NO741983L - - Google Patents

Description

"Process for the production of 3-(4_biphenylyl)-propionic acids and their amides, nitriles and salts."

The present invention relates to new ^-biphenylyl-pr(ojpionic acids, their amides and nitriles and pharmacologically compatible salts, which are distinguished by valuable pharmacological properties, especially ■ anti-inflammatory properties, as well as pharmaceuticals containing these compounds.

Substituted 2-biphenylalkanoic acids, for example 2-(4~biphenylyl)-butyric acid (known under the trade name LIOSOL (<R>) from the company Maggioni), 2-(4-biphenyl)-propionic acids with three halogen substituents on the biphenyl residue, described in DT -OS 2 214 56I, or 2-/~4-(1<*->cyclohexyl)-phenyl 7~Propionic acid, a compound where the phenyl ring is partially hydrogenated, described in BE-PS 740 099, are known anti-inflammatory funds. Substituted 4-(4<*->biphenylyl)-butyric acids are also attributed, for example in DT-OS 2 112 84O, to antiphlogistic effects.

Compounds of the type 3-(4-Diphenylyl)-butyric acids have surprisingly not yet been prepared, and their pharmacological properties have not previously been investigated. In the literature, one finds in a Russian work (Chim. v. (sjeL^sk Choz., 7>(Up'69), No. 9j page 40) only a general reference regarding fungistatic effects on a rice pathogenic fungus of a-, | 3- and ^-arylbutyric acid which can be

substituted with phenyl in the p-position without any further details and chemical characterization of the mentioned compounds, however, is not found in the aforementioned work. Furthermore, in recent times (Ann.. Rep. Med. Chem. 1970, page 185) it has been written about the anti-inflammatory effect of 3_(4-cyclohexyl)-phenylbutyric acid.

The number of described anti-inflammatory or antiphlogistic agents is large, but their effect is not always satisfactory.

A method was now found for the preparation of new 3-(4-biphenylyl)-pyribionic acids, their amides, nitriles and pharmacologically compatible salts of the formula I

where

R^" is hydrogen, OH, halogen or an carboxylic acid residue with 1-4 carbon atoms,

R 2 means a lower alkyl residue with 1-4 carbon atoms,

R^ o means hydrogen or a lower alkyl residue with 1-4 carbon atoms,

and

X • means OH or the residue

AS''

where R^ and R-^ are equal - or for-

different and means hydrogen or an unbranched or branched alkyl residue with 1-4 carbon atoms, or and R^ together with the nitrogen atom to which they are bound, form a heterocyclic 5-, 6-_ or 7-membered ring, which'optionally contains an additional heteroatom and may be substituted, or 0-X means a triple bonded N atom.

It was found that the compounds of formula I are very

effective anti-inflammatory drugs.

For R"'" as a halogen, fluorine, chlorine and bromine are taken into account and as an carboxylic acid residue. for example methoxy, ethoxy, propoxy and butoxy.

As lower alkyl residues for R 2 ' and R 9 J are mentioned: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. In accordance with the above-mentioned formula I, the derivatives of the new 3-(4-biphenylyl)-propionic acids are the primary, secondary or tertiary acid amides and, when 0-X stands for a triple bonded N atom, the nitriles.

As alkyl or dialkyl amines which form the basis of the acid amides, the following are mentioned, for example, in accordance with the stated meanings for R 1 and R .

methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, sec-butylamine, tert-butylamine or dimethylamine, diethylamine, dipropylamine, diisopropylamine, di-n-butylamine.

In the event that the nitrogen atom to which R^" and R^ are bound • is a component of a 5~7-membered heterocyclic ring, which may optionally contain a further heteroatom in the ring, in particular an oxygen, nitrogen or sulfur atom , the following are highlighted: pyrrolidine, piperidine, hexamethyleneimine, morpholine, thiomorpholine, piperazine and N-methylpiperazine rings. The aforementioned rings may optionally be substituted with one or more lower alkyl residues, especially methyl. As substituted heterocyclic rings can be mentioned, for example: 2-methylpiperidine, 4-methylpiperidine, 2,6-dimethylpiperidine, 2,6-dimethylmorpholine.

In the preferred compounds, R"'* stands for hydrogen. When R"'" is a substituent with the above meaning, this is preferably in the p- or o-position. R-^ preferably means hydrogen or methyl. R 2 preferably means methyl or ethyl Among the preferred meanings for X, mention is made in particular: OH, NHg and alkyl-anino- or dialkylamino residues.

As compounds according to the invention, for example, the following are mentioned: 3_(4-biphenylyl)-3-methyl-propionic acid

3-(4-hiphenylyl)-3-ethyl-propionic acid

3-(4-biphenylyl)-fj-[bu/ty ly, ~1-propionic acid

3-(4-biphenylyl)-2-methyl-3-methyl-propionic acid

3-(4-biphenylyl)-3-methyl-propionic acid amide

3-(4-biphenylyl)-3-methyl-propionic acid-N,N-dimethylamide 3-(4-biphenylyl)-3-methyl-propionic acid-isopropylamide

3-(4-Biphenylyl)-3-methyl-propionic acid piperidide

3-(4-Biphenylyl)-3-methyl-propionic acid morpholide

3-(4<*->fluoro-4-biphenylyl)-3-methyl-propionic acid

3-(4'-fluoro-4-biphenylyl)-3-methyl-propionic acid amide 3-(2*-fluoro-4-biphenylyl)-3-methyl-propionic acid

3-(2<*->fluoro-4-biphenylyl)-3-methyl-propionic acid amide 3-(4<*->chloro-4-biphenylyl)-3-methyl-propionic acid

3-(4<*->chloro-4-biphenylyl)-3-methyl-propionic acid amide

3-(2'-chloro-4-biphenylyl)-3-methyl-propionic acid

3,1-(2'-chloro-4-biphenyl)-3-methyl-propionic acid amide

3-(4<*->hydroxy-4-biphenylyl)-3-methyl-propionic acid

3-(4'-Methoxy-4-biphenylyl)-3-methyl-propionic acid

3-(4-Biphenylyl)-3-methyl-propionic acid nitrile

3-(4-Biphenylyl)-3-ethyl-propionic acid nitrile

3-(4-biphenylyl)-3-butyl-propionic acid nitrile

3-(4-biphenyl)-2-methyl-3-methyl-propionic acid nitrile

3-(4'-fluoro-4-biphenylyl)-3-methyl-propionic acid nitrile.

The compounds according to the invention can be produced according to the following methods:

1. In the catalytic hydrogenation of compounds with the formula II

12?

where R , R , RJ and X have the meaning indicated above, under conditions known per se.

As a rule, the hydrogenation is carried out with hydrogen in a solvent, such as lower alcohols, for example methanol, ethanol, isopropanol, ether, e.g. tetrahydrofuran, dioxane, glacial acetic acid or mixtures of these solvents, in the presence of a noble metal catalyst, in particular platinum metal catalysts, such as palladium and platinum oxide, or a Raney catalyst, such as Raney nickel, at room temperature or elevated temperature, under normal pressure or optionally elevated pressure ..

The starting compounds with the general formula II can, for example, be prepared

a) with carbonyl olefination of ketones of the formula III

where R 1 and R 2 have the meaning indicated above, with suitable phosphoranes of the formula IV

where Ry has the meaning given above, and where Y means O-alkyl Y avved bleedti yet r and f-Nfrom o"C^r e"^ ns^eg lakvhvejorer ne tRae ^ lkbooehtg oilRng^ , ehlsapsr eersdi, ee lst oom vmeneekftaosr nemopal neoglvig tits ete abbneoesktlry, dévneliet nlgereir,

Organic Reactions 14, 270 (1965). It is obtained by the reaction α,|3-unsaturated esters or amides, which are saponified into the corresponding acids and hydrated.

b) By carbonyl-olefination of ketones of the formula III with suitable phosphonates of the formula V

where R' means a lower alkyl, especially methyl or ethyl, R^ 3 means hydrogen or lower alkyl, as indicated above, and Y means O-alkyl

A

or

as stated above, according to methods known in and of themselves, as for example described in DT-PS 1 109 67I. Herein, the ketone of the formula III is reacted with the phosphonate in the presence of a base, such as sodium methylate, sodium ethylate, sodium hydride or sodium amide, in a solvent such as benzene, tetrahydrofuran, dioxane or dimethylformamide, at room temperature or elevated temperature up to 80°C. c) /V|ed Reformatzky reaction starting from ketones of the general formula III by reaction with an α-halocarboxylic acid ester, e.g. a-bromo-propionic acid methyl ester, in the presence of zinc, whereby compounds of the general formula VI 12 3 are obtained where R , R and r have the same meaning as above, and where R" means lower alkyl, especially methyl or ethyl, and subsequent water splitting at elevated temperature. Saponification yields the a,p-unsaturated acids with the formula II, where R-^ means hydrogen and X means OH. d) In the Doebner variant of the Perkin reaction from a ketone with the general formula III with malonic acid in the presence of pyridine.

The ketones of the general formula III are prepared according to known methods, for example as described in OLAH, Friedel Crafts and related reactions, III/1, p. 235 ff* (Interscience, I964) and are partially known.

Of the methods mentioned under a-d, b is particularly preferable.

2. Furthermore, the 3-biphenylyl-propionic acids with the formula I can be prepared by saponification of nitriles with the formula VII

where R 1 , R 2 and r 3 have the same meaning as above, according to methods known per se by acidic or alkaline saponification, whereby the compounds of the formula I with X = OH..

Appropriate saponification conditions are aqueous medium

in the presence of mineral acids, especially hydrohalic acids such as HC1 or HBr, or sulfuric acid, or in the presence of alkali or alkaline earth bases, especially NaOH or KOH, during which one. as a rule, 5-35 percent by weight acid or base is used, calculated for the entire mixture, and where the saponification is carried out at a temperature between room temperature and the mixture's boiling temperature.

The nitriles with the formula VII can be prepared according to known methods from the corresponding halides, preferably from chlorides and bromides, with the formula VIII

3. A further preparation method for 3-biphenylyl-propionic acids of the formula I consists in a Grignard reaction of organometallic compounds of the formula IX with carbon dioxide, whereby the compounds of the formula I with X = OH are obtained. Grignard compounds with the formula IX are, for example, 2-(4-biphenylyl)-propylmagnesium chloride-1, 2-(4-biphenylyl)-butylmagnesium chloride-1, 2-(4*-methoxy.-4-biphenylyl)-propylmagnesium -chloride-1. The corresponding acid amides with the formula I where X or nitriles can be prepared from the acids obtained, e.g. via the acid chlorides, by reaction with the corresponding amines. The free β-phenylyl propionic acids can be converted in the usual way by reaction with a base with a pharmacologically acceptable cation into the corresponding salt. Examples of usable bases are alkali hydroxides, alkali carbonates and alkali bicarbonates, especially of Li, Na, K, alkaline earth salts, especially of magnesium and calcium, ammonia or organic amines, especially ethanolamine.

The compounds according to the invention are obtained as racemates, which can optionally be separated with optically active auxiliaries via their crystalline esters or salts, so that the optical antipodes or their diastereomers are obtained, provided that R-^ is not hydrogen.

The compounds according to the invention have valuable pharmacological properties. They are distinguished by a distinct anti-inflammatory effect.

The compound 3~(4-biphenylyl)-3-methyl-propionic acid and pharmacologically acceptable salts thereof show in experiments with mice, rats and guinea pigs a similar intensity of action as the known phenylbutazone, and the effect lasts significantly longer than with butazone. In kaolin edema in the rat paw (table 1, figure) as well as in adjuvant arthritis (table 2) (curative application), this compound proves to be significantly (P^^OjOl) more effective than phenylbutazone. In vitro, the cytotoxicity is significantly (P<0.01) lower than that of the comparator (table 3)•

In the figure, the time-effect curve for 3~(4-biphenylyl)-3-methyl-propionic acid (A) in kaolin edema in the rat paw is shown graphically together with the curve for phenylbutazone (B) and the curve for the control values (C). On the X-axis, 1 unit corresponds to 50 minutes, and on the Y-axis, 1 unit corresponds to 0.05 ml of paw edema. The number of test animals, n, was 30 in each case.

Methodology for Kaolin edema:

According to that of Riesterer, L. and Jaques, R. (Heiv.

Physiol. Pharmacol. Acta, 25, pages 156-159>19^7) described method, 15 rats (Sprague-Dawley, male rats weighing 160-190 g) receive the test substance orally in 0.5 ^ carboxymethyl cellulose (FLUKA), using 25 ml/kg body weight. 60 minutes later, 0.05 ml of a 10% bolus alba suspension (Merck, D.A.B. 6) in 0.9% saline is injected subplantarly into the left hind paw. Paw volume is measured plethysmometrically on the living animal at the beginning and after 5 hours. The volume difference i'percent - calculated for the control is indicated as inhibition.

It will be seen from the test results that the examined compound is approx. 2.5 times more effective with Kaolin edema than phenylbutazone. The difference is secured with P<0.01.

Methodology for adjuvant arthritis:

According to that of Pearson, C.M., Proe. Soc. Exp. Biol.

With. 91>95 (1956) described method, Sprague-Dawley rats (male rats weighing about 160-180 g) are injected under the skin in the distal third of the tail with 0.1 ml of adjuvant with the following composition:

12 mg Mycobact, tube. hmm. (jdlrept by heat treatment) suspended i

1 ml Paraffinum liquidum (Merck).

The test substance in 0.5% carboxymethyl cellulose is administered orally (10 ml/kg body weight). 21 days after the adjuvant administration, the animals are killed, and the potato verm size (dorsoplantar and talocrural) is measured.

Indications regarding inhibitory effects and protection are based on the untreated control. The following treatment core is chosen: I. Treatment from the day of the adjuvant administration until the 20th day. II. Preventive treatment: Treatment-3 days before the adjuvant administration until the 6th day thereafter (10-fold substance application). III. Curative treatment: Treatment from the 11th day after the adjuvant administration to the 20th day (10-fold substance application).

From the test results (table 2), it appears that the substance, in contrast to phenylbutazone, when applied continuously (scheme I) almost completely prevents (31.6 mg/kg) the formation of joint swelling. "It must be assumed that this is an exclusively antiphlogistic and not immunosuppressive effect, as an inhibitory effect cannot be ensured by preventive application (scheme II). The test result regarding hemagglutinin formation must be interpreted in the same way.

The curative administration (scheme III) shows a significantly (P 0.01) stronger inhibitory effect of the test substance on the manifest adjuvant arthritis. is about 1/4 of the value found for phenylbutazone.

Methodology in the experiment regarding hemagglutinin formation: As a supplement to treatment core II (preventive treatment of adjuvant arthritis), the course of hemagglutinin formation is checked using inbred mice after administration of heterologous erythrocytes to assess the test substance's immunosuppressive properties.

For the investigated compound, no effect was found at an oral dose of 31>6 mg/kg body weight.

Methodology for the cell kinetic studies:

According to that of Karzel, K., Arch. Int. Pharmacodyn. 169, no. 1, page 70-82, 1977, the effect of the test substance on the proliferation kinetics of Ehrlich-Ascites tumor cells in suspension culture is examined for a culture duration of approx. 22 hours.

The change in cell number and cell volume distribution is determined using an electronic counter (Coulter-Counter ZB), and the inhibition concentrations are determined for a 16, 50 and 84% reduction in the cell proliferation rate compared to the control.

Assessment: Cell proliferation is inhibited ^ >Ofo in vitro at an approx. 2.5 times higher concentration than with phenylbutazone. Cell volume analyzes and the mitosis index indicate that cell proliferation is inhibited during the intraphase, although not phase-specifically.

Corresponding pharmacological and anti-inflammatory effects can also be demonstrated for the other compounds' according to . the invention, of which the following are for example highlighted: 3-(4--biphenylyl)-3-methyl-propionic acid amide

3-(4-biphenylyl)-3-methyl-propionic acid-N,N-dimethylamide, 3-(4f<->fluoro-4-biphenylyl)-3-methyl-propionic acid amide.

Therapeutic agents, characterized by a content of at least one compound with the formula I as active substance, can be prepared in a manner known per se with usual carrier materials or diluents and the commonly used pharmaceutical-technological excipients in accordance with the desired type of application and with a dosage unit suitable for the application.

A preferred pharmaceutical preparation has a presentation form suitable for oral or parenteral use. Such forms of presentation include in particular tablets, film-coated tablets, tablets, capsules, suppositories and preparations containing the active substance, especially a pharmacologically acceptable salt, in aqueous suspensions, sterilized water, isotonic salt solutions or other solutions.

The pharmaceutical preparations contain as an appropriate dosage unit 20-250 mg, preferably 80-150 mg, per dose. Dose-none depends on the nature of the disease and how serious it is. For therapeutic purposes, daily doses of up to 2 g can be used with advantage.

The preparations generally consist of the active substance used according to the invention, together with a carrier material or diluted with a carrier material, or filled or encapsulated by means of a carrier material in the form of capsules, ampoules, medicinal capsules or other containers, the carrier material being can serve as a mediator, as a flavoring agent or as a diluent for the therapeutically active ingredient. This carrier material can be a solid, a semi-solid or a liquid substance.

As a carrier material, you can for example use lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, potassium phosphate, liquid paraffin, coconut butter, cocoa butter, alginate, tangat, gelatin, invert sugar syrup, methyl cellulose, polyoxyethylene sorbitan monolaurate, methyl and propyl hydroxybenzoate. When producing tablet patches, an agent can be added to prevent the powdery components from sticking to the tablet form and the stamp. Such funds can e.g. be talc, aluminium, magnesium or calcium stearate.

EXAMPLE

3-(p-biphenylyl)-3-methyl- propionic acid

a) g-methyl-p-phenyl-cinnamic acid methyl ester

Dissolve 50 g (0.25 mol) of 4-phenylacetophenone in 200 ml of dimethylformamide. To this is added dropwise, while stirring, a mixture of 73>2 g (0.35 mol) diethyl carbomethoxymethylphosphonate and 56.96

30% sodium methylate solution (0.35 mol) in 50 ml of dimethylformamide during one hour. The reaction solution is kept at 40-45°C i

6 hours, after which it is poured over for approx. 1.5 1 ice water; the fixed

material is filtered off and washed with water. After recrystallization, 54 g of 6-methyl-p-phenyl-cinnamic acid methyl ester with melting point 135-137°C is obtained (yield: 83%).

b) g-methyl-p-phenyl-cinnamic acid

54 g of the ester prepared above is heated under reflux

together with 50 g KOH, 150 ml water and 200 ml ethanol for 4 hours. The reaction solution is added to 1 1 of water, acidified with hydrochloric acid, and the defatted acid is filtered off, washed with water and recrystallized from ethanol. 39.7 g of p-methyl-p-phenyl-cinnamic acid with melting point 200-202°C is obtained (Yield: 78%).

c) 3-(p-biphenylyl)-3-methylpropionic acid

Dissolve 6 g of the acid obtained above in 50 ml of ethanol and 50

ml of tetrahydrofuran and is hydrated in the presence of 0.6 g of Pd/C at room temperature and normal pressure. After hydrogen absorption has ended, the catalyst is filtered off, the solvent is suctioned off and the residue is recrystallized from benzene/petroleum ether. 3.9 g of 3_(p-biphenylyl)-3-methyl-propionic acid with a melting point of 122-ÉL23°C are obtained (Yield: 66%).

The following compounds are prepared according to the example:

Preparation of 3~(4-biphenyl)-3-methyl-propionic acid from 3~(4-biphenylyl)-3-methyl-propionic acid nitrile: 5 g of 3~(4-biphenylyl)3-methyl-propionic acid nitrile in 50 ml 25% by weight aqueous Najtron liquor is heated under reflux until ammonia no longer escapes. After dilution with 100 ml of water, the solution is acidified with 20% by weight sulfuric acid under cooling, and the precipitated 3-(4-biphenylyl)-3-methyl-propionic acid is filtered off, washed with water and recrystallized from benzene/petroleum ether (1:1). The yield was 4.4 g and the melting point 112/123°C.

Under the same conditions, saponify: 3-(4-biphenylyl)-3-ethylpropionic acid nitrile

3-(4-biphenylyl)-3-butyl-propionic acid nitrile

3-(4-Biphenylyl)-2-methyl-3-methyl-propionic acid nitrile

3-(4<*->fluoro-4-biphenylyl)-3-methyl-propionic acid nitrile

Example regarding. pills

The active substance is moistened with polyvinylpyrrolidone in a 10% aqueous solution, it is filtered through a sieve with openings of 1.0 mm and the substance is dried at >0°C. This granule is mixed with polyethylene glycol (average molecular weight 4000), hydroxypropyl methyl cellulose, talc and magnesium stearate and pressed into tablets of 180 mg.

Example regarding dragées

The mixture of active substance, lactose and corn starch is granulated with a Qfo aqueous solution of the indicated polyvinylpyrrolidone on a; 1.5 mm sieve, dried at 5Q°C and passed repeatedly through a 1.0 mm

term. The granules thus obtained are mixed with magnesium stearate and pressed into dragé cores. These are usually given a coating consisting mainly of sugar and talc.

Example regarding ampoules

The. active substance is dissolved in a mixture of glycerol formal and 1,2-propylene glycol and water. One fills j~jbpp with water. The solution is sterile filtered, filled into colorless 10 ml ampoules and sterilized for 1 hour at 100°C.

Claims (6)

1. Process for the preparation of 3_(4-biphenylyl)-propionic acids, their amides, nitriles and pharmacologically acceptable salts, of the formula I where R"1" means hydrogen, OH, halogen or an carboxylic acid residue with 1-4 carbons atoms, R 2 means a lower alkyl residue with 1-4 carbon atoms R^ means hydrogen or a lower alkyl residue with 1-4 carbon atoms and X means OH or the residue where R^" and R^ are equal or different and means hydrogen or an unbranched or branched alkyl residue with 1-4 carbon atoms, or R^ and R^ together with the nitrogen atom to which they are bound, to form a heterocyclic 5-" to 7-membered ring, which optionally contains a further heteroatom and is substituted with one or more lower alkyl residues with 1-4 carbon atoms, or 0-X means a triple-bonded N atom, characterized in that a compound of the formula II 12 3 where R , R , R^ and X have the meanings given above, is hydrogenated with hydrogen in the presence of a noble metal or Raney catalyst in a solvent, or a nitrile of the formula VII 12 3 where R , R and R; has the meanings given above, is saponified under acidic or alkaline conditions, or a meta-inorganic compound with the formula IX 12 3 where R , R and RJ have the meanings given above, and where Hal means chlorine or bromine, is reacted with carbon dioxide, and that if an acid is obtained, it is converted into a derivative or a pharmacologically acceptable salt. 2. Method according to claim 1 for the preparation of compounds with the formula I, where R- means hydrogen. 3- Process according to claim 1 for the preparation of compounds with the formula I, where R 1 means hydrogen or methyl. 4. Method according to claim 1 for the production of 3-(4~biphenylyl)-3-methyl-propionic acid" or its pharmacologically acceptable salts. 5. Process according to claim 1 for the production of 3"(4-biphenylyl)-3-methyl-propionic acid amide. 6.. Process according to claim 1 for the production of 3~(4-biphenylyl)-3-methyl-propionic acid-N,N-dimethylamide.