DE2261965A1 - DERIVATIVES OF PYRROE ACETIC ACID AND ITS SALTS AND OF PYRROL ACETONITRILE, PROCESS FOR THE PREPARATION OF THESE COMPOUNDS, PHARMACEUTICAL PRODUCTS CONTAINING THESE COMPOUNDS AND USES OF THESE COMPOUNDS AND PRODUCTS - Google Patents

Description

22519S5

Depositor: ■ · · Stuttgart, December 14th, 3rd 1972

Continental Pharma P .262? S / nu 2, rue au Buisson

Ixelles, Belgium ■ '

Derivative of pyrroiacetic acid and its salts as well of pyrrole acetonitrile, process for the preparation of these compounds, these compounds entaltenae pharmaceutical products and uses of these compounds and products

The invention relates to new derivatives of pyrrole acetic acid and other salts, in particular their alkali metal salts and their amino alcohols and Amines, as well as synthesis and pharmaceutical application of these derivatives and salts.

3Q9826M15 '

2201965

The new derivatives according to the invention were by aie general? orn> el

CH-COOH

reproduced in aer R ^ is an optionally by riyarox.yl-, Pher.yioaer heterozykliscne 'groups, such as furan, substituted alkyl of 1 to 4 carbon atoms, a cycloalkyl with re st' j to 6 carbon atoms, Alkenyl radical with t> Dis ^L * C-citoins, a benzoyl radical which may be substituted by an alkylator, a heterocyclic radical such as lyridine, an aurcn alkyl radicals with 1 to 4 carbon atoms, halogens, alivox; / rescc with 1 up to 5 carbon atoms, alkylthio radicals with 1 to 5 carbon atoms, amino groups, trii'luorometnyl radicals, hydroxyl groups, carboxyl groups, carboxymethyl radicals and alkenyloxymethyl radicals or groups formed from various combinations of these radicals and groups, such as alkyl halogen or alkoxy halogen groups, substituted phenyl radicals, Ro and R ,, all can be the same or different, are a lower alkyl radical, a phenyl radical optionally substituted by a lower alkyl radical or preferably in the para position by a halogen atom, and R ^ is a lower alkyl radical or hydrogen , but Rp and R, -not at the same time an iVIethylrest if R ^ a

3098 26/1158

unsubstituted phenyl radical and R ^ are hydrogen, and R ^ is not a methyl or phenyl radical, if Ep una E * both one substituted in the para position by chlorine Phenyl radical and R ^ are hydrogen.

.1

The present invention also relates to salts of acids according to the general formula, (I)., The can be obtained by adding a non-toxic base, for example on the metal salts such as the sodium, Potassium, calcium and magnesium salts, as well as the salts with an organic base such as an amino alcohol or an amine.

If in a compound according to the general formula (I) an asymmetric carbon atom is present, for example "R ^ not Is hydrogen, enantiomeric mixtures can be separated by conventional methods, for example through the formation of diastereomeric salts with optically active bases, e.g. with brucine, strychnine, quinine, Cinchonidine, Sphedrine, etc.

The compounds of the formula (I) have excellent properties analgesic and anti-inflammatory effect combined with a good antipyretic effect and a low toxicity, the compounds therefore form an effective means of treating painful inflammatory processes, such as in the case of progressive rheumatoid arthritis. The excellent pain reliever Effect £; allows the indication to be extended

on all painful processes, regardless of their origin. -__

309826/1158

ORIOINAL INSPECTED

The topical application of the inventive compounds allowed in case of skin inflammation and eczema also the effective treatment of such ailments.

• ι:. <-

The present invention consequently also has the use of the derivatives of pyracetic acids and their Salts as remedies with analgesic, anti-inflammatory and antipyretic effects as well as pharmaceutical products containing these derivatives, alone or in conjunction with carriers and / or other therapeutic agents that have a similar or different effect.

The active dose of the product depends on the nature of the too treating ailment. The daily dose in the treatment of humans can advantageously be 50 to 3000 mg.

The active compounds according to the invention can according to the invention in the form of pharmaceutical products in connection with various pharmaceutical excipients administered orally, parenterally, rectally and topically.

Dragees, granules, tablets, capsules, solutions, syrups, emulsions and suspensions are used for oral administration used, which contain common carriers and additives in galenical pharmaceuticals.

For parenteral administration, the salts of the active Products are used, for example, in the form of aqueous solutions.

309826/1168

Suppositories are used for rectal administration and lotions, ointments or the like for typical administration Pomades.

■ ι: .ι.

The active products can be used alone or in combination used with other active products that have a similar or different effect.

Among the compounds that are particularly interesting pharmaceutical Have effects, those compounds of the general formula (I) may be mentioned in which R * is a p-chlorophenyl, p-bromophenyl, p-fluorophenyl, m-chlorophenyl, lower alkoxy or 2 ', 3'-dimethylphenyl radical, 1 * 2 and E> each a methyl radical and R ^ hydrogen or a Is methyl radical. The following compounds are very special to mention:

- 1-p-chlorophenyl-2,5-ditaethyl-3-pyrrolacetic acid,

- i-p-fluorophenyl ^^ - ethyl-I-pyrrolacetic acid,

- 1-p-fluorophenyl-2-diethyl-5-phenyl - $ - pyrrolacetic acid,

- 1-m-chlorophenyl-2,5- <iimethyl-3-pyi ^; rolacetic acid,

- 1-p-chlorophenyl-2-methyl-5-phenyl-5 »pyrrole acetic acid,

- 1-p-fluorophenyl-2-: ethyl-5-P'-methylphenyl-3-pyrrole acetic acid,

- 1-p-bromophenyl-2,5-dimethyl-3-pyrrolacetic acid,

- 1- (2 ', 3'-dimethylphenyl) -2,5-dimethyl-3-pyrrole acetic acid,

- 1-p-methoxyphenyl-2,5- & imethyl-3-pyrrolacetic acid,

- o * · - (1-p-Chlorophenyl-2,5-dimethyl-3-pyrrole) propionic acid.

The present invention further relates to compounds which have the general formula

309828/1158

2201965

CH-Y

(II)

obey, in the R

Rp>

^and -

^0The specified

Have meaning and Γ either -CN, -COOHc, -CONBU or () R ₁ -, where R ₅ , E ₆ and R ^ are alkyl radicals with 1 to

C atoms sinduna

and

with the nitrogen atom too

a piperidine or morpholine type heterocyclic ring can form.

The present invention further relates to a process for the preparation of derivatives according to the general Formula (I) and the salts of these derivatives.

The process is characterized in that the derivatives mentioned start out according to formula (I) and their salts from a compound represented by the above formula (II) by hydrolysis.

According to the invention, this hydrolysis takes place preferably in an alcoholic solvent at one temperature instead of that between the ambient temperature and the reflux temperature of the selected solvent.

When in compounds according to the general formula (II) given above, Y is either -CN or -COORc, the

309826/1158

Hydrolysis by the presence of a base such as i \ aOH or KOH promoted in the alcoholic solvent. .

V / enn in the formula (^ i) 1 is either COBH ₂ or C (= o) iiHgxU, the derivatives del; Pyrrole acetic acid can advantageously be obtained by a reaction which is known as the V / ill ^ eroat or V / illgerodt-Kihdler reaction and the last stage of which is hydrolysis in a basic or acidic medium. '

The compounds according to the general formula (II) can can easily be prepared by various methods, which are illustrated by the reaction equations below will:

N (Rn) ₂ I- «Vr-CHg-CN Method 1

Pyr-CHO-HVr-CH ₂ OH-HVr-CH ₂ X-HVr-CH ₂ CN Method Z.

(X- a halogen or tosyl radical)

-CH-CN . method 3 4- -CH ₂ COOI method 4th ig- —HVr-CH-COORc
O ι O

Pyr-CHpCN

►Pyr-CH-CN— »Pyr-C-CN --- i-Pyr-CH-CN COOC ₂ H ₅ COOC ₀ H:

. y

Method 5

3098267T158

with Pyr

In the case of the method 1 we get 1,2,5-trisubstituted pyrrole, in which Rr _{7 is} a lower alkyl radical or forms an unsaturated heterocyclic ring of the piperidine or itforpholine type with nitrogen, in a solvent such as ethanol, acetic acid or toluene by the action of formaldehyde and a secondary amine carried out a Mannich reaction. The quaternary salt is easily obtained by the action of an alkyl halide such as methyl iodide in a solvent such as ethanol or acetone. The nitrile is produced by the action of an alkali metal cyanide on the quaternary salt according to a known method. The reaction takes place at leichtesten in a solu- ■ ^ sun agents like ethanol, isopropanol, Diraethylsulfoxid or dimethylformamide at a temperature between 50 and 100 ⁰ C instead.

According to method 2, the formylation of a 1,2,5-trisubstituted pyrrole takes place very easily, for example by the action of dimethylformamide and phosphorus oxychloride in a solvent such as toluene or 1,2-dichloroethane. The reduction of the aldehyde is carried out by customary methods and most easily by the action of an alkali metal hydride such as. B. sodium borohydride. The intermediate alcohol can also be obtained by reducing ! Pyrrole

309826/11 & 8

of the type Pyr-GOOS ^, which has been prepared by confluence of a Dikaion of the type R ₂ -CO-CK ₂ -CH- (COOr ₆ ) COH ^ with a primary amine.

In method 3 '- (lie introduction of the radical R ^ easiest by treating the nitrile with a basic condensing agent such as sodium, sodium amide, Sodium hydroxide or sodium hydride and with an alkyl halide R ^ X (X = halogen) in a solvent such as Ammonia, ether, tetrahydrofuran, dirnethylsulfoxia or Dimethylformamide.

With the method 4 · the nitrile is made according to the classical method converted to an ester. The introduction of the radical R ^ takes place according to the JJeth'ode described above.

Method 5 involves selective monoalkylation by a previous ethoxycarbonylation of the nitrile according to methods well known from the literature.

The 1, 2, 5-trisubstituted pyrroles used as starting material are obtained by an Enorr-Paal condensation of a ^ -diketone of the R ₂ -CO- (CHg) ₂ CO-Rx ^un ö- of an amine R ₁ ME ₂ . The condensation occurs very easily in a solvent such as benzene, toluene or acetic acid.

Further details and embodiments of the invention, which however do not limit the scope of the invention, result from the following examples for the preparation of various compounds according to the general formula. my (I) and (II), from the different, pharmacological

309826/1158

// Effects of these compounds and from some formulations for tablets, ampoules, suppositories and pomades.

Example '-I ip-chlorophenyl ^ jS-dimethyl-i-pyrrolacetic acid:

a) Iodine methylate of 1-p-chlorophenyl-2,5-diaiethyl-3-dimethyl-aminomethylpyrrole

To 47 g (0.23 M) of finely ground i-pr-chlorophenyl-2,5-diüöthylpyrrol a solution is slowly added with stirring, which consists of 47.5 ml of a 40% aqueous solution of diethylamine, 57-5 al iassic acid and 27 _t 5 of 35% formaldehyde. The mixture is stirred overnight at room temperature and then extracted twice with 100 ml of ether. 700 ml of a 20% strength solution of NaOH are added to the aqueous phase. Then it is extracted again with ether. The organic phase is _{dried over MgSO 4} , filtered and evaporated. 60 ml of absolute ethanol are added to the residue obtained, and then 34.1 g of methyl iodide are added dropwise with stirring. The mixture is stirred for 1 hour. The precipitate obtained is then filtered off. In this way, 5 9 g of the substance are obtained. Yield: 92.5 % - Melting point: 197 to 201 ⁰ C with decomposition.

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b) 1-p-chlorophenyl-2, ^ -cL

•• I ·

To 166 g (0.41 is) of the above product in 600 ml of dimethyl oxide, 66.6 g of iatrium cyanide are added. The mixture is stirred η «au! Heated to 100 ° C. and held at this temperature under a stream of nitrogen for 3.5 hours. After cooling, the solution is poured into 1500 ml of water and extracted with ether. The ether phase was washed v / ira with water, over Iv ¹ IgSO ^. dried and evaporated.

The residue is rectified under vacuum. In this way, 62.1 g of a yellow oil which solidifies quickly and which is recrystallized in aqueous methanol are obtained. Finally, 57.4 g of the product are obtained. Melting point: 86 to 88 ⁰ C. Koch point: I58 (0.4 mm) to 161 ⁰ C. Yield: 56%.

Analysis: CH N

% calculated 68.71 .., 5.35 11,

% found, 66.75 5.30 11,

c) 1-p-chlorophenyl-2,5-cLimethyl-3-pyrrolacetic acid

64 g of KOH and 300 ml are added to 64 g of the above citrile Given ethanol. The mixture is on for 15 hours Brought to reflux. Then the alcohol is evaporated and the mixture diluted with 300 ml of water. The aqueous phase is washed with ether and then with 20% HCl acidified. The precipitate obtained is filtered off and with petroleum ether and a minimal amount of ether

309826/1158

to wash. , Jan receives 58 ^ 5 β ues Froaukts in this way. Melting point: 101 ⁰ C. .99,5 to yield: 85/3. The product can be recrystallized in diisopropyl alcohol or in a mixture of diethyl ether and pentane. Ia the first case, the product has a melting point of 112-114 ⁰ C (Form β), and in the case ζwateη a melting point 102 to 104.5 ⁰ C (oil form).

Analysis: C. H 55 5 , 50 % calculated 65.75 5, 26th 5 , 45 % found 65.60 5, Example 2

1-p-chlorophenyl-2,5-dimethyl-5-pyrrole acetic acid a) 1-p-Chlorophenyl-2,5-dimethyl ~ 5-acetylpyrrole

To 9.5 6 5-acetyl-2,5-hexanedione in 50 ml of benzene are 7i? S p-chloroaniline added. The mixture is refluxed for 5 hours with simultaneous azeotropic separation of the water formed. The excess of the solvent is evaporated off and the residue is rectified under vacuum. In this way 12 g of an orange-colored oil are obtained which quickly crystallizes. Boiling point: 144 to 146 ⁰ C (0.1 mm). Yield: 80%. The product can be recrystallized from hexane. Melting

point: ÖO to 81 ⁰ C. C. H ^v K Analysis: 67, öö 5.70 5.65 % calculated 67.75 5.70 5.65 Yo found

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-. 13 -

2,4-Dinitrophenylhydrazone Melting point: 239 to 241 ⁰ C (AcOH)

b) i-p-Chlorophenyl-a ^ -dimejthyl-i-pyrrolacetic acid

.1

To 5 g of the above ketone are added 0.7 g of sulfur and 2.7 ml of iviorpholine. The mixture is refluxed for 5 hours. Then 20 ml of a 20% aqueous solution of KOH are added. The mixture is then refluxed for a further 4 hours. It is then washed with ether, acidified with 20% HCl and extracted with ether. The organic phase is extracted with a 10% bicarbonate solution which has been acidified with 5% HCl. The pesticide obtained on this “verse” is filtered off and recrystallized several times with a mixture of diethyl ether and pentane. In this way 1.1 g of product are obtained. Melting point: 100 to 103 ⁰ C. Yield: 20 ° / o.

Example 3

1-p-Chlorophenyl-2-methyl-5-: PheQyl-3-pyrrole acetic acid

a) Iodine methylate of 1-p-chlorophenyl ~ 2 "methyl-5-phenyl-3-dimethyl-aminomethylpyrrole

To 50 g of 1-p-chlorophenyl-2-methyl-5-phenylpyrrole (0.2 l, ".) a solution of 75 nil of a 40% strength is added dropwise aqueous solution of dimethylamine, 60 ml of acetic acid and 36 ml of a 35% aqueous solution of formaldehyde

309826/1158

added. The mixture is heated to 105 ° C for 5 to 4 hours under a stick. After cooling, it is washed twice with 100 ml of ether and then with 500 ml of 20% HaCH. Finally, it is extracted with zither and the organic phase is dried over UgSO ^ and then evaporated. 1CO al absolute ethanol and then 28 g of methyl joaia are added dropwise to the solid obtained, which has a melting point of 93 to 95 ° C. The mixture is stirred for one hour at room temperature. Then the product is filtered off and washed in a minimal amount of alcohol. Alan receives 67 S yield: 67 %

b) i-p-Chlorophenyl-S-methyl ^ -phenyl-J-pyrrole acetonitrile

I »

22 g of sodium cyanide are added to 67 g of the above product in 220 ml of dimethyl sulfoxide. The mixture wira overnight under nitrogen atmosphere at 110 ⁰ C. The organic phase is then washed with water, dried over MgSOn and evaporated. The residue is rectified under vacuum. This gives 25 g of a dense üles.mit a boiling point 210-215 ⁰ C (0.1 mn), which is treated with a mixture of pentane and ether. In this way 20 g of a solid white product are obtained. Melting point: 105 to 107 ^° C. Yield: 45 %.

c) i-p-Chlorophenyl - ^ - methyl - ^ - phenyl-J-pyrrole acetic acid

20 g of the above product, 20 g of KOH and 100 ml of ethanol are kept under reflux for 20 hours. Because the solvent is evaporated and the Bucks'tana

309826 / 11S8

diluted with 100 uil of water. Then twice with Washed 100 ml of ether and acidified with 20% HCl. The precipitate obtained in this way is filtered off, washed with water and with petroleum ether and dried under vacuum and in a mixture of benzene and petroleum ether

installed. 11 g of product are obtained in this way. Melting point.

170 to 171 ⁰ C. • P. H 4.29 Analysis: 70.95 4.95 4.15 % calculated 70.68 5.20 / 0 found Example 4

1 -p-fluorophenyl-2,5-dimethyl-. $ - pyrrolesic acid

24 g of KOH are added to 24 g of 1-p-fluorophenyl-2 _i 5-diaiethyl »3-pyrrole acetonitrile in 240 ml of ethanol. The mixture is refluxed for 6 hours. The solvent is then evaporated and 400 ml of water are added. It is then extracted twice with 100 ml of ether. The aqueous phase is acidified with 50% HCl. To this end, the product obtained is added and then recrystallized from a mixture of benzene and petroleum ether. 15 g of the product are obtained in this way. Melting point: 125 to 127 ° C.

Analysis:

% calculated Yq found

. C. H H 68.00 5.71 5.66 68.10 5.75 • 5.30

30982S / 11B8

-Ib-

Example 5 ^:

* 11

i-p-tiethylphenyl ^^ - dimethyl ^ -pyrrolacetic acid

¹ ·

34 g of 1-pi »ethylpfienyl-2y5-climethyl- $ - pyrrolacetoaitrile in 3 ^ 0 ml of ethanol are added 34 g of KOH. The sample is refluxed for 7 hours. Then the alcohol is evaporated and the residue is diluted with 200 ml of water. The aqueous phase is washed with ether and then acidified with 50% HCl. The product is filtered off, dried and added to a mixture of zither uno. Recrystallized petroleum ether. One gets in this way
24.7 g. Yield: 67 #. Melting point: 110 to 112 ⁰ C.

Analysis: C "H ti

% calculated 74.05 7.04 5.76

% found 73.95 6.95 5.78

Example 6

1-p-Chlorophenyl-2-meth ^ 1-5-p-methylphenyl-; 5 ~ pyrrole acetic acid

34 |> ß ( ^{0.1 M} ) 1-p-ChI orphenyl-2-methyl-5-p-methylphenyl-3 "-pyrrolessigsuureäthylester _f 200 ml of ethanol and 20 g of KaOH are in a water bath for 2.5 hours heated to 50 ⁰ C. Thereafter, the solvent evaporated in vacuo and the residue diluted with 200 ml of water. Then, washed with ether and is acidified with 20 #iger HCl. the obtained
The solid is filtered off, washed with petroleum ether,
dried and in a mixture of benzene and petroleum ether

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Uincrystall ised. tin α receives on this ^; Weiae 27 g of the product. Yield ^
ter decomposition.

Product. Yield: 80 %. Melting point: 165 to 167 ° C un-

Analysis: .1 C 5 H 4th N % calculated ".70.69 ■ 5 , 34 4th , 12 % found 71.02 , 60 , 05 Example 7

Ethanolamine salt of 1- (2-pyridyl) -2,5-dimethyl -;> - pyrrole acetic acid

14 g of KOH and 150 ml of ethanol are added to 14 g of 1- (2-pyridyl) -2 _t 5-dim'ethyl-3-pyrrole acetonitrile. The mixture is then refluxed for 5 hours. After evaporation of the alcohol, the mixture is diluted with 150 ml of water. Then it is washed twice with 100 ml of ether and acidified with 20% HCl. The oil obtained is extracted with ether.

After the organic phase has dried, the theoretical Amount of a solution of monoethanolamine in ether added. The precipitate obtained is recrystallized from a mixture of methanol and ether. Melting

point: 78 to 81 ⁰ C.
* C. H N. Analysis: 61.84 7.27 14.40 % calculated 61.62 7.42 14.58 % found

Tables 1 and 2 show the preparation according to the invention

30982ο / 115β

a number of compounds according to the general formula (I). The "Table 3 relates to the pharmaceutical
Effects of a number of the compounds listed in Tables 1 and 2 The numbers given in the first column of the table correspond to the concerns in the first column of Tables 1 and 2 and are used to designate the respective compounds.

Below are some more specific examples of uie
Composition of pharmaceutical products indicated in the form of tablets, ampoules, suppositories and jellies:

1. Tablets a 250 mg

a) i-p-chlorophenyl ^^ - dimethyl - ^ - pyrrole acetic acid 250 mg magnesium peroxide 20 mg Avicel pH 101 microcrystalline cellulose 125 mg

b) 1-p-chlorophenyl-2,5-dimethyl-3-pyrrole acetic acid 250 mg Starch 75 213 milk sugar 40 rag Magnesium peroxide 10 g gelatin 5 mg

c) ip-chlorophenyl ^^ - dimethyl ^ -pyrrolacetic acid 250 mg Priaojel (iv sodium starch glycolate) 50 ag STj ^ -RX I5OO (pretreated starch) 95 ag hydrogenated castor oil 5
tiagnesium peroxide 25

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1.5 mg 3 ml 250 mg 6th mg 3 mg 3 ml 250 mg 0.25 mg 3

2. 250 mg ampoules

a) 1-p-chlorophenyl-2 _r 5-dimethyl ~ 3-pyrrolacetic acid ethanolamine (acid) ■ 250 benzyl alcohol ' \

double distilled water ad.

b) 1-p-chlorophenyl-2,5-dimethyl-3-pyrrolessigsäureäthanolamin (acid)
p-chlorometacresol
Uatrium metabisulfite
distilled water ad.

c) liatriUxii-1-p-chlorophenyl-2,5-cLimethyl-3-pyrrole acetate (Acid)

Thioglycolic acid
double distilled water ad

3. Suppository

a) 1-p-chlorophenyl-2,5- <iimethyl-3-pyi ^v rolacetic acid 250 mg · polyoxyethylene sorbitan monostearate 2050 mg

b) 1-p-chlorophenyl-2,5-dimethyl-3-pyrrole acetic acid 250 mg Syndermin GMR (glycerol monoricinoleate) 115 ag Adeps solidus (mixture of mono-, di- and triglycerides of fatty acids). 1935 nig

c) 1-p ~ chlorophenyl-2,5- «dimethyl-3-pyrrole acetic acid . 250 mg Aerosil simple (pure silica) 30 mg Adeps solidus 2020 mg

309826/11 pp

d) 1-p-Ct

acetic acid dibucaine HCl Adeps solidus

e) K

pyrrolacet & .t (acid) butylhydroxyanisole Citric acid Aaeps solidus

f) i-p-

essio acid ethanolamine al-et-tocopherol acetate Adeps solidus

(Pig-xe)

250 approx 4th ffirf 2046 Eg 250 0.4 a « 0.2 ras 204 ^, 4 ² pp mg 0.15 ag 204 ^ 5 ag

4. Jellies

a) 1-p-Chlorophenyl-2,5-dimethyl - $ - pyrrole vinegar whore

cry petrolatum lanolin "al-oc-tocopherol acetate

b) 'ip-chlorophenyl-2,? - diiiietiiyl-i> ^ ssigsaure liquid faraffin ceryl alcohol propylene ^ lye oil folyoxyethylensoroitanmonostearat sorbitaninonostearat; 5 g

& 5 .3

5

O ₁ O ^ g

5 p

11 | 2p β 9 g

9 2 1, c2 g "i, 06 g 0.1b g

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'-C, 02, -g

dl-c * .- tocopherol acetate '0.0 ^ 5 5

distilled water 62.775 S

c) 1-p-chlorophenyl-2,5-ä, iiiiethyl-3-pyrrolacetic acid ⁿ *. . ·, 5,000 g of sodium lauryl sulfate. 12.820 g methyl p-oxybenzoate 0.095 S glycerin ■ ■. ^ »500 g. distilled water 71.1cO g

d) 1-p-Ciilophenyl-2,5-cLiittethyl-3-pyrrolacetic acid. "■ .5,000 g Am ^ oc.e ^ i ^{11 x} (mixture of Fettaikoholea,

■ wax esters and fats) - · '& δ, 600 g Eutanol G (saturated liquid fatty alcohol '

hole, predominantly octyldodecanol) 20.300 g

Polyethylene glycol monoricinoleate 5.515 g

dl-c ^ tocopherol acetate 0.075 g

Citric acid · 0.010'g

5 lozenges a 100

a) i-p-chlorophenyl ^^ - aiinethyl - ^ - pyrrole-

acetic acid. . 100 mg

, ■ / ι λ I / ^ I ^ rjf Λ ι ^ \ i ^ f ^ ~ γ \ J ** \ τη γ * ϊ *

MJl X KsLlti UO IVti X fy ^^ f>

Magnesium peroxide 10 mg

b) 1 -p-chlorophenyl-2,5-dimethyl-3-pyrrole -

acetic acid 100 mg

STA -PJC 15wO 50 mg

Magnesium pGroxia. $ 0 uig

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c) i-p-

acetic acid '1CO

Avicel. . 50 ag

Milk sugar, _{1; t} ■ 25 ffig

Magnesium peroxide f \ * 25 ng

Table 4 also given below gives the physical Properties of fyrroacetonitrile derivatives indicate which intermediates according to the specified in this table general formula (III), which intermediates in the preparation of compounds according to of the general formula (I) can be used. The one in the in the first column of Table 4 those in the same column of Table 1, so that a compound of Table 4 · which is the same Has number like a compound of Table 1, a Intermediate product in the preparation of the corresponding compound according to Table 1 is. .

Finally, the following are more complete pharmacological Results for i-p-chlorophenyl ^^ - äiflöthyl-J-pyrrolacetic acid specified.

1. Pain relieving effect

*
1.1 Torsion test with acetic acid in the mouse

30 minutes before the intraperitoneal injection of acetic acid orally administered 1-p-chlorophenyl-2,5-c \ imethyl-3-pyrrolacetic acid has the same analgesic effect like alclofenac.

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Mc. _Ί (mg / kg per «I:. i. os) Tilt Achieved U.N. Trust maximum
(• 'Ä - Tin ς IQ ^ product border 1-p-chlorine- t> henyl-2,5- - .5 (15.9-29) aimethyl-3- .0 (16.6-58) 1.94 pyrrole vinegar .0 (11.3-25, 5.34 acid 21 '3.80 85 (50) klclofenac. 25th 65 (200) Soctein 17th 5) 100 (SO)

1.2 Bandall and Selitto's test

Determining the pain threshold or response to a pressure exerted on by the injection of a yeast extract inflamed paw is exerted in Wistar rats zoom in. The response will be $ 0 minutes after oral administration of i-p-chlorophenyl-2,5-dimethyl-3-pyrrole acetic acid and keep the calibration standards. The difference between the mean maximum weight in grams tolerated by the treated and untreated pigs is given below.

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1-p-Chlorphenyl-2,5-dimethyl-3-pyrro !.acetic acid

Pentazocine

Alclofenac aiainopyrin

Codeine

12.5 m

O a. ^ /

50 me

60 83 52 7ö 117 50 mcr / kfs 100 in «Ας 200 m ^ / ki? 22nd 47 102 19th 60 66 10 msAk 20 ΐηκΑ « 40 K-r / k ^ 38 40 Λ JfI
IQ /
(Look
tung; of
Central
vssystems)

The 1-p-chlorophenyl-2,5-dimethyl-3-pyrrolessifj; acid proves half as active as codeine, practically as active as pentazocine, four times as active as alclofenac and five times as active as aminopyrine, what a difference is very significant.

2. Anti-inflammatory effects
2.1 'Carraflhenin abscess in rats

The effectiveness of i-pacetic acid does not differ in this test from the effectiveness of phenylbutazone. The effectiveness ver ratio is 0.781 which is irrelevant.

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2.2 Pi'otenödeia in rats ■■

2.2.1 In the normal rat

The veffectiveness p

■ i pyrroiessigs & ure will be ait of those regarding

Phenylbutazone compared in terms of udema, which by the injection of garraghenin into the paws of the satiated have been caused. The oral in doses of 20, About 80 og / tcg one hour before the injection of aes carraghenin injected 1-p-chlorophenyl-2,5-δ-dimethyl - ^ - pyrrolesic acid shows the same effect as equivalent doses of phenyloutaζone. The effect of 1-p-chlorophenyl-2,5-climethyl ~ 3-pyrrolessetic acid is 1.1 times the dose of phenylbutazone, which is of no particular importance.

2.2.2 £ eggs eggs rat with adrenal glands removed

The activity of 1-p-chlorophenyl-2,5-dimethyl - ^ - pyrrolacetic acid is retained and remains that of
Phenylbutazone comparable. "

09826/1158

2.3 granulomas

On the gaps of 160 hats got under the skin Planted cotton pellets. From the third "to the sixth day the liatten were given a daily Dose of 35, 70 and 140 mg / kg 1-p-chlorophenyl ~ 2,5-dimethyl-3-pyrracetic acid or treated with phenylbutazone. The products were administered orally. On the seventh day the hats were sacrificed, the granulomas removed and dried until a constant weight was reached. Under these conditions the anti-inflammatory we * -; '. kung of 1-p-chlorophenyl-2,5-dimethyl-3-pyrrole acetic acid very close to that of phenylbutazone (1-p-chloropheny-2,5-dimethyl-3 pyrrclacetic acid = 0.73 phenylbutazone). In the tested cans, the products have the weight of animals is not affected.

2.4 Induced by Freund's adjuvant in rats arthritis

In male Hatten of 400 to 500 g weight of Freund's adjuvant is caused at the base of the tail under the skin of arthritis by injection. Freun's adjuvant consists of a suspension of killed Nycobacterium butyricum in paraffin oil. 0.1 ml with a content of 0.7 ^ S of the Mycobacterium are injected per rat.

2.4.1 Preventive effect of i-p-chlorophenyl-2,5-dimethyl-3-pyrrolesic acid

When the 1-p-chlorophenyl-2,5-dimethyl-3-pyrr acetic acid from the first to the twentieth day after the injection

309826/1 158

of the adjuvant in daily doses of 25 and 50 mg / kg orally
is administered, it is found that 1-p-chlorophenyl-2,5-dimethyl-3-pyi'i'olacetic acid exerts significant protection with regard to the severity of the arthritis
(see following table).

Treatment η dose success · '(mean value

mg / kg / day had dSF)

, 14 days 17 days 21 days

Change in weight in g ά Sl

Controls 4-5

12.18 12.89 13-36 + 0.48 + 0.42 + 0.46

-79 +.

1-p-.
Chlorophenyl-2,5-dimethy1-3-pyrrolacetic acid 17

25th

3Ö € 'HK 3ö £

6.82 5.12 4.63 -58 +10

+1.08 + 0.92 + 0.93

50

3 nights £ 3 € 3 £ acap

5.11 3.78 3.00 -38 +

+ 0.84 + 1.79 + 0.50

Phenylbutazone. 15 50

0.68

5.07

3 € 3E

+ 0.72

Clear difference to the controls at the threshold Clear difference to the controls at the threshold GF = standard error.

0 9 8 2 6/1158

This protection is statistically significant (in the
Threshold ei : 0.01) and · is statistically identical for
Daily doses of 25 or 50 mg / kg of 1 p-chlorophenyl-2,5-dimethyl-3-pyrrc! Acetic acid or 50 μg / kg of phenylbutazone. The weight loss observed in the control animals

• r. ι.

is also reduced by the treatment. In this

Respects are those after treatment with 1-p-chlorophenyl-2,5-dimethyl-3-pyrrole acetic acid and differences observed with phenylbutazone at a daily dose of 50 mg / kg statistically significant (α: 0.01) and for both

Products identical.

2.4.2 Healing effects of 1-p-chlorophenyl-2,5-diaethyl-3-pyrrolacetic acid

If from the 21st day after the injection of the adjuvant

under the skin 1-p-chlorophenyl-2,5-dimethyl-3-pyrrolessi (3; _ acid administered orally at a daily dose of 25 mg / kg may reduce the severity of arthritis which is just as strong as in rats given 50 mg / kg per day under the same conditions Phenylbutazone. After three days of treatment with i-p-chlorophenyl-2,5-dimethyl-3-pyrric acetic acid the severity of arthritis (p = 0.001) is significantly reduced, while none is significant spontaneous Development is found in the control animals and also phenylbutazone at a daily dose of 50 iag / ^ S has no significant effect. After 15 days of administration

309826/1158

of 1-p-chlorophenyl-2,5-dimethyl-3-pyrrolacetic acid (25-mgAc per "day) and phenylbutazone (50 mgAg. P ^ o day) the severity of arthritis is reduced by half. The i_p-chlorophenyl-2,5-dimethyl-3-pyrrclacetic acid is As active as phenylbutazone at half dose. Against it Phenylbutazone significantly corrects the weight loss observed in the controls. (Ct: 0.01), whereas 1-p-chlorophenyl-2,5-dimethyl-3-pyrrolacetic acid has no effect in this respect (see table below).

Products

Success (mean / had ά SF)

21st day 24th day 28th day 31st day 35th day Weight

before the changed

Handled 1. '. ■ in g J SF

Dose mg / kg

Controls

13.7 14.0 13.0 + 0.6 + 0.6 r 0.6

12.1 11.2 -22.6 + O.7 +0.6 + Q

Chlorophenyl-2,5-dimethYl-3-pyrro ! acidic vinegar

Phenylbutazone 50

14.5
+ 0.6 13.5
+ 0.6 1
+ 11
+ .6
0.6 9
+ *
.5
0, 7th 6th
+ .9
1.2 -19
+ .0 14.2
+ 0.7 13.8
+ 0.9 1.
1 2
.1 8th
+ κ
.3
0. 8th 5
+ € 3 £ 3
.8th
0.9 +15
+ .3
5.C

309826/1158

- 50 -

2-5 Conclusions from the investigations for anti-inflammatory effects

1-p-chlorophenyl-2,5-dimefchyl-3-pyrrole acetic acid appears to be just as effective against severe inflammation (carraghenin edema on the paw) as phenylbutazone. While ip-chlorophenyl-2,5- <limethyl-3-pyrrole acetic acid is equivalent to phenylbutazone in the test of cotton pellet granulomas, it is superior to phenylbutazone in arthritis caused by Freund's adjuvant, both as a preventive and as a preventive measure as a remedy. The anti-inflammatory effect of 1-p-chlorophenyl-2,5-dimethyl-3-pyrrcle _SS igsäure is not changed by an adrenal ectomy.

3. Antipyretic effect

The 1-p-chlorophenyl-2,5-diniethyl-3-pyrrolacetic acid was tested at doses of 50 and 200 mg / kg in rabbits that by intravenous injection of an antigonococcal vaccine had been made feverish. A relationship between effect and dose has been established. That Product was found to be more effective than Alclofenac, and therefore much more effective than acetylsalicylic acid, namely at least six times more effective.

309826/1158

■ 2261365

4. General pharmacology

4.1 Effects on the cardiovascular system

Daily oral administration in doses of 12.5 * 25 and 50 mg / kg changed for three months in the Rat neither the blood pressure nor the heart rhythm. -

4.2 Effect on the central nervous system

When checked for a calming effect, it was found that the 1-p-chlorophenyl-2,5-dimethyl-3-pyrrodacetic acid From a dose of 50 mg / kg, the duration of sleep triggered by barbiturates increases.

4.3 Effect on the digestive system

1-p-chlorophenyl-2,5-dimethyl-3-pyrrole acetic acid has doses of up to 100 mg / kg no retarding effect on intestinal activity in the mouse «At a dose of A retarding tendency is noticeable at 200 mg / kg.

5 · Toxicology

5.1 Lethal dose for oral administration

Home:? 80 mg / kg (655-928) rats: 560 mg / kg (439-714).

3 0 9 8 2 6/1158

5 ° tolerance level for oral administration

Administration of 1-p-chlorophenyl-2,5-dimethyl-3-pyrroacetic acid in daily doses of 12.5, 25 and 50 mg / kg

while two weeks leave no sign of one in rats Recognize toxicity. Even a daily dose of 100 mg / kg seems to be well tolerated.

5.3 Study of long-term toxicity after oral administration

5 x 3 x 1 three month study in rats

Tests with daily doses of 12.5 * 25i 50 and 100 mg / kg carried out. Daily doses of 12.5 and 25 mg / kg did not result in any symptoms of intoxication.

5.3 · 2 three-month experiment with monkeys

There were daily doses of 251 50, 100 and more than 100 mg / kg used.

The daily doses of 25, 50 and 100 mg / kg were completely tolerated by the animals and resulted in these animals to no poisoning.

5 Λ Test for teratogenic effects in rats

No embriotoxicity was observed at daily doses of 25 * 50 and 100 mg / kg. It could also be detected no anomalies on fetus treated with these doses Hatten.

3 0 9 8 2 6/1158

ο -

225.1965

Table 1

• ι: · '·

CH ₂ -COOH

309826/1158

■ Ο "

W-Ci

W-F

CH.

CH.

CH.

CH.

CH.

CH

3-

CH.

Boiling point in ⁰ C (1)

118-120
(CH)

78-81

(2)

(1-IeOH-At ₂ O)

83-84 ''
(fbntan)

96-97

93-96

(C, ll _r - petroleum ether
6 ο

102-104.5

At ₂ O petroleum ether)

125-127

(C ₆ H ₅ - petroleum ether)

110-112

(Et ^ O- petroleum ether

ber.

71.46

61.84

60.60

69.50

74.68

63.75

68.00

74.05

71.70

61.62

60.85

69.30

74.85

63.60

68.10

analysis
H

8th,

7.27

4.75
6.60

7.44
5.35
5.71

!

73.95! 7.04

IT ber.! found

O O "nor P. Γ *

7.42 jl4.4O 14.5 3

4.70 4.70

6.65

7.30

5.26

5; 75

5.40

5.44

5.30

5.66

6.95 5.76

5.0 =

5.40

5.45

5.80

5, J 3

8S I I / 9Ζ86 2251965

Cl

egg

CH

^CH

CH

^CH

^CH

3 ■

CH

CH

^CH

Boiling point in ⁰ C (1)

128- ^ 130

172-175

(At ₂ O petroleum ether)

105-106 (hexane)

164-166

102-105 ■,. (MeOH -It ₂ O). ^k '

115-117

(ÄtpO-Petrolather

Analysis H

IT

ber.

59; 16

70.95

.64,9.0 above

78.66

60.25

63.75

ber. ber.!

59.02

70.68 ^r 65, O5

78.52 60.30 63.90

6.52

4.95

• 5 ",

6.27-

6, .S4 -

5,

6.40

5.20

5.80

8.62

4.29

5, CO

6.20 ι 4.5

6.70

5.40

4.50

S /

5.30 j 5.3C '

to co σ>

_τ - co

. I.

to

Cl)

CD

V "

(O

* * he" *> 4 Vj ' O O Ml rH vf O vl ' CS! - ^ 4 ■ ' CM in 'o ■ CO 0 "> H Vf l-J ω b m t ^ m O in CTi m tn Γ- in co " r- in ι-! CN in CS! rH in CO CO r- in ■ jC

Ü - ■ -

trt in,

CO

CO O

VO

CO

CM

O in CN CO VD -P ™ co rH ^ VD iH vD VD I. I. U I. O O rtj CO I. in H O r- O co I. α rH CN vf -P O : <^ rH

ι O O

0 ^ vD

VC

r:

ro ϋ

rH [

ι

ir,

-τ-ΐ-f-

,, rri; VO

in.

co

VT ₄ "-: -

fO

ro

OO

ro

1 * 1

OO OO rn O U

«.0

IN

.23

% 24.

25th

26th

27

/ 9286O

-Cl

Cl

Cl

J N \ cH.

Cl

Cl

CH.

CK,

CH,

CI-I.

CH.

CH.

CHU

CrL

CH.

CH.

Boiling point in G (1)

123-0: 24.5

O-petroleum ether)

191-193

183-184

108-109 ^<C 6 ^H 12 »

112.5-113.5

-Petrolether)

97-99

t ₂₀ _Petrolether).

analysis

ber. f

II IT

ber. ber. j gef.

55.40

63.35

70.69

70.30

56.40

74.00

56.70

63.70 4.20

70.95

70.60

56.35

74.30

5.31

7.00

4.40

7, CO

4.55

4.30

5.50

7.15

4.45

4.70

3.90 3.70

4.12

5.10

4.70

i / 7C

7.05 I 5.75 5.9D

8St t / 93 860ε

.

Boiling point in ° C (1)

analysis

C H- N

ber.. found ber. | ber. found

-CH.

-? Λ

■ o-

Cl

egg

-F

f W

CH ₃ O

CH.

CH.

VCH,

CH.

100-101
(Hexane)

95-96
(Petroleum ether)

165-167
(C ₆ H ₆ - petroleum ether)

161-163

(C ₆ H ₆ - petroleum ether)

135-137

(C ₆ H ₆ - petroleum ether)

96-98
(Hexane)

74.70

64.85

70.69

74.29

70, OS

66.40

74.60

. 7.45

7.50

64.65

71.02

74.50

5.80

5.34

5 -, - 61

5.75

5.60

5.65

70.00

4, .5-5

5.00

66.60

6, eo ■ 6.05 4.30

5.45

5, .3C

5.00

4.12

4.33

4.05

4,: o

4.30

4.20

4.70

.Cl

J / ν

2161965

3-CH3

-OH,

CH.

CH,

CH,

CH,

CH.

CH,

CH.

CH,

CH,

CH,

CH

Koehpukt in ⁰ C (1)

81.5-82.5
, (Petroleum ether)

71-72

(Pentane)

139-142
(Hexane)

132t133

197-200 · '

(C ₆ H ₆ - petroleum ether)

103-104
(Petroleum ether)

165-166

Analysis H

"ber. 'J gef,] per. I n; ef> |. ber. 'i pef.

75.75

64.85

68.85

65.90

70.04

72.35 '

• 4.75

75 95 T34, 70 68, 55 66 » OS 69 85. 72, 15th 74,

B _f 10

5.80

6, GQ.

5, .55

4.95

8.00

5.95

8.2 ¹ O

5.90

6.50

5.63

• 5.00

7.90

4.90

5.05

11.45

5.15

4.30

4.45

6.15 4.35

11.30

4.2? 4,3D

■!

89L-l / 9g860e "

R.

Boiling point in ⁰ C (1)

analysis

C H

ber. I found. | ber. j gef.

ber.

Q- ¹

CiT ₃

^ H ₃

-CH (G ₆ H ₅

COOH

CH,

CH,

CH.

CH.

CH.

CH.

CH.

CH.

CH.

156-157
( ^C 6 ^H S ~ hexane)

131-133

(C ^ H ^ -. Petroleum ether)
6 6

109, S-TIl
C pentane)

70.70

70.85

5.30

5.3b

70.70

70.70

5.30

5.40

65.45

65.35

6.20

6.20

112-113
(ÄtgO-pentane)

iSS-156 '.
Xbenzene)

6β, '94

78.95

66.95

79.00

6.43

6.155

6.25

6.65

229-230 (decomposition) | δ2.28] δ2.4Ο
ICAther-Pentane). '

5.23 j 5.50

1961922

4.10

4.10

5.00

6 ", OO

4.40

4.8C ί 4, i; S

σ to co «ο

crt co

O O ω O '' "a ■ IO -P ■ 1. ' to - ro H -V4 * co • ■ ■ P. LO -P - ■ ■ IO 3 u » (CH. CN PJ VH -P ro I. φ H CP ' -P ;. φ '<* Ö. ■ VD- to O ι d
OJ-cd ν) «Ph LO , * ° IO C ^ · Γ- Η © O ro Ö • ro VD '.
ι CO • o I.
co ο £ j IO ! *>. - |. OJ VD CTi ιό ^{: <1} ! I OJ ■ ^^ C \ J j3 H vo "P _v ^! - (N +? ■ 4- ^ ro : s φ
MS ω oj ι — 1 ^{; <ϊ} ί VD "* ' H P-i VD ^{: <3} < ld [> » ^{: <; I} J ω : ο * CN LO. cn. CN H '"r -p LO σ. ^ CQ O VO ro ro σ » CO LO OK ö ro LO ro r-1
CO M. Φ . ■ * ' ro IO W. VD * • W-. . CD ir! . VD ω CTv U H O ro cn Pk CJ O O ro CJ H r-i. t- to LO ^ - ^ VD. PS Φ
fsO to CQ VD to ro VD I. CN O co CO co JxJ ro CN "ro "^ ro ro IO VD VD O U JU VD W. rN S. CN H VD O CTi CJ in ^U VD VD r- VD VD Φ f ro VD ro to CN ' O IO ro. IO to cn O·· LO " • st ' Η CN H LO CN ' cn in VO -VO · 'R ~ - VO O VD ; · Il ■ ΐ Kr * ί • φ ! - ■ I CJ
I. CJ ^ Ύ r-1
(?, -P
trp ( I.
CN ORIGINAL ol έ > -OCH Q • Ρ T O ίο ω BATH ■ 8 0 H OJ I "^ cn ^ s ro - ο · ro K U

co

cn

Jf \\ - CH.

CH.

W CH.

CH.

CH.

.

CH.

CH.

(f Λ-

CH.

CH

3:

CH.

CH

Boiling point in ⁰ C (1)

70-72 (hexane)

fluid

130-131.5

_C HJ ο ο

137-139 (itgO-Betroläther!

Analysis H

ber.

75.25

74.7O

73.35

74.00

75/40

74.90

73.70

73.70

ber. j ge f. f ber.

found

7, CO

7.45

6.60

7.04

7.95

7.40

6.80

7/20

5.15

5.45

5.10

5.75

• 6.05

(1) The Uncristc

(2) melting point

llization solution is in brackets iminsalies

specified

of ethanol

OJ

ο to co

«Ο

ΟΧ »

cn co

CD

U O

<H lit. • CD O CO ω I. —Ι co Ö

CD

CD

U CD

, a

O O

-P

Ph

O O "

ro

C *

vj '

in

in

IO

vj

■ in

VO

IO ro VD

in

Γ

ΙΟ

in ω

in ro

vd * cn

VD IO

G.

-P ti ω C4
I. he" I. • P co

V ro

P-I CD

ι I

CvJ

.! U

ro U ro

ro

VO

IO

ti VD

in

O vi ¹

VD in

as

-S

CD

cn

1-4

fO

in in

IO

vD>

SAD'ORK *

ο co

in O

v?

■ -Η VO

m vo

Rome

I W CO «β.

CM

cn: ro ro ■ · a. ro a a U α. U "

ro ro ■ a ο. U

in

89U / 92 8605

/~~VoisoC.,H

7th

Cl

Cl

-Cl

Vd

CH

CH

22519SS

CH.

CH.

CH,

CH.

CH.

R.

CH.

CH.

CH.

CH,

CH.

Boiling point in ⁰ C (1)

61-63 · ■ (hexane)

127-129 ■ (cyclohexane)

84-86 (hexane)

220-222.

fluid

79-80.5 (hexane)

Analysis H

ber.

71.05

56.40

56.40

74.32

68.87

74.70

found

70.90

56.50

56.20

74.60

68.9O

74, 8O

ber. j gef. I ber. J ge

7.3.5

4.39

4.39

4.67

9.15

7.45

7.50

4.87

4.50

4.70

4.60

4.80

4.70 ■

3.61

8.90

7.60

6.69

5.45

OJ

(D

■ S

00 no

cn οο

BAD ORlGINAt

ο , O
ο · - O ■ " * co • ς? ω If) in CD fco m 3 OJ ¹ ^ η " O -P OV • cn ti Q) OY Often ■ I Q) O \ If) H ^ ^ * O IPl ^: fT * ti Ä to ω • Η H-
ω CN - U ω -p; ο
ω νη VD - a. 'ιη 00: OO - ■ A. I ^ W. "'· H K About, νρ - O O O LO O «Η ro CO t < . -M ' (D
.ω ra
VO ι: OO Ί ω O pi ₍ *. H ^: * VO O OK VO ρΓ ΰ '- I. ω 0 co co VO VD H pi ο ij *. - - *

Table 3

68 Toxicity Anti-inflammatory effect Edema Pain relieving effect Randall & Selitto (M- t • >'*·>
* ■ ' f * 4th Mouse oral 0.14 95 (400) ■, - J ] 6th Process 0.52 Siegmund (3) 77 (4CO) ■ 7th 2250 (14O6-36CO) +++ 1.10 ··. > - loo - " 83 (50), 8th +++ . 1.20 25 (13-48) 54 (50) 9 780 (655-928) +++ " O, 06 21.5 (15.9-2! D) . . 83 (100) 10 740 (649-844) +++ '0.72 23 (15-34) 13 8 (400) 11 2850 (2151-3776) . +++ '' 75 (34-165) _: 130 (400) 14th 1650 (1320-2063). +++ 0.10 160 (67-3Ö4 ") 56 (400) 18th + 0.90 28.5 (19-43) 80 (400). 25th 1700 (1308-2210) +++ 0.27 '46, 5 (34-63) . 133 (25) 27 1400 (966-2030) +++ 49 (29-S3) 111- (100) 28 +2850 O 41 (24-70) 31 1230 (1088-1390) O 67 (33-137) 47 1125 (833-1519) +++ 59 (35-100) ISOO (1397-2584) 53 (34-82) + 4000 +++ 20.5 (14.1-29.7) 1350 (1595-1728) +++ AB ^f 3? ~ 67 )

Oral toxicity mouse ' ₀ mg / kg

Anti-inflammatory effect

abscess

Edema

Pain reliever effect Siegmund (3)

Randall & Selitto (4)

2170 1000 (806-1240)

400

64 (29-141)
98 (41-235)

(400)

O CD OO PO CD

(1) Carraghenin abscess in rats; Method of Benitz and Hall; Screening test (unit dose 5QO mg (kg); denotes the percentage reduction in abscess weight, which corresponds to +++ a clear effect, which can also be seen in the comparison with phenylbutazone Carraghenin edema test results. · - - ■

(2) carraghenin edema in rats; the efficacy is compared to that of ^v 'phenylbutazone (= 1) specified. ·. ■

(3) Siegmund test:

in mg / kg orally in mice

(4) Randall and Selitto's test: increase in the endurance of the inflamed paw of rats • of their own weight. The orally administered dose in mg / kg is given in brackets.

Tabel

• ι:. ··

CH CN

(HI)

Ν · R ₁ R ₂ . .. ^R 3 The melting or boiling point is ⁰ C 1 Λ ^Η / ^Cli 3 CH ₃ 152-156 (1 Ba) ft _D ²⁵ * 1.5243 2 -Ö CH ₃ 58-62 "(MeOH ^ H ^ O) 3 CF ₃ CH ₃ CH ₃ ,
■ » 130-135 (0.2 "" Y n _D ²⁵ - 1.5146 4th , Q-OCH ₃ . CH ₃ ^CH 3 64-64.5 (MeCH-H ^ O)
• * - '■ ",. · * ..
■ "■■■■■. ^! ■ ■■ '. ι
5 - (CH ₂ ) ₂ -f3 CH ₃ CH ₃ 76-78 (Hexaa) '

309826/1 1 58

N °

ί ίο

11

13th

14th

15th

18th

-Cl

Cl

CH

V Vci

Cl

^CH 3

ci

Cl

Cl

Cl

cn.

CIL

CLL

CH,

CIL

CIL

CH,

CH,

CH

3 -

cn.

CIL

^CH 3

CH,

CH,

CH,

CH,

Melting or co-clipping in o _c

84-85 (MeOII-H 0)

25th

142-145 (0.7 mm) η = 1.5470

CH.

38-40.5 (MeOH)

60-62 (isoPrOH) 105-107 (pentane et _o 0) 145-150 (0 *, 5 mm) η _β ²⁵ = 1.5670 96-99 (et ₀ 0-petroleum etlier)

87-88 (hexane).

CH,

CH-

CH

3.

CH

CH

.3

826/1 1

86-88 (MeOH-H ₀ O)

54-55.5 (MeOH-H ₀ O) 156-160 (1 mm) n _ß ²⁵ = 1.5522 90-91 (ÄtoO-Tetolether)

87-89 (Petan-Ät ₂ 0)

BATH

-C] I-CH = CiL

CLL

VciI _o C00C..H _r , CIL, __ / 2 2 5 'ο

CII ₃ O

Cl

CIL

Cl

Cl

_ / ~ ^Π 3

_ / °° 2 ^Η 5

Cl

CH.

CH

CH,

CH,

CH,

CH,

CII.

CH.

CH.

^CH 3

CII,

CH,

CH,

CH,

CH.

CH,

Fast or Kocliptink ik

113-115 (0.5mm)

183-194 (0.4 πυιι)

87-89 (isοPrOH-HO)

68-69 (ΜβΟΠ-Η, Ο) 115-117 (itgO petroleum ether.

110-112

58-60 (MeOH-H ₂ O)

76-77.5 (MeOH-H 0)

60-61.5 (MeOH-H ₂ O)

51-53 (MeOH-H ₂ O)

BAD ORIEiNAL 309826/1158

cn,

Cl

Cl

Cl

CH,

38-

CH

Cl
V Λ- NIICOCH,

Cl

-OisoC H _η

-O-

NV-CH.

CH,

CIL

CH,

CH,

CH,

CH,

^CII 3

OPHGSNAl INSPE0TH3

R-

^CH 3

CH.

CH,

CIL

CH,

CH

CH

CH,

CH ".

CH,

'-51 "

Melting or boiling point in ⁰ C

67-68 (MeOH-HO )

97-99 (it ₂ 0 petrolather)

110-112 (Ät ₂ 0 petroleum ether) 122-124 (Ät ₂ 0 petroleum ether)

"7 5-77. (MeOH-H ₂ O)

168-170 (0.2mm)

"68-69 (MeOH-H ₂ O)

202τ206 (MeOH)

19 7 r 200 (1 mm)

130-133 (It ₂ O petroleum ether)

47-49 (pentane) 309) 326/1 1 B8

40

! 41

42 43

44 45

46 47 '48 49

50 51

ΓΛ-ci

Cl

CH ₃ S

-CH.

-CH (C ₆ H)

COOCH,

Br

CH ₀ O 3 '

// Vci

OH

OCH "CH = CH,

COOC ₂ H ₅

CH,

CIL

CIL

CK,

CH.

CII,

CIL

CII.

CH ₃ I.

CH,

CH,

CH,

CH,

CH,

CH.

CH,

CH,

1Ο4-1Ο5 (ÄtgO-Betroläther)

125-127

117-119 (It ₂ O petroleum ether)

79-8O, 5

64-66 (MeOH) 106-107

88-90.5 96-97 (MeOH-HO) 96-98.5 (MeOH) 167-172 (O, 2 well)

55.5 - 56.5 (MeOH-H ₀ O) 48-50 (MeOII-H ₂ O)

'309826/1158

ORIGINAL INSPECTED

ocn

Y \

Cl '

, Cl

CH.

Ή.

Cl, .Cl

J /

-co

OiSOC ₃ II ₇

Cl

FX egg

nc

9

CIL

CH,

CH,

CH,

CIL

CIL

CIL

CH.

CtL

CIL

CH,

CH,

CH-

CtL

CH,

CH

CH, lciimelz- or Koclip-ankt in C 163-168 (0.5

88-89 (MeOII)

=? 1.5642

261965

72-73. (MeOII-H ₀ C) from 67 to 68.5 (MeOH)

69-70 (MeOH-H ₀ O)

131-133 (pentane) 66-67 (MeOH-II ₀ O).

164-167 (0.1 mm)

87-89 (MeOH-H ₀ O) 178-179 (pentane)

112 (0.4 mm) η _η ° = 1.4979

ORIGINAL INSPECTED 309 8 26 / .1 158

63

64 65

67

! • ¹ V- ■ * ^K 3 • Tendon ?, ζ - or Koohpunkt -in ^R i
I. ^{£ H} 3 CIi ₃ ■ CH ₃ Ö5-86f I.
' CM
-C ^{C: i} 3 ^ai 3 CII ₃ 91-92 i .
(MeOII) CiI ₃ ^CII 3 , I. CH ₃ 'U * CH CH ₃ ^CT 3 58-60 (MeOII) O- ^C \ . 59-60; (MeOII-II ₂ O) CH ₃ CH ₃ 63-65 (MeOII) CII ₃ a
• 30th 9826/1158 *
i

Claims (1)

V1 .) Derivatives of pyrroacetic acid and its salts, in particular its alkali metal and alkaline earth metal salts and also acidic amino alcohols and amines, according to the general formula L ·. in the R; - an optionally by hydroxyl, phenyl or heterocyclic Groups such as furan-substituted alkyl radical with "Ibis 4 carbon atoms, a cycloalkyl radical with 5 to 6 C atoms, an alkenyl radical with 5 to 4 C atoms benzoyl radical optionally substituted by "a halogen atom, ■ a heterocyclic radical such as a pyridine radical, an optionally substituted by alkyl radicals with 1 to ^ carbon atoms, halogens, Alkoxy radicals with 1 to 5 carbon atoms, alkylthio radicals with 1 up to 5 carbon atoms, amino groups, trifluoromethyl radicals, Hydroxyl groups, carboxymethyl groups and alkanyloxymethyl groups or groups formed from various combinations of these radicals and groups, such as alkylhalogen or alkoxyhalogen group-substituted phenyl radical, R ^ and R ^, the. same or 30 9 826/1158 2251965 can be different * a lower alkyl radical, a fSgf. phenyl radical substituted by a lower alkyl radical or preferably in para position by a halogen atom and R ^ is a lower alkyl radical or V / aa-carbon, but ^ Rp and R * are not at the same time a ethyl radical »if E ^. an unsubstituted phenyl radical and R 'is hydrogen are una ^ K, if Rp and Eu both in a no Fiiiastellun .ietn.yl "or Pnenylreab is, by chloro substituted phenyl and B are $ ₁₄ Wasserstoi'f!. 2 * derivatives according to claim 1, characterized » dna R ^ a ^ -Chlorophstiyl-, p-BrouiiJhenyl-, p-Fluororphsnyl-i m-Gnlorphenyl ^» lower AlKOxy * ödsr 2 ¹ ,, ^ '-DimothylphQnylrest, R ^ and ti. each is a Uöthylrest and R ^ Waseefstoff or a Methylrest * 3. derivatives according to claim 1 _1, characterized in that de ^ R ^ is a chloropnenyl oaer fluorophonyl radical, H «a methyl radical, R ^ a phenyl or p ^ MifJhylphenylrest and R ^ is hydrogen. ^ 4 derivatives according to claim 5, characterized in that duii it is an i-psäure. 5 · derivatives of pyrrole acetonitrile according to def formula COCK 3 0 9 8 2 6/1158 in over R., an alkyl radical with 1 to 4 carbon atoms, a cycloalkyl radical with 5 to 6 carbon atoms, an alkenyl radical with j>, optionally substituted by hydroxyl, phenyl or heterocyclic groups such as furan up to ^ carbon atoms, a benzoyl radical possibly substituted by a halogen atom, a heterocyclic radical such as pyridine, an optionally substituted by alkyl radicals with 1 to 4 carbon atoms, halogens, alkoxy radicals with 1 to 5 carbon atoms, alkylthio radicals phenyl radicals substituted with 1 to 5 carbon atoms, amino groups, trifluoromethyl radicals, hydroxyl groups, carboxyniethyl radicals and alkenyloxymethyl radicals, or groups formed from different com′biiiies of these radicals and groups, such as alkylhalogen groups or alkoxyhalogen groups, Rp and Ή, -, which are the same as or may be different, a lower alkyl radical, a phenyl radical optionally substituted by a lower alkyl radical or preferably in the para position by a halogen atom, and R ^ is a lower alkyl radical or hydrogen. 6. A process for the preparation of the derivatives of pyrrole acetic acid and its salts according to claim '], characterized in that dais a connection after the general Formula - CH-Y 3 0 9 8 26/1158 in the Ii ^, R ,, E-, una R. aie given meanings have una Y "either -Ci ¹ J, -COoH ₁ -J-COi ⁴ IHp or -C (S) AIi H., where Rc" R and R ₁ ^ are alkyl radicals with 1 to 4 carbon atoms and R, - and R--, with the nitrogen atom can also form a heterocyclic ring of the piperidine or wörphoüntyp, is hydrolyzed. 7. The method according to claim 6, characterized in that »j uie hydrolysis of the compound according to formula (II) in an alcoholic solvent at a temperature stacc-.finds, aie zv / iscnen the ambient temperature and the reflux temperature of the solvent. 8. A process for the preparation of the derivatives of Pyrrolace.fconitril according to Claim 5, characterized by a fjtrrole of the formula Pyr-CHpiI (R _r i) p, in which R, a lower one, substituted in 1, 2 a ^ - '^ position Is alkyl radical or bilaet with the nitrogen atom an unsaturated heterocytic ring of the piperidine or driorpholine type, the action of an alkyl halide and then the quajiternary salt obtained in this way is exposed to the action of an alkali metal cyanide. 9. Process for the preparation of the derivatives of pyrrole acetonitrile according to claim 5 »characterized in that an aldehyde of the formula Pyr-CHO or a pyrrole ester of the formula Pyr-COOR, in which R ^ is an alkyl radical means, is reduced, that the alcohol thus obtained is exposed to the action of a halide, so that a compound of the formula Pyr-CHpX is formed, 309826/1158 BATH in viol ' Ά a lluloge-n iat, and dau> cmalieh hurry so. he kept in touch with vain allcalimetalcyahid üm ^ se tat 10 * PhariiiazeutiSGhes Produlft ₄ thereby! Jökejanzeidhtie.t _t . d & ii. it at least, a compound flat of the general formula (i) nacii claim ^ ehthal-t ». 11. * Use of compounds according to claim 1 - as well as-aga pnuriuasäeutiisGhen. froaukts according to claim 10, as. painkiller _v eritzündungshemmendss and iLeber senlcendes iuittel alone or in conjunction with änderen j is a similar or different Wirküfig have agents. "- · ■ 12 »VervrencLung according to claim 11 _s characterized- that Ö-ie administration in daily doses of 50 to $ ÖDO with the compounds according to claim 1 e £ follows * · 0 9 8 2 6/1158 BATH ORIGINAL