DE2605419A1 - 3-AMINO-4-CARBAMYLPYRROLE DERIVATIVES AND PROCESS FOR THE PREPARATION - Google Patents

Description

LAWYERS 2 6 O 5 4 Ί

DR. JUR. γ ·· '.- """M. WALTER BEIL β« -,

i.-. = .. · ..-. '- ■ -, HL WOLFP DK. } .. ΐ · ... . · ■.:.:. Ci.2. ütii.

FkA: · -. <; ^: U RTAM MAJ H - HIGH?

Our no. 20 366 Pr / br

Gruppo Lepetit S.p.A. Milan / Italy

3-Amino-4-carbamylpyrrole derivatives and methods too their manufacture

The invention relates to 3-amino-4-carbamylpyrrole derivatives general formula

wherein R is a hydrogen atom, a (C _1-11 ) AIlCyI, benzyl or halogen-substituted benzyl radical, R ^{A is} a hydrogen atom,

6098 8 2/1203

a (C _1-1 J) alkyl, phenyl or phenyl radical substituted by 1 to 3 radicals, the radicals being independent of one another

, Benzyloxy, fluorine, chlorine, bromine or

₁ y

Are hydroxy,

R is a hydrogen atom, a (C _1-1 J) alkyl, formyl, ( ^c ₂ _i | ^ ~ aliphatic acyl, benzoyl, carbamyl, phenylcarbamyl, (C _1-1 J) alkylsulfonyl, benzenesulfonyl -, toluenesulfonyl or phenacylsulfonyl radical,

R · ^ a hydrogen atom or a (C ₁ ^ alkyl radical, or

2 3 J - * t

R and R ^ together a (C _2-11 ) alkylidene, benzylidene or Holgen-substituted benzylidene radical, R and R ^ independently of one another a hydrogen atom, a (Cp _-1 J) alkyl or substituted phenyl radical, but not simultaneously hydrogen or together with the adjacent nitrogen atom form a dimethylamino radical or a 5-6-membered heterocyclic ring which can contain a further oxygen or nitrogen atom and which is optionally _{substituted by 1 to 3 (C 1-1} J) alkyl radicals or a phenyl radical, and

R is a (C _1-1 J) alkyl radical,

their salts with pharmaceutically acceptable acids and a process for their preparation.

In the description and claims, the expression ¹¹ (C _1-1 J) alkyl "means an alkyl radical with 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl; the expression" (C ₂ _ii) Alkyl "means the same radicals with the exception of methyl; the term" halogen-substituted benzyl "means essentially a benzyl radical which is substituted on the aromatic ring with fluorine, chlorine or bromine, such as, for example, p-chlorobenzyl, o-chlorobenzyl , p-fluorobenzyl,

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o-bronbenzyl and m-bromobenzyl; the term "substituted phenyl" means phenyl radicals which are substituted by 1 to 3 groups which, independently of one another, are (C _1- ^) AlkYl, (C _1- U) AlkOXy, fluorine, chlorine, bromine, hydroxy, nitro, amino, ( Cp _-1 ,) aliphatic acylamino, Ca ^ o (C _1- ^) alkoxy, carboxy, carbamyl or trifluoromethyl; the expression “(C _2-11 ) aliphatic acyl” relates to an aliphatic acyl radical having 2 to k carbon atoms, such as acetyl, propionyl, butyryl or isobutyryl; "(C _1-1 J) AlkOXy" relates to alkoxy groups with 1 to 4 carbon atoms, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy; a "(Cpn) alkylidene" radical essentially means ethylidene, propylidene, isopropylidene, butylidene or isobutylidene; the term "halogen-substituted benzylidene" means a benzylidene radical which is substituted on the aromatic ring with chlorine, fluorine or bromine, such as, for example, o-chlorobenzylidene, m-chlorobenzylidene, p-chlorobenzylidene, p-fluorobenzylidene, o-fluorobenzylidene or m- Bromobenzylidene.

A preferred group of compounds relates to compounds of the formula I in which R is a hydrogen atom, a benzyl or a halogen-substituted benzyl radical, R a phenyl radical,

ρ
R is a hydrogen atom, a (C.jj-alkyl radical, a (C ₂ h) -aliphatic acyl radical or a toluenesulfonyl radical, R ^ is a hydrogen atom or a (C _1-1 .) Alkyl radical, R and R ^ independently of one another are a hydrogen atom, a ( Cph) alkyl or a _{phenyl radical substituted with (C 1-11} ) alkYl, (C _2-1} ) aliphatic: acyl, (C _1-11 ) alkOXy, halogen, carboxy, carbο- (C ^ ^) alkoxy or trifluoromethyl , but not at the same time hydrogen or together with the neighboring nitrogen atom form a dimethylamine, piperidino, morpholino, (C ₁ njAlkylpiperazino- or phenylpiperazino radical and R has the above meaning and their salts with pharmaceutically acceptable acids.

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A second preferred group of compounds relates to those compounds of the formula I in which R is a hydrogen atom, R is a phenyl radical, R is a hydrogen atom, a (C _1-2 ) alkyl, (C ₀ ι.) Aliphatic acyl or toluenesulfonyl radical, R ^ a hydrogen atom or a (C _1-1 ,) alkyl radical, R and R ³ independently of one another a hydrogen atom, a (C _2-1 ^) alkyl, an acyl with (C ^ alkyl, (C ^) aliphatic , (C _1-14 ) AlkOXy, halogen, carboxy, carbo (C _1-1 .) Alkoxy or trifluoromethyl-substituted phenyl radical, but not at the same time hydrogen or, together with the adjacent nitrogen atom, a dimethylamino, piperidino, morpholino, (C _1-1 ^) - Form alkylpiperazino or phenylpiperazino and R has the above meaning
compatible acids.

R has the above meaning and its salts with pharmaceutical

Another preferred group of compounds relates to those Compounds of formula I wherein R, R and R ^ a

1 U ζ

Hydrogen atom, R a phenyl radical, R and R ^ independently of one another a hydrogen atom, a (Cp _-1 ,) alkyl-, with (C _1-2i ) alkyl, (C ₂ -Ij) aliphatic acyl, (C _1-1 ^ ) AlkOXy, halogen, carboxy, Ca ^ o (C _1-1 .) Alkoxy or trifluoromethy ^ substituted phenyl radical, but not at the same time hydrogen or, together with the adjacent nitrogen atom, a dimethylamino, piperidino, morpholino, (C,.) Form alkylpiperazino or phenylpiperazino radicals and R denotes a methyl radical, and their salts with pharmaceutically acceptable acids.

The compounds of the invention are prepared by a 3-amino-4-carboxy-pyrrole derivative of the general formula

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COOH

II

or an acid addition salt thereof, in which R _3, R and R are as defined above, is reacted with carbonyl chloride and the intermediate product of the general formula which is formed in the process

If

III

wherein R, R and R have the preceding meaning, with a molar excess over the starting compound of the formula II of an amine of the formula

HN

Ii κ
converts, in which R and R have the preceding meaning, under

ρ · τ.

Obtaining compounds of the formula I in which R and R are V / ater st off mean atom and R, R, R ^ and R above

Have meaning. If compounds of the formula I are desired,

• 2 3

where R and / or R ^ do not mean a hydrogen atom, they will by common methods as described below, obtain.

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According to a preferred embodiment of the process according to the invention, a molar amount of the starting compound of the formula II is dissolved in an anhydrous inert organic solvent, preferably dioxane or tetrahydrofuran, although many other solvents, such as halogenated hydrocarbons having 1 to 4 carbon atoms, are also expediently used can. The resulting solution is heated to about 40 to 70 ⁰ C while allowing bubbled about 1 to 3 hours, the phosgene in this solution. The unreacted phosgene is preferably removed from the reaction mixture by a stream of dry nitrogen.

The intermediate of formula III obtained, which can be regarded as the anhydride of a 3- (N-carboxamino) -4-pyrrolecarboxylic acid and formally a 4H, oH-pyrrole / l ", 4-d7 (l, 3) oxazine-2 (1H) _a 4-dione derivative can optionally be isolated and characterized, but can also be used as a crude product for the subsequent condensation stage with the selected amine of the formula

HN

be used. This step is carried out by dissolving the anhydride of the formula III .. in a suitable organic solvent, which is preferably a halogenated hydrocarbon having 1 to 4 carbon atoms. The resulting solution is added to the amine-containing solution or to the amine itself, if it is a liquid substance. The amine is used in a molar ratio corresponding to approximately 3 to 10 times the molar amount of the starting material of the formula II. Suitable solvents for the amine are again halogenated hydrocarbons having 1 to k carbon atoms. The addition takes place at room temperature,

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-but the reaction mixture obtained is preferably about 1 up to about 3 hours to 30 to 40 ° C, possibly even up the boiling temperature is heated in order to accelerate the formation of the desired end product of the formula I.

2 3

Compounds of the formula I are obtained in which R and R are hydrogen. They are recovered from the reaction mixture by well known methods. These methods include removing the solvent from the reaction mixture by evaporation, taking up the residue in a solvent, re-evaporating the solvent and purifying the solid, liquid or oily substance thus obtained by column chromatography, recrystallization, fractional distillation or distillation under reduced pressure. If a crystalline solid arises directly from the reaction, it is simply recovered by filtration and, if necessary, purified by recrystallization. Solvents for recrystallization are preferably (C ₁ J-alkanols, diethyl ether, water

2 "3 or mixtures thereof. If the substituents R and R ^ are not to be hydrogen, they are introduced by known processes by reacting the compounds of the formula I with the appropriate reactants. For example, the reaction with (C ₁ i. ) Alky! Halides or

2 3 (C ₁ j.) Alkyl sulfates Compounds in which R and / or R

2 is (C _1-1 .) Alkyl. Compounds in which R is a (C j.) Aliphatic acyl radical or benzoyl radical are obtained by reaction with halides or anhydrides of (Cp _-1 .) Aliphatic or benzoic acids, whereupon the benzenesulfonyl, toluenesulfonyl, (C. ^ alkylsulfonyl and Phenacylsulfonyl groups can be introduced in a simple manner by reaction with benzenesulfonyl, toluenesulfonyl, (C ^ alkylsulfonyl or phenacylsulfonyl halides.

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The carbamyl and phenylcarbamyl groups are reacted

ρ -ζ

of the aminopyrrole of the formula I ₉ in which R and R ^ represent a hydrogen atom, introduced with an alkali metal isocyanate or phenyl isocyanate.

The replacement of one of the hydrogen atoms of the amino group in 3 ~ Positioning by Pormyl takes place by mixing a predetermined 3-aminopyrrole with formic acid in essentially equimolar amounts

ρ -z

Bringing amounts in contact, whereupon substances in which R and R together (CU ^ alkylidene, benzylidene or halogen-substituted Benzylidene mean easily according to the reactions as they are used to obtain Schiff's bases from amines and carbonyl compounds are known to be produced.

The sulfonylation of the amino group in the 3-position. also represents a suitable route for the preparation of compounds of the formula I in which R is a hydrogen atom and R ^ is a (C ₁ h) alkyl group. This route consists in alkylating the amine nitrogen of a compound of the formula I in which R is benzenesulphonyl, (CL ^ alkylsulphonyl, toluenesulphonyl or phenacylsulphonyl and R ^ is a hydrogen atom, by the usual processes for the alkylation of amines (CL,.) Group R, as defined above, is removed by hydrolytic cleavage with acids or by the method described by JB Hendrickson and R. Bergeron, Tetrahedron Letters, pp. 3-5, 1970, when R is a phenacylsulfonyl group.

The compounds of formula I can be used either as free bases or as the corresponding salts of pharmaceutically acceptable Acids are obtained.

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These salts essentially include the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, benzoate, oxalate, acetate, methanesulfonate, cyclohexylsulfonate and their analogues. These salts have the same degree of pharmacological activity as the free bases and are thus included in the invention. They are easily obtained by treating a compound of formula I as the free base with a certain pharmaceutically acceptable acid. On the other hand is it? ¹⁰ * =} ¹⁰ to release the free base from the corresponding acid salt by reaction with at least an equimolecular amount of a basic agent.

The starting amines of the formula HN are commercially available

Products or are manufactured by obvious modifications of commercially available products.

The starting compounds of the formula II are prepared by that one cc-aminonitrile in a first stage formula

CN
t

/ CHv V

R ¹ NH ₂

or an acid salt thereof, in which R has the preceding meaning (The compounds of the formula V are prepared according to the method as described by Steiger in Organic Synthesis, 22, 12, 1942 and 22, 23, 19 ^ 2 is described, prepared) with a ß-ketoester of the formula

CH ₂ -COO- (C _± _κ) alkyl

CO VI

, 6

R ¹
wherein R has the preceding meaning, condensed. The

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dende ß-aminopyrrole intermediate of the formula

VII Λ R ⁶

becomes the basic with the help of 10 ^ igem aqueous lithium hydroxide Subjected to hydrolysis, starting compounds of the Formula II is obtained in which R and R are as defined above and R is hydrogen. When starting materials of the formula II where R is (C. ^ alkyl, benzyl ^ or halogen substituted Is benzyl, the above amino ester of the formula VII is converted into the Schiff's base of the formula

00- (C ^ ₄ ) alkyl

VIII

• 7

converted, where R is a divalent radical which comes from the carbony compound used, such as benzylidene, p-chlorobenzylidene, butylidene, isopropylidene, ethylidene and their analogues. This substance is then reacted in an anhydrous medium at about 0 to 5 ° C. with sodium hydride and with a (C _1- Ji) alkyl, benzyl or halogen-substituted benzyl halide, a compound of the formula

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R.
obtained, wherein R and R have the preceding meaning and R

₁ Ji denotes benzyl or halogen-substituted benzyl. The product of the formula IX obtained, which can optionally be isolated and characterized, is subjected to acid hydrolysis, the corresponding starting substances of the formula II being formed.

A number of compounds according to the invention, namely those wherein R, R and R- * mean a hydrogen atom can can be advantageously prepared by another further process which consists in making the above α-aminonitrile of the formula V

CN

NH ₂

or an acid salt thereof with a β-ketoamide of the general formula

CH ₀ -CON

I ²

CO

converts, in which R, R and R have the preceding meaning.

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The β-ketoamides of formula X are prepared by conventional methods such as those described by Williams and Krynitsky, Organic Synthesis, 21, 4, 1941, and by Kaslow and Cook, Journ.Am.Chem. Soc., 67, 1969 , 19 ^ 5 , starting from diketenes of the formula

R ^f -CH-CO = C ■ R ' ⁶ -CH = O -O

XI

where R ¹ denotes an alkyl radical having 1 to 3 carbon atoms, and amines of the formula _R 4

The compounds of the formula XI are known compounds and are described by Wagner and Zook in Synthetic Organic Chemistry, Page 409, John Wiley and Sons, Inc., New York, 1965. The reaction between compounds V and X generally proceeds with the formation of an open-chain intermediate compound of the general formula XII or their tautomeric imine form

CON

Cl

XII

which can be isolated, purified and characterized, but generally as a raw material for the subsequent cyclization step is used.

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The reactants V and X are essentially equimolar Quantities in the presence of an anhydrous organic solvent, which is preferably benzene, dioxane, tetrahydrofuran or their analogues.

A small amount of toluenesulfonic acid or molecular sieves that act as catalysts and water blocking agents, is added to the reaction mixture, which takes about 2 to 28 hours is kept at temperatures between room temperature and reflux temperature.

The subsequent cyclization stage is carried out in the presence of basic agents such as alkali carbonates; -., Hydroxides, alkoxides, Hydrides or amides, in the presence of a solvent, which is preferably an anhydrous lower alkanol with at most 4 carbon atoms is carried out.

The cyclization can be done at room temperature, however it is sometimes necessary to apply some heat or that To heat the reaction mixture to reflux temperature to this Speed up stage, which is completed within 1 to 30 hours. The compounds of the formula I thus obtained, in which R, R and R represent a hydrogen atom, are used as free bases obtained or as the aforementioned salts of pharmaceutically acceptable acids by known methods such as described above, and can undergo the chemical transformations described above to introduce the substituents R and / or R ^ are subjected if one of both or both should not be hydrogen. Accordingly, compounds of the formula I in which R, R, R and R above Have meaning, R means a hydrogen atom and R and R- ^ have the above meaning, as free bases or obtained as the already mentioned salts of pharmaceutically acceptable acids.

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The compounds according to the invention are very interesting pharmacological properties, in particular, they are effective as anti-inflammatory agents, antipyretics and as prostaglandin synthetase inhibitors. In addition, some of them show interesting C.N.S. suppressive and antihypertensive properties and have a considerable degree of effectiveness on the hydric balance of warm-blooded animals.

The anti-inflammatory activity was determined with the aid of the "carrageenan-induced edema test" in rats, which was essentially carried out according to the method described by CA. Winter et al. in Proc.Soc. Expl.Biol.Med., 111, 544, 1962, proposed scheme. Representative examples have shown that the compounds of Examples 3 »4, 5 and 11 are particularly effective in this test, that is to say that they cause a percentage reduction in induced edema which is substantially greater than 30 when at doses far from that lethal dose are removed, ie at about 1/5 of the LD ₁ -Q. These LD 50 values are very favorable in that they are generally higher than 500 mg / kg po in mice.

The table below gives a more detailed summary of the above anti-inflammatory efficacy.

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T A BELLE ^ Reduction of the
induced edema link
from Bei
game LD ₅₀ mg / kg
po mice Dose mg / kg
po rats 16.9
30.0
45.9 3 1000 50
100
200 26.1 4th 1000 50 30.4 100 35.2 200 17.4
27.7
52.1 VJl 1000 50
100
200 20.0
28.0
35.2 I 11 500 20th
50
100

The compounds according to the invention can be via various Ways to be administered.

While the preferred routes of administration are the oral and rectal routes, parenteral administration can also be used can be applied. For oral administration, the compounds are formulated into pharmaceutical dosage forms » such as tablets, capsules, elixirs, solutions and the like. The dosage unit can contain the usual auxiliaries contain, e.g. starch, gums, fatty acids, alcohols, sugars, etc. For rectal administration, the compounds are in the form administered from suppositories, mixed with conventional carriers, such as cocoa butter, wax, spermaceti or polyoxyethylene glycols and their derivatives. The dosage range is between about 0.05 to about 2.00 grams per day, preferably administered in multiple doses.

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The invention thus also relates to a therapeutic agent that as an active ingredient a compound according to the invention together with a pharmaceutically acceptable carrier.

The following examples serve to further illustrate the invention.

example 1

3-Amino-4-diethylcarbamyl-5-methyl-2-phenyl-pyrrole hydrochloride

A) Carbonyl chloride was blown into a solution of 12.0 g (0.0556 mol) of 3-amino-4-carboxy-5-methyl-2-phenylpyrrole in 600 ml of anhydrous dioxane for about 2 hours, the reaction solution with vigorous stirring about 55 ° C was maintained. Nxchtumgesetztes carbonyl chloride was removed from the reaction mixture using a dry nitrogen stream, the reaction solution was cooled to room temperature _t and the solid thereby obtained was recovered by filtration and washed with hexane. Yield 7.3 g of the anhydride intermediate of the formula III, in which R is a hydrogen atom, R is a phenyl radical and R is a methyl radical, namely 5-methyl-7-phenyl-4H, 6H-pyrrolo £ 3,4-d7 (l, 3) oxazine-2 (1H), 4-dione; Melting point 247 to ⁰

B) A solution of 7 ₃ 0 g (0.029 mol) of the compound obtained according A) compound in 100 ml chloroform was added dropwise at room temperature 30 ml (0.29 mol) of diethylamine. After refluxing for 2 hours, the reaction mixture was evaporated to dryness and the residue obtained was taken up in 40 ml of diethyl ether. The ether solution was washed first with water and then with aqueous sodium bicarbonate and finally separated from the aqueous phase.

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The title compound of this example is obtained by bubbling gaseous hydrogen chloride into the ethereal solution. Yield 2.0 gj melting point 212 to 214 ° C. (from ethanol / diethyl ether).

Examples 2 to 18

The following compounds were prepared according to Example 1, starting from 3-amino-4-carboxy-5-πlethyl-2-phenyl-pyrrole hydrochloride and a selected amine of the formula

2) 3-Amino-4-ethylcarbamyl-5-methyl-2-phenyl-pyrrole hydrochloride. ^! Yield 35 % \ melting point 261 to 263 ^° C. (from ethanol / water).

3) 3-Amino-4-isopropylcarbamyl-5-methyl-2-phenyl-pyrrole, yield 33 %, melting point 197 to 198 ^° C. (from methanol).

4) 3-Amino-4- (p -chlorophenylcarbamyl) -5-methyl-2-phenyl-pyrrole hydrochloride.

Yield ^ 0 %; Melting point 231 to 233 ° C (from methanol / water).

5) 3-Amino-5-methyl-2-phenyl-4- (p-tolylcarbamyl) pyrrole hydrochloride

Yield 52 % \ melting point 250 ^° C. (with decomposition).

6) 3-Amino-4- (p-anisylcarbamyl) -5-methyl-2-phenyl-pyrrole. Yield 43 % \ melting point 190 to 192 ° C (from ethanol).

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7) 3-Amino-4- (p-carbethoxyphenylcarbamyl) -5-methyl-2-phenylpyrrole

Yield 61 %; Melting point 217 to 219 ° C (from ethanol).

8) 3 ~ amino-4- (p-carboxyphenylcarbamyl) -5-methyl-2-phenylpyrrole

Yield 37 % \ melting point 200 to 210 ⁰ C (from methanol / water;

9) 3 ~ Amino-5-methyl-2-phenyl-4-piperidinocarbonyl-pyrrole hydrochloride

Yield 50 % \ melting point 245 to 249 ° C. (from methanol / water).

10) 3-Amino-5-methyl- ⁱ t- (4-methyl-1-piperazinylcarbonyl) -2-phenyl-pyrrole.

Yield 46 %; Melting point 104 to 106 ° C (from ethanol). ,

11) 3-Amino-5-methyl-2-phenyl-4- (4-phenyl-1-piperazinylcarbonyl) pyrrole hydrochloride

Yield 44 Jt; Melting point 220 to 222 ° C (from ethanol / water). The fn
(from methanol).

Water). The free base melts at 154-156 ° C

12) 3-Amino-4- (o-chlorophenylcarbamyl) -5-methyl-2-phenylpyrrole hydrochloride

Yield 47 % \ melting point 268 to 272 ° C. (from methanol / water).

13) 3-Amino-5-methyl-4-morpholinocarbonyl-2-phenyl-pyrrole hydrochloride

Yield 81 %; Melting point 236 to 238 ° C (from methanol / water).

14) 3-Amino-4- (p-ethylphenylcarbamyl) -5-methyl-2-phenyl ~ pyrrole hydr ο chloride

Yield 62 %; Melting point 250 to 252 ° C (from ethanol /

^Ether) 609882/1203

15) 4- (p-Acetylphenylearbamyl) -3-amino-5-methyl-2-phenylpyrrole

Yield 80 %; Melting point 234 to 237 ° C (from dimethylformamide).

16) 3-Amino-5-methyl-2-phenyl- ⁱ l- (m-trifluoromethylcarbamyl) pyrrole

Yield 46 %; Melting point 150 to 151 ° C (from ethanol / water).

17) 3-Amino-5-methyl-2-phenyl-4- (o-tolyl) pyrrole yield 33 %; Melting point 28 ° C (from ethanol / water).

18) 3-Amino-5-methyl-2-phenyl- ¹ l- (m-tolyl) pyrrole

Yield 31 %; Melting point 11-173 ° C (from ethanol / water).

Example 19

3-Amino-1- (p-chlorobenzyl) -5-methyl-2-phenyl-4-piperidinocarbonyl-pyrrole hydrochloride

from 3-amino-4-carboxy-1- (p-chlorobenzyl) -5-methyl-2-phenylpyrrole hydrochloride and piperidine following the procedure of Example 1. Yield 44 %; Melting point 195 to 197 ° C (from methanol / water). The corresponding intermediate of the formula III was not isolated in this case.

Example 20

4-Ethylcarbamyl-5-methy1-2-pheny1-3- (p-toluenesulfonamido) pyrrole

A solution of 5.0 g (0.018 mol) of the compound of Example 2,

6.09882 / 1203

3 ^ g (0.018 mol) of p-toluenesulfonyl chloride and 1.8 g of triethylamine in 250 ml of pyridine was at room temperature for about 15 minutes

man ^

stirred for a long time, whereupon / she subsequently at about 5 ° C overnight left standing. The reaction mixture was then poured into 250 ml Poured aqueous hydrochloric acid and crushed ice and extracted the resulting solution with ethyl acetate. The one while cooling down The precipitate which formed was recrystallized from ethanol / water. Yield 2.0 g of the title compound of this Example; Melting point 219 to 221 ° C.

Example 21

3-acetylamino-5-methyl-2-phenyl- ¹ i-piperidinocarbonyl-pyrrole hydrochloride

5.0 g (0.016 mol) of the compound of Example 9 was dissolved in 250 ml of pyridine and the resulting mixture was added to 25 ml of acetic anhydride. After standing for about 90 minutes at room temperature, the whole was poured into 250 ml of 10% aqueous hydrochloric acid. The resulting pesticide was collected by filtration and recrystallized from ethanol. Yield 2.5 g of the title compound of this example; Melting point 289 to 29O ⁰ C.

Example 22 to 25

The following compounds were prepared by following the procedure of the previous example.

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22) 5-acetylamino- ' ¹ J- (p-ethylphenylcarbamyl) -5-methyl-2-phenyl pyrrole from the compound of Example 14 and acetic anhydride. Yield 67% \ mp 23O ⁰ C (decomposition); (from methanol / water).

23) 3-Acetylamino-4-isopropylcarbamyl-5-methyl-2-phenyl-pyrrole from the compound of Example 3 and acetic anhydride. Yield 71 % \ melting point 275 ° C. (from methanol / water).

2 ² O 3-acetylamino-4- (o-chlorophenylcarbamyl) -5-methyl-2-phenylpyrrole from the compound of Example 12 and acetic anhydride. Yield 56 %; Melting point 255 to 257 ° C (from ethanol).

25) 5-methyl-2-phenyl-3-propionylamino-4- (o-tolylearbamyl) pyrrole from the compound of Example 17 and propionic anhydride. Yield 60 % \ melting point 254 ° C. (from acetone / water).

Example 26

3-Dimethylamino-5-methyl-2-phenyl-4-piperidinocarbonyl-pyrrole

A solution of 5.0 g (0.016 mol) of the compound of Example 9 in 70 ml of methanol and 20 ml of water was admixed with 5 ml of dimethyl sulfate and 15.0 g of potassium carbonate. The resulting mixture was refluxed for about k hours, then poured into water and the resulting pesticide recovered by filtration. Yield 2.8 g of the title compound of this example; Melting point 207 to 209 ° C (from acetone).

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Example 27

! - (p-Chlorbenzy ^^ - flimethylamino-S-methyl ^ -phenyl - ^ - piperi dinoearbonyl pyrrole

from the compound of Example 19 and dimethyl sulfate by following the procedure of the preceding example. Yield 42 % \ melting point 199 to 201 ° C. (from ethanol / diethyl ether).

Typical compounds of formula I, which are according to the above Have examples produced are

1 1

Κ

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2605A19

At- R! "game

R ^J

R ⁶

'28

; 29

30 31

j 32.

j 33

j 34

: 35

I 36

^: 29

OCH.

3 ·

OCH

CH

H I. H H H H H · H • H H • H ' H H H H H H . H. H H. H H H H . H •

^C 2 ^H S

/ Λ:

NHCOCH.

^C 2 ^H S

^C 2 ^H S

-Cl

CH

^C 2 ^H S

^C 3 ^H 7

-CF:

CH_

CH.

CH,

CH.

CH.

CH,

approx.

CH_

^C 2 ^H 5

CH.

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4CM

^CH

^C 3 ^H 7

,H

C H

• 4

OCH.

CH

CH.

. CH

'CH "

C_H

5

CF

CH

■ /

CH

CH

C_H

CH.

CH,

^NvCH 2
^C 2 ^k 5

5

₂
\

CH.

: ^C 4 ^H 9 ^S0 2

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^C 2 ^H

2 ^H 5

pi·

CH ₃ :. CH ₃

CH ₃

CH.

C.H

2 5

^C 2 ^H 5

CH.

CH

^C 2 ^H 5

^C 3 ^H 7

C H 2 5

51

ft Cl

CH.

53.

r ^

Cl CH.

OCH-

KH CO 2.

NHCO

CH ₂ COSO,

C H 2 5

^C 2 ^H 5

^C 2 ^H 5

Cl

NO.

CH

4th

CK

ClI

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CH

η s

CH

9.

CH.

C.H

2

Il

CH.

Cl

OCH.

OH

OCH ₀

CH CO

^C 2 ^H 5

GHO

CH.

CH.

CH.

H ·

CH

H-

CH

5

^C 2 ^H 5

'2 "5

C ₂ H ₅

C_H

5

NH.

»Η,

^C 2 ^H 5

CH.

CH.

^C 2 ^H 5

.CH.

CH.

CH.

CH,

CH.

. ^CH 3

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CH.

Cl

Cl

OCH ₃

<V XS-

CH

CH.

C =

ClY /

CH =

CH =

I = ί

NH

- CH

^C 2 ^H

2 ^H 5

^C 2 ^H 5

^C 2 ^H 5

CH.

CH.

CH.

CH.

CH

609882/1203

The compounds of Example 1 can also be used using the further procedure described in the example below.

Example 70

3-Amino-il-diethylcarbamyl-5-methyl-2-phenyl-pyrrolehydrο-chloride

A) A solution of 12.0 g (0.318 mol) of 2-amino-2-phenylaeetonitrile, 50.0 g (0.318 moles) of α-acetyl-NjN-diethylacetamide and 2.1 g of p-toluenesulfonic acid in 700 ml of benzene was 7 hours refluxed for a long time under a nitrogen atmosphere, then allowed to stand at room temperature overnight. After the benzene had been distilled off at atmospheric pressure, the residue obtained was taken up in diethyl ether, the the resulting solution is filtered off from any insoluble substances and then concentrated to dryness. There were 95 g of a residue obtained, that of the intermediate compound

1 4

corresponded to formula XII in which R is a phenyl radical, R and Br are an ethyl radical and R is a methyl radical. The compound was used as such for the subsequent cyclization step.

B) 14.0 g of sodium were dissolved in 36O ml of ethanol and the resulting solution with a solution of 95.0 g of the crude compound prepared according to A) in 360 ml of methanol offset. After stirring for 5 hours and standing overnight at room temperature, the reaction mixture was released by evaporation of the ethanol concentrated to a small volume and then with 300 ml of a »mixture of aqueous 10 ^ iger hydrochloric acid and Diethyl ether added. The resulting precipitate was

609882/1203

filtered off and recrystallized from ethanol / diethyl ether. Yield 67.0 g of the title compound of this example; Melting point 212-214 ° C.

The compounds of Examples 2 to 38, 28 to 46 and 63 can be prepared essentially by the method described in the preceding example.

Preparation of the starting amino acids of the formula II A) 3 ~ amino-4-carboxy-5-methyl-2-phenyl-pyrrole

a) A solution of 6 g (0.042 mol) of 2-amino-2-phenyl-acetonitrile and 5 g (0.042 mol) of ethyl acetoacetate in 30 ml of anhydrous Benzene was in the presence for 4 hours on an oil bath of 100 mg of p-toluenesulfonic acid heated under reflux. To After cooling, the reaction mixture was filtered and then the solvent was evaporated to give an oily residue, which was distilled under reduced pressure. Boiling point 140 ° C / 0.05.

b) 0.80 g of sodium were dissolved in 15 ml of anhydrous ethanol and then a solution of 5 g of the imaginary compound in 35 ml of anhydrous ethanol was added dropwise, whereupon the mixture was allowed to stand at room temperature for 4 hours.

After blowing dry hydrogen chloride into the ethanol solution A precipitate formed, which was filtered off and recrystallized from a mixture of ethanol and diethyl ether became. Yield 4 g of 3-amino-4-carbethoxy-5-methyl-2-phenyl-pyrrole hydrochloride. Melting point 249-252 ° C (from ethanol / ethyl ether).

609882/1203

A solution of 4 g (0.0143 mol) of the compound prepared according to b) in 60 ml of dimethyl sulfoxide was treated with a solution of 6 g of lithium hydroxide monohydride in 90 ml of water and the resulting mixture was heated to about 80 to 85 ^° C. for 3 to 4 hours heated for a long time. After cooling, pouring into 160 ml of ice water and adjusting the pH to 7, the solution was extracted 4 with 60 ml of ethyl acetate each time. The organic extracts were collected and dried over sodium sulfate and the solvent was evaporated in vacuo. 2.58 g of an oily residue were obtained, which were taken up in chloroform, from which a pesticide crystallized out on cooling. Yield 1.3 g of the title compound of this example; Melting point 153 to ° the chloride melted at 200 to 2OO _S 5 ° C (decomposition, from water).

B) 3-Amino-4-carboxy-1-p-chlorobenzyl-5-methyl-2-phenyl-pyrrolfaydrο-chloride

3-Amino-4-carbethoxy-5-πlethyl-2-phenyl-pyrrole hydrochloride, prepared as under point b) of the previous example, was with p-chlorobenzaldehyde according to known methods for Manufacture of marine bases from amine and carbonyl compounds manufactured. The 4-carbethoxy-3- (p-chlorobenzylidenearaino) -5-methyl-2-phenyl-pyrrole that forms (Melting point 180 to 182 ° C, from ethanol / water) was in a strongly alkaline medium with p-chlorobenzyl chloride according to the usual Process for introducing a substituent into the nitrogen atom of a pyrrole nucleus implemented. The thereby obtained 4-carbethoxy-1- (p-chlorobenzyl) -3- (p-chlorobenzylideneamino) -5-methyl-2-phenyl-pyrrole was not isolated and was hydrolyzed under acidic conditions to give the title compound this example made. Melting point 170 to 171 ° C (from methanol / ether).

609882/1 203

Claims (11)

Patent claims: 1. 3-Amino -. ^ - carbamyl-pyrrole derivatives of the general formula wherein R is a hydrogen atom, a (C _1-11 ) AllCyI, benzyl or halogen-substituted benzyl radical, R is a hydrogen atom, a (C * ^) alkyl, phenyl ^ · or phenyl radical substituted by 1 to 3 radicals, the radicals independently of one another (C * u) alkyl, (C. ^ alkoxy, benzyloxy, fluorine, chlorine, bromine or hydroxy, R is a hydrogen atom, a (C j.) alkyl, formyl, (C ₀ ι.) aliphatic acyl -, benzoyl, carbamoyl, Phenylcarbamyl-, (. C _1-1) alkylsulfonyl, benzenesulfonyl, toluenesulfonyl or Phenacylsulfonylrest, R ^ is a hydrogen atom or a (C. i.) alkyl radical, or R and B. ^J together a (Cp_ |.) alkylidene, benzylidene or halogen-substituted benzylidene radical, R and Br independently represent a hydrogen atom, a (Cp_2.) alkyl or substituted phenyl radical, but not simultaneously hydrogen or, together with the adjacent nitrogen atom, a dimethylamino radical or a 5- to 6-membered heterocyclic ring » ^the one - 609882/1203 260541 may contain another oxygen or nitrogen atom and which is optionally _{substituted by 1 to 3 (C 1-1} ,) alkyl radicals or a phenyl radical, and R is a (C j.) alkyl radical, and their salts with pharmaceutically acceptable acids. 2. A compound according to claim 1, wherein R is a hydrogen atom, a benzyl or halogen-substituted benzyl radical,
R is a phenyl radical, R ^{2 is} a hydrogen atom, a (C _{1-1 {} ) alkyl, (C _2-11 ) aliphatic acyl or toluenesulfonyl radical, for a hydrogen atom or a (C. i.) Alkyl radical, Ii κ 1 - ** R and R ^ independently represent a hydrogen atom, a (C _2-1J) alkyl or a with (C _1-1 J) alkyl, (C _2-1}) aliphatic acyl, (C ^) alkoxy, halogen, carboxy, Carbo (C _1-1 ^ aIkOXy or trifluoromethyl substituted phenyl radical, but not simultaneously denote hydrogen or together with the adjacent nitrogen atom form a dimethylamino, piperidino, morpholino, (C _1-1 .) Alkylpiperazino or phenylpiperazino radical and
R is a (C _{1-1 {} ) alkyl radical
and their salts with pharmaceutically acceptable acids. 3. The compound of claim 2 wherein
R is a hydrogen atom,
R is a phenyl radical, R ^{2 is} a hydrogen atom, a (C _1-1 J) alkyl, (C _{2 -Ij} aliphatic acyl or toluenesulfonyl radical, R ^ is a hydrogen atom or a (C ₁ O alkyl radical, R and R independently of one another are a hydrogen atom, j 609882/1203 one (Cp _-21 ) alkyl, one with (C _1-21 ) AIlCyI, ( ^c ₂ -4) aliphatic »acyl, (C _1-21 ) alkOXy, halogen, carboxy, carbo- (C _1-2 J ) alkoxy or trifluoromethyl substituted phenyl radical, but not at the same time hydrogen or together with the adjacent nitrogen atom form a dimethylamino, piperidino, morpholino, (C _1-2 j) alkylpiperazino or phenylpiperazino radical and
R is a (C _1-2 ,) alkyl radical,
and their salts with pharmaceutically acceptable acids. 4. A compound according to claim 2, wherein 2 3 R, R and R represent a hydrogen atom, R is a phenyl radical, 4 5
R and R independently of one another a hydrogen atom, a (Cp _-2 J) alkyl, one with (C _{-2 {} ) alkyl, (C_ _-2 ,) aliphatic acyl, (C _1-2 J) alkoxy, halogen, carboxy, Carbo (C ^) alkoxy or trifluoromethyl substituted phenyl radical, but not at the same time hydrogen or together with the adjacent nitrogen atom form a dimethylamine, piperidino, morpholino, (C _1-2 J) alkylpiperazino or phenylpiperazino radical, and
R denotes a methyl radical,
and their salts with pharmaceutically acceptable acids. 5. 3-AmInO- ^ iSOPrOPyI-carbamyl-S-methyl-S-phenyl-pyrrole. 6. 3-Amino-4- (p -chlorophenylcarbamyl) -5-methyl-2-phenyl-pyrrole hydrochloride. 7. 3-Amino-5-methyl-2-phenyl-4- (p-tolylcarbamyl) pyrrole. 8. 3-Amino-5-methyl-2-phenyl- ⁱ J- (4-phenyl-1-piperazinylcarbonyl) pyrrole hydrochloride. 609882/1203 9 · Compound of the general formula where R is a hydrogen atom, a (C.) alkyl, phenyl or phenyl radical substituted by 1 to 3 radicals, the radicals independently of one another being (C. ^ j-alkyl, (C J-alkoxy, benzyloxy, fluorine, chlorine, bromine or hydroxy, R is a hydrogen atom, a (C _14-1 .) Alkyl, formyl-, (C-p_ j. ) Aliphatic acyl, benzoyl, carbamyl, phenylcarbamyl, (C _1-1 .) Alkylsulfonyl, Benzenesulfonyl, toluenesulfonyl or phenacylsulfonyl radical, R ^ a hydrogen atom or a (C 1) alkyl radical or l " ⁴ R and R ^ together a (Cp_ _1. ) Alkylidene, benzylidene or halogen-substituted benzylidene radical, R and R ^ independently of one another a hydrogen atom, a (C _2-1 .) Alkyl or substituted phenyl radical, but not simultaneously hydrogen or together with the adjacent nitrogen atom form a dimethylamino radical or a 5- to 6-membered heterocyclic ring, which can contain a further oxygen or nitrogen atom and which is optionally substituted by 1 to 3 (C h) alkyl radicals or a phenyl radical, and R a ( C ^ alkyl radical means
and their salts with pharmaceutically acceptable acids. 609882/1203 10) Process for the preparation of one of the compounds of claims 1 to 9, characterized in that one Compound of the general formula COQH II Ί ft wherein R, R and R as defined above or a Säureadditionssalζ thereof, is reacted with carbonyl chloride, about 1 to about 3 hours in an inert organic solvent at a temperature of about kO to about 70 ° C, then about 3 to about 10 molar equivalents of an amine of Formula. HN h 5
worxn R and R have the preceding meaning, added, the reaction mixture between room temperature and the boiling point of the reaction mixture for about 1 to about 3 hours, and 2 3 a) if the radicals R or R or both are not intended to mean a hydrogen atom, they are alkylated, acylated, sulfonylated, carbamylated, formylated in the usual way or processes for the formation of Schiff bases are used by using them with (C _1-1 J) alkyl ! halides, (C ^^ alkyl sulfates, (C _1- Ij) aliphatic acyl halides or anhydrides, benzene sulfonyl halides or anhydrides, (C.,.) alkyl sulfonyl halides, toluenesulfonyl halides, phenacyl sulfonyl halides, formic acid , Alkali metal cyanates, phenyl isocyanates, (Cp _- ^) aliphatic aldehydes, 609882/1203 (C__2j) aliphatic ketones, benzaldehyde or substituted on the aromatic ring by halogen atoms? Converts benzaldehyde and optionally the (C ₁ _ _ii ) alkylsulfonyl, benzenesulfonyl, toluenesulfonyl or phenacylsulfonyl groups removed by hydrolysis, b) when a compound of formula 1 is desired in the form of a salt with a pharmaceutically acceptable acid is, reacting the corresponding free base with a certain pharmaceutically acceptable acid and optionally to obtain a free base, treat the corresponding salt with aliphatic agents. 11. A process for the preparation of one of the compounds according to claim S _3, characterized in that one cc-aminonitrile of the formula CN CH,
i with a molar equivalent of a compound of the formula CH - CON
CO wherein R, R, R and R have the meaning given in claim 9, in the presence of an anhydrous organic Solvent and a catalytic amount of p-toluenesulfonic acid between room temperature for two to 28 hours 609882/1203 and the reflux temperature of the mixture reacted, then a slight molar excess over the starting aminonitrile of a basic condensation agent, such as Alkali carbonates, hydroxides, alkoxides, hydrides or amides are added, the resulting reaction mixture.; until 30 Hours at room temperature to the boiling point of the reaction mixture and holds a) if the radicals R or R or both are not intended to mean a hydrogen atom, they are alkylated, acylated, sulfonylated, carbamylated, formylated in the usual way or processes for the formation of Schiff bases are used by haliding them with (C. ^) alkyl , (C ^) alkyl sulfates, (C ^ jpaliphatis-chen acyl halides or anhydrides, benzyl halides or anhydrides, benzenesulfonyl halides, (C._2,) alkylsulfonyl halides, toluenesulfonyl halides, phenacylsulfonyl halides, formic acid, alkali metals Isocyanates, (C _2- ^) aliphatic aldehydes, (C, _2j) aliphatic ketones, benzaldehyde or benzaldehyde substituted on the aromatic ring by halogen atoms and optionally the (0 _1-Ζι ) alkylsulfonyl, benzenesulfonyl, toluenesulfonyl or phenacylsulfony1 groups removed by hydrolysis, b) when a compound of formula I is in the form of a salt with a pharmaceutically acceptable acid is desired, man. the corresponding free base with a certain pharmaceutically acceptable acid reacts and optionally to obtain a free base, treat the corresponding salt with aliphatic agents. For: Group Lepetit S.p ..-. Milan / Italy Lawyer \ cV