 3 times with 25 ml each Diethyl ether extracted. The aqueous phase is filtered through cellite and the filtrate with 2N hydrochloric acid acidified to pH 4 and then cooled. The precipitate obtained is filtered off, washed with ether, Air-dried by suction and then dried in a high vacuum at 50 °. This gives 3- (p-biphenylyI) -3-n-butenoic acid.

Example 6;

Using the procedures described in Examples 1 and 2, but replacing 4-acetylbiphenyl by equivalent shares of:

a) 4'-methyl-4-acetylbiphenyl or

b) 4 ^f -methoxy-4-acetylbiphenyl

one arrives at

a) 3-Hydroxy-3- (4'-methy1-p-biphenyIyI) -n-butyric acid ethyl ester or

b) 3-Hydroxy-3- (4'-methoxy-p-biphenylyl) -n-butyric acid ethyl ester.

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Example 7;

Using those described in Examples 3 or 4 Procedure, however, when replacing 3-hydroxy-3- (pbiphenylyl) -n-butyric acid ethyl ester by equivalent proportions of

a) 3-Hydroxy-3- (4'-methyl-p-biphenylyl) -n-butyric acid ethyl ester or

b) 3-Hydroxy-3- (4'-methoxy-p-biphenylyl) -n-butyric acid ethyl ester

one arrives at

a) Ethyl 3- (4'-methyl-p-biphenylyl) -2-n-butenoate and

Ethyl 3- (4'-methyl-p-biphenylyl) -3-n-butenoic acid ester or

b) Ethyl 3- (4'-methoxy-p-biphenylyl) -2-n-butenoate and

Ethyl 3- (4'-methoxy-p-biphenylyl) -3-n-butenoate.

Example 8;

Using the procedure described in Example 5, but replacing ethyl 3- (p-biphenylyl) -3-n-butenoate by roughly equivalent proportions of

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a) 3-Hydroxy-3- (4'-methoxy-p-biphenyIy1) -n-butyric acid ethyl ester,

b) Ethyl 3- (4'-methyl-p-biphenylyl) -2-n-butenoate or

c) Ethyl 3- (4'-methoxy-p-biphenyIyI) -2-n-butenoate one arrives at

a) 3-Hydroxy-3- (4'-methoxy-p-biphenyIyI) -n-butyric acid,

b) 3- (4'-methyl-p-biphenylyl) -2-n-butenoic acid, or

c) 3- (4'-Methoxy-p-biphenyIyI) -2-n-butenoic acid.

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Claims (1)

- 15 - 600-6658 Claims 1. Process for the production of new biphenylylalkanol and alkenoylic acid derivatives of the formula I, wherein X is hydrogen or an alkyl, or an alkoxy group each having 1-4 carbon atoms, B denotes hydrogen or an alkyl group having 1-4 carbon atoms and A for a group of the formulas II, III or IV, OH
I.
-C-CH ₀ - -C-CH ₀ - or -C = CH- I ² I! ² I. CH ₃ CH ₂ CH ₃ ': II III IV stands, with the proviso that if X and B each represent Are hydrogen, A is a group of the formula III, characterized in that either a) to compounds of the formula Ia * Yes arrives, wherein ¹ X and A have obiqe meaning, by compounds of the formula Ib, 509884/1205 600-6658 AC OB ¹ Ib wherein X and A have the above meanings and B ^{1 is} an alkyl group having 1-4 carbon atoms, saponified, or b) to compounds of the formula Ic A'-C-OB Ic arrives, in which X and B have the above meaning, and A ^{1 represents} groups of the formulas III or IV, by adding compounds of the formula Id, O C-CH-C-OB I * wherein X and B have the above meaning, subjecting them to dehydration, or c) to compounds of the formula Ie Ie 509884/1205 - 17 - 600-665Ö arrives, in which X and B ^{1 have the} above meaning by adding compounds of the formula V, wherein X has the above meaning with compounds of the formula O
ZnBrCH ₂ C-OB ¹ VI wherein B ^{1 has the} above meaning, is reacted in an aprotic solvent under anhydrous conditions and the reaction product is then hydrolyzed. 509884/1205 600-6658 Germany j2. New biphenylylalkanoyl and alkenoyl acid derivatives of formula I, A-C-OB I where X is hydrogen or an alkyl or an alkoxy group each having 1-4 carbon atoms, B is hydrogen or denotes an alkyl group with 1-4 carbon atoms and A denotes a group of the formulas II, III or IV, OH
I.
-C-CH- -C-CH- or -C = CH- CH II CH ₂ III I.
CH IV with the proviso that if X and B each represent hydrogen, A denotes a group of the formula III. 3. Therapeutic composition, characterized by the content of compounds of the formula I. 3700 / ST / SE SA WDOZ-PATE NT-GMBH 76 ^ 0 Loerrach 509884/1205