DE2329037A1 - 3-BIPHENYLYL PROPIONIC ACIDS AND MEDICINAL PRODUCTS CONTAINING THESE - Google Patents

Description

Our reference: O.Z. 29 924 D / Wil

67OO Ludwigshafen, 6.6.1973 3-Biphenylyl-propionic acids and medicinal products containing them

The present invention relates to new 3-biphenylyl propionic acids, their amides and pharmacologically acceptable salts, which have valuable pharmacological properties, in particular anti-inflammatory properties, distinguish and drugs containing them.

Substituted 2-biphenylalkanecarboxylic acids, for example 2- (4-biphenylyl) butyric acid (known under the trade name LIOSOL '' from Maggioni), on the biphenyl radical by halogen trisubstituted 2- (4-biphenyl) propionic acids, described in the DT-OS 2 214 56I, or 2/4 "- (l'-cyclohexenyl) -phenyl ^ -propionic acid, a compound in which a phenyl ring is partially hydrogenated, described in BE-PS 740 099, are known as anti-inflammatory agents.

Also for substituted 4- (4'-biphenylyl) -butyric acids, for example, in DT-OS 2 112 840 anti-inflammatory effects specified ·

Compounds of the 3- (4-biphenylyl) butyric acid type have surprisingly not yet been prepared and their pharmacological properties have not been investigated. In the literature, in a Russian work (Chim. V. SeL'sk Choz., X » (1969), No. 9, page 40) there is only a general reference to fungistatic effects on a rice pathogenic fungus of a-, Q. - And f-ary! butyric acid, which can also be substituted by phenyl in the p-position. However, there is no further information or chemical characterization of the compounds mentioned in this work. Furthermore, the anti-inflammatory effect of 3- (4-cyclohexyl) -phenyl-butyric acid has recently been reported (Ann. Rep. Med. Chem. 197O on page 185).

The number of described anti-inflammatory or anti-inflammatory Means are great, but their effect is satisfactory

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not always.

There were new 3- (4-biphenylyl) propionic acids, their amides and pharmacologically acceptable salts of the formula I

CO-X

I,

in the

R is hydrogen, OH, halogen or an alkoxy radical with 1 to 4 carbon atoms,

R is a lower alkyl radical with 1 to 4 carbon atoms, R- ^{5 is} hydrogen or a lower alkyl radical with 1 to 4 carbon atoms

Atoms and _D 4

y 4 ^

X OH or the radical -N ^ 5, in which R and R ^ are the same or different

are different and denote hydrogen or a straight-chain or branched alkyl radical with 1 to 4 carbon atoms,

4 ^
or R and R ^ form together with the one connecting them

Nitrogen atom is a heterocyclic 5- to 7-membered ring, which may optionally contain a further heteroatom and be substituted,
found.

It has been found that the compounds of the formula I are highly effective anti-inflammatory drugs.

Possible halogen atoms for R are fluorine, chlorine and bromine and as alkoxy radicals, for example, methoxy, ethoxy, propoxy and Butoxy.

2 "5
Lower alkyl radicals for R and Br are: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec, -butyl and tert-butyl.

According to the formula I given above, the derivatives of the new 3- (4-biphenylyl) propionic acids are the primary, secondary or

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S'vureamide.

ΛΙε alkyl or dialkyl amines on which the acid amides are based are according to the meanings given for R and R ^ to name for example:

Methylamine, "thylamine, propylamine, iso-propylamine, butylamine, Isobutylamine, sec-butylamine, tert-butylamine or dimethylamine, Diethylamine, dipropylamine, diisopropylamine, di-η-butylamine.

In the event that the nitrogen atom connecting R and R "^ Part of a heterocyclic ring with 5 to 7 members, which optionally has a further heteroatom, in particular one Oxygen, nitrogen or sulfur atom, may be contained in the ring, are to be mentioned in particular: pyrrolidine, piperidine, Hexamethyleneimine, morpholine, thiomorpholine, piperazine or N-methylpiperazine rings. The rings mentioned can optionally be substituted by one or more lower alkyl radicals, especially by methyl. Ms substituted heterocyclic rings may be mentioned, for example: P-methylpiperidine, 4-methylpiperidine, 2,6-dimethylpiperidine, 2,6-dimethylmorpholine.

In the preferred compounds, RV stands for water. If Π represents a substituent as defined above, this is preferably in the p- or o-position. The preferred radical for R ^ is hydrogen or methyl. The preferred radicals for R ^ are methyl and ethyl. Preferred radicals for X are: OH, NH ₀ and alkylamino or dialkylamino radicals.

Examples of compounds according to the invention are:

3- (4-biphenylyl) -3-methyl-propionic acid 3- (4-biphenylyl) -> - ethyl-propionic acid 3- (4-biphenylyl) -3-butyl-propionic acid 3- (4-biphenylyl) -2-methyl -3-methyl-propions ^: 'ure 3'- (4-biphenylyl) -3-methyl-propions. "' Ureamide 3- ('! -Biphenylyl) -3-methyl-propions?' Ure-M, N-dimethylamide

A 0 9 8 5 1/1 1 h _9/4

- 4- - O.Z. 29 924

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 '-Pluoro-4-biphenylyl) -3-methyl-propionic acid 3- (4 ¹ -fluoro-4-biphenylyl) -3-methyl-propionic acid ^{amide 3- (2!} -Fluoro-4-biphenylyl) -3-methyl-propionic acid 3- (2 ^f -Fluoro-4-biphenylyl) -3-methyl-propionic acid amide 3- (4'-chloro-4-biphenylyl) -3-methyl-propionic acid 3- (4 ¹ -chloro-4-biphenylyl) -3 -niethyl-propionic acid amide 3- (2 ¹ -chloro-4-biphenylyl) -3-methyl-propionic acid 3- (2'-chloro-4-biphenylyl) -3-diethyl-propionic acid amide 3- (4'-hydroxy-4- biphenylyl) -3-methyl-propionic acid 3- (4'-methoxy-4-biphenylyl) -3-methyl-propionic acid.

The compounds of the invention can be prepared by the following methods getting produced:

1. By catalytic hydrogenation of compounds of the formula II

, 2

II,

12 3
in which R, R, Br and X have the meanings given above, under conditions known per se.

As a rule, the hydrogenation is carried out with hydrogen in a solvent, such as lower alcohols, ether, glacial acetic acid or mixtures of these solvents in the presence of a catalyst such as palladium, platinum oxide or Raney nickel, at room temperature or elevated temperatures, under normal pressure or possibly increased pressure.

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

a) by carbonyl olefination of ketones of the formula III

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III,

1 2
In which R and R have the meanings given above, with suitable phosphoranes of the formula TV

P = C - CO - Y IV,

in which R ^ has the meanings given above and Y for O-alkyl, which is different from a lower alcohol, in particular

Methanol and ethanol derived, or for -N ^ j- with the

4 ■ ί
for R and R- ^ given meanings, under conditions known per se, as described, for example, in Organic Reactions _1_4, 270 (1965). The reaction gives ix, ß-unsaturated esters or amides, which are saponified and hydrogenated to give the corresponding acids.

b) By carbonyl-01efinierung of ketones of the formula III with suitable phosphonates of the formula V

P-CH-CO-Y V,

in which R ^{1 is} lower alkyl, in particular methyl or ethyl, R ^ is hydrogen or lower alkyl, such as

4 given above, and Y for O-alkyl or _H - ^ ^R

as stated above, according to methods known per se, as described, for example, in DT-PS 1 109 67I. In this case, the ketone of formula III with the phosphonate in the presence of a base such as sodium methylate, sodium ethylate, sodium hydride or sodium amide, in a solvent, for example benzene, tetrahydrofuran, dioxane or dimethylformamide, is reacted at room temperature or elevated temperatures up to 80 ⁰ C.

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c) By Reformatzky reaction from the ketones of the general Formula III by reaction with an α-halocarboxylic acid ester, z. B. rt-bromopropionic acid methyl ester, in the presence from zinc to compounds of the general formula VI

VI,

12 3
in which R, R and R ^ have the meanings given above, and R "stands for lower alkyl, in particular methyl or ethyl, and subsequent V / a ss cleavage at elevated temperature. Subsequent saponification leads to the αί, β-unsaturated Acids d <
and X is OH.

saturated acids of the formula II, in which V? hydrogen

d) By the Doebner variant of the Perkin reaction from a ketone of the general formula III with malonic acid in the presence of pyridine.

The ketones of the general formula III are prepared by known methods , for example as described in OLAH, Friedel Crafts and related reactions, III / 1, p. 235 ff (Intersclence, 1964), and some of them are known.

2. Another possibility for the preparation of the 3-biphenylylpropionic acids of the formula I consists in the saponification of nitriles of the formula VII

C = N

VII,

in which R, R and R ^ have the meanings given above, by methods known per se by acidic or alkaline saponification, the compounds of the formula I where X = OH

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receives.

The nitriles of the formula VII are prepared from the corresponding halides, preferably the Chlorides and bromides, of formula VIII

Another way of producing 3-biphenylylpropionic acids of the formula I consists in a Grignard reaction of organometallic compounds of the formula IX

, 2

^ Mg-HaI

_ IX

R ¹ ""'

with carbon dioxide ', the compounds of the formula I with X = OH being obtained.

The corresponding acid amides of the formula I with X = -N ^ are generally obtained from the acids obtained via the acid chlorides by reaction with the corresponding amines.

The free 3-biphenylyl-propionic acids can in the usual way converted into the corresponding salt by reaction with a base with a pharmacologically acceptable cation. Examples Bases that can be used are alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates, in particular of Li, Na, K, alkaline earth metal salts, especially of magnesium and calcium, ammonia or organic amines, especially Ethanolamine.

The compounds according to the invention are obtained as racemates, the

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- 8 - O.ζ. 29 924

optionally via their crystalline esters or salts into the optical antipodes or their diastereomers, if R is not hydrogen, can be separated.

The compounds of the invention have valuable pharmacological properties Properties. They are characterized by a pronounced anti-inflammatory effect.

The compound 3 - (^ - biphenylyl) -j5-methyl-propionic acid shows im Animal experiments on mice, rats and guinea pigs showed an intensity of action similar to that of the well-known phenylbutazone.

On the kaolin edema of the rat paw (Tab. 1, figure) and on the Adjuvant arthritis (Tab. 2) (! Curative application) proves itself this compound was found to be significantly (P <0.01) more potent compared to phenylbutazone. In vitro is the cytotoxicity significantly (P <0.01) lower than that of the reference substance (Tab. 3).

On the methodology of kaolin edema:

Based on that by RIESTERER, L. and JAQUES, R. (HeIv. Physiol. Pharmacol. Acta, 25 I56 to I59, 1967) 15 rats (Sprague-Dawley, male, Weight 160 to 190 g) orally in 0.5% carboxymethyl cellulose (PLUKA), with 25 ml / kg body weight being applied, the Test substance. 60 minutes later, 0.05 ml of a 1Obigen bolus alba suspension (Merck, D.A.B. 6) injected in 0.9% saline solution. Plethysmometric the paw volume is measured on the living animal at the beginning and after 5 hours. The volume difference is applied to the Based on control and expressed as a percentage as inhibition.

The test results show that the investigated compound is about 2.5 times more effective than kaolin edema Phenylbutazone. The difference is secured with P <^ 0.01.

On the methodology of adjuvant arthritis:

Based on that of PEARSON, C. M., Proc. Soc. Exp. Biol. Med. 91, 95 (1956) are male

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/ 9

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Sprague-Dawley rats, weight approx. 160 to 180 g, subcutaneously in the distal third of the tail 0.1 ml of adjuvant of the following composition: Mycobact 12 mg. tub. hum. heat-killed, suspended in 1 ml Paraffinum liquidum (Merck).

The test substance is taken orally in 0.5% carboxymethyl cellulose given (10 ml / kg body weight). 21 days after administration of the adjuvant, the animals are sacrificed and the paw diameters (dorsoplantar and talocrural).

Information on inhibitory effects and protection refer to the untreated control. The following treatment regimens are used chosen:

I. Treatment from the day of adjuvant administration to the 20th day

II. Preventive treatment: treatment 3 days before the adjuvant administration up to the 6th day afterwards (10 times substance application)

III. Curative treatment: Treatment from the 11th day after the adjuvant administration up to the 20th day (10 times substance application).

From the test results (Tab. 2) it can be seen that the substance In contrast to phenylbutazone, with continuous application (scheme I) the development of joint swellings almost completely prevented (31 * 6 mg / kg). It must be assumed that this is an exclusively anti-inflammatory and not immunosuppressive effect, since it is more preventive Application (scheme II) an inhibiting effect cannot be ensured. In the same sense, the result of the hemagglutinin formation test be interpreted.

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

The method of the hemagglutinin formation test:

In addition to treatment regimen II (preventive treatment of adjuvant arthritis), immunosuppressive treatment is used to assess Properties of the test substance the time course of hemagglutinin formation by inbred mice after administration of heterologous Checked erythrocytes.

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For the compound investigated, there is no influence in a dose of 31.6 mg / kg body weight orally.

On the methodology of the cell kinetic investigations; Based on the KARZEL, K., Arch. Int. Pharmacodyn. 169 j No. 1, 70 to 82, 1967, the influence of the test substance on the proliferation kinetics of Ehrlich ascites tumor cells is investigated in suspension culture during a culture period of about 22 hours.

The change in cell number and cell volume distribution will checked with an electronic counter (Coulter Counter ZB) and with reference to the control, the inhibitory concentrations for a 16, 50 and e ^ ige reduction in the rate of cell proliferation certainly.

Assessment: The ZellproH. Feration is inhibited by 50% in vitro at a concentration approx. 2.5 times higher than that of phenylbutazone. Cell volume analyzes and the mitotic index indicate that cell proliferation is inhibited during the intraphase, but not phase-specifically.

Appropriate pharmacological or anti-inflammatory Effects can also be shown on the other compounds according to the invention, of which, for example 3- (4-biphenylyl) -3-methyl-propionic acid amide, J5- (4-biphenylyl) -3-methyl-propionic acid-N, N-dimethylamide 3- (V-fluoro-4-biphenylyl) -3-methyl-propionic acid amide are to be emphasized.

409851 / 1U9 ^{/ U}

co OO cn

co

test dose number of inhibition in % ± 19.2 1 dose Phenylbutazone inhibition in 1o , 2 mg / kg animals ± S. Z + 15.7 mg / kg number of , 3 5.16 60 5.1 + 10.0 animals , 5 KAOLIN- 5.62 60 21.5 + 20.8 , 3 Tabel EDEMA 10.00 45 22.2 + 17.2 10.00 2.7 ■ + 18 3- (4-3iphenylyl) ~ 3-methyl-propionic acid 51.60 45 56.9 + 17.2 51.60 45 50.5 i ¹⁵ 56.20 45 66.4 56.20 45 58.7 + 11 100.00 45 59.8 100.00 45 52.9 i ¹⁵ 45

IN

ro

vo ro

ro co ro CO ο co

O (O OO

• Ρ "»
(O Table 2 test dose
mg / kg number of
animals inhibition + in $>
S χ Protection in # dose
mg / kg Phenylbut az one inhibition
± s + in # Protection in io ¹ no effect 3- (4-biphenylyl) -3-methyl-propionic acid ADJUVANS- 3.16 15th 59.3 + 22.2 - 7.5 number of
animals ARTHRITIS 10.00 27 96.2 + 22.4 64.3 + k I. 31.60 30th 99.1 21.7 93.0 31.6 80.7 13.2 11.7 ADJUVANS- + 30th ARTHRITIS 31.6o 30th 20.5 19.5 no effect 31.6 -5.2 + 28.5 no effect II
(preventive) + 30th +
+ ADJUVANS- 1.00 30th 30.40 + 23.2 + ARTHRITIS 1.78 30th 61.20 +
+ 18.8 1.78 36.5 + 21.4 III
(curative) 3.16
5.62 30th
30th 63.10
68.50 + 16.1
21.5 no effect 3.16
5.62 45 29.5
49.1 + 18.2
16.5 10.00 30th 81.60 + 17.5 10.00 45
30th 44.9 24.9 17.80 30th 90.30 + 19.3 17.80 30th 74.5 13.1 31.60 30th 77.40 14.6 31.60 30th 75.4 13.4 30th

Tabel

3- (4-biphenylyl) -3-methyl-propionic acid ED ₅₀ + S _x ID ₅₀ , 7) Phenylbutazone ID ₁₆ ID ₅₀ ID64 test 53.8 (
mg / l 26.2 / 43
eg g / ml .29) ED ₅ O + S £ g / ml 1,8x1 θ " ⁵
g / ml 6, bx10
g / ml KAOLIN-
EDEMA 1.78 (1.38 / 2
mg / kg ID ₈ 4 87.8 (75.5 / 102.1)
mg / kg ADJUVANS-
ARTHRITIS
(curative) ID ₁₆ 2.1x10 " ⁴
g / ml 6.93 (5.63 / 8.52)
mg / kg CYT0T0XICITY 1.1x 10-5
g / ail

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Therapeutic agents with the compounds to be used according to the invention can be mixed with suitable carriers or diluents and the commonly used pharmaceutical-technical auxiliaries according to the desired type of application be produced in a conventional manner. A preferred pharmaceutical preparation is a dosage form, which is suitable for oral application. Such dosage forms include, in particular, tablets, Dragees, capsules which can be produced by the person skilled in the art in a manner known per se.

example

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

a) ß-Methyl-p-phenyl-cinnamic acid methyl ester

50 g (0.25 mol) of 4-phenyl-aeetophenone are dissolved in 200 ml of dimethylformamide. To this end, a mixture of 73 * 2 g (0.35 mol) of diethyl carbomethoxymethylphosphonate and 56.9 g of 30% sodium methylate solution (0.35 mol) in 50 ml of dimethylformamide is added dropwise over the course of one hour. The reaction solution is kept at 40 to 45 ° C. for a further 6 hours, then poured into about 1.5 l of ice water, filtered off with suction and washed with water. After recrystallization, 54 g of β-methyl-p-phenyl-cinnamic acid methyl ester with a bp. 135 ° to 137 ° C. are obtained (yield: 85% ).

b) ß-methyl-p-phenyl-cinnamic acid

5 ^ g of the above ester are refluxed for 4 hours together with 50 g of KOH, 150 ml of water and 200 ml of ethanol. The reaction solution is mixed with 11 V / water, acidified with hydrochloric acid, the acid which has precipitated is filtered off with suction, washed with water and recrystallized from ethanol. 39.7 g of β-methyl-p-phenyl-cinnamic acid with a melting point of 200 ° to 202 ° C. are obtained (yield: 78 %).

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c) 3- (ρ-Blphenylyl) -3-methylpropionic acid β g of the above acid are dissolved in 50 ml of ethanol and 50 ml of tetrahydrofuran and hydrogenated in the presence of 0.6 g of Pd / C at room temperature and normal pressure. After the uptake of hydrogen has ended, the catalyst is filtered off, the solvent is drawn off and the residue is recrystallized from benzene / petroleum ether. 3> 9 g of 3- (p-biphenylyl) -3-methylpropionic acid of melting point 122 to 123 ^° C. (yield: 66 fo) are obtained.

The following connections are established according to the example:

0OH

Pp (° C)

122 to 123

co-NH-ch:

• CH • CH

146 to 148

121 to 123

CO-N

co-

COOH

COOH

83 to 84.5

Bp: 204 to 207 / 0.4 mm Hg

Bp: 182 to 188 / 0.15 mm Hg 123 to I26 114 to 117

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COOH

O.Z. 29 924

140 to 141

CH ^ O

COOH

142 to 143

40985 1 / 1U9

Claims (10)

Claims R is a lower alkyl radical with 1 to 4 carbon atoms, R ^ is hydrogen or a lower alkyl radical with 1 to 4 X OH or the radical -N ^, -, in which R and R ^ are the same or R ⁵
are different and are hydrogen or a straight-chain or branched alkyl radical having 1 to 4 carbon atoms 4 ^ mean or R and R- ^ form together with the connecting them Nitrogen atom a heterocyclic 5- to 7-membered ring, which optionally has another Contain heteroatom and substituted by one or more lower alkyl radicals with 1 to 4 carbon atoms can be. 2. Compounds of the formula I in which R is hydrogen, 3. Compounds of the formula I in which Br is hydrogen or methyl. 4. 3- (4-Biphenylyl) -j5-methyl-propionic acid. 5 x 3- (4-biphenylyl) -3-methyl-propionic acid amide. 6. 3- (4-Biphenylyl) ^ - methyl-propionic acid-NiN-dimethylamide. 7. Therapeutic agent containing a compound of Claim 1 as an active ingredient. 409851 / 1U9 - 48 - O.Z. 29 924 8. Therapeutic agent containing> (4-biphenylyl) -> methyl propionic acid as an active ingredient. 9. Therapeutic agent containing 3- (4-biphenylyl) -3-methylpropionamide as an active ingredient. 10. Therapeutic agent containing j5- (4-biphenylyl) -j5-methylpropionic acid-N, N-dimethylemide as an active ingredient. Badische Anilin- & Soda-Fabrik AG Sign. 409851/11 (9