HK1051855B - Substituted pyrrole mannich bases to combat pain and allergic reactions - Google Patents

Description

The invention relates to substituted pyrrol-mannitic bases, methods of their manufacture, medicinal products containing these compounds and the use of these compounds in the manufacture of medicinal products.

Pain is one of the basic symptoms in the clinic. There is a worldwide need for effective pain therapies. The urgent need for patient-centred and targeted treatment of chronic and non-chronic pain conditions, including successful and satisfactory pain management for the patient, is documented in the large number of scientific papers that have recently appeared in the field of applied analgesics or basic research on nociception.

Traditional opioids, such as morphine, are effective in treating severe to very severe pain, but have side effects such as respiratory depression, vomiting, sedation, constipation and development of tolerance.

Tramadol hydrochloride - (1RS, 2RS) - 2-[dimethylamino) methyl]-1- ((3-methoxyphenyl) cyclohexanol - is a special class of centrally acting analgesic because it produces a strong analgesic effect without the known side effects of opioids (J. Pharmacol. Exptl.

EP 038 536 and US 5 935 990 describe anti-inflammatory medicinal products with a pyrrole base structure.

The present invention was therefore intended to provide new compounds which are particularly suitable as active substances in medicinal products.

These active substances are intended in particular for the treatment of pain and inflammatory and allergic reactions, drug and/or alcohol abuse, diarrhoea, gastritis, ulcers, cardiovascular diseases, urinary incontinence, depression, shock, migraines, narcolepsy, obesity, asthma, glaucoma, hyperkinetic syndrome, lack of movement, bulimia, anorexia, catalepsy, anxiety, increased alertness and/or increased libido.

According to the invention, this task is solved by providing substituted pyrrol-manichloidal bases of the general formula I below, which have a marked analgesic effect, especially in chronic pain, and are also used to treat inflammatory and allergic reactions, drug and/ or alcohol abuse, diarrhoea, gastritis, ulcers, cardiovascular diseases, urinary incontinence, depression, shock states, migraines, narcolepsy, obesity, asthma, glaucoma, hyperkinetic syndrome, loss of motivation, bulimia, anorexia, epilepsy, anxiety, vignette and/ or catabolism.

Err1:Expecting property name enclosed in double quotes: line 1 column 754 (char 753)CH2CO(OR11), COR15, means a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably = H, a C1-6 alkyl residue or an aryl residue bound by a C1-2 alkyl group, preferably = H, R4 = an unsubstituted phenyl residue or a phenyl residue at least simply substituted with C1-4 alkyl, C1-3 alkoxy, halogen, CF3, CN, O-phenyl or OH, preferably an unsubstituted phenyl residue or at least simply substituted with methyl, tert-butyl, methoxy, F, Cl, Br, or CF3 phenyl residues, in particular preference being given to an unsubstituted phenyl residue or a 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-methoxyphenyl, 2-methoxyphenyl, 2-methoxyphenyl, 2-methoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-methoxyphenyl, 4-methoxyphenyl, 4-methoxyphenyl, 4-methoxyphenyl, 4-methoxyphenyl, 4-methoxyphenyl, 4-methoxyphenyl, 4-methoxyphenyl, 4-methoxyphenyl, 4-methoxyphenyl, 4-methoxyphenyl, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 2-methoxy, 2-methoxy, 2-methoxy, 2-methoxy, 2-methoxy, 2-methoxy, 2-methoxy, 2-methoxy, 2-methoxy, 2-methoxy, 2-methoxy, 2-methoxy, 2-methoxy, 2-methoxy, 4-methoxy, 4-methoxy, 4-methoxy, 4-metThe term 'methyl alcohol' means a substance which is a mixture of two or more of the substances listed in Annex I to Regulation (EC) No 1907/2006, and which is classified in Annex II to that Regulation as a substance which is classified in Annex II to that Regulation. R5, R6, equal to or different, means a branched, unbranched, saturated, unsaturated, unsubstituted or at least simply substituted C1-6 alkyl residue or an unsubstituted or at least simply substituted phenyl, benzyl or phenethyl residue, preferably a saturated, unsubstituted or at least simply substituted C1-6 alkyl residue, preferably a CH3 residue, or R5 and R6 together (CH2) n with n = an integer from 3 to 6 or (CH2) 2O ((CH2) 2), preferably (Ch2) n with n = 4 or 5, means R7 = H, COR12, a C1-10 alkyl, an aryl,a heteroaryl means an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably a C1-6 alkyl or an aryl residue bound by a C1-2 alkyl group, R8 = H, means a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably a C1-6 alkyl or an aryl residue bound by a C1-2 alkyl group, R9 = H, COR13 means a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably a C1-6 alkyl or an aryl residue bound by a C1-2 alkyl group, R10 = H, means a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably a C1-6 alkyl or an aryl residue bound by a C1-2 alkyl group,Other R11 = H, means a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably a C1-6 alkyl or an aryl residue bound by a C1-2 alkyl group, R12 = means a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably a C1-6 alkyl or an aryl residue bound by a C1-2 alkyl group, R13 = means a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably a C1-6 alkyl or an aryl residue bound by a C1-2 alkyl group, R14 = H, means a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably a C1-6 alkyl or an aryl residue bound by a C1-2 alkyl group,Err1:Expecting ',' delimiter: line 1 column 558 (char 557)

Alkyl residues are preferably at least simple with halogen, OH, CN or CF3, and especially preferably with F, Cl, Br or OH substituted hydrocarbon residues. If these contain more than one substituent, these substituents may be the same or different. The alkyl residues may be branched, unbranched or cyclic.

An aryl residue is preferably at least simple, with an OH, a halogen, preferably F, Br or Cl, a CF3, a CN, a C1-6 alkyl, a C1-6 alkoxy or a phenyl residue substituted for phenyl or naphthyl residues. The unsubstituted or substituted phenyl residues may also be condensed with further rings. In particular, the aryl residues are preferably 2-, 3-, 4-bromphenyl, 4-brom-2-fluorphenyl, 5-brom-2-fluorphenyl, 3-brom-4-fluorphenyl, 4-fluorethyl-butyl-4-methyl, 2-cetoxy-fluorethyl, 2-cetoxy-fluorethyl, 2-cetoxy-fluorethyl, 2-cetoxy-phenylen, 2-cetoxy-pheny, 2-cetoxy-pheny, 2,3-diphenyl, 2,4-diphenyl, 2,3-diphenyl, 2,4-diphenyl, 2,3-diphenyl, 2,4-diphenyl, 2,3-diphenyl, 2-dimethyl, 2,4-diphenyl, 2-dimethyl, 2,4-diphenyl, 2-dimethyl, 2,4-diphenyl, 2-dimethyl, 2,4-diphenyl, 2-dimethyl, 2-dimethyl, 2,4-diphenyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dimethyl, 2-dim

A heteroaryl residue is an aromatic compound containing at least one heteroatom, preferably nitrogen and/or oxygen and/or sulphur, preferably nitrogen and/or oxygen, which may preferably be substituted with a halogen, a CF3, a CN or an OH residue.

The following substituted pyrrol-mannitol bases are particularly preferred: The term 'methyl methacrylate' means a compound containing a single methyl methacrylate with a specific structure and functional group, which is a compound that is a mixture of methacrylate and methyl methacrylate, and which is a mixture of methacrylate and methyl methacrylate.

The invention also relates to methods for the production of substituted pyrrole-mannitic bases of general formula I, which are characterized by the fact that they are used in the manufacture of Aldehyde aromatic compounds of general formula II where R4 has the meaning according to the general formula I, in solution, preferably in an organic solvent, preferably in toluene, in the presence of a base, preferably potassium carbonate or boric anhydride, at a temperature of preferably - 10 °C to +110 °C with secondary amines of general formula III, where R5 and R6 have the meanings given in the General Formula I, to amines of the General Formula IV and those amine compounds of generic formula IV without further purification with acid chlorides,Err1:Expecting ',' delimiter: line 1 column 436 (char 435)

Preferably, the synthesis of the substituted pyrrol-mannitic bases of the invention is performed on an automatic Zymark plant as described in Figures 1 and 2 below.

The compounds of general formula I may be transferred to their salts in a manner known to the professional by means of physiologically compatible acids, preferably hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, formic acid, acetic acid, oxalic acid, amber acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid.

The pyrrol-manichoke bases of the generic formula I substituted according to the invention are toxicologically safe and therefore suitable pharmaceutical active substances.

The invention also relates to medicinal products containing as active substance at least one substituted pyrrol-mannitic base of general formula I and, where appropriate, other active substances and/or excipients; preferably, the medicinal product may also contain as active substance a mixture of enantiomers of at least one substituted pyrrol-mannitic base of general formula I, preferably not containing the enantiomers in equimolar amounts; in particular, the relative proportion of one of the enantiomers is preferably 5 to 45 mole, and preferably 10 to 40 mole, depending on the mixture of the enantiomers.

Preferably, the medicinal products are used for the treatment/ control of pain, in particular chronic pain, and/ or inflammatory and/ or allergic reactions and/ or drug and/ or alcohol abuse and/ or diarrhoea and/ or gastritis and/ or ulceration and/ or cardiovascular disease and/ or urinary incontinence and/ or depression and/ or shock and/ or migraine and/ or narcolepsy and/ or overweight and/ or asthma and/ or glaucoma and/ or hyperkinetic syndrome and/ or loss of motivation and/ or bulimia and/ or anorexia and/ or epilepsy and/ or cataxiolysis and/ or libido balance and/ or for the purpose of monitoring and/ or reducing libido.

The use of at least one generic formula I pyrrol-manich base substituted in accordance with the invention for the manufacture of a medicinal product for the treatment/control of pain, in particular chronic pain, and/or inflammatory and/or allergic reactions and/or drug abuse and/or abuse and/or diarrhoea and/or gastritis and/or ulceration and/or cardiovascular disease and/or urinary incontinence and/or depression and/or shock and/or migraine and/or narcolepsy and/or overweight and/or asthma and/or glaucoma and/or hyperkinetic syndrome and/or impulsivity and/or bulimia and/or anorexia and/or cataclysmic cataclysms is also the subject of this invention and is also for the purpose of the present study and the release of the product.

For the preparation of pharmaceutical formulations, the use of auxiliary substances depends on whether the product is intended to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or topically, for example on infections of the skin, mucous membranes and eyes. For oral application, the preparations are in the form of tablets, drops, capsules, granules, drops, syrups and syrups, the parenteral, inhalation and inhalation solutions, and easily reconstitutable suspensions and syrups.

The pyrrol-mannitic bases of the generic formula I according to the invention in a soluble depot or in a patch, where appropriate with the addition of skin-penetrating agents, are suitable percutaneous application preparations.

The dose to be given to the patient will vary depending on the patient' s weight, the type of application, the indication and the severity of the disease.

Pharmacological tests: In vitro tests

The wide efficacy testing of the pyrrol-mannitic bases of the invention was performed using the standard high throughput screening methods described in John P. Devlin, High Throughput Screening, 1997, Marcel Dekker Inc. They are hereby introduced as a reference and are therefore part of the disclosure.

The action of the pyrrol-mannitic bases of the invention is determined in particular by affinity for the N-methyl-D-aspartate (NMDA) receptor family, α-adrenergic receptors and opioid receptors.

The studies on serotonin reuptake inhibition (5-HT-uptake inhibition) were carried out according to the methods described in M. Ch. Frink, H.-H.-Hennies, W. Englberger, M. Haurand and B. Wilffert, Pharmaceutical Research/Drug Res. 46 (III), 11, 1996, pp. 1029-1036.

Err1:Expecting ',' delimiter: line 1 column 173 (char 172)

The following characteristics were determined for the 5-HT transporter: The test chemical is used to determine the concentration of 5-HT:

The results of the studies are each given as the mean of 2 parallel tests.

2) Analgesia test in the mouse writhing test

The enhanced analgesic study was performed in the mouse with phenylquinone-induced writhing (modified from I.C. Hendershot, J. Forsaith, J. Pharmacol. Exp. Ther. 125, 237-240 (1959)), using male NMRI mice weighing 25-30 g. Groups of 10 animals were administered 0.3 ml/mouse of 0.02 % aqueous solution of phenylquinone (phenylbenzoquinone, Fa. Sigma, Deisenhofen; preparation of the solution under addition of 5% ethanol and storage in a bath at 45 °C) 10 minutes after intravenous administration of the test substances. The number of animals was individually administered.

The substances were tested at the standard dose of 10 mg/kg. The inhibition of the wrist-wringing reactions by one substance was calculated according to the following formula:

The following examples are intended to illustrate the invention but do not limit the general idea of the invention.

Examples: General synthesis rules for the preparation of aminal compounds of general formula IV: General rule of synthesis 1:

The solution was then stirred for another 30 minutes at 80°C, then cooled to room temperature and mixed with 0.57 potassium carbonate equivalents, forming two separate phases, with the aqueous phase extracted three times with 100 ml of acetic acid each. The combined organic phases were dried over potassium carbonate and released from the solvent. The resulting amine compounds of general formula IV were then incorporated into the subsequent reactions without further stirring.

General rule of synthesis 2:

A solution of 1.0 equivalent of the respective aromatic aldehyde compound of general formula II in 80 ml of absolute toluene was given 1.6 equivalent of boric anhydride. A solution of 2.4 equivalent of a secondary amine of general formula III in 85 ml of absolute toluene was then added under strong stirring. The start of the reaction was detected by a significant increase in temperature. The reaction solution was then stirred for another two hours at a temperature of 45 to 50°C. After cooling to room temperature, the excess boric acid anhydride was separated and the filtrate removed from the solution. The resulting amine compounds of general formula IV were incorporated into the subsequent reactions without further stirring.

General synthesis rule for the synthesis of iminium salts of general formula V: General rule of synthesis 3:

A solution of 1.0 acetyl chloride equivalent in absolute diethyl ether was slowly dripped to 1.0 equivalent of an ice-cold solution or suspension of the amine compound of general formula IV produced according to the general synthesis rule 1 or 2. The reaction mixture was then stirred overnight at about 20 °C. This produced precipitation which was sucked under nitrogen and then dried in the oil pump. The resulting iminium salts of general formula V were used in the following reactions without further purification.

General synthesis rule for the synthesis of pyrrol-mannitic bases of general formula I: General synthesis rule 4:

The pyrrol-mannitic bases of the invention were synthesized on an automatic Zymark plant as shown in Figure 1 and Figure 2 respectively:

Figure 1 comprises a capper station (point 1) for closing the reaction tubes, a robot 1 (point 2) and a robot 2 (point 3) where robot 1 moves the reaction tubes and robot 2 pipettes the reagents into the reaction tubes, a tempered reactor block (point 4), stirring blocks (point 5) and a filtration station (point 6) where the reaction solution is filtered.

Figure 2 also includes a robot 1 (point 1) and a robot 2 (point 2) which both bring the vessels with the reaction products to the various stations where the synthesis products from the automatic synthesis plant are processed as shown in Figure 1.

For the synthesis, a round glass tube (diameter 16 mm, length 125 mm) with threads was manually stirred and sealed with a screw cap with septum on the capper station (figure 1) as shown in Figure 1. The tube was placed by robot 1 (figure 2) in the reactor block, which had been cooled to 0°C. Robot 2 (figure 3) pipetted the following reagents in succession: (1) 1 ml of a 0.1 M solution of pyrrol or a substituted pyrrol compound of the general formula VI in acetoneitrile. (2) 1.2 ml of a 0.1 M solution of an imini acetic of the general formula Vetonitrile.

The iminium salts were prepared as shown in the following examples. The reaction mixture was then stirred at 18°C in one of the stirring blocks (fig. 5) for 960 min. The reaction solution was then filtered at the filtration station (fig. 6). The solvent was first removed in a vacuum centrifuge. The rack containing the tubes was then manually placed on a pre-excavator (fig. 3) as shown in Fig. 2. There the reaction mixture was transferred with 2 ml of acetone. The spin reactor (fig. 4) was thoroughly mixed for 10 minutes and finally the acetone was decanted. This process was carried out three more times and the solvent was removed in a vacuum centrifuge.

Example 1:

The following substances are to be classified in the same heading as the active substance:

Stage one 4- (methylbenzylidene) -morpholine 4-ium chloride, whether or not chemically defined

The implementation of 18.8 ml (0.216 mol) morpholine and 12.4 g (0.09 mol) 2-methoxybenzaldehyde according to the general synthesis rule 2 and the subsequent reaction with 5.3 ml (0.110 mol) acetyl chloride according to the general synthesis rule 3 yielded 7.61 g (corresponding to 38 % of the theoretically calculated yield) of 4-methoxybenzylides) morpholine-4-ium chloride.

Stage two. The following substances are to be classified in the same heading as the active substance:

It was produced according to the general synthesis rule 4 from 1-phenyl-1H-pyrrol and 4- ((2-methoxybenzylides) morpholine-4-ium chloride.

An ESI MS has been included for characterisation: The number of employees in the company is not limited to the following:

Example 2:

The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 1- (-2-fluorophenyl) - 1H-pyrrol and 4- (-2-methoxybenzylides) -morpholine-4-ium chloride, which was produced according to example 1.

An ESI MS has been included for characterisation: The number of employees in the company is calculated as follows:

Example 3:

The following substances are to be classified in the same heading as the active substance:

Stage one 1- (β-methoxybenzylides) piperidinium chloride, whether or not chemically defined

The implementation of 18.4 g (0.216 mol) piperidine and 25.9 g (0.090 mol) 2-methoxybenzaldehyde according to the general synthesis rule 2 and the subsequent reaction with 5.3 ml (0.11 mol) acetyl chloride according to the general synthesis rule 3 yielded 13.4 g (corresponding to 62% of the theoretically calculated yield) of 1-methybenzylidene) piperidinium chloride.

Stage two. The following substances are to be classified in the same heading as the active substance:

The product was produced according to the general synthesis rule 4 from 1-furan-2-yl-1H-pyrrol and 1- ((2-methoxybenzylides) piperidinium chloride.

An ESI MS has been included for characterisation: The Commission has also received information from the Member States on the implementation of the measures taken by the Member States.

Example 4:

The following substances are to be classified in the same heading as the active substance:

Stage 1 1- (β-methoxybenzylides) pyrrolidinium chloride, whether or not chemically defined

The implementation of 6.9 ml (0.084 mol) pyrrolidine and 4.8 g (0.035 mol) 2-methoxybenzaldehyde according to the general synthesis rule 2 and subsequent reaction with 2.1 ml (0.035 mol) acetyl chloride according to the general synthesis rule 3 yielded 6.2 g (corresponding to 78% of the theoretically calculated yield) of 1- (((2-methoxybenzylides) pyrrolidinium chloride.

Stage two. The following substances are to be classified in the same heading as the active substance:

The product was produced according to the general synthesis rule 4 from 1-phenyl-1H-pyrrol and 1- ((2-methoxybenzylides) pyrrolidinium chloride.

An ESI MS has been included for characterisation: The Commission has also received information from the Member States on the implementation of the measures taken by the Member States.

Example 5:

4-{2-[2-Methoxyphenyl) -piperidin-1-yl-methyl]-pyrrol-1-yl-methyl}-pyridine

Production was carried out according to the general synthesis rule 4 from 4-Pyrrol-1-yl-methyl pyridine and 1- ((2-Methoxybenzylides) piperidinium chloride, which was produced according to example 3.

An ESI MS has been included for characterisation: The Commission has also received information from the Member States on the implementation of the measures taken by the Member States.

Example 6:

The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 1- ((4-fluoro-phenyl) - 1H-pyrrol and 1- ((2-methoxy-benzylides) -pyrrolidinium chloride, which was produced according to example 4.

An ESI MS has been included for characterisation: The number of employees in the company is not limited to the following:

Example 7:

The following substances are to be classified in the same heading as the active substance:

Stage 1 Other, of a kind used for the manufacture of rubber or plastics

The implementation of 17,0 ml (0.135 mol) of dimethylamine solution and 6,8 g (0.050 mol) of 2-methoxybenzaldehyde according to the general synthesis rule 1 and subsequent reaction with 3,0 ml (0.050 mol) of acetyl chloride according to the general synthesis rule 3 yielded 4,8 g (48% of the theoretically calculated yield) of 2-methoxybenzylidene dimethylammonium chloride.

Stage two. The following substances are to be classified in the same heading as the active substance:

It was produced according to the general synthesis rule 4 from 1-ethyl-1H-pyrrol and (2-methoxybenzylides) dimethylammonium chloride.

An ESI MS has been included for characterisation: The number of employees in the company is calculated as follows:

Example 8:

3-{2-[dimethylamino- ((2-methoxyphenyl) -methyl]-pyrrol-1-yl}-propionitrile

The manufacture was carried out according to the general synthesis rule 4 from 3-Pyrrol-1-yl-propionitrile and (2-Methoxybenzylids) dimethylammonium chloride, which was produced according to example 7.

An ESI MS has been included for characterisation: The number of employees in the company is not limited to the following:

Example 9:

Dimethyl [phenyl- ((1-phenyl-1H-pyrrol-2-yl) -methyl]amine

Stage one Benzylides and their salts

The implementation of 32.0 ml (0.213 mol) of dimethylamine solution and 8.0 ml (0.079 mol) of benzaldehyde according to the general synthesis rule 1 and the subsequent reaction with 4.7 ml (0.079 mol) of acetyl chloride according to the general synthesis rule 3 yielded 9.5 g (corresponding to 70.7% of the theoretically calculated yield) of benzylidene dimethyl ammonium chloride.

Stage two. Dimethyl [phenyl- ((1-phenyl-1H-pyrrol-2-yl) -methyl]amine

It was produced according to the general synthesis rule 4 from 1-phenyl-1-H-pyrrol and benzylidene dimethyl ammonium chloride.

An ESI MS has been included for characterisation: The number of employees in the company is not limited to the following:

Example 10:

The following substances are to be classified in the same heading as the active substance:

Production was carried out according to the general synthesis rule 4 from 2-pyrrol-1-yl-phenylamine and benzylidene dimethyl ammonium chloride, which was produced according to example 9.

An ESI MS has been included for characterisation: The number of employees in the company is calculated as follows:

Example 11:

[1-Benzyl-1H-pyrrol-2-yl) -phenylmethyl]-dimethylamine

The product was produced according to the general synthesis rule 4 from 1-benzyl-1H-pyrrol and benzylidene dimethyl ammonium chloride, which was produced according to example 9.

An ESI MS has been included for characterisation: The Commission has also received information from the Member States on the implementation of the measures taken by the Member States.

Example 12:

The following substances are to be classified in the same heading as the active substance:

Production was carried out according to the general synthesis rule 4 from 2-pyrrol-1-yl thiobenzamide and benzylidene dimethyl ammonium chloride, which was produced according to example 9.

An ESI MS has been included for characterisation: The number of employees in the company is not limited to the following:

Example 13:

[1-[tert-butyl-1H-pyrrol-2-yl) -phenylmethyl]-dimethylamine

The product was produced according to the general synthesis rule 4 from 1-tert butyl-1H-pyrrol and benzylidene dimethyl ammonium chloride, which was produced according to the example 9.

An ESI MS has been included for characterisation: The number of employees in the company is not limited to the following:

Example 14:

The following substances are to be classified in the same heading as the active substance:

Stage one 1- (β-methylbenzylides) pyrrolidinium chloride

The implementation of 8,2 ml (0.100 mol) pyrrolidine and 7,0 g (0.050 mol) 2-methylbenzaldehyde according to the general synthesis rule 2 and subsequent reaction with 3,9 g (0.050 mol) acetyl chloride according to the general synthesis rule 3 yielded 6,6 g (63% of the theoretically calculated yield) of 1- ((2-methylbenzylides) pyrrolidinium chloride.

Stage two. The following substances are to be classified in the same heading as the active substance:

It was produced according to the general synthesis rule 4 from 2-pyrrol-1-yl-phenylamine and 1- ((2-methylbenzylides) pyrrolidinium chloride.

An ESI MS has been included for characterisation: The number of employees in the company is not limited to the following:

Example 15:

The following substances are to be classified in the same heading as the active substance:

Stage one It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The conversion of 16.4 ml (0.200 mol) of pyrrolidine and 10.1 ml (0.100 mol) of benzaldehyde according to the general synthesis rule 2 and subsequent reaction with 6.0 ml (0.100 mol) of acetyl chloride according to the general synthesis rule 3 yielded 14.1 g (corresponding to 72% of the theoretically calculated yield) of 1-benzylidene pyrrolidinium chloride.

Stage two. The following substances are to be classified in the same heading as the active substance:

The product was produced according to the general synthesis rule 4 from 1-Methyl-1H-pyrrol and 1-Benzylidene-pyrrolidinium chloride.

An ESI MS has been included for characterisation: The number of employees in the company is not limited to the following:

Example 16:

Dimethyl[[[[1-methyl-1H-pyrrol-2-yl) -phenylmethyl]amine

The product was produced according to the general synthesis rule 4 from 1-Methyl-1H-pyrrol and benzylidene dimethyl ammonium chloride, which was produced according to example 9.

An ESI MS has been included for characterisation: The number of employees in the company is limited to the following:

Example 17:

The following substances are to be classified in the same heading as the active substance:

Stage one The following substances are to be classified in the same heading as the product:

The implementation of 9.5 ml (0.096 mol) piperidine and 4.7 ml (0.040 mol) 2-methylbenzaldehyde according to the general synthesis rule 2 and the subsequent reaction with 2.4 ml (0.040 mol) acetyl chloride according to the general synthesis rule 3 yielded 5.8 g (corresponding to 65% of the theoretically calculated yield) of 1- (b) 2-methylbenzylides) piperidinium chloride.

Stage two. The following substances are to be classified in the same heading as the active substance:

It was produced according to the general synthesis rule 4 from 2-pyrrol-1-yl-thiobenzamide and 1- ((2-methylbenzylides) piperidinium chloride.

An ESI MS has been included for characterisation: The number of employees in the company is limited to the following:

Example 18:

The following substances are to be classified in the same heading as the active substance:

Stage one Dimethyl (((2-methylbenzylides) ammonium chloride

The implementation of 14.0 ml (0.108 mol) of diethylamine solution and 4.6 ml (0.040 mol) of 2-methylbenzaldehyde according to the general synthesis rule 1 and the subsequent reaction with 2.4 ml (0.040 mol) of acetyl chloride according to the general synthesis rule 3 yielded 5.3 g (corresponding to 73% of the theoretically calculated yield) of dimethyl (((2-methylbenzylides) ammonium chloride.

Stage two. The following substances are to be classified in the same heading as the active substance:

It was produced according to the general synthesis rule 4 from 2-pyrrol-1-yl-thiobenzamide and dimethyl ((2-methylbenzylides) ammonium chloride.

An ESI MS has been included for characterisation: The Commission has also received information from the Member States on the implementation of the measures taken by the Member States.

Example 19:

The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 2-Pyrrol-1-yl-thiobenzamide and 1-Benzylidene-pyrrolidinium chloride, which was produced according to example 15.

An ESI MS has been included for characterisation: The Commission has also received information from the Member States on the progress made in the implementation of the measures.

Example 20:

The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 2-Pyrrol-1-yl-thiobenzamide and 1- ((2-Methoxybenzylides) pyrrolidinium chloride, which was produced according to example 4.

An ESI MS has been included for characterisation: The number of employees in the company is estimated at approximately 5 000 in the year 2000.

Example 21:

2-[3,4-dimethoxyphenyl) -morpholine-4-yl-methyl]-pyrrol-1-yl}-thiobenzamide

Stage one 4- (2,3-dimethoxybenzylides) morpholine 4-ium chloride

The conversion of 7.3 ml (0.084 mol) of morpholine and 5.8 g (0.035 mol) of 2,3-dimethoxybenzaldehyde according to the general synthesis rule 2 and subsequent reaction with 2,1 ml (0.035 mol) of acetyl chloride according to the general synthesis rule 3 yielded 5,6 g (corresponding to 59% of the theoretically calculated yield) of 4-dimethoxybenzylid) morpholine-4-ium chloride.

Stage two. 2-[3,4-dimethoxyphenyl) -morpholine-4-yl-methyl]-pyrrol-1-yl}-thiobenzamide

It was produced according to the general synthesis rule 4 from 2-pyrrol-1-yl-thiobenzamide and 4- (2,3-dimethoxybenzylides) morpholine-4-ium chloride.

An ESI MS has been included for characterisation: The number of employees in the company is estimated at around 5 million.

Example 22: 3-{2-[2-fluorophenyl) -piperidine-1-yl-methyl]-pyrrol-1-yl}-propionitrile

The manufacture was carried out according to the general synthesis rule 4 from 3-Pyrrol-1-yl-propionitrile and 1- (-2-fluorobenzyl) piperidinium chloride, which was produced from 2-fluorobenzaldehyde and piperidine as described in example 3.

Example 23: The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 1-phenyl-1H-pyrrol and 1- (4-bromo-benzylides) pyrrolidinium chloride, which was produced from 4-bromobenzaldehyde and pyrrolidine as described in example 4.

Example 24: The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 2-Pyrrol-1-yl-phenylamine and 1- (3-methylbenzylides) piperidinium chloride, which was produced from 3-methylbenzaldehyde and piperidine as described in example 3.

Example 25: The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 4-Pyrrol-1-yl-methyl pyridine and 1- ((4-Brom-2-Fluor-benzylides) pyrrolidinium chloride, which was produced from 4-Brom-2-Fluorbenzaldehyde and pyrrolidine as described in example 4.

Example 26: The following substances are to be classified in the same heading as the active substance:

Production was carried out according to the general synthesis rule 4 from 4-Pyrrol-1-yl-methyl pyridine and 1- (3-phenoxy-benzylides) piperidinium chloride, which was produced from 3-phenoxybenzaldehyde and piperidine as described in example 3.

Example 27: The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 2-Pyrrol-1-yl-thiobenzamide and 1- (3-phenoxybenzylides) piperidinium chloride, which was produced from 3-phenoxybenzaldehyde and piperidine as described in example 3.

Example 28: The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 2-Pyrrol-1-yl-chlorethane and 1- (4-Fluor-benzylides) piperidinium chloride, which was produced from 4-Fluor-benzaldehyde and piperidine as described in example 3.

Example 29: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The manufacture was carried out according to the general synthesis rule 4 from 2-Pyrrol-1-yl ethanol and 1- (3-Phenoxybenzylids) piperidinium chloride, which was produced from 3-Phenoxybenzaldehyde and piperidine as described in example 3.

Example 30: 3-[2-[piperidin-1-yl-m-tolyl-methyl) -pyrrol-1-yl]-propane-1-ol, whether or not chemically defined

The manufacture was carried out according to the general synthesis rule 4 from 3-Pyrrol-1-yl-propanol and 1- (3-methylbenzylides) piperidinium chloride, which was produced from 3-methylbenzaldehyde and piperidine as described in example 3.

Example 31: The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 3-Pyrrol-1-yl-propanol and 1- (4-fluorobenzyl) piperidinium chloride, which was produced from 4-fluorobenzaldehyde and piperidine as described in example 3.

Example 32: The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 1-methyl-1H-pyrrol and 1- (4-fluorobenzyl) piperidinium chloride, which was produced from 4-fluorobenzaldehyde and piperidine as described in example 3.

Example 33: The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 1-methyl-1H-pyrrol and 1- (4-trifluoromethylbenzylides) piperidinium chloride, which was produced from 4-trifluoromethylbenzaldehyde and piperidine according to example 3.

Example 34: The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 2-Pyrrol-1-yl-phenylamine and 1- ((2-Chlor-6-Fluor-benzylides) -Pyrrolidinium chloride, which was produced from 2-Chlor-6-Fluorbenzaldehyde and Pyrrolidine as described in example 4.

Example 35: The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 4-Pyrrol-1-yl-methyl pyridine and 1- ((3-brombenzylides) pyrrolidinium chloride, which was produced from 3-brombenzaldehyde and pyrrolidine as described in example 4.

Example 36: The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 4-Pyrrol-1-yl-methyl pyridine and 1- ((3-Brom-4-Fluorbenzylides) pyrrolidinium chloride, which was produced from 3-Brom-4-Fluorbenzaldehyde and pyrrolidine as described in example 4.

Example 37: The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 4-Pyrrol-1-yl-methyl pyridine and 1- ((2-Chlor-6-Fluor-benzylides) -Pyrrolidinium chloride, which was produced from 2-Chlor-6-Fluorbenzaldehyde and Pyrrolidine as described in example 4.

Example 38: The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 4-Pyrrol-1-yl-methyl pyridine and 1- ((4-Cyano-benzylides) pyrrolidinium chloride, which was produced from 4-Cyanobenzaldehyde and pyrrolidine as described in example 4.

Example 39: The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 1- (4-fluorophenyl) - 1H-pyrrol and 1- (3-bromo-4-fluorobenzyl) - pyrrolidinium chloride, which was produced from 3-bromo-4-fluorobenzaldehyde and pyrrolidine as described in example 4.

Example 40: 2-[5-[bromo-2-fluorophenyl]-pyrrolidine-1-yl-methyl]-pyrrol-1-yl] benzoic acid, whether or not chemically defined

The manufacture was carried out according to the general synthesis rule 4 from 1-benzoic acid-1H-pyrrole and 1- ((5-bromo-2-fluorobenzyl) -hydro) pyrrolidinium chloride, which was produced from 5-bromo-2-fluorobenzaldehyde and pyrrolidine as described in example 4.

Example 41: 2-[5-[bromo-2-fluorophenyl]-pyrrolidine-1-yl-methyl]-pyrrol-1-yl]-thiobenzamide, whether or not chemically defined

The manufacture was carried out according to the general synthesis rule 4 from 2-Pyrrol-1-yl-thiobenzamide and 1- ((5-Brom-2-Fluor-benzylides) pyrrolidinium chloride, which was produced from 5-Brom-2-Fluorbenzaldehyde and pyrrolidine as described in example 4.

Example 42: The following substances are to be classified in the same heading as the active substance:

The manufacture was carried out according to the general synthesis rule 4 from 1-tert butyl-1H-pyrrol and 1- ((4-tert butyl benzylides) pyrrolidinium chloride, which was produced from 4-tert butyl benzaldehyde and pyrrolidine as described in example 4.

Pharmacological tests: In vitro tests

The efficacy of the pyrrol-mannitic bases of the invention was tested as described above.

The compounds of the invention studied showed an inhibition of serotonin reuptake.

The results of selected studies on serotonin reuptake inhibition are presented in Table 1: Other Tabelle 1:

Beispiel Nr.	Hemmung 5HT-Aufnahme in %
22	83
23	57
24	59
25	52
26	71
27	44
28	40
29	48
30	43
31	50
32	42
33	55
34	39
35	43
36	63
37	39
38	45
39	37
40	51
41	41
42	53

2) Analgesia test in the mouse writhing test

The in-depth analgesic study was performed in the mouse in phenylquinone-induced writhing, as described above.

The compounds of the invention tested showed analgesic effects.

The results of selected writhing studies are summarised in Table 2 below. Other Tabelle 2:

Analgesieprüfung im Writhing-Test an der Maus
Beispiel Nr.	Hemmung der Writhingreaktion in %
15	87
16	17

Claims (65)

1. Substituted pyrrole Mannich base of the formula I in which R¹ is H, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl, heteroaryl, CN, Br, Cl or OH radical which is bonded via a C_1-6-alkylene group, R³, R^3', R^3" are, identically or differently, H, F, Cl, Br, CF₃, CN, NO₂, SO₂NH₂, NHR⁷, SR⁸, OR⁹, CO(OR¹⁰), CH₂CO(OR¹¹), COR¹⁵, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, R⁴ is an unsubstituted phenyl radical or a phenyl radical which is substituted at least once by C_1-4-alkyl, C_1-3-alkoxy, halogen, CF₃, CN, O-phenyl or OH, R⁵, R⁶ are, identically or differently, a branched or unbranched, saturated, unsaturated, unsubstituted or at least monosubstituted C_1-6-alkyl radical or an unsubstituted or at least monosubstituted phenyl, benzyl or phenethyl radical, or R⁵ and R⁶ together are (CH₂)_n with n = an integer from 3 to 6, or are (CH₂)₂O(CH₂)₂, R⁷ is H, COR¹², a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, R⁸ is H, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, R⁹ is H, COR¹³, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, R¹⁰ is H, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, R¹¹ is H, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, R¹² is a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, R¹³ is a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, R¹⁴ is H, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, R¹⁵ is NHNH₂, NHR¹⁴, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, and/or the racemates, enantiomers or diastereomers thereof and/or corresponding bases and/or corresponding salts of physiologically tolerated acids, where the racemate of the compound of the formula I in which the radicals R¹, R³, R^3' and R^3" are each H, the radical R⁴ is a phenyl radical and the radicals R⁵ and R⁶ are each CH3 is excluded.
2. Substituted pyrrole Mannich base according to Claim 1, characterized in that the radical R¹ is a C_1-6-alkyl radical, and the radicals R² to R¹⁵, and R^3' and R^3" have the meaning according to Claim 1.
3. Substituted pyrrole Mannich base according to Claim 1, characterized in that the radical R¹ is an aryl, CN, Br, Cl or OH radical which is bonded via a C_1-3-alkylene group, and the radicals R² to R¹⁵, and R^3' and R^3" have the meaning according to Claim 1.
4. Substituted pyrrole Mannich base according to Claim 1, characterized in that the radical R¹ is a phenyl, Furoyl, thienyl or pyridyl radical which is unsubstituted or substituted at least once by F, Cl, Br; NH₂, NO₂, NH₂-(C=S), COOH, preferably a phenyl or pyridyl radical which is unsubstituted or substituted at least once by F or NH₂-(C=S), and the radicals R² to R¹⁵, and R³' and R^3" have the meaning according to Claim 1.
5. Substituted pyrrole Mannich base according to any of Claims 1 to 4, characterized in that at least one of the radicals R³, R³' or R³" is H, and the remaining radicals R³, R³' or R³" in each case, and R⁴ to R¹⁵ have the meaning according to Claim 1.
6. Substituted pyrrole Mannich base according to any of Claims 1 to 4, characterized in that at least one of the radicals R³, R³' or R³" is a C_1-6-alkyl radical, and the remaining radicals R³, R³' or R^3" in each case, and R⁴ to R¹⁵ have the meaning according to Claim 1.
7. Substituted pyrrole Mannich base according to any of Claims 1 to 4, characterized in that at least one of the radicals R³, R^3' or R^3" is an aryl radical which is bonded via a C_1-2-alkylene group, and the remaining radicals R³, R^3' or R^3" in each case, and R⁴ to R¹⁵ have the meaning according to Claim 1.
8. Substituted pyrrole Mannich base according to any of Claims 1 to 7, characterized in that the radical R⁴ is an unsubstituted phenyl radical or a phenyl radical which is substituted at least once by methyl, tert-butyl, methoxy, F, Cl, Br or CF₃, preferably an unsubstituted phenyl radical or a 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-tert-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 5-bromo-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-6-fluorophenyl, 4-bromo-2-fluorophenyl, 3-bromo-4-fluorophenyl, 3-bromo-2-fluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl or a 4-trifluoromethylphenyl radical, particularly preferably an unsubstituted phenyl radical, and the radicals R⁵ to R¹⁵ have the meaning according to Claim 1.
9. Substituted pyrrole Mannich base according to any of Claims 1 to 8, characterized in that at least one of the radicals R⁵ and R⁶ is a saturated, unsubstituted or at least monosubstituted C_1-6-alkyl radical, preferably a CH₃ radical, and the other radical R⁵ or R⁶ in each case, and the radicals R⁷ to R¹⁵ have the meaning according to Claim 1.
10. Substituted pyrrole Mannich base according to any of Claims 1 to 8, characterized in that the radicals R⁵ and R⁶ together are (CH₂)_n with n = 4 or 5, and the radicals R⁷ to R¹⁵ have the meaning according to Claim 1.
11. Substituted pyrrole Mannich base according to any of Claims 1 to 10, characterized in that the radical R⁷ is a C_1-6-alkyl radical, and the radicals R⁸ to R¹⁵ have the meaning according to Claim 1.
12. Substituted pyrrole Mannich base according to any of Claims 1 to 10, characterized in that the radical R⁷ is an aryl radical which is bonded via a C_1-2-alkylene group, and the radicals R⁸ to R¹⁵ have the meaning according to Claim 1.
13. Substituted pyrrole Mannich base according to any of Claims 1 to 12, characterized in that the radical R⁸ is a C_1-6-alkyl radical, and the radicals R⁹ to R¹⁵ have the meaning according to Claim 1.
14. Substituted pyrrole Mannich base according to any of Claims 1 to 12, characterized in that the radical R⁸ is an aryl radical which is bonded via a C_1-2-alkylene group, and the radicals R⁹ to R¹⁵ have the meaning according to Claim 1.
15. Substituted pyrrole Mannich base according to any of Claims 1 to 14, characterized in that the radical R⁹ is a C_1-6-alkyl radical, and the radicals R¹⁰ to R¹⁶ have the meaning according to Claim 1.
16. Substituted pyrrole Mannich base according to any of Claims 1 to 14, characterized in that the radical R⁹ is an aryl radical which is bonded via a C_1-2-alkylene group, and the radicals R¹⁰ to R¹⁵ have the meaning according to Claim 1.
17. Substituted pyrrole Mannich base according to any of Claims 1 to 16, characterized in that the radical R¹⁰ is a C_1-6-alkyl radical, and the radicals R¹¹ to R¹⁵ have the meaning according to Claim 1.
18. Substituted pyrrole Mannich base according to any of Claims 1 to 16, characterized in that the radical R¹⁰ is an aryl radical which is bonded via a C_1-2-alkylene group, and the radicals R¹¹ to R¹⁵ have the meaning according to Claim 1.
19. Substituted pyrrole Mannich base according to any of Claims 1 to 18, characterized in that the radical R¹¹ is a C_1-6-alkyl radical, and the radicals R¹² to R¹⁵ have the meaning according to Claim 1.
20. Substituted pyrrole Mannich base according to any of Claims 1 to 18, characterized in that the radical R¹¹ is an aryl radical which is bonded via a C_1-2-alkylene group, and the radicals R¹² to R¹⁵ have the meaning according to Claim 1.
21. Substituted pyrrole Mannich base according to any of Claims 1 to 20, characterized in that the radical R¹² is a C_1-6-alkyl radical, and the radicals R¹³ to R¹⁵ have the meaning according to Claim 1.
22. Substituted pyrrole Mannich base according to any of Claims 1 to 20, characterized in that the radical R¹² is an aryl radical which is bonded via a C_1-2-alkylene group, and the radicals R¹³ to R¹⁵ have the meaning according to Claim 1.
23. Substituted pyrrole Mannich base according to any of Claims 1 to 22, characterized in that the radical R¹³ is a C_1-6-alkyl radical, and the radicals R¹⁴ and R¹⁵ have the meaning according to Claim 1.
24. Substituted pyrrole Mannich base according to any of Claims 1 to 22, characterized in that the radical R¹³ is an aryl radical which is bonded via a C_1-2-alkylene group, and the radicals R¹⁴ and R¹⁵ have the meaning according to Claim 1.
25. Substituted pyrrole Mannich base according to any of Claims 1 to 24, characterized in that the radical R⁴ is a C_1-6-alkyl radical, and the radical R¹⁵ has the meaning according to Claim 1.
26. Substituted pyrrole Mannich base according to any of Claims 1 to 24, characterized in that the radical R⁴ is an aryl radical which is bonded via a C_1-2-alkylene group, and the radical R¹⁵ has the meaning according to Claim 1.
27. Substituted pyrrole Mannich base according to any of Claims 1 to 26, characterized in that the radical R¹⁵ is a C_1-6-alkyl radical.
28. Substituted pyrrole Mannich base according to any of Claims 1 to 26, characterized in that the radical R¹⁵ is an aryl radical which is bonded via a C_1-2-alkylene group.
29. Substituted pyrrole Mannich base according to Claim 1:

    4-[(2-methoxyphenyl)-(1-phenyl-1H-pyrrol-2-yl)-methyl]-morpholine

    4-[[1-(2-fluorophenyl)-1H-pyrrol-2-yl]-(2-methoxyphenyl)-methyl]-morpholine

    1-[(1-furan-2-yl-1H-pyrrol-2-yl)-(2-methoxyphenyl)-methyl]-piperidine

    2-[(2-methoxyphenyl)pyrrolidin-1-yl-methyl]-1-phenyl-1H-pyrrole

    4-{2-[(2-methoxyphenyl)-piperidin-1-yl-methyl]-pyrrol-1-yl-methyl}-pyridine

    1-(4-fluorophenyl)-2-[(2-methoxyphenyl)-pyrrolidin-1-yl-methyl]-1H-pyrrole

    [(1-ethyl-1H-pyrrol-2-yl)-(2-methoxyphenyl)-methyl]-dimethylamine

    3-{2-[dimethylamino-(2-methoxyphenyl)-methyl]-pyrrol-1-yl}-propionitrile

    dimethyl-[phenyl-(1-phenyl-1H-pyrrol-2-yl)-methyl]-amine

    2-[2-(dimethylaminophenylmethyl)-pyrrol-1-yl]-phenylamine

    [(1-benzyl-1H-pyrrol-2-yl)-phenyl-methyl]-dimethylamine

    2- [2-(dimethylaminophenylmethyl) -pyrrol-1-yl]-thiobenzamide

    [(1-tert-butyl-1H-pyrrol-2-yl)-phenylmethyl]-dimethylamine

    2-[2-(pyrrolidin-1-yl-o-tolylmethyl)-pyrrol-1-yl]-phenylamine

    1-methyl-2-(phenylpyrrolidin-1-yl-methyl)-1H-pyrrole

    dimethyl-[(1-methyl-1H-pyrrol-2-yl)-phenylmethyl]-amine

    2-[2-(piperidin-1-yl-o-tolylmethyl)-pyrrol-1-yl]-thiobenzamide

    2-[2-(dimethylamino-o-tolylmethyl)-pyrrol-1-yl]-thiobenzamide

    2-[2-(phenylpyrrolidin-1-yl-methyl)-pyrrol-1-yl]-thiobenzamide

    2-{2-[(2-methoxyphenyl)-pyrrolidin-1-yl-methyl]-pyrrol-1-yl}-thiobenzamide

    2-{2-[(3,4-dimethoxyphenyl)-morpholin-4-yl-methyl]-pyrrol-1-yl}-thiobenzamide

    3-{2-[(2-fluorophenyl)-piperidin-1-yl-methyl]-pyrrol-1-yl}-propionitrile

    2-[(4-bromophenyl)-pyrrolidin-1-yl-methyl]-1-phenyl-1H-pyrrole

    2-[2-(piperidin-1-yl-m-tolylmethyl)-pyrrol-1-yl]-phenylamine

    2-{2-[(4-bromo-2-fluorophenyl)-pyrrolidin-1-yl-methyl]-pyrrol-1-ylmethyl}-pyridine

    2-{2-[(3-phenoxyphenyl)-piperidin-1-yl-methyl]-pyrrol-1-ylmethyl}-pyridine

    2-{2-[(3-phenoxyphenyl)-piperidin-1-yl-methyl]-pyrrol-1-yl}-thiobenzamide

    1-[[1-(2-chloroethyl)-1H-pyrrol-2-yl]-(4-fluorophenyl)-methyl]-piperidine

    2-{2-[(3-phenoxyphenyl)-piperidin-1-yl-methyl]-pyrrol-1-yl}-ethanol

    3-[2-(piperidin-1-yl-m-tolylmethyl)-pyrrol-1-yl]-propan-1-ol

    3-{2-[(4-fluorophenyl)-piperidin-1-yl-methyl]-pyrrol-1-yl}-propan-1-ol

    1-[(4-fluorophenyl)-(1-methyl-1H-pyrrol-2-yl)-methyl]-piperidine

    1-[(1-methyl-1H-pyrrol-2-yl)-(4-trifluoromethylphenyl)-methyl]-piperidine

    2-{2-[(2-chloro-6-fluorophenyl)-pyrrolidin-1-yl-methyl]-pyrrol-1-yl}-phenylamine

    2-{2-[(3-bromophenyl)-pyrrolidin-1-yl-methyl]-pyrrol-1-ylmethyl}-pyridine

    2-{2-[(3-bromo-4-fluorophenyl)-pyrrolidin-1-yl-methyl]-pyrrol-1-ylmethyl}-pyridine

    2-{2-[(2-chloro-6-fluorophenyl)-pyrrolidin-1-yl-methyl]-pyrrol-1-ylmethyl}-pyridine

    4-[(1-pyridin-2-ylmethyl-1H-pyrrol-2-yl)-pyrrolidin-1-yl-methyl]-benzonitrile

    2-[(3-bromo-4-fluorophenyl)-pyrrolidin-1-yl-methyl]-1-(4-fluorophenyl)-1H-pyrrole

    2-{2-[(5-bromo-2-fluorophenyl)-pyrrolidin-1-yl-methyl]-pyrrol-1-yl}-benzoic acid

    2-{2-[(5-bromo-2-fluorophenyl)-pyrrolidin-1-yl-methyl]-pyrrol-1-yl}-thiobenzamide

    1-tert-butyl-2-[(4-tert-butylphenyl)-pyrrolidin-1-yl-methyl]-1H-pyrrole.
30. Process for preparing substituted pyrrole Mannich bases of the general formula I according to any of Claims 1 to 29, characterized in that aromatic aldehyde compounds of the general formula II in which R⁴ has the meaning according to the general formula I, are reacted in solution in the presence of a base at a temperature of, preferably, from -10°C to 110°C with secondary amines of the general formula III in which R⁵ and R⁶ have the meaning according to the general formula I, to give aminal compounds of the general formula IV and these aminal compounds of the general formula IV are, without further purification, reacted with acid chlorides in absolute solvent to give iminium salts of the general formula V and these iminium salts of the general formula V are, without further purification, reacted in solution with pyrrole and/or substituted pyrrole compounds of the general formula VI in which R² is H, and the radicals R¹, R³, R^3', R^3" and R⁷ to R¹⁵ have the meaning according to the general formula I, and the pyrrole Mannich bases of the general formula I obtained in this way are purified by washing and isolated by conventional methods.
31. Process according to Claim 30, characterized in that the aromatic aldehyde compounds of the general formula II are reacted in an organic solvent, preferably in toluene, with the secondary amines of the general formula III.
32. Process according to Claim 30 or 31, characterized in that the aromatic aldehyde compounds of the general formula II are reacted in the presence of potassium carbonate or boric anhydride as base with secondary amines of the general formula III.
33. Process according to any of Claims 30 to 32, characterized in that the aminal compounds of the general formula IV are reacted with acetyl chloride to give iminium salts of the general formula V.
34. Process according to any of Claims 30 to 33, characterized in that the aminal compounds of the general formula IV are reacted in absolute diethyl ether to give iminium salts of the general formula V.
35. Process according to any of Claims 30 to 34, characterized in that the iminium salts of the general formula V are reacted in acetonitrile with pyrrole and/or substituted pyrrole compounds.
36. Process according to any of Claims 30 to 35, characterized in that the resulting pyrrole Mannich bases of the general formula I are purified by washing with acetone.
37. Medicament comprising as active ingredient at least one substituted pyrrole Mannich base of the formula I in which R¹ is H, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl, heteroaryl, CN, Br, Cl or OH radical which is bonded via a C_1-6-alkylene group, preferably a C_1-6-alkyl radical, a phenyl, Furoyl, thienyl or pyridyl radical which is unsubstituted or substituted at least once by F, Cl, Br; NH₂, NO₂, NH₂-(C=S), COOH, or an aryl, CN, Br, Cl or OH radical which is bonded via a C_1-3-alkylene group, particularly preferably a phenyl or pyridyl radical which is unsubstituted or substituted at least once by F or NH₂-(C=S), R³, R³', R³" are, identically or differently, H, F, Cl, Br, CF₃, CN, NO₂, SO₂NH₂, NHR⁷, SR⁸, OR⁹, CO(OR¹⁰), CH₂CO(OR¹¹), COR¹⁵, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, preferably H, a C_1-6-alkyl radical or an aryl radical which is bonded via a C_1-2-alkylene group, particularly preferably H, R⁴ is an unsubstituted phenyl radical or a phenyl radical which is substituted at least once by C_1-4-alkyl, C_1-3-alkoxy, halogen, CF₃, CN, O-phenyl or OH, preferably an unsubstituted phenyl radical or a phenyl radical which is substituted at least once by methyl, tert-butyl, methoxy, F, Cl Br or CF₃, particularly preferably an unsubstituted phenyl radical or a 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-tert-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 5-bromo-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-6-fluorophenyl, 4-bromo-2-fluorophenyl, 3-bromo-4-fluorophenyl, 3-bromo-2-fluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl or a 4-trifluoromethylphenyl radical, very particularly preferably an unsubstituted phenyl radical, R⁵, R⁶ are, identically or differently, a branched, unbranched, saturated, unsaturated, unsubstituted or at least monosubstituted C_1-6-alkyl radical or an unsubstituted or at least monosubstituted phenyl, benzyl, or phenethyl radical, preferably a saturated, unsubstituted or at least monosubstituted C_1-6-alkyl radical, particularly preferably a CH₃ radical, or R⁵ and R⁶ together are (CH₂)_n with n = an integer from 3 to 6 or (CH₂)₂O(CH₂)₂, preferably (CH₂)_n with n = 4 or 5, R⁷ is H, COR¹², a C_1-10-alkyl, an aryl, a heteroaryl radical, an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, preferably a C_1-6-alkyl radical or an aryl radical which is bonded via a C_1-2-alkylene group, R⁸ is H, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, preferably a C_1-6-alkyl radical or an aryl radical which is bonded via a C_1-2-alkylene group, R⁹ is H, COR¹³, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, preferably a C_1-6-alkyl radical or an aryl radical which is bonded via a C_1-2-alkylene group, R¹⁰ is H, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, preferably a C_1-6-alkyl radical or an aryl radical which is bonded via a C_1-2-alkylene group, R¹¹ is H, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, preferably a C_1-6-alkyl radical or an aryl radical which is bonded via a C_1-2-alkylene group, R¹² is a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, preferably a C_1-6-alkyl radical or an aryl radical which is bonded via a C_1-2-alkylene group, R¹³ is a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, preferably a C_1-6-alkyl radical or an aryl radical which is bonded via a C_1-2-alkylene group, R¹⁴ is H, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, preferably a C_1-6-alkyl radical or an aryl radical which is bonded via a C_1-2-alkylene group, R¹⁵ is NHNH₂, NHR¹⁴, a C_1-10-alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical which is bonded via a C_1-6-alkylene group, preferably a C_1-6-alkyl radical or an aryl radical which is bonded via a C_1-2-alkylene group, and/or the racemates, enantiomers or diastereomers thereof and/or corresponding bases and/or corresponding salts of physiologically tolerated acids and, where appropriate, other active ingredients and/or excipients.
38. Medicament according to Claim 37, characterized in that it comprises as active ingredient a mixture of enantiomers of at least one substituted pyrrole Mannich base of the formula I, the mixture comprising the enantiomers in non-equimolar amounts.
39. Medicament according to Claim 38, characterized in that the relative proportion of one of the enantiomers in the mixture is 5 to 45 mol%, preferably 10 to 40 mol%, based on the mixture of enantiomers.
40. Medicament according to any of Claims 37 to 39 for the treatment/control of pain, preferably of chronic pain, and/or inflammatory reactions and/or allergic reactions and/or drug abuse and/or alcohol abuse and/or diarrhoea and/or gastritis and/or ulcers and/or cardiovascular disorders and/or urinary incontinence and/or depression and/or states of shock and/or migraine and/or narcolepsy and/or obesity and/or asthma and/or glaucoma and/or hyperkinetic syndrome and/or athymia and/or bulimia and/or anorexia and/or catalepsy and/or for anxiolysis and/or for increasing vigilance and/or for increasing libido.
41. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for controlling pain.
42. Use according to Claim 41 for controlling chronic pain.
43. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating inflammatory reactions.
44. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating allergic reactions.
45. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating drug and/or alcohol abuse.
46. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating diarrhoea.
47. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating gastritis.
48. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating ulcers.
49. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating cardiovascular disorders.
50. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating urinary incontinence.
51. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating depression.
52. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating states of shock.
53. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating migraine.
54. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating narcolepsy.
55. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating obesity.
56. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating asthma.
57. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating glaucoma.
58. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating hyperkinetic syndrome.
59. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating athymia.
60. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating bulimia.
61. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating anorexia.
62. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for treating catalepsy.
63. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for anxiolysis.
64. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for increasing vigilance.
65. Use of at least one compound of the formula I according to any of Claims 1 to 29 for producing a medicament for increasing libido.