DE3316187A1 - 2-(Aminomethyl)pyrrole derivatives, process for their preparation, and their use - Google Patents

Abstract

2-(Aminomethyl)pyrrole derivatives of the formula <IMAGE> in which R denotes hydrogen or alkyl; R<1> denotes, for example, hydrogen, alkyl, alkoxycarbonyl, aryl, substituted aryl or heteroaryl; and R<2> and R<3> denote, for example, hydrogen, alkyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl or arylenedicarbonyl, and their acid addition salts are used as pharmacological active compounds for combating cerebral ageing processes.

Description

SRef.3276 Dr.Eu/Ll

2- (Aminoroethyl) pyrrole derivative € -, process for their manufacture and their use

The invention relates to new 2- (aminomethyl) pyrrole derivatives of the general formula I.

-R

R ³ V CH ₂ - I. N \ 10 wherein

R: hydrogen, alkyl (C -C _r ); '

R: is hydrogen, -alkyl _(C1-C5), cyano, alkyl (C ₁ -C ₄₎ alk oxy (C ₁ -C ₄₎ carbonyl, -alkoxy (C ₁ -C ₄₎ carbonyl-alkyl (C, - C ₄ ), R (R ⁸ ) N-carbonyl-alkyl (C- ₁ -C ₄ ), aryl, aryl-alkyl (C ₁ -C ₄ ), where the aryl or the aryl of the aryl-alkyl can also be replaced by halogen , AIkOXy (C ₁ -C ₄ ), alkyl (C ₁ - C ₄ ), 'R ⁴ (R ⁵ ) N-, hydroxy, mercapto, alkyl mercapto (C.-C.), Nitro, cyano, alkoxy (C, C ₄ ) carbonyl, alkoxy (C ₁ -C ₄ ) carbonyl alkyl (C ₁ -C ₄ ) can be substituted one or more times, heteroaryl, heteroaryl-alkyKC.-C.), R ⁴ (R ⁵ ) NR ⁶ -,

2 3
R, R: independently of one another hydrogen,

C ^ C ^) by amino, AlkOXy (C ₁ -C ₄ ), hydroxy, alkanoyloxy (C ₁ -C ₄ ), phenyl, halogen, mono-, di- or trisubstituted alkanoyl (C ₉ -C _1. ), Arylcarbonyl,

by halogen, alkoxy (CC), alkyl (C ₁ -C.), amino,

4 5 11

R (R) N-, hydroxy, alkanoyloxy (C ₁ -C ₄ ), mercapto, alkyl mercapto (C ₁ -C ₄ ), nitro, cyano, alkoxy (C ₁ -C ₄ ) carbonyl, amidosulfonyl monosubstituted or polysubstituted Arylcar-

2 3 bonyl, heteroarylcarbonyl, or R and R together vici-

Nales arylene dicarbonyl, vicinal heteroarylene dicarbonyl, arylene-1-sulfonyl-2-carbonyl, alkylene (C ₁ -C ₀ ) -dicarbonyl, alkenylene (C ₄ -C ₈ ) -dicarbonyl, whereby the Kphleristoffkette of the alkylene and alkenylun-dicarbonyls even

4th
interrupted one or more times by -0-, -S-, -N (R)

or a spiroatom contained canoe, over d.in. »in 4 ·, 5-, 6- or 7-ring can be connected,

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4 5
R, R: hydrogen,

R ⁶ :

Ref. 3276 Dr.Eu/Ll

7 8
R, R: independently of one another hydrogen, alkyl (C. -C-) or, together with the nitrogen atom to which they are attached, form a 5- or 6-membered, saturated heterocyclic ring which is also -0- or -N - contain

R ⁹

can

R ⁹ : hydrogen, alkyl (C ₁ -C ₄ ), AlkOXy (C ₁ -C ₄ ), phenyl, alkyl (C ₁ -C -) phenyl, alkoxy (C ₁ -C ₄ ) phenyl, and • their acid addition salts, where for the cases in which R

2 3

Methyl or ethyl and at the same time R and R together mean 1,2-phenylenedicarbonyl, R no ethoxycarbonylmethyl, Can be ethoxycarbonyl or methoxycarbonylphenyl.

The invention also relates to processes for the preparation of the compounds I and their acid addition salts, as well as their Use as a medicine.

The alkyl, alkoxy, alkanoyl, alkanoyloxy, alkylene, Alkenylene, alkyl mercapto, alkoxycarbonyl radicals can, even if they occur in connection with other radicals, straight-chain or branched. The aryl grids have even if they occur in connection with other residues, . In particular the meaning phenyl now Niiphthyl, from for which the Phenylr-est is preferred .. For arylalkyl comes especially phenethyl, preferably denzyl, into consideration. Arylcarbonyl is preferably benzoyl.

Hc.1eroaryl.rer.te lead r.ich, even if:; ie in combination with other residues, especially 5- or 6-membered ones aromatic HeLe! aeyd en, especially with one or two. Heteroal omen from the series oxygen, Sulfur or nitrogen, for example from furan, Thiophene, l'yrrole, oxazole, imidazole, thi.azole, isox.izole, Pyrazol, Isot liiazol, Pyridtn, Pyrazine, Pyridazine, Pyrimi-

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"Γ" 1 {· -f. Λ21 u

. * ·? · Dr .Ku / Ll

din. At this hot orocyi-lon can also ι · ϊη i "lor two Benzolkeriii; ankoinleiis i or L sein, wi ·· '.' .. IJ. at i m l) enzi> (b) thiophane, tsobenzofuran, Isoir.dol, chinwlin, (.'arb.r / .o 1. ilcteroaryl alkyl rest c. are preferably IloLemaryl me

S thylreote. Halogen is before dllfin fluorine, '' hlor inJor Π rom. ¹ Jn t.er vicinaJoiii Aryl en- di ca rbony.1 Wonlcu sol'-he Aryl re: .. te understood, which differ from aroma ι isehen 1, 2 - Derive diearbic acids, for example rhthaloyl. Alkyl on <1 i carbonyl is in particular alkylene-1,2 ·, -1,3- or -1,4 di "arbonyl., Preferably succinyl. Alkenylon dicarbony I i:> ti n.'jbenonder ο alkenyl en- 1,2, 1,3- or 1,4-di ca rbonyl, for example citrai.-o-noyl , but preferably malooyl.

Examples of the alkyl res te for R are methyl, ethyl, isopropyl. Methyl is preferred for the Subr.tilm-nl ph K. Examples I: For gubst i tuonten, which can rüv K rl-eheti, are: hydrogen, methyl, HthyL, Propyl, I pyl, Iiutyld), butyl. (2), tsobutyl, rert. Ru ty 1, isopentyl, aminomethyl, 2-aminoethyl, 3-amino -η propyl, 2 (N, N diynes methylamino) - ethyl, x (N, N -Diethy lam.i no) -ethyl, Cyannmethyl, 2?. -Cyanoethyl, 3-cyano-propyl, methoxy-carbonyl, η -propoxy carbonyl, i-propoxy-farbonyl, η-butoxy-cirbonyl, f. Butoxy c.irbonyl, methoxycarbonylniethyl, η propoxycarbonylmethyl, i-butoxycarbonylmothyl, 2- (Mrthoxycarbony 1) -ethyl, 2- (ethoxycarbonyl) ethyl, 2 - (i propoxycarbonyl) · ■ ethyl ·, 2- (methoxycarbonyl) -propyl, 2- (ethoxycarbonyl) propyl, Amj.nocarbonylmet hy 1, 2 (Ami noc. irbonyl) ethyl,. NjN-Dinu I hylaminocarbonyl methyl, (N, N - Di met. Hy I amino ι hyl) amlnocarbonylmethyl, Ki hy 1 amino (.: Ai: bonyl.

ethyl, Morpholinoear bonylmet.hy 1, 4 Methy 1 pi perazin (1) yl '. • arbonyliiu-t hyl, 4 -Phenylpi peraz in (1) yl carbonyl -methyl., 4- (u-, πι-, ρ Met hoxyphenyl) pi pe ri ¹ , '. i η (1) yl - ei r bony 1 im · thyl, pyrrolidino- cai bonyl methyl, N, N I.) i me i: hyl ami noc-.u bonyl-ethyl, 2 (4 methyl pi pet az in (1) y 1 -carbonyl) ι ι! .Yl, phenyl, 2 Met hy1 phenyl, 3 Methy! Phenyl, 4 -Me thy1 phenyl, 2 Methoxypheny1, 3 MeLhoxyphenyl, 4 MothoxyphenyL, 3,4-Diiuethoxyphenyl, o-, in-, p- Chi ο r.phenyl, 4 dimethyl ami no -

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Ref. 327 6 Dr.Eu/Ll phenyl, 4-mercaptophenyl, 4-methoxybenzyl, 2-thienylmethyl, 2-furylmethyl, 2-, 3-, 4-pyridylmethyl, 2-, 3-, 4-pyridyl.

Preferred radicals for the substituent R are: water

4 5 G
substance, RRN-R-, benzyl, phenethyl, where the phenyl group in the benzyl or phenethyl radical can also be substituted by one, two or three methyl and / or methoxy groups, phenyl, which can also be substituted by AlkOXy (C ₁ -C. ) -carbonyl, alkyl (C ₁ -C ₄ ), halogen, AlkOXy (C ₁ -C ₄ ), hydroxy can be mono-, di- or trisubstituted, imidazolylethyl, cyanoethyl, methoxycarbonyl-methyl, acetamino-.ethyl. Examples of preferred radicals R are: hydrogen, dimethoxyphenyl-ethyl, in particular 3,4-dimethoxyphenyl-ethyl, methoxycarbonyl-methyl, imidazolyl-ethyl, in particular 2- (4-imidazolyl) -ethyl, 3- (1 Imidazolyl) propyl, acetaminoethyl, (methoxycarbonyl) dimethoxyphenyl, in particular 2- (methoxycarbonyl) -4,5-dimethoxyphenyl, 2- (dimethylamine) ethyl, aminocarbonylmethyl, 0 2-cyanoethyl .

2 3

For R and R, for example, independently of one another, can also stand: hydrogen, methyl, ethyl, propyl, isopropyl, Butyl (1), butyl (2), isobutyl, isopentyl, pentyl, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, Isovaleryl, pivaloyl, chloroacetyl, aminoacetyl, methoxyacetyl, dichloroacetyl, trichloroacetyl, 3-methoxypropylcarbonyl, Benzoyl, o-, m-, p-methylbenzoyl, dimethylbenzoyl, o-, m-, p-methoxybenzoyl, dimethoxybenzoyl, 3,4-0 dimethoxybenzoyl, o-, m-, p-chlorobenzoyl, o-, m-, p-bromobenzoyl, o-, m-, p-aminobenzoyl, o-, m-, p-hydroxybenzoyl, 4-hydroxy-3-methoxy-benzoyl, 4-acetoxy-3-methoxybenzoyl, 2-phenyl-2-hydroxyacetyl (mandeloyl), 2-phenyl-2-acetoxy-acetyl, 2-phenyl-3-hydroxy-propionyl (tropoyl), 2-phenyl-3-acetoxy-propionyl, 2-, 3-, 4-pyridyl-carbonyl, 2-thienylcarbonyl, 2-furylcarbonyl.

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Examples of R ^ and R ³ together: T'lithaloyl fUcarbonyl, Pyridyl-2, 3 -dicarbonyl, Succi.nyl, Glutaryl, MaIeoyl, Citraconoyl, Butene-1, 4-dicarboriyl, Phenyl-1-sulfonyl-2- carbonyl, 2-thiabutanedioyl (= -CO-S-CH-CO-), 2,2-

f
Tetramethyl] / n-1, 3-propan-dicarbonyl. Preferred radicals for R ² / R ³ are, for example: H / H, nicotinoyl / H, 3, 4-dimethoxybenzoyl / H, acetamino / H, phenylene-1-sulfonyl-2-carbonyl, phthaloyl.

The 2- (aminomethyl) pyrrole derivatives of the formula I are in a manner known per se thereby that a 1,4-diketone of the formula II with an amine of the formula III

^ 1
^ n-CH ₂ -CO-CH ₂ -CH ₂ -CO-R ■ + H ₂ NR ^ (D

(II) (HD

is reacted in a suitable inert solvent or solvent mixture at temperatures of 20 to 200.degree. In compounds II and III, the radicals R, 12 have 3
R, R and R have the meanings already mentioned.

In many cases, temperatures from 20 to 100 ^° C. are sufficient. Suitable solvents are, for example, alcohols, in particular those with 1 to 6 carbon atoms, such as, for example, Me-

2'5 ethanol, ethanol, i- and n-propanol, i-, sea- and tert- -Butanol, n-, i-, sea-, tert-pentanol, n-hexanol, cyclopentanol, Cyclohexanol; Ethers, especially those with 2 to 8 carbon atoms in the molecule, such as diethyl ether, methyl ethyl ether, Di-n-propyl ether, diisopropyl ether, methyl n-butyl ether, Ethyl propyl ether, dibutyl ether, tetrahydrofuran; 1,4-dioxane, 1,2-dimethoxyethane, bis-ß-methoxyethyl ether; Polyethers such as polyethylene glycols having a molecular weight up to about 600; Oligoethylene glycol dimethyl ether such as pentaglyme; aliphatic carboxylic acids, especially formic and acetic acid; Glycols and partially etherified glycols, such as ethylene glycol, propylene glycol, trimethylene glycol, ethylene

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-0- Ref. 3 27 6

• / 10 · Dr.Eu/Ll glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether; Ketones, especially those with 3 to 10 carbon atoms in the molecule, such as acetone, methyl ethyl ketone, methyl n-propyl ketone, diethyl ketone, 2-hexanone, 3-hexanone, di-n-propyl ketone, di-iso-propyl ketone, di -iso-butyl ketone, cyclopentanone, cyclohexanone, benzophenone, acetophenone; aliphatic hydrocarbons, such as, for example, low-boiling and high-boiling petroleum ethers; aromatic hydrocarbons such as benzene, toluene, o-, v \ - and p-xylene; halogenated aliphatic or aromatic hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene; Nitriles such as acetonitrile; Amides, such as dimethylformamide, N-methyl-pyrrolidone; Hexamethylphosphoric triamide; Sulfoxides such as dimethyl sulfoxide; Water. Mixtures of different solvents can also be used.

In the preparation of the compounds of the formula I, the starting components are normally approximately equimolar Amounts used. The amine III can also be used in the form of an acid addition salt. The work-up the approaches are carried out according to customary methods. The reaction can optionally also in the presence of a base or a mixture of bases. Suitable bases are e.g. tertiary aliphatic amines, such as triethylamine, tri-n-propyl and tri-iso-propylamine, also pyridine, as well as alkali carbonates, hydrogen carbonates and formates and acetates.

The amines of the formula III required as starting materials are known or can be easily found for the Manufacture of primary amines using customary methods. The 1,4-diketones of the formula required as starting materials II can, if they are not already known, easily by catalyzed addition of an aldehyde of the formula IV to a vinyl carbonyl compound of the formula V

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-ti- Ref. 3276 Dr.Eu/Ll

.N-CH ₀ -N ^ + CH ₀ = CH-CO-R ^ (II)

R ^% H

(IV) (V)

according to the method of H. Stetter, Angew. Chem. 88 (1976), 695 to 704, where in the compounds IV and

2 3

V the radicals R, R and R have the meanings already mentioned. Suitable catalysts are this process cyanide ions in the form of alkali metal cyanides or thiazolium salts such as 5- (2-hydroxyethyl) -3-benzyl-4-methyl-1,3-thiazolium chloride or other azolium salts in the presence of a base such as triethylamine or sodium acetate. The reaction is carried out with or without a solvent at temperatures from 0 C to The reflux temperature of the solvent used is carried out. It may be appropriate to use the aldehyde of the formula Use IV in the form of its hydrate.

Aldehydes of the formula IV can easily be obtained by acylation of aminoacetaldehyde acetals with carboxylic acid derivatives are, where the carboxylic acid derivatives are especially carboxylic acids, carboxylic acid esters, carboxylic acid anhydrides and Find carboxylic acid chlorides use. The reactions are carried out in a manner known per se, optionally under Carried out with the aid of suitable catalysts. on the other hand the compounds of the formula IV are also available by alkylation of suitably substituted amines, amides or imides accessible by processes known from the literature.

From compounds of the formula I according to the invention you can

2 3

the substituents R and R according to processes known from the literature split off and replaced by hydrogen. This separation is particularly easy when it comes to

2 3

the substituents R and R around acyl radicals, in particular around 1,2-arylenedicarbonyl, alkylenedicarbonyl or alkenylenedicarbonyl acts. In these cases, the cleavage can usually be achieved by boiling with hydrazine or hydrazine hydrate

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■ / (- Ref. 3 276

Dr.Eu/Ll

be performed. This leads to the invention 2- (aminomethyl) pyrroles of the formula Ia or Ib

HLN-CH _n -

-R

T \

RH ₂ NCH ₂ [

IT ^> N

I 1 (

R H

(la) (Ib)

The 2-aminomethylpyrroles of the formulas Ia and Ib to other compounds according to the invention of Formula I are implemented. It is advantageous to adjust the order of the individual reaction steps as required To adapt to the circumstances.

The 2- (aminomethyl) pyrrole derivatives of the formula I form acid addition salts with inorganic or organic acids. To form such acid addition salts are inorganic and organic acids suitable. Suitable acids are, for example: hydrogen chloride, hydrogen bromide, Naphthalene disulfonic acids, in particular naphthalene-1,5-disulfonic acid, Phosphorus, nitric, sulfur, oxal, milk, wine, vinegar, salicylic, benzoin, ant, Propionic, pivalic, diethylene acetic, malonic, amber, pimeline, fumaric, maleic, apple, sulphamine, Phenylpropionic, gluconic, ascorbic, nicotinic, isonicotinic, methanesulphonic, p-toluenesulphonic, citric or adipic acid. Pharmacologically acceptable acid addition salts are preferred. The acid addition salts are like Usually by combining the components, expediently in a suitable solvent or diluent, manufactured. In the synthesis of the compounds of the formula I, the acid addition salts in the Incurred in the course of reconditioning. From the acid addition salts The free compounds of the general formula I can, if desired, in a known manner, for example by Dissolve or suspend in water and make alkaline, e.g. with caustic soda, and subsequent isolation,

copy I.

- {- Ref. 3276

/ fg. Dr.Eu/Ll be won.

The compounds of the formula I according to the invention and their pharmacologically acceptable acid addition salts have valuable pharmacological properties.

The aminomethylpyrroles of the formula I according to the invention and their pharmacologically acceptable salts are centrally active, for example they show nootropic effects and are used to treat diseases that are characterized by a restriction of brain function, in particular memory, and to reduce cerebral aging processes. Surprisingly, they are considerably superior to the previously known compounds with the same direction of action. They show excellent effectiveness in various tests, such as, for example, in extending the survival time under sodium nitrite hypoxia according to Gibsen and Bless (J. Neurochemistry 22.1 (1976)), in improving nitrogen-induced hypoxia tolerance, with test animals after premedication with the investigated preparations pure nitrogen and the increase in the period between the start of ventilation and electrical neutrality of the electroencephalogram and lethality are measured.

Also in tests that aim directly at recording learning and memory performance, such as the known "Avoidance" tests are the products according to the invention very effective.

The test in the above and a number of other tests shows that the compounds according to the invention in low doses with low toxicity surprisingly a particularly favorable one, in the case of known preparations have an active profile that is not present in this form.

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-VO- Ref. 3276 - 4k ' Dr.Eu/Ll The compounds of formula I and their physiologically compatible salts are thus an enrichment for pharmacy.

The compounds of formula I and their pharmacological Acceptable acid addition salts can therefore be used as medicinal products on their own in humans, in mixtures with one another or are administered in the form of pharmaceutical preparations which enteral or parenteral

Allow IQ turn and be active. Component an effective dose of at least one compound of the formula I or an acid addition salt thereof, -in addition to conventional pharmaceutically acceptable carriers and additives. The preparations normally contain about 0.5 to 90 percent by weight of the therapeutically active compound.

The remedies can be taken orally, e.g. in the form of pills, tablets, coated tablets, coated tablets, granules, hard and Soft gelatin capsules, solutions, syrups, emulsions or suspensions or aerosol mixtures are administered. It can also be administered rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions, or percutaneously, e.g. in the form of ointments or tinctures.

The pharmaceutical preparations are produced in a manner known per se, with pharmaceutically inert ones inorganic or organic carriers are used

3Q the. For the production of pills, tablets, coated tablets and hard gelatin capsules can include, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. use. Carriers for soft gelatine capsules and suppositories are e.g. fats, waxes, semi-solid and liquid polyols, natural or hydrogenated oils etc. As carriers for the 'production of solutions and syrups e.g. water, sucrose, invert sugar, GIu-

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kose, polyols etc. As a carrier for the production of interaction solutions, r.irh ■ /. . B. Wanner, alcohols, glycerine, polyols, vegetable oils, etc.

The phaiina / .eut ischi.Mi preparations can be used in addition to the active and Carriers nor additives, such as /..B. Fillers, Stretching, blasting, binding, gliding, net, stabilizing, Emulsifying, preservation, sweet, coloring, flavoring or aromatization. *; , - thickening :; , Thinner

-Means, buffer substances, also solvents or Solubilizers or means to achieve a depot effect, as well as salts to change the osraotic pressure, coating agents or antioxidants. she can also use two or more compounds of the formula I or their pharmacologically acceptable acid addition salts and one or more others therapeutically contain active substances.

Such other therapeutically active substances are, for example, agents that promote blood flow, such as dihydroergocristine, Nicergolin, Duphenin, Nic: otinsäur «i and their F.ster, Pyridylcrarbinol, Dencyclan, Ci nnar.izin., Naf tidrofuryl, Raubasin, and Vincamin; positive inotropic compounds such as digoxin, acetyldigoxin, metildigoxin and Lanato glycosides; Coronary dilators, such as carbocromene, Üipyridamol, nifedipine and perhexiline, antianginal compounds, like isosorbide dinitrate, isosorbidium nitrate, Glycerolni joined :, Molsidomin and Verapam.il, ß-blockers, such as Propoanolol, oxprenolol, atenolol, metoprolo] and penbutolol. In addition, the compounds can be combined with other nootropically active substances, such as Piracetam, or CNS-active substances such as Piilindole, Sulpirid etc. combine.

The compounds of the formula I, their pharmacologically acceptable acid addition salts and phaxm.r / .eutic preparations, which the compounds of the Funnel J or their

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Ref. 3276 Dr.Eu/Ll pharmacologically acceptable acid addition salts as active ingredients can be used in humans as a remedy, e.g. in the fight against or prevention of diseases that due to impairment of the hearing impairment, and in the treatment and prevention of cerebral Al-:

application processes. The dosage can ^!

vary within wide limits and must be adapted to the individual circumstances in each individual case. i

i In general, in the case of oral administration, a daily

^ o dose of about 0.1 to 1 mg / kg, preferably 0.3 to 0.5 mg / kg body weight is appropriate for achieving effective results; for intravenous application this is

Daily dose generally about 0.01 to 0.3 mg / kg, before;

preferably 0.05 to 0.1 mg / kg body weight. The day

• jc dose is normally divided into several, eg 2, 3 or 4, partial ^! Split administrations. If necessary, depending on j

depending on individual behavior, become necessary, from the specified daily dose up or down-:

to give way. Pharmaceutical preparations normally contain j

wise 0.1 to 50 mg, preferably 0.5 to 10 mg active ingredient >.

of formula I or a pharmacologically acceptable salt per dose. '

The compounds according to the invention are tested through various test procedures, each for itself, but especially in their combination, the effectiveness and show the value of the substances.

1 · "Nitrithypoxia"

In this test, using the method of Gibsen and Bless (J. Neurochem. 21, 1976), cerebral hypoxia is produced in mice with NaNO ₂ (250 mg / kg sc), which ends with the death of the test animals. It is determined whether the survival time is influenced by premedication with the test substance.

The minimum active dose is the one that

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Ref. 3276 Dr.Eu/Ll

^ to a significant extension of the time to think about it (t-test) of the test animals.

2. "Nitrogen hypoxia"

To determine the effects of nitrogen ventilation On the electrical activity of the brain, rats are chronically implanted electrodes to measure the Encephalogram (EEG) used.

■ j_q One hour after administration of control and preparation injections the animals are ventilated with nitrogen under hexobarbital anesthesia under EEG control. As a hypoxia tolerance becomes the time between the start of ventilation and the complete disappearance of electrical activity

- ■ ε (isoelectric EEG) denotes. Another brief one Ventilation with nitrogen and subsequent air ventilation usually leads to the death of all control animals. The minimum active dose of a preparation is that which leads to a significant prolongation of the Hypoxia tolerance (t-test) leads and / or significantly reduces lethality (chi-square test).

3. "Passive avoidance"

The test apparatus is a light-dark box with an electrifiable Grid floor in the dark part.

90 minutes after the administration of the control and preparation injections, inexperienced male mice are given scopolamine hydrobromide (3 mg / kg s.c.) treated. 5 minutes later

-, Q the mice are placed in the light part of the box. To they get transferred to the dark part of the box an electric shock to them that is uncomfortable for them. After 24 hours, each mouse is once in the light part of the Test apparatus set and the dwell time (max 180 sec)

-, ι- measured. The significant effect of the test substance in the The comparison to the control group is calculated using a median test.

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Ref. 3 27 6

• AS * Dr .Eu / Ll 2_ The minimum active dose of a preparation is the one that shows a significant effect against scopolamine. The animals treated with the active dose of a preparation and scopolamine show a long dwell time, as do the animals not treated with scopolamine, whereas those treated with control injection and scopolamine show a short dwell time.

1- (ethoxycarbonyl or ethoxycarbonylmethyl or o- ■ i Q methoxy-carbonyl-phenyl) -2- (phthalimido-methyl) -5-methyl- or -ethylpyrroles are from the literature ursteile H. ' Stetter and P. Lappe, Liebigs Ann. Chem., 190O, 703-714, as Intermediate products for the production of bicyclic and tricyclic Pyrrole systems known. This reference • However, there are no indications that the Compounds of the present invention are useful pharmacological Possess properties.

example 1

on 1 - (2 - D ime t h y! amino-ethyl) -2- (ph thai imido-methyl) -5-methyl-pyrrole

7.8 g (0.03 mol) 6-phthalimido-2,5-hexanedione (cf. Example 2) and 2.7 g (0.03 mol) N, N-dimethylamino-ethylamine are stirred in 150 ml of acetic acid at 80 ° C. for 3 h. After concentration, it is dissolved in aqueous sodium hydrogen carbonate taken up, extracted with methylene chloride, dried, concentrated and recrystallized from methanol.

Yield: 6.5 g, 70% of theory; Mp: 125 to 126 ° C.

2Q analysis: C. 69 4th H 6, 8th N 13, 5 0 10, 3 Ber. : C. 69 1 H 6, 6th . N 13, 6th 0 10, 6th Found : 2 example

a) The starting product 6-phthalimido-2 required in Example 1, 5-hexanedione. can be made as follows:

/ Ref. 3276

• / 3 · Dr.Eu/Ll 66g (0.32 mol) phthalimido-acetaldehyde hydrate (see example 3), 70.1 g (1.0 mol) methyl vinyl ketone, 31.5 g 3-benzyl-5- (2-hydroxyethyl) -4-methyl-1,3-thiazolium chloride and 155ml triethylamine are in 600ml ethanol for 16h under Heated to reflux. After concentration, it is dissolved in aqueous sodium hydrogen carbonate solution taken up, extracted with methylene chloride, filtered through activated charcoal and concentrated and recrystallized from methanol.

Yield: 55.1 g, 67% of theory; Mp: 117 to 119 ° C. Analysis:

Calc .: C 64.9 H 5.1 N 5.4 0 24.7

Found: C 64.8 H 5.4 N 5.5 0 24.7

"L5 In a similar way, for example, can be produced:

b) 6-succinimido-hexane-2,5-dione

c) 6-maleimido-hexane-2,5-dione

d) 6-acetamido-hexane-2,5-dione

e) 6- (N, N-dimethylamino) -hexane-2,5-dione 2Q f) 6-benzamido-hexane-2,5-dione

g) 6- (4-methylbenzamido) -hexane-2,5-dione

h) 6- (4-chlorobenzamido) hexane-2,5-dione

i) 6- (4-Methoxybenzamido) -hexane-2,5-dione

j) 6- (3,4-Dimethoxybenzamido) -hexane-2,5-dione

k) 6- (thiophene-2-carboxamido) -hexane-2,5-dione

1) 6- (Nicotinamido) -hexane-2,5-dione

m) 6- (pyridine-2,3-dicarboximido) -hexane-2,5-dione

n) 6- (o-sulfobenzoic acid imido) -hexane-2,5-dione

Example 3

The starting product required in Example 2 phthalimidoacetaldehyde hydrate can be produced according to the teachings of the German federal patent 982 711 as follows:

■ se a) 500g acetamide are melted in an oil bath. After adding of 243.5g (1.31 mol) phthalimide potassium is heated to 130 ° C

Ref. 327 G Dr.Eu/Ll warms and at this temperature 259g (1.31 mol) bromoacetaldehyde diethylacetal admitted. When the addition is complete, the mixture is heated to 170 ° C. for 30 minutes, cooled, with 1 l of water added and stirred overnight. The unusual Fenti> The substance is filtered off with suction, extracted with methylene chloride, the Methylene chloride phase dried and concentrated.

Yield: 256,6g phthalimido aceta.ldehyd- diethyl = 7To of theory, mp: 70-71 C. · ^Q.

256.6g (0.975 mol) phthalimido-acetaldehyde-diethylacetal, 270ml formic acid, 25ml concentrated hydrochloric acid and 40ml Waaser are heated to 100 C for 10 minutes, after which Cooling, diluted with 3 l of water and concentrated to 2 l of solution and cooled. The precipitated product is filtered off with suction and dried.

Yield: 162 g = 80% of theory of phthalimido acetaldehyde hydrate of m.p .: 112 to 113 ° C.

In the above process, instead of bromoacetaldehyde diethylacetal Chloracetaldehyde diethylacetal can also be used with similar success.

b) 100g (0.54 mol) phthalimide potassium, 90g (0.46 mol) bromoacetaldehyde diethylacetal and 1 g of potassium iodide are stirred in 800 ml of dimethylformamide at 100 ° C. for 66 h. After this EituMigen to 100ml is mixed with 200ml of water and sucked off and with 145ml formic acid, 20ml water and 15ml

3Q concentrated hydrochloric acid added, heated to 100 C for 10 min, 1 l of water were added, the mixture was filtered through activated charcoal, cooled, filtered off with suction and dried.

Aus'bf- »ute: 62.4g ^; 6CV. the theory Phth.ilim Ldo-acetaldehydhydrnl from l-'p: 111 to <: 113 ° C.

BATH

COPY

-ΧΙ- Ref. 3276. £ / f, Dr.Eu/Ll

^ According to the method a) and b) can be in analogous Way to produce e.g.

Pyridine-2, S-dicarboximido-acetaldehyde and --acetaldehyddiethy] acetal, Succinimido-acctaldehyde-diethylacetal, Succinimido-acetaldehyde, maleimido-acetaldehyde-diethylacetal, Maleimido-acetaldehyde, (1,2-benzisothiazol-1,1-dioxide-3 (2H) -on-2-yl) -acetaldehyde and -acetaldehyde - diethylacetal (= o - sulfobenzoesäureimi do-cicetaldchyd and o-sulfobenzoic acid imido-acetaldehyde acetal).

Any Diethylacetaüe that have arisen are analogous the following example in the corresponding hydrates. transferred:

c) 256.6g (0.975 mol) phthalimido-acetaldehyde-diethylacetal, 270 ml of formic acid, 25 ml of concentrated hydrochloric acid and 40 ml of water are heated to 100 ° C. for 10 minutes. After this Cooling is diluted with 3 l of water and then concentrated to a volume of 2 l and cooled. The unusual one

2Q phthalimido-acetaldehyde hydrate is suctioned off and dried.

Yield: 162 g = 80% of theory, mp: 112 to 113 ^P C.

or example 4

1 - (2- (3, 4-Diinethoxvphenvl) -ethyl) -2- (phthalimido-methvl) - 5-methyl-pyrrole

13.0g (0.05 mol) 6-phthalimido-2,5-hexanedione and 9.1g

(0.05 mol) 2- (3,4-dimethoxyphenyl) -ethylamine are in 2Q 250ml acetic acid fermented for 7 h at 80 ° C. After work-up as in Example 1, 7.3 g of product are obtained.

Yield: 36% of theory; Fp-. 112 to 113 ° C.

Analysis: C. 71 3 H 6, 0 N 6, 9 0 15, 8th 35 Ber. : C. 70 9 H 6, 0 N 6, 8th 0 16, 1 Found :

COPY

VfT tire. 327 6 '

, ££. Dr.Eu/Ll

At a pi πι 5

J., -ίί'ί .: t ho.yyca t bony! met liy JJ 2 ..; _. {±> h Lyja .. '! , hnido methyl) -5-nu. -

H., 1'J (0.07 ml) 6 phthalimides 2, S ¹ IiCMaHdIOn, 10, Og (0.08 mill) Glyv inmot hyle.s terhydrochlor id and G, Gy (0.08 mol) NaLi iiiin.irciat be .in JOOmI Kr.:. ^c ; i y .'-. aur e for 3 h box 80 ° C. After concentration, nuiijenomraen is extracted in aqueous sodium hydrogen carbonate solution, extracted with methylene chloride, dried, concentrated and isolated from methanol.

Yield: 14 %, 6 <5% of theory, melting point: 134.degree. Analysis:
Of the. C 6 5.4
0t: f ..: C 65, 1

FI 5, 2 N 9 , 0 0 20, 5 H 5, 1 N 9 , 0 0 20, 8th

j - (2 Met hoxy- carbonyl 4, \> - dimcthoxy-phr'nyl) - 2 - (ρ h t.ha 1 i in i -do-methyl) -5-me. t hvl -pyrrole

13.0q (0.05 mol) G -phthalimido-2,5-hexanedione and 10.6g (0.05 mol) 2-amino-4,5-dimet.hoxybenzoic acid methyl ester are stirred in 250 ml of acetic acid for 30 hours at 100 ° C. and worked up as in Γ3ιί ispiol 1.

Yield: 10.3 g, 47% of theory, mp 184 to .185 ⁰ C.

A η λ] y r. f .. ·: Γ 6C ₁ 4th ti 5 , 1 N 6, 4th 0 22nd 1 Of the . : C. GG, 4th H 5 .0 N 6, 6th 0 22 5 G ei ".:

ÜLl-Üi iii.il 1 .2

? .- (Phth.tl imido -methyl) - 5- methy l -pyrrole.

3C, Uj (0.14 mol) G -phthalimido-2,! 3-hexanedione and 54g (0.7 nuil) Aiumoniuiiiacetat and 1g ammonium chloride are in 700ml acetic acid stirred for 1 h at 80 C and as in example 1 au 1 ge.u at ι et.

BATH ORIGINAL

COPY

Ref. 3276 Dr.Eu/Ll Yield: 32.2 g, 96% of theory, melting point: 173 to 174 ° C. Analysis · .-

Calc .: C 70.0 H 5.0 N 11.7 0 13.3 Found: C 69.7 H 5.3 N 11.4 013.8

Example 8

1- (2-Cimidazol-4 (5) -yl) -ethyl) -2- (phthalimido-methyl) -5-roethyl-pyrrole hydrochloride

5.2 g (0.02 mol) 6-phthalimido-2,5-hexanedione and 3.7 g ^ Q (0.02 mol) histamine dihydrochloride and 3.4 g (0.04 mol) sodium acetate are added to 70 ml acetic acid for 3 hours 80 ° C stirred. After working up as in Example 1, ethanolic hydrochloric acid is added, the mixture is filtered off and dried.

Yield: 4.0 g, 54% of theory, melting point: 218 to 219 ° C.

Analysis:

Calc .: C-61.5 H5.2 N 15.1 08.6 Cl 9.6 Found: C 61.2 H 5.3 N 14.8 0 9.0 Cl 9.4

Example 9

1- (methoxycarbonyl-methyl) -2- (phthalimido-methyl) -5-methyl-pyrrole

11.4g (0.044 mol) 6-phthalimido-2,5-hexanedione and 27.6g (0.22 mol) glycine methyl ester hydrochloride and 9.1 g (0.11 mol) sodium acetate are refluxed in ethanol for 16 hours heated and worked up as in Example 1.

Yield: 6.1 g, 44% of theory, melting point: 134 to 135 ° C.

30th Analysis -. C 65.4 H 5, 2 N 9.0 0 20.5 Ber. : C 65.7 H 5, 2 N 9.0 0 20.1 Found: 10 example 1- (2-acetylamino-ethyl) I- (phthalimido-methyl) -5-methvl- τ ε; pyrrole

4.6g (0.018 mol) 6-phthalimido-2,5-hexanedione and 1.8g

COPY '

Ref. 3276 Dr.Eu/Ll

j ^ (0.018 mol) of 2- (acetylamino) ethylamine are stirred in 120ml of acetic acid for 4 hours at 80 ⁰ C. The work-up is carried out as indicated in Example 1:

Yield: 1.5 g, 26% of theory, melting point . 191 to 192 ° C analysis:

Calc .: C 66.4 H 5.9 N 13.2 014.8

Found: C 66.2 H 6.0 N 12.9 0 14.9

Example 11

2- (Amino-methyD-S-methvl-pyrrole 60.9 g (0.23 mol) 2- (phthalimido-methyl) -5-methyl-pyrrole) (cf. Example 7) and 114 ml (2.3 mol) hydrazine hydrate are refluxed in 1 l of ethanol for 15 min. To

2 ^ 5 the cooling is suctioned off, concentrated and the residue taken up in methylene chloride, filtered off, the filtrate concentrated and recrystallized from toluene.

Yield: 23.1 g, 91% of theory.

Example. 12th

1- (2- (3,4-Dimethoxyphenyl) ethyl) -2- (amino-methyl) -5-methoxy-pyrrole

6.0 g (0.015 mol) 1- (2- (3,4-dimethoxyphenyl) ethyl) -2- (phthalimido-methyl) -5-methyl-pyrrole (cf. Example 4) and 7 ml (0.15 mol) of hydrazine hydrate are refluxed for 30 minutes. After concentration, it is dissolved in methylene chloride taken up, filtered off, concentrated and chromatographed over a silica gel acid.

Yield: 3.0 g, 74 % of theory.

Example 13

1- (2-dimethylamino-ethvl) -2- (aminomethyl) -5-methyl-pyr-

5.0 g (0.014 mol) 1- (2-dimethylamino-ethyl) -2- (phthalimidomethyl) -5-methyl-pyrrole (see example 1) and 7 ml

-2Π- Ref. 3276 « & £ ' Dr.Eu/Ll (0.15 mol) hydrazine hydrate are heated under reflux for 30 min. After cooling, the phthalic hydrazide is filtered off with suction, concentrated, taken up in methylene chloride, filtered again and concentrated.

Yield: 2.4 g, 94% of theory.

Analysis:

Calc .: C 66.3 H 10.6 N 23.2 Found: C 66.5 H 10.1 N 22.8

Example 14

1- (2-Dimethvlamino-ethyl) -2- (3,4-dimethoxy-benzoylaminomethyl-5-methyl-pyrrole

2.3 g (0.013 mol) of 3,4-dimethoxybenzoic acid are mixed with 2.1 g (0.013 mol) carbonyldiimidazole in 40 ml tetrahydrofuran was heated under reflux for min. After adding 2.3 g (0.013 mol) 1- (2- (Dimethylamine) -ethyl) -2- (aminomethyl) 5-methyl-pyrrole (see Example 12) is stirred for 3 h at room temperature, concentrated, with aqueous sodium hydrogen carbonate solution added, extracted with methylene chloride,

2Q dried, concentrated and chromatographed over a silica gel acid. .

Yield: 1.8 g, 41% of theory.

Example 15

1- (2- (3,4-Dimethoxyphenyl) ethyl) -2- (pvridyl-3-carbonylamino-methyl) -5-methyl-pyrrole

1.4 g (0.011 mol) pyridine-3-carboxylic acid and 1.8 g (0.011 mol) carbonyldiimidazole) are in 40ml tetrahydrofuran

3Q refluxed for 15 min. After adding 3.0g (0.011 mol) 1- (2- (3,4-Dimethoxyphenyl) -ethyl) -2- (aminomethyl) -5-methyl-pyrrole (cf. Example 12) is at Stirred at room temperature, concentrated, with aqueous sodium hydrogen carbonate solution added, extracted with methylene chloride, dried, concentrated and recrystallized from isopropanol.

- Ref. 3276 Dr.Eu/Ll Yield: 1.9 g, 46 ° i> the theory, mp: 116 to 117 ° C. Analysis:

Der .: C 69.6 H 6.6 N 11.1 0 12.6 Found: C 69.8 H 6.5 N 11.0 0 12.6

Example 16

2- (3,4-Dimethoxy-benzoylamino-methyl) -5-methyl-pyrrole 18.1 g (0.1 mol) 3,4-dimethoxybenzoic acid are mixed with 17.8 g (0.11 mol) carbonyldiimidazole and 11.0 g ( 0.1 mol) 2-AmijLq 'nomethyl-5-methyl-pyrrole (see. Example 11), as described in Example 15, implemented.

Yield: 24.4 g, 89% of theory, mp-. 125 to 126 ° C. Analysis:

Calc .: C 65.7 H 6.6 N 17.5 0 10.2

Found: C 65.8 H 6.6 N 17.4 0 10.1 ·

Example 17

2- (Pyridyl-S-carbonylamino-methyl) -5-methyl-pyrrole ^ _n 12.9 g (0.1 mol) pyridine-3-carboxylic acid, 17.8 g (0.11 mol) carbonyldiimidazole and 11.0 g (0 , 1 mol) 2- (aminomethyl) -5-methyl-pyrrole (see. Example 11), are as described in Example 15, implemented.

Yield: 14.1 g, 66% of theory, melting point: 157 to 158 ° C. Analysis:

Calc .: C 67.0 H 6.1 N 19.5 07.4

Found: C 66.7 H 6.0 N 19.5 0 7.6

ολ Example 18

2- (Acetylamino-methyl) -5-methvl-pyrrole To 6.4 g (0.06 mol) of 2- (amino-methyl) -5-methyl-pyrrole (cf. Example 11) in 20 ml of methylene chloride are added at 10 C 6 , 0g (0.06 mol) acetic anhydride in 20ml methylene

_ ,. chloride was added dropwise. After a reaction time of 2 hours at room temperature is concentrated and chromatographed over a silica gel acid.

COPY

-τη-

• η-

Yield: 5.2 g, 5 9% of theory,

Ref. 3276 Dr.Eu/Ll

Example 19

1- C 2-cyanoethyl) -2- (3,4-dimethoxvbonzovIamino-methyl) -5-

5 methyl pyrrole

To 5.1 g (0.019 mol) 2- (3, 4-Dimo.thoxybruizoylamino-methyl) 5-methyl-pyrrole (cf. Example 16) and 15 ml (0.23 mol) of acrylonitrile are cooled with 3 ml of benzyltrimethylammonium hydroxide (4 Ö solution in methanol)

j_0 added dropwise. After 30 min, methylene chloride is added, filtered off, water was added, the methylene chloride phase was separated off and concentrated. Recrystallization from Ethyl acetate gives 4.3 g of product with a melting point of 175 to 176 C.

25 Yield: 4.3 g, 71% of theory. Analysis ·.

Calc .: C 66.0 H 6.5 N 12.8 014.7

Found: C 65.7 H 6.2 N 12.6 015.1

Example 20

1- (aminocarbonyl-methyl) -2- (phthalimido-methyl) -5-methylpyrrole
5.2g (0.02 mol) 6-phthalimido-2,5-hexanedione, 2.3g (0.02 mol) glycine hydroxide and 1.7g (0.02 mol) sodium

o acetate are stirred in 70 ml of acetic acid at 80 ° C. for 3 h and worked up as in Example 1.

Yield: 2.3 g, 39% of theory, melting point: 169 to 171 ° C. Analysis:
Calc .: ■ C 64.6 H 5.1 N 14.1 0 16.1

Found: C 64.3 H 5.2

N 14.2 0 16.3

Example 21

1- (3- (1-imidazolyl) propyl) -2- (phthalimido-methyl) -5-

methyl pyrrole hydrochloride

5.2g (0.02 mol) 6-phthalimido-2,5-hexanedione and 2.5g

Copy

Ref. 3276. 2.2 ' Dr.Eu/Ll (0.02 mol) 3 ~ (1 -imidazolyl) -propylamine were stirred in 70ml acetic acid for 2 h at 80 ° C and worked up as in Example 1. After adding ethanolic hydrochloric acid, the mixture is evaporated and recrystallized from ethanol.

Yield: 1.1 g, 14 ° of theory, melting point: 217 to 218 ° C Analysis:

Der .: C 62.4 H 5.5 N 14.6 08.3 Found: C 62.3 H 5.7 N 14.9. 08.6.

.

In the following examples, pharmaceutical Preparations described:

Example 22

] _5 tablets can be produced according to the following formulation

will:

Active ingredient 2mg

Lactose 60mg

Corn starch 30mg

2Q soluble starch 4mg

Magnesium stearate 4mg

100mg

Example 23

For the production of soft gelatine capsules with 5mg The following composition is suitable for the active ingredient per capsule:

Active ingredient Hing

Mixture of triglycerides from coconut oil 150mg

3Q capsule content 155mg

Example 24

The following formulation is suitable for the production of coated tablets

COPY

-25- Ref. 3276 Dr.Eu/Ll

Active ingredient 1mg

Corn starch 100mg

Lactose 60mg

see calcium phosphate 30mg

soluble starch 3mg

Magnesium stearate 2mg

colloidal silica 4mcr

200mg

Example] 25

^ q Injection solutions with 1 mg of active ingredient per ml can be used according to the following recipe can be produced:

Active ingredient 1.0mg

Polyethylene glycol 400 0.3mg

■ | c sodium chloride 2.7mg

Inference water to 1 ml

Example 26

Emulsions with 3mg active ingredient per 5ml can follow-2Q according to the recipe:

Active ingredient 0.06g

Neutral oil q.s.

Sodium carboxymethyl cellulose 0.6g

Polyoxyethylene stearate q.s.

«J- Pure glycerine 0.2 to 2g

Flavorings q.s.

Water (demineralized or

distilled) ad 100ml

on Example 27

Dragees containing an active ingredient according to the invention and another therapeutically active substance:

copy '

Ref. 3276 * 3θ Dr.Eu/Ll

■ ^ active ingredient 6mg

Propranolol 40mg

Milk sugar 90mg

Corn starch 90mg

see calcium phosphate 3 4mg

soluble starch. 3mg

Magnesium stearate 3mg

colloidal silica 4mg

270mg

Example 28

Dragees containing an active ingredient according to the invention and another therapeutically active substance:

Active ingredient 5mg

,,. Molsidomine 5mg

Milk sugar 60mg

Corn starch 90mg

see calcium phosphate 30mg

soluble starch 3mg

₂ _ Magnesium stearate 3mg

colloidal silica 4mg

200mg

Example 29

J ₁ . Capsules containing an active ingredient according to the invention and another therapeutically active substance: active ingredient 5mg

Prazosin 5mg

Corn starch 185mg

Claims (10)

Ref. 3276 Dr.Eu/Ll claims 1. 2- (aminomethyl) pyrrole derivatives of the general formula -R N-CH, R ^ N wherein R: hydrogen, alkyl (C ₁ -C ₅ ); R ¹ : hydrogen, alkyl (C ₁ -C ₅ ), cyano-alkyl (C ₁ -C ₄ ), alkoxy (Cj-C ^ -carbonyl, alkoxy (C ₁ -C ₄ ) -carbonyl-alkyl (C ₁ -C ₄ ), R ⁷ (R ⁸ ) N-carbonyl-alkyl (C ₁ -C ₄ ), aryl, aryl-alkyl (C ₁ -C ₄ ), i ^ where the aryl or the aryl of the aryl-alkyl also by · _ΐΛ 'H ^ log ^ n, .. Alkoxy (C ₁ -C ₄ ), Al] CyI (C ₁ -C ₄ ), R ⁴ (R ⁵ ) N-, Hydroxy,' Merkapto, "" Alkylmerkapto ( C ₁ -C ₄ ), nitro, cyano, alkoxy (C.- -, _ _Λ ..ΰ ₄ ) -carbonyl ^. Alkoxy (C ₁ -C ₄ ) -carbonyl-alkyl (C ₁ -C ₄ ) monor- may be polysubstituted, heteroaryl, heteroaryl-alkyl (C -C.), R ⁴ (R ⁵ ) NR ⁶ -, 2 3 11 R, R ·. independently of one another hydrogen, alkyl (C ₁ -C ₁ -), 10 AlkanoyKC -C ₅ ) by amino, AlkOXy (C ₁ -C ₄ ), hydroxy, alkanoyloxy (C ₁ -C ₄ ), phenyl, halogen, mono-, di- or trisubstituted alkanoyl (C "-C, -), Arylcarbonyl, through halogen, AlkOXy (C ₁ -C ₄ ), alkyl (C ₁ -C ₄ ), amino, R ⁴ (R ⁵ ) N-, hydroxy, alkanoyloxy (C ₁ -C.), Merkapto, alkyl merkapto (C ₁ -C ₄ ), nitro, cyano, alkoxy (C ₁ -C ₄ ) carbonyl, amidosulfonyl mono- or polysubstituted arylcar- 2 3 bonyl, heteroarylcarbonyl, or R and R together are vicinales Arylendxcarbonyl, vicinal heteroarylene-dicarbo- nyl, arylene-1-sulfonyl-2-carbonyl, alkylene (C _o -C _Q ) -dicar- bonyl, alkenylene (C ₄ -C _R ) -dicarbonyl, the carbon chain of the alkylene and alkenylene dicarbonyl also 4th
interrupted one or more times by -0-, -S-, -N (R) - or can contain a spiro atom to which a 4-, 5-, 6- or 7-ring can be attached, COPV \ Ref. 3276 Dr.Eu/Ll ^J : hydrogen, alkyl (C ₁ -C ₄ ), R ⁶ : alkylene (C -C), 7 8 ι »
R ₁ R: independently of one another hydrogen, alkyl (C. -C.) or, together with the nitrogen atom to which they are attached, form a 5- or 6-membered, saturated heterocyclic ring which also has -0- or N - contain R ⁹ can R ": hydrogen, alkyl (C ₁ -C ₄ ), AlkOXy (C ₁ -C ₄ ), phenyl, alkyl (C ₁ -C -) - phenyl, alkoxy (C ₁ -C.) - phenyl, as well as its acid addition number, whereby for those cases in which R 2 3 methyl or ethyl and at the same time R * and R together 1,2-phenylenedicarbonyl mean, R no ethoxycarbonylmethyl, Ethoxy-carbonyl or methoxy-carbonyl-phenyl can be. 2. 2- (Amino-methyl) -pyrrole derivatives according to claim 1, characterized characterized in that R is methyl. 3. 2- · (Amino-methyl) -pyrrole derivatives according to Claim 1 and / or 2, characterized in that R is hydrogen, 2-dimethylaminoethyl, 3,4-dimethoxyphenyl-ethyl, 4,5-dimethoxy-2-methoxycarbonyl-phenyl, Imidazolyl (-4 (5)) ethyl, Methoxycarbonyl-methyl, acetamino-ethyl, cyanoethyl, Means 3- (1-imidazolyl) propyl, aminocarbonylmethyl. 4. 2- (Amino-methyl) -pyrrole derivatives according to one or more of claims 1 to 3, characterized in that 2 3
R, R independently of one another are hydrogen, 3,4-dimethoxybenzoyl, acetyl, nicotinoyl, or together with the N atom to which they are bonded, phthalimides). 5. 2- (Amino-methyl) pyrrole derivatives according to claim 1, characterized characterized in that R is methyl, R is hydrogen, dimethylaminoethyl, 3,4-dimethoxyphenyl-ethyl, 4,5-dimeth- COPY . 3 Ref. 3276 Dr.Eu/Ll oxy-2-methoxy-carbonyl-phenyl, imidazolyl (-4 (5)) -ethyl, Amino-carbonyl-methyl, methox-carbonyl-methyl, acetyl 2 1 aminoethyl, 3- (1-imidazolyl) propyl, cyanoethyl, R, R ° independently of one another hydrogen, 3,4-dimethoxybenzoyl, Acetyl, Nicotinoyl, or together with the N atom to the they are bound to mean phthalimido, and their pharmacological acceptable acid addition salts. 6. 1- (Methoxycarbonyl-methyl) -2- (phthalimido-methyl) -5-methyl-pyrrole and its pharmakologir.ch acceptable acid addition salts. 7. Process for the preparation of the compounds of the formula I according to one or more of claims 1 to 6, characterized in that a 1,4-diketone of the formula II RR ³ N-CH ₂ -CO-CH ₂ CH ₂ -CO-R with an amine of the formula III
20th is reacted in an inert solvent or solvent mixture at temperatures from 20 to 200 ⁰ C. 8. Use of the compounds of claims 1 to 6 or their pharmacologically acceptable acid addition salts as nootropic agents, especially for combating and preventing diseases caused by a restriction of brain function and. for the treatment of cerebral aging. 9. Method of treating people to control and prevent diseases caused by a restriction the brain function, and for the treatment of cerebral aging processes, thereby COPY I Ref. 3276 " Dr.Eu/Ll ■, indicates that an effective dose of a compound of claims 1 to 6 or their pharmacologically acceptable acid addition salts is administered. c 10. Pharmaceutical preparation, characterized in that that it is a compound of claims 1 to 6 or a pharmaceutically acceptable acid addition salt as active ingredient thereof, along with a pharmaceutically acceptable tray first off and gcgrbenenf al Ir. phcirma / .fully acceptable , ₀ additives and possibly one or more other pharmacological active loops included. BATH ORIGINAL COPY _J