DE1937869C3 - 2-alkyl-4,5-diphenylpyrrole derivatives - Google Patents

Description

(II)

in which R has the meaning given in claim 1 and X 'and Y' can be identical or different and each represents a methoxy group or a chlorine atom, where at least one of the substituents X ' and Y 'is a methoxy group.

3. 2-methyl-4,5-bis (p-methoxyphenyl) pyrrole.

4. Medicament consisting of a compound according to any one of claims 1 to 3 and one inert, non-toxic carrier, diluent or coating.

in which R has the abovementioned meaning and X 'and Y' can be identical or different and are each one Methoxy group or a chlorine atom, where at least one of the substituents X 'and Y' is a Is methoxy group.

In the formulas (I) and (II), the radical R can be a straight or branched-chain lower alkyl group, z. B. a methyl, ethyl, n-propyl, isopropyl, η-butyl or isobutyl group.

ίο It was unexpectedly found that the invention Compounds high anti-inflammatory activities and an extremely low one Have toxicity to humans and a low tendency to produce side effects.

So far only 2,3-diphenyl-5-methylpyrrole and 2,3-bis- (p-methoxyphenyl) -pyrrole are in Australian Journal of Chemistry, Vol. 19, p. 1871 (1966), and in Journal of Medicinal Chemistry, Vol. 9, p. 527 (1966),

supra, without disclosing anti-inflammatory activity for these compounds. Rather, according to the Journal of Medicinal Chemistry, it has been known that 2,3-bis (p-methoxyphenyl) pyrrole has no anti-inflammatory activity.

The medicaments according to the invention consist of one of the 2-alkyl-4,5-diphenylpyrrole derivatives according to the invention and an inert non-toxic

Carrier, extender or coating.

These drugs can generally be administered orally in unit dosage forms such as tablets or capsules. Although the optimal doses of the 2,4,5-trisubstituted pyrroles according to the invention depend on the particular compound used and the particular type of disease, the total daily dose for adults is about 50 to 500 mg, preferably in multiple administrations, such as three times a day .
Examples of compounds according to the invention are:

The invention relates to 2-alkyl-4,5-diphenylpyrrole derivatives of the general formula I.

(D

in which X is a hydrogen or chlorine atom, a methyl, Methoxy or dimethylamino group, Y a methyl, methoxy or dimethylamino group or represents a chlorine atom and R represents a lower alkyl group.

Preferred 2-alkyl-4,5-diphenylpyrrole derivatives according to of the invention are those of the general formula

(II)

2-methyl-4,5-bis (p-methoxyphenyl) pyrrole,
Melting point 127.5 to 128.5 ⁰ C,

2-ethyl-4,5-bis- (p-methoxyphenyl) -pyrrole,
Melting point 152 to 153.5 ° C;

2-methyl-4- (p-chlorophenyl) -5- (p-methoxyphenyl) pyrrole,
Melting point 112.5 to 113.5 ⁰ C;

2-methyl-4- (p-methoxyphenyl) -5- (p-chlorophenyl) -pyrrole,
Melting point 78 to 82 ° C;

2-n-butyl-4,5-bis- (p-methoxyphenyl) -pyrrole,
Melting point 85.5 to 87.5 ° C;

2-isobutyl-4,5-bis- (p-methoxyphenyl) -pyrrole,
Melting point 119 to 120.5 ⁰ C;

2-n-propyl-4,5-bis (p-methoxyphenyl) pyrrole,
Melting point 101.5 to 102 ⁰ C;

2-methyl-4,5-bis (p-methylphenyl) pyrrole,
Melting point 104.5 to 105 ⁰ C;

2-methyl-4- (p-dimethylaminophenyl) -5- (p-melhoxyphenyl) pyrrole,
Melting point 190.5 to 191.5 ⁰ C;

2-methyl-4,5-bis (p-dimethylami nopheny l) pyrrol,
Melting point 110.5 to 112 ° C;

2-methyl-4,5-bis (p-chlorophenyl) pyrrole, Melting point 132.5 to 133.5 ° C;

2-methyl-4-phenyl-5- (p-chlorophenyl) -pyrroI, Boiling point 173 to 176 ° C / 0.05 mm Hg;

2-methyl-4-phenyl-5- (p-dimethylaminophenyl) pyrrole,
Melting point 138.5 to 140.5 ⁰ C;

2-methyl-4-phenyl-5- (p-methoxyphenyl) pyrrole, Melting point 131 to 132 ° C.

10

The following test results apparently show that the compounds according to the invention have very strong anti-inflammatory activities and have extremely low toxicities.

Anti-inflammatory activity in rats

The anti-inflammatory activity is caused by the inhibition time of paw edema in rats by injecting a 1% carrageenin suspension after oral administration of the test Connection, measured. A volume of 0.05 ml of a suspension of Kanagenin in a saline solution is made Injected subcutaneously in the area of the sole of the foot of the hind paw 30 minutes after the administration of the drug.

The volume of the foot is measured before and 3 hours after the injection of carrageenin. the The degree of inhibition is calculated according to the following equation:

% Inhibition = / K 3 hours U _ Λ _ / Γ 3 hours T _ \ \ V vor- UJ \ V \ orf)

/ V3Std.U _ \ \ V \ otU ')

¥ before · U: The volume of the foot of the untreated group before the injection of carrageenin.

V 3 hrs. U: The volume of the foot of the untreated group 3 hours after the injection of carrageenin.

V before * T: = The volume of the foot of the treated

Group before injection of carrageenin.

V 3 hrs. T: The volume of the foot of the treated

Group 3 hours after injection of carrageenin.

The results are summarized in Tables I and II. In Table I the results are expressed as percent inhibition be ^! a certain dose, ICO mg per kg of body weight. In Table II, in which the most active compounds are listed, the anti-inflammatory effectiveness of the same is expressed by the values ED ₅₀ , namely the dose which is required for a 50% inhibition of the edema.

acute toxicity

The acute toxicity is determined after oral administration of the test compound to mice by the Number of animals that died within a week is determined.

The lethal efficacy is expressed as xjn, where χ is the number of animals that died and η is the total number of animals examined. The results are given in Table I.

Table I.

Anti-inflammatory effectiveness and acute toxicity of compounds according to the invention after oral

Administration.

connection

Inhibition of

Carrageenin

edema (% inhibition,
100 mg / kg)

acute toxicity
dose

(rag / kg)

x / n

2-methyl-4,5-bis (p-methoxyphenyl) pyrrole

2-ethyl-4,5-bis- (p-methoxyphenyl) -pyrrole, 2-methyl-4- (p-chlorophenyl) -5- (p-methoxyphenyl) -pyrrole 2-methyl-4- (p-methoxyphenyl) -5- (p-chlorophenyl) -pyrrole, 2-n-butyl-4,5-bis- (p-methoxyphenyl) -pyrrole 2-isobutyl-4,5-bis- (p-methoxyphenyl) -pyrrole, 2-n-propyl-4,5-bis- (p-methoxyphenyl) -pyrrole 2-methyl-4,5-bis (p-methylphenyl) pyrrole, 2-methyl-4- (p-dimethylaminophenyl) -5- (p-methoxyphenyl) pyrrole

2-methyl-4,5-bis- (p-dimethylaminophenyl) -pyrrole, 2-methyl-4,5-bis- (p-chlorophenyl) -pyrrole 2-methyl-4-phenyl-5- (p-dimethylaminophenyl) -pyrrole, 2-methyl-4-phenyl-5- (p-chlorophenyl) -pyrrole

72 900 υ / 5 (LD ₅₀ : 3500) 62 900 0/5 58 900 0/5 57 900 0/5 55 900 0/5 55 900 0/5 52 900 0/5 47 900 0/5 39 900 0/5 36 900 0/5 34 900 0/5 32 900 0/5 32 900 0/5 55 (LD ₅₀ : 490)

Table II

Anti-inflammatory effectiveness of compounds according to the invention, expressed as ED ₅₀ .

connection

ED _M (dose mg / kg required for 50% inhibition of carrageenin edema

i-methyl-4,5-bis (p-methoxy-7

phen ^ O-pyrrole

j-ethyl-4,5-bis- (p-methoxy- 24

phenyi) pyrrole

2-methyl-4- (p-chlorophenyl) - 52

5- (p-methoxyphenyl) pyrrole

2-methyl-4- (p-methoxyphenyl) - 74 S- (p-chlorophenyl) pyrrole

2-n-butyl-4,5-bis- (p-methoxy-80

phenyO-pyrrole

2-isobutyl-4,5-bis- (p-methoxy-84 phenyO-pyrrole

Phenylbutazone 76

Examples of these inert organic solvents are hydrocarbons such as benzene, toluene and xylene; lower alkanols such as methanol and ethanol; cyclic ethers such as dioxane and tetrahydrofuran, and lower aliphatic carboxylic acids such as acetic acid and propionic acid. Most suitably, a lower aliphatic carboxylic acid such as acetic acid is used.
The ammonia used can be considered as ammonia

ίο be such or an ammonium salt of a weak one Acid capable of supplying ammonia in the reaction system. Examples of these ammonium salts are ammonium carbonate, ammonium acetate, ammonium formate, ammonium oxalate and

Ammonium cyanate Usually ammonium acetate is used used because it is easily available and stable. The reaction temperature at this stage is not critical, but it has been found that the reaction in this stage is accelerated favorably by heating

ao can be. Conveniently the reaction is carried out at the reflux temperature of the reaction solvent used, and if no reaction solvent is used, it is advantageous to the reaction at a temperature of about 100 to 150 ⁰ C.

Way by reacting a benzoin derivative of the general Formula III

OH

(III)

where X and Y have the meaning given, with ammonia and a keto compound of general Formula IV

H ₂ C Z O = CR

(IV)

wherein R has the meaning given and Z is

The 2-alkyl-4,5-diphenylpynol derivatives of the general carry out.

my formula (I) is obtained in a manner known per se. The reaction time is also not critical, and

it can be varied, for example from 1 hour to 5 hours, depending on the type of used Starting material and the reaction solvent used, the reaction temperature used and other factors.

After the reaction has ended, the intermediate (V) can be removed from the reaction mixture by customary means "Methods are easily obtained. For example, the reaction product can be obtained by the reaction mixture is poured into ice water and the precipitate formed is separated off by filtration. If the desired product does not separate or separates out only incompletely, the reaction product can by extraction with a suitable extraction solvent such as benzene, by washing and drying the extracts and then removing the extraction solvent. If desired, the raw

an esterified carboxyl group such as methoxycarbonyl, 45 product purified by one of the usual methods Ethoxycarbonyl, phenoxycarbonyl and benzyloxy are, for example by recrystallization or carbonyl; a cyano group or a carbamoyl by means of chromatography.

group which can be alkyl or phenyl substituted, The conversion of the compound (V) thus obtained

is, and then heating the so obtained into a compound of the invention of the general 3-substituted pyrrole of the general formula V 50 Formula I can by heating the compound (V) with

an acidic or an alkaline substance are carried out in the presence of an inert solvent, with hydrolysis and decarboxylation occurring. Water and aqueous organic solvents can be used as solvents Solvents such as aqueous ethanol and aqueous dioxane can be used. Examples of the in Acidic substances used at this stage are mineral acids such as sulfuric acid and hydrochloric acid, and strong organic acids such as benzenesulfonic acid and

where X, Y, R and Z have the meaning given being 60 p-toluenesulphonic acid.

sit, with an acidic or an alkaline sub- Examples of the alkali resistance used in this stage, see substance are alkali metal hydroxides, such as Na-

In the production of the compound (V) from the verium hydroxide and potassium hydroxide, as well as earth bonds (III) and (IV) are preferably used in alkali metal hydroxides, such as calcium hydroxide and the presence of Ba an inert organic solvent. 65 rium hydroxide.

Any organic solvent can be used as the solvent

solvents are used, which the reaction 80% aqueous sulfuric acid,
not adversely affected at this stage. The reaction temperature at this stage is not

(V)

critical, but it is convenient to carry out the reaction at a temperature of about 80 to 140 ⁰ C, if an acidic substance is used and at about 100 to 250 ° C, if an alkaline substance is used.

The reaction time is also not critical and it depends largely on the nature of the reactants and the reaction temperature used. When an acid is used, the reaction time is about 15 minutes to 5 hours. When an alkaline substance is used, the reaction time is about 10 hours to 48 hours.

After the reaction has ended, the desired compound of the formula (I) can be extracted from the reaction mixture can be obtained by conventional methods. For example, the reaction product is obtained by pouring the reaction mixture into ice water and the precipitate formed through Separation by filtration. If the desired product does not separate or is only incompletely deposited, it can Reaction product by extraction of the desired product with a suitable extraction solvent, such as benzene, washing and drying the extract and then removing the extraction solvent. If desired, the crude product thus obtained can by one of the usual methods, such as recrystallization or chromatography, getting cleaned.

The following examples are intended to explain the preparation of the compounds according to the invention in more detail.

A) Preparation of the intermediate products
of the general formula V:

2-methyl-3-ethoxycarbonyl-4,5-bis (p-methoxyphenyl) pyrrole

9.5 g of ethyl acetoacetate and 15 g were added to a solution of 12.9 g of p-anisoin in 100 ml of acetic acid Ammonium acetate added. The mixture obtained was heated under reflux for 2 hours. To Completion of the reaction, the reaction mixture was poured into 1.5 l of ice water and 1 hour ditched. The precipitate formed was separated off by filtration, successively with water, washed with an aqueous solution of sodium bicarbonate and water and dried in a dryer, whereby 16.4 g of the desired product were obtained as a crude crystalline substance. This was made with activated charcoal Purified in 95% aqueous ethanol and recrystallized from aqueous ethanol, whereby one the pure product was obtained as white needles which melt at 136.5 to 138 ° C.

Analysis values for C _n H ₂₃ O ₄ N:

Calculated ... C 72.31, H 6.34, N 3.83%;
Found ... C 72.18, H 6.30, N 3.89%.

By the same procedure, the following pyran compounds were obtained from the corresponding benzoin derivatives produced with good yields:

2-methyl-34 «iizyloxycarbonyl-4,5-bis-
<p ^ methoxypb.enyl> pyrrole,
Melting point 118 ° C;
Aib

phenyQ-ipyiiol,
Melting point 137 to 140 "C;

2-n-propyl-3-ethoxycarbonyl-4,5-bis- (p-methoxy-

phenyl) pyrrole,

Melting point 103 to 104.5 ° C;
2-n-Butyl-3-ethoxycarbonyl-4,5-bis- (p-methoxyphenyl) -pyrrole,

Melting point 94 to 95.5 ⁰ C;
2-methyl-3-ethoxycarbonyl-4-phenyl-5- (p-methoxyphenyl) pyrrole,

Melting point 168 to 170 ⁰ C;
ίο 2-methyl-3-ethoxycarbonyl-4,5-bis- (p-methyl-

phenyl) pyrrole,

Melting point 162.5 to 163.5 ° C;
2-methyl-3-ethoxycarbonyl-4,5-bis (p-chlorophenyI) -

pyrrole,
is melting point 198 to 201 ^c C;

2-methyl-3-ethoxycarbonyl-4- (p-methoxyphenyl)

5- (p-chlorophenyl) pyrrole,

Melting point 206 to 208 ⁰ C;
2-methyl-3-ethoxycarbonyl-4-phenyl-5- (p-dimethylaminophenyO-pyrrole,

Melting point 172.5 to 174.5 ° C;
2-methyl-3-ethoxycarbonyl-4,5-bis (p-dimethyl-

aminophenyl) pyrrole,

Melting point 226.5 to 228.5 ° C;
as 2-methyl-3-ethoxycarbonyl-4- (p-chlorophenyl) -

5- (p-dimethylaminophenyl) pyrrole,

Melting point 195 to 197 ° C;
2-methyl-3-phenylcarbamoyl-4,5-bis (p-methoxy-

phenyl) pyrrole,
Melting point 198 to 199 ° C;

2-methyl-3-carbamoyl-4,5-bis (p-methoxyphenyl) pyrrole,

Melting point 219.5 to 220.5 ⁰ C;
2-methyl-3-cyano-4,5-bis (p-methoxyphenyl) pyrrole,

Melting point 180 to 181 ⁰ C;
2-methyl-3-cyano-4,5-bis (p-chlorophenyl) -pyrroi,

Melting point 267-269 ° C.

example 1

2-methyl-4,5-bis (p-methoxyphenyl) pyrrole

(1) 10 g of 2-methyl-3-ethoxycarbonyl-4,5-bis (p-methoxyphenyl) pyrrole were added to 150 ml of 80% strength aqueous sulfuric acid. The mixture obtained was ^{stirred at 80 °} C. for 10 minutes. After the reaction had ended, the reaction mixture was poured into 300 g of ice water. The precipitate formed was separated off by filtration, washed with water and dried, 6.7 g of the desired product being obtained as a crude crystalline substance, which was recrystallized from a mixture of benzene and petroleum ether to give colorless prisms received, the zen-melting, at 127.5 to 128.5 ⁰ C.

Analysis values for C ₁₉ H ₁₈ OgN:
Calculated ... C 77.79, H 6.53, N 4.77%;
found ... C77.89, H6.48, N4.78%.

(2) To 6 ml of 80% aqueous sulfuric acid was added 0.5 g of 2-methyl-3-phenylcarbamoyl-4,5-bis (p-methoxyphenyl) pyrrole ⁰ C. After the reaction had ended, the reaction mixture was poured into 15 g of ice water. The precipitate formed was filtered off and washed with water. The obtained crystalline substance was dissolved in benzene, the insolubles were through

609620/121

Filtration removed and the solvent was distilled off. There remained 0.2 g of the desired product, which is then from a mixture of benzene and Petroleum ether was recrystallized to give colorless prisms which melt at 127.5 to 128.5 ° C.

Example 2

2-methyl-4,5-bis (p-chlorophenyl) pyrrole

0.3 g of 2 - methyl - 3 - cyano - 4.5 - bis (p - chlorophenyl) pyrrole were added to 5 ml of 80% strength aqueous sulfuric acid. The mixture obtained was ^{heated to 130 °} C. for 2 hours. After the reaction had ended, the reaction mixture was poured into 10 g of ice water. The mixture was extracted with benzene. The benzene extract was sequentially using

Water, a saturated aqueous solution of sodium bicarbonate and water, dried over anhydrous sodium sulfate, and then there! Solvent distilled off. , Was recrystallized from a mixture of ether and petroleum ether which was a pale brown prisms obtained which melt at 132.5 to 133.5 ⁰ C to give 0.1 g of the desired product as a crystalline ge · substance au.

Analysis values for Ci ₇ H _{13 NCl 2} :

Calculated ... C 67.57, H 4.33, N 4.61, Cl 23.46% found ... C 67.33, H 4.58, N 4.36, Cl 23.27%

Analogously to the reactions described in Examples 1 and 2, the corresponding reactions were obtained Intermediate compounds of the general formula V include the other compounds according to the invention listed at the outset Links.

Claims (2)

Patent claims: 1. Z-AlkyM.S-dipb.enylpyrrole derivatives of the general Formula I. (D in which X is a hydrogen or chlorine atom, a methyl, methoxy or dimethylamino group, Y is a methyl, methoxy or dimethylamino group or a chlorine atom and R is a lower one Means alkyl group. 2. Compounds according to claim 1 with the general Formula II