DE19840611A1 - GABA uptake inhibitors with pyrrolidine structure - Google Patents

Abstract

The invention relates to compounds of general formula (I) wherein R<1> to R<7>, A<1>, A<2>, X and Z are defined as in Claim No. 1. These compounds are suited as GABA uptake inhibitors for treating diseases such as epilepsy.

Description

The present invention relates to GABA uptake inhibitors with a pyrrolidine structure. The present invention further relates to pharmaceutical compositions which contain such compounds, and the use of these compounds for Treatment of diseases of the central nervous system (CNS) in which GABA uptake inhibitors play a role, for example of epilepsy and chorea Huntington.

Epilepsy always makes around 50 million affected patients worldwide still one of the most common diseases of the brain. Due to the large ver Diversity of seizure forms and an aetiology that is still missing understanding, the therapeutic approaches are still limited to one Control symptoms, such as suppressing seizures.

The beginnings of modern therapy go back to the middle of the past year hundreds back where inorganic bromides were used to treat epileptics were hit. It wasn't until 1912 that the anticonvulsant effect of phenobarbital discovered. Soon after, the first hydantoin derivative became an anti-epileptic used. Phenytoin, a hydantoin derivative introduced in 1938, is located as well as phenobarbital still on the market today and becomes one at Grand Mal primary generalized form of seizure of epilepsy.

At the end of the 1960s the list of anti-epileptics around the group of benzodia zepine expanded. Examples include diazepam and clonazepam called.

The principles of action of the individual representatives are very different. It It turned out, however, that a main starting point was that of γ-aminobutyric acid (GABA) mediated inhibition of excitation transmission in the CNS.  

After almost a century of purely empirical development of antiepileptics only in the last two decades when you started molecular biology To understand relationships, methods for the targeted development of Antiepileptics.

In the 1950s, the discovery of GABA in the brains of mammals and humans was described without understanding its function. At this time it was first assumed that GABA may have inhibitory functions in the CNS. In 1971, the presence of GABA receptors was finally detected. Today, GABA _A and GABA _B receptors are differentiated, although it is now known that the GABA _A receptor is an ion channel protein that is composed of different subunits.

As early as 1968, a high-affinity GABA transport system was used in the rat cortex discovered which one for the uptake of in the synaptic cleft released neurotransmitter and thus for the termination of the Neurotransmitter signal provides. The isolation of such a GABA transport protein first succeeded in 1978.

According to recent studies, GABA uptake proteins come with 0.1% of the Membrane proteins are relatively common in the nervous system. In the meantime, four different representatives of neurotransmitter transport proteins by cloning and heterologous expression can be demonstrated.

The first member of this family, who was able to clone from cDNA, was designated GAT-1. This protein is also the first neurotransmitter transporter that has been successfully cloned and expressed. A short time later human GAT-1 was cloned.

In 1992, two other transport proteins were identified, GAT-2 and GAT-3 were designated. Of these, the GAT-3 protein could also be cloned and be expressed. GAT-2 is likely to be one in the brain of mammals play a subordinate role. It is found only in the soft meninges, as well in the liver. So far, it has not been demonstrated neuronally.  

The fourth member of the uptake protein family is a common transport system for betaine and GABA, which among other things in the Kidney occurs and has been designated as BGT-1.

As early as 1975, studies with nipecotic acid, guvacin and arecaidin, Active ingredients from the Bethelnut (Areca catechu) the inhibitory effect of Nipe cotinic acid and guvacin discovered on GABA reuptake. With the knowledge of the interrelationships in GABAergic neurotransmission new strategies in the treatment of epilepsy. For example, it is possible to strengthen the neuronal GABA transmission by direct GABA mimetics. GABA itself is not suitable for this because it does not cross the blood-brain barrier can. One problem with direct GABA mimetics is that this one Can develop tolerance. They also enhance GABAergic neurotransmission in an unspecific way in general in the GABAergic synapses and not only where signals arrive. The mechanisms of action are one particularly useful therapeutic approach that GABAergic neurotransmission only reinforce if the transmitter is distributed. This can be done on the one hand by a Inhibition of degradation of the transmitter and on the other hand by inhibition its resumption can be achieved. The development of corresponding Inhibitors for GABA readmission had their starting point in the already mentioned compounds nipecotinic acid and guvacin. However, these can Similar to GABA, it does not cross the blood-brain barrier or only very poorly.

In the meantime, some compounds have been described in the literature, the CNS are common and at the same time have a considerable affinity for GABA uptake Have proteins. So far, however, these connections have only been high GAT-1 selectivity, while compounds that are GAT-3 selective still today still essentially missing.

In general, the object of the present invention was to provide it new GABA uptake inhibitors and in particular the provision of GABA uptake inhibitors with high selectivity towards GAT-3 (or at least high Affinity for GAT-1).  

The above object is achieved according to the invention by the compounds of the general formula (I)

wherein
R ¹ to R ^{7 are} independently selected from H, optionally substituted C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, optionally substituted aryl or heteroaryl, OH, halogen (in particular F and C1), CN, OR ¹² , SR ¹² , COR ¹² , COOR ¹² , SOR ¹² , SO ₂ R ¹² , NR ¹³ R ¹⁴ , CONR ¹³ R ¹⁴ , SO ₂ NR ¹³ R ¹⁴ , where R ¹³ and R ¹⁴ independently from H and C _1-3 alkyl are selected and R ^{12 is} C _1-6 alkyl; in each case two of R ¹ to R ⁷ can be combined to form a 3- to 6-membered ring system which can also contain one or more heteroatoms; R ¹ and R ² and / or R ³ and R ⁴ and / or R ⁵ and R ^{6 can be} replaced by an optionally substituted alkylidene group or = O; and each two of R ¹ to R ⁷ , which are located on adjacent C atoms, can be replaced by a CC bond;
A ^{1 stands} for (-CR ⁸ R ⁹ -) _n , optionally substituted C _3-6 cycloalkylene or a combination of these groups, where R ⁸ and R ⁹ independently of H, C _1-6 - alkyl, halogen, OH, OR ¹² and NR ¹³ R ^{14 are} selected and for n ≧ R ⁸ and R ⁹ can be different in each grouping and two groups of R ⁸ and R ⁹ on adjacent C atoms can be replaced by a CC bond and between two adjacent groupings CR ⁸ R ^{9 can be} a grouping -O- or -CO; and wherein one of R ⁸ and R ^{9 can be combined} with one of R ¹ to R ⁷ to form a 5- to 7-membered ring structure; and n = 0, 1, 2, 3 or 4;
X represents COOM or a group that can be converted to COOM under physiological conditions, where MH represents a pharmaceutically acceptable cation;
A ^{2 represents} (-CR ¹⁰ R ¹¹ -) _m , where R ¹⁰ and R ^{11 are} independently selected from H, C _1-2 - alkyl and halogen; where for m ≧ 2 the groups R ¹⁰ and R ¹¹ can be different in each grouping, there can be a grouping -O- or -S- between two neighboring groups and two groups of R ¹⁰ and R ¹¹ each on adjacent C atoms can be replaced by a CC bond; and wherein one of R ¹⁰ and R ^{11 may be combined} with one of R ¹ to R ⁹ to form a 5- to 7-membered ring structure; and m is 1, 2, 3, or 4;
Z is selected from Y ₃ CO, Y ₂ C = CR ¹⁵ and Y ₂ C = NO, where R ^{15 is} H, C _1-3 alkyl or halogen and the groups Y independently of one another are optionally substituted C _6-12 - Aryl or optionally substituted C _2-5 heteroaryl having up to three heteroatoms selected from N, O and S, and the groups Y by a covalent bond or by groupings selected from -O-, -S-, -NH-, -O-, -CH = CH-, -CH = N-, -CH ₂ - and -CH ₂ CH ₂ -, can be connected between atoms belonging to different groups Y;
as well as the individual stereoisomers of these compounds.

The present invention also relates to pharmaceutical compositions settlements containing at least one pharmaceutically acceptable carrier or exc pients and contain at least one compound of general formula (I).

The present invention is also based on the use of the compounds of the general my formula (I) for the manufacture of a medicament for the treatment of the sick units where GABAergic neurotransmission enhancement is beneficial especially epilepsy, Huntington's disease and related CNS disorders directed. Can also be used as anticonvulsants, sedatives, anxiolytics and antidepressants the compounds of the invention are used with success.  

In the following, the present invention is based on preferred embodiments the same explained in more detail.

Meanings of the radicals R ¹ to R ⁷ :
The expression "optionally substituted C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl" is intended to represent groups which are unsubstituted or (preferably one or two) substituents which are in particular selected from OH, Halogen (in particular F, Cl, Br and particularly preferably F), CN, NO ₂ and OR ¹² . However, the substituents can also (and additionally) be (optionally substituted) aryl or heteroaryl radicals (as defined in more detail below). Methyl, ethyl, propyl, CF ₃ , CH ₂ OCH ₃ , CH ₂ OH, benzyl and phenethyl can be mentioned as concrete examples of the radicals R ¹ to R ⁷ just discussed.

"Optionally substituted aryl or heteroaryl" includes aryl groups with preferably 6 to 12 carbon atoms and heteroaryl radicals with 5 to 12 ring members, from which up to three heteroatoms can be (generally selected from N, O and S). These aryl or heteroaryl radicals can be unsubstituted or (preferably with one to three substituents). Preferred examples of such substituents are C _1-3 alkyl, C _2-4 alkenyl, OH, halogen (in particular F, Cl, Br), CN, NO ₂ , OR ¹² and NR ¹³ R ¹⁴ . As specific examples, phenyl, thienyl, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyranyl and corresponding radicals can be mentioned in this connection, which have one to three (preferably one) substituent from the group methyl, ethyl, CF ₃ , methoxy , Ethoxy, F, Cl, CN, NH ₂ , dimethylamino and diethylamino.

If R ¹ to R ⁷ is halogen, this halogen is preferably fluorine or chlorine, particularly preferably fluorine. R ¹ , R ² and R ^{7 are} preferably not halogen, OR ¹² , SR ¹² and NR ¹³ R ¹⁴ , since in these cases there is the possibility of enamine formation.

The radical R ¹² is preferably C _1-3 alkyl, in particular methyl and ethyl. R ¹³ and R ¹⁴ are preferably identical and are preferably methyl and ethyl. However, R ¹³ and R ¹⁴ can also form an alkylene group, which, for. B. would result in a pyrrolidinyl or piperidinyl residue.

In particularly preferred compounds of the general formula (I), R ¹ to R ^{6 are} independently selected from H, optionally substituted C _1-3 alkyl, halogen, OH, CN, optionally substituted phenyl and optionally substituted heteroaryl with five to ten ring members and one or two heteroatoms selected from O, N and S, and especially hydrogen, C _1-3 alkyl and phenyl. R ⁷ preferably represents H. In general, it is preferred when not more than two different and in particular not more than one of R ¹ to R ⁷ of _H. It can be particularly advantageous if R ¹ to R ^{7 are} all hydrogen.

In each case two of R ¹ to R ⁷ can also form a 3- to 6-membered ring system (preferably a 5- or 6-membered ring system); which can also contain one or more (preferably one or two) heteroatoms. The heteroatoms are preferably O, N or S. Furthermore, R ¹ and R ² and / or R ³ and R ⁴ and / or R ⁵ and R ^{6 can be} replaced by an optionally substituted alkylidene group or oxo (= O) . Preferably, if at all, only one such alkylidene or oxo group is present on the ring. The substituents which are optionally present on the alkylidene group (preferably one to three) are preferably those which have been given above as examples of substituents on alkyl, alkenyl and alkynyl radicals R ¹ to R ⁷ . Finally, two of R ¹ to R ⁷ , which are located on adjacent C atoms, can also be replaced by a CC bond. This leads to the presence of double or triple bonds in the ring system. In this context, a double bond between the 3 and 4 positions of the pyrrolidine skeleton is preferred. A pyrrole structure is also worth mentioning in this context.

If A ^{1 is} a combination of (-CR ⁸ R ⁹ -) _n and (optionally substituted) C _3-6 - cycloalkylene, this should mean that A ¹ in particular alkylene-cycloalkylene, cycloalkylene-alkylene and alkylene-cycloalkylene-alkylene can represent. A ¹ is preferably (-CR ⁸ R ⁹ -) _n . With regard to the possible meanings of R ⁸ and R ⁹ , reference can be made to the corresponding explanations in connection with the groups R ¹ to R ⁷ above. Particularly preferred meanings of R ⁸ and R ⁹ are H and C _1-3 alkyl, especially methyl. Preferably only one of R ⁸ and R ^{9 is} different from H and both are particularly preferably hydrogen. N has in particular the value 0, 1 or 2, 1 or 2 being preferred. In the latter case, the compounds according to the invention are derivatives of acetic or propionic acid (for R ⁸ , R ⁹ = H). These are particularly preferred according to the invention.

When A ¹ represents or includes optionally substituted C _3-6 cycloalkylene, preferred examples of the cycloalkylene group are cyclopropylene, cyclopentylene and cyclohexylene. Any substituents present are preferably selected from C _1-3 alkyl, halogen (eg F or Cl) and OH. However, the cycloalkylene radical preferably does not have any substituents.

If A ^{1 stands} for (-CR ⁸ R ⁹ -) _n or comprises it, for n ≧ 2 R ⁸ and R ⁹ both CR ⁸ R ⁹ and each other can be different. In this case, two groups of R ⁸ and R ⁹ on adjacent C atoms can also be replaced by a CC bond (which can lead, for example, to a derivative of acrylic acid) and there can be CR ⁸ between two adjacent groups R ^{9 is} a -O- or -CO- group, although this is not preferred. Finally, one of R ⁸ and R ⁹ (preferably located on a carbon atom directly attached to the ring) can be combined with one of R ¹ to R ⁷ (preferably R ⁵ , R ⁶ or R ⁷ ) to form a 5- to 7-membered ring structure be combined. This ring structure can be saturated or unsaturated and also contain one or more heteroatoms, preferably selected from O, N and S.

In the general formula (I), X stands for COOM or a group which is classified under physio logical conditions can be converted into COOM. Among the last named groups are, for example, esters, nitrile and salts. Prefers M stands for hydrogen and corresponding cations of sodium, potassium, calcium and magnesium and ammonium. H and Na are still meanings for M. more preferred, with the most preferred meaning for M being hydrogen.

A ² in the above general formula (I) stands for (-CR ¹⁰ R ¹¹ -) _m , where R ¹⁰ and R ¹¹ preferably denote H, methyl, ethyl and halogen (in particular F or Cl). Before preferably only one of R ¹⁰ and R ^{11 is} different from H and particularly preferably R ¹⁰ and R ^{11 are} both hydrogen. If R ¹⁰ and / or R ^{11 represent} halogen, the halogen should not be located on the C atom adjacent to the N atom (risk of enamine or iminium ion formation). m preferably has the value 2 or 3, 2 being particularly preferred. If m ≧ 2, the groups R ¹⁰ and R ¹¹ can be different both from one another and from each group CR ¹⁰ R ¹¹ . In particular for m <2, two adjacent CR ¹⁰ R ¹¹ groups can be separated by a -O- or -S- group and two groups of R ¹⁰ and R ¹¹ on adjacent C atoms can be replaced by a CC bond, which leads to a double (or triple) bond. In these cases too, the C atom adjacent to the N atom should be free of structural elements which (can) result in an enamine or iminium ion structure. Finally, one of R ¹⁰ and R ¹¹ (preferably located on the carbon atom attached to N) can be combined with one of R ¹ to R ⁹ (preferably one of R ¹ , R ² , R ⁷ , R ⁸ and R ⁹ ) combined to form a 5- to 7-membered ring structure, which ring structure can be saturated or unsaturated and can also contain one or more heteroatoms selected from O, N and S. in addition to the ring nitrogen atom.

When Z is Y ₃ CO, the groups Y are preferably identical. Furthermore, preferred meanings for Y are optionally substituted phenyl and, if appropriate, substituted thienyl, furanyl and pyrrolyl. Optionally substituted phenyl is particularly preferred. If substituents are present, their number preferably does not exceed 3 and in particular 2, with (only) one substituent being more preferred. Preferred substituents are selected from C _1-3 alkoxy, C _1-3 alkyl, halogen, OH, NO ₂ , CN and NR ¹³ R ¹⁴ . Specific examples of such substituents are methoxy, ethoxy, methyl, ethyl, F, Cl, NH ₂ , dimethylamino and diethylamino. A particularly preferred substituent is C _1-3 alkoxy, especially methoxy. In the case of a phenyl ring, this grouping is preferably in the 2- and / or 4-position, more preferably in the 4-position.

If Z is Y ₂ C = CR ¹⁵ , the two groups Y are also preferably identical. Further preferred meanings for Y in this case are optionally substituted phenyl or optionally substituted heteroaryl with 5 or 6 ring members and one or two heteroatoms selected from O, N and S. With regard to the substituents which may be present, reference may be made to the above statements regarding groups Y. When Y is phenyl, the phenyl ring preferably has no substituents. If Y is heteroaryl, Y is preferably optionally substituted thienyl, in particular 3-methyl-2-thienyl.

R ¹⁵ is preferably H or methyl, more preferably H.

If Z is Y ₂ C = NO, the two groups Y are preferably also identical. With regard to the preferred meanings for Y, reference can be made to the above explanations regarding the preferred groups Y for the other meanings of Z.

In particularly preferred embodiments of the compounds of the general formula (I) according to the invention, the various groups have in particular the following meanings:
R ¹¹ to R ⁷ : hydrogen;
A ¹ : -CH ₂ - or -CH ₂ CH ₂ -, as well as -CH = CH-;
X: COOH;
A ² : -CH ₂ CH ₂ -;
Z: (C ₆ H ₅ ) ₂ C = CH -, (3-methyl-2-thienyl) ₂ C = CH- and (4-CH ₃ OC ₆ H ₄ ) ₃ CO-.

The present invention also includes the individual isomers (enantiomers, diastereomers, optionally cis / trans isomers) of the compounds of the general formula (I) according to the invention. It should be pointed out that regardless of the meaning of the individual radicals in the general formula, the carbon atom bearing R ⁷ and A ¹ -X is a chiral center, so that the compounds according to the invention are at least present as enantiomers. The present invention is intended to include both the individual enantiomers and racemates of these compounds.

The compounds according to the invention have a remarkably high selectivity compared to GAT-3 and / or GAT-1 and can accordingly be used to treat Disease states are used in which these transport proteins play a role play. In this context, epilepsy and chorea in particular Mentioning Huntington.

The compounds according to the invention and the precursors thereof can be according to conventional methods described in the literature or in analogy to such processes. Some of these procedures are outlined below are briefly presented. Individual isomers (enantiomers) can in addition to one usual separation (e.g. by racemate splitting) also produced via processes who use chiral auxiliaries in their manufacture. examples for Such methods are also briefly outlined below.

Reaction scheme 1

Rac-3 is synthesized by reacting 1 with malonic acid monoethyl ester (2) according to the instructions by H. Fukawa et al., Chem. Letters, 1982, 231-232.

Compound rac-3 is also accessible by catalytic hydrogenation of 4 with Pt-C as a catalyst according to the following procedure: Clemo, Melrose, J. Chem. Soc., 1942, 424.

Reaction scheme 2

The compound rac-9 can be started from pyrrole-2-carbaldehyde 5 according to the reaction scheme 2 shown three-step processes can be synthesized. The condensation product 7 is by reaction from 5 to 6 according to the instructions of Ch. Robinson, L. J. Wiseman, J. Leonhard, C. D. Slater, Tetrahedron, 1989, 45, 4103-4112. Subsequent catalytic hydrogenation, ester hydrolysis and Decarboxylation according to the instructions of Clemo et al., J. Chem. Soc., 1950, 1140 leads to rac-9.

Reaction scheme 3

The N-substituted amino acids rac-12 can be started analogously to known processes of the amino acid esters rac-10 by alkylation with a suitable electrophile and subsequent ester hydrolysis can be synthesized: K.E. Andersen et al., J Med. Chem. 1993, 36, 1716-1725. T. G. M. Dhar et al., J. Med. Chem. 1994, 37, 2334-2342.

Representation of the enantiomerically pure compounds

• A) To represent the enantiomerically pure compounds z. B. the racemate of amino Acid esters rac-11 according to known methods using chiral enantiomerically pure Acids are split into their enantiomers. Hydrolysis of the enantiomerically pure so obtained Ester 11 according to the processes already described for the racemates leads to the enantiomerically pure amino acids 12.
• B) In addition, compounds according to the invention can be converted into enantiomers by special processes pure form. The reactions of the following reaction schemes 4 to 8 are explained in more detail below in the exemplary embodiments.

Pyrrolidin-2-ylacetic acid base body

Reaction scheme 4

Reaction scheme 5

Pyrrolidin-2-ylpropanoic acid base body

Reaction scheme 6

Reaction scheme 8

Examples General information on the chemical tests

Melting points: Melting point apparatus according to Dr. Tottoli (Büchi company, No. 512). The Melting points were not corrected.

Optical rotations: Polarimeter 241 MC (from Perkin Elmer).

IR spectra: FT-IR spectrometer 1600 and Paragon 1000 (from Perkin Elmer). The inclusion of the Spectra took the form of a KBr compact or a film between NaCl plates.

NMR spectra: JNMR-GX 400 (Jeol, 400 MHz), TMS as internal standard. The Coupling constants were specified with an accuracy of 0.5 Hz. The Nachbear The spectra were processed with NUTS, 2D version 4.35, Acorn NMR, 1994.

Mass spectra: Mass Spectrometer 5989 A with 59980 B Particle Beam LC / MS Interface (Fa. Hewlett Packard).

Thin layer chromatography: TLC ready-made silica gel 60 F-254 plates (Merck). Detection was carried out in UV (254 nm) or by using a cerium (IV) ammonium molybdate immersion reagent (5% (NH ₄ ) _x Mo ₇ O ₂₄ and 0.2% Ce (SO ₄ ) ₂ , dissolved in 5% aqueous H ₂ SO ₄ ). The detection was carried out by subsequent heating.

Column chromatography (SC): Flash chromatography ^[113] on silica gel 60 (particle size 0.040-0.063 mm, from Merck).

Analytical HPLC: Chromatography pumps L-6200 Intelligent-Pump and L-6000 (Merck-Hitachi), UV-VIS detectors L-4000 and L-7400 (242 and 254 nm, Merck-Hitachi), integrators D -7500 and D-2500 (Merck-Hitachi), columns: LiChroCart® cartridge system (Merck):

• A) LiChrospher® Si 60 (5 µm, 250 × 4 mm with guard column 4 × 4 mm)
• B) LiChrosorb® Si 60 (5 µm, 250 × 4 mm with guard column 4 × 4 mm).

Preparative HPLC: Chromatography pump L-6000 (Merck-Hitachi), UV-VIS detector L- 4000 (242 or 254 nm, Merck-Hitachi), integrator D-2000 (Merck-Hitachi), Column: Hibar RT ready column (Merck) LiChrosorb® Si 60 (7 µm, 250 × 25 mm).

Reagents and Solvents: All reagents were of commercial quality. Dried and distilled solvents were used for the reactions. For  Chromatographic purposes were distilled solvents which were additionally degassed for HPLC used.

Reaction conditions: Unless otherwise stated, the reactions were carried out in heated glassware under an N ₂ atmosphere.

The following abbreviations were used to describe the experiments:

DBU 1,8-diazabicyclo [5.4.0.] Un-7-decene
DIBAH diisobutyl aluminum hydride
DIPEA diisopropylethylamine
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
Ether diethyl ether
THF tetrahydrofuran
TMEDA N, N, N ', N'-tetramethylethylenediamine
i. Vac. in a vacuum

Production Example 1

(1S, 5R) -1- (2,5-dihydropyrrol-1-ylcarbonyl) -5,8,8-trimethyl-3-oxabicyclo [3.2.1] octan-2-one (13)

3.79 g (14.4 mmol) (1S, 5R) -5,8,8-trimethyl-3-oxabicyclo [3.2.1] octan-2-one-1-carboxylic acid were suspended in 60 ml CH ₂ Cl ₂ , to 0 ° C cooled and mixed with 1.78 g (14.5 mmol) oxalyl chloride. DMF (10 drops) was then added with vigorous stirring and the mixture was slowly warmed to room temperature. After gas evolution ceased, the flask was purged with a nitrogen stream for one hour to remove HCl. After the solution had cooled to 0 ° C., 3.54 g (2.5 eq.) Of triethylamine and 1 g (14.4 mmol) of 3-pyrroline were added. The mixture was then brought to room temperature and stirred for 12 h. The mixture was then diluted with 30 ml of CH ₂ Cl ₂ , washed several times with 0.5 N HCl, the organic phase was dried with MgSO ₄ and concentrated. Column chromatography purification of the residue (petroleum ether / ethyl acetate = 7/3) and recrystallization from petroleum ether / ethyl acetate (7/3) gave 3,254 g (86%) of colorless crystals; Mp: 108 ° C. [α] 20 | D = + 97.9 (c = 0.65, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 0 ° C): δ = 0.91 (s, 3 H, CH ₃ ), 1.09 (s, 3 H, CH ₃ ), 1.38 (s, 3 H, CH ₃ ), 1.86- 1.97 (m, 2 H, CH ₂ CH ₂ ), 2.27 (dt, J = 11.0 / 5.1 Hz, 1 H, CH ₂ CH ₂ ), 2.43 (ddd, J = 13.9 / 11.0 / 5.9 Hz, 1 H, CH ₂ CH ₂ ), 3.94 (d, J = 11.3 Hz, 1 H, CH ₂ O), 4.15 (dd, J = 11.3 / 2.2 Hz, 1 H, CH ₂ O), 4.12-4.18 (m, 1 H, NCH ₂ ), 4.23 (ddd, J = 13.9 / 4.4 / 2.2 Hz, 1 H, NCH ₂ ), 4.39 (ddd, J = 13.9 / 5.1 / 2.2 Hz, 1 H, NCH ₂ ), 4.56 (ddd, J = 16.9 / 5.1 / 2.2 Hz, 1 H, NCH ₂ ), 5.75 (ddd, J = 6.6 / 4.4 / 2.2 Hz, 1 H, HC =), 5.85 (ddd, J = 6.6 / 4.4 / 2.2 Hz, 1 H, HC =).

Production Example 2

(1S, 5R) -1- (2,3-dihydropyrrol-1-ylcarbonyl) -5,8,8-trimethyl-3-oxabicyclo [3.2.1] octan-2-one (14)

A mixture of 1.0 g 13 (3.8 mmol) and 15 mg hydridotetrakis (triphenylphosphine) rhodium dissolved in 4 ml abs. Xylene was stirred in a closed pressure tube at 140 ° C. for 44 h. The reaction mixture was then filtered off, concentrated, purified by column chromatography (petroleum ether / ethyl acetate / ethyl dimethylamine = 80/20 / l) and recrystallized from cyclohexane. Yield: 700 mg (70%); colorless crystals; Mp: 105 ° C. [α] 20 | D = + 46.3 (c = 0.68, CHCl ₃ ). - ¹ H NMR ([D ₅ ] nitrobenzene, 130 ° C): δ = 0.91 (s, 3 H, CH ₃ ), 1.07 (s, 3 H, CH ₃ ), 1.35 (s, 3 H, CH ₃ ) , 1.80-2.00 (m, 2 H, CH ₂ CH ₂ ), 2.18-2.33 (m, 1 H, CH ₂ CH ₂ ), 2.45-2.70 (m, 3H, NCH ₂ CH ₂ , CH ₂ CH ₂ ), 3.89-3.96 (m, 2 H, NCH ₂ ), 3.99 (d, J = 11.0 Hz, 1 H, CH ₂ O), 4.19 (dd, J = 11.0 / 2.2 Hz, 1 H, CH ₂ O), 5.11 -5.20 (m, 1H, NCH = CH), 6.71-6.79 (m, 1H, NCH =).

Production Example 3 (α) Electrophilic α-amidoalkylation, general working procedure

At -85 ° C, HCl gas was introduced into anhydrous CH ₂ Cl ₂ (1 ml 0.1 mmol 14) over a period of 20 min. Then, with vigorous stirring, enamide 14, dissolved in CH ₂ Cl ₂ (0.5 ml each 0.1 mmol), was slowly added dropwise. The introduction of gaseous HCl was not interrupted and continued for a further 10-20 minutes. Excess HCl gas was then removed in a high vacuum at -78 ° for 1 h. A solution of the respective organometallic reagent was then added dropwise to the reaction mixture obtained. After the specified reaction time, hydrolysis (H ₂ O) took place at -78 °. After separation of the phases, the aqueous phase was extracted four times with CH ₂ Cl ₂ , the organic phases with sat. NaCl solution. washed, dried with MgSO ₄ and i. Vac. constricted. The residue obtained was treated as indicated.

(b) Preparation of (1,1-dimethylethyl) - {(2S) -N - ((1S, 5R) -5,8,8-trimethyl-2-oxo-3-oxabicyclo [3.2.1] octane-1 -yl carbonyl] pyrrolidin-2-yl} acetate (16) and (1,1-dimethylethyl) - {(2R) -N - ((1S, 5R) -5,8,8-trimethyl-2-oxo-3 -oxabicyclo [3.2.1] octan-1-yl carbonyl] pyrrolidin-2-yl} acetate (17)

Representation of the reagent:
1.5 ml (2.4 mmol) of n-butyllithium (1.6 M in hexane) were added dropwise to a solution of 315 μl (2.4 mmol) of diisopropylamine in 2.4 ml of anhydrous THF at -78 ° C. After stirring for 30 min, 320 μl (2.4 mmol) of tert-butyl acetate were added. The mixture was stirred for a further 40 min and warmed to -30.degree. Thereafter, 2.4 ml (2.4 mmol) of diethyl aluminum chloride solution. (1 M in hexane) and stirred again for 20 min. The entire amount of reagent was used.

Electrophilic α-amidoalkylation, general working instructions: 0.158 g (0.6 mmol) 14, 6.6 ml (= 4 eq.) Organometallic reagent (see above), 16 h, -78 ° C. SC (petroleum ether / ethyl acetate = 7/3) provided 203 mg (89.1%) 16 and 17 as a mixture of diastereomers. HPLC analysis (column B; heptane / ethyl acetate = 80/20; 1.5 ml / min): 16: t _ret = 16.1 min. 81.2%; 17: t _ret = 20.4 min. 18.8%.

The separation was carried out by preparative HPLC (n-heptane / ethyl acetate = 82/18; 13.5 ml / min; 16: t _ret = 33.8 min. 17: t _ret = 43.6 min).
16: Yield: 154 mg (67.6%); colorless crystals, mp: 135 ° C. - [α] 20 | D = + 18.2 (c = 1.07, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 0.88 (s, 3 H, CH ₃ ), 1.03 (s, 3 H, CH ₃ ), 1.35 (s, 3 H, CH ₃ ), 1.43 ( s, 9 H, C (CH ₃ ) 3), 1.63-1.69 (m, 1 H, NCH ₂ CH ₂ CH ₂ ), 1.74-1.96 (m, 4 H, NCH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ ), 2.14-2.24 (m, 2 H, CH ₂ CH ₂ ), 2.31-2.43 (m, 2 H, CH ₂ CH ₂ , CH ₂ COO), 2.85 (dd, J = 15.5 / 3.8 Hz, 1 H, CH ₂ COO), 3.21 (td, J = 9.5 / 6.5 Hz, 1 H, NCH ₂ ), 3.72 (ddd, J = 9.5 / 7.3 / 2.4 Hz, 1 H, NCH ₂ ), 3.91 (d, J 11.0 Hz , 1 H, CH _{2 °} C = O), 4.12 (dd, J = 11.0 / 2.2 Hz, 1 H CH _{2 °} C = O), 4.42 (qd, J = 8.1 / 3.8 Hz, 1 H, NCHC).
17: Yield: 36 mg (15.8%); colorless crystals, m.p .: 89 ° C. - [α] 20 | D = + 56.6 (c = 1.1, CHCl ₃ ). - ¹ H NMR ([D ₅ ] nitrobenzene, 140 ° C): δ = 0.88 (s, 3 H, CH ₃ ), 1.07 (s, 3 H, CH ₃ ), 1.35 (s, 3 H, CH ₃ ) , 1.51 (s, 9 H, C (CH ₃ ) 3), 1.82-2.06 (m, 6 H, NCH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ ), 2.26 (ddd, J = 15.0 / 10.0 / 5.6 Hz , 1 H, CH ₂ CH ₂ ), 2.35 (dd, J = 15.6 / 9.3 Hz, 1 H, CH ₂ COO), 2.61-2.72 (m, 1 H, CH ₂ CH ₂ ), 3.18 (dd, J = 15.613.7 Hz, 1 H, CH ₂ COO), 3.43-3.50 (m, 1 H, NCH ₂ ), 3.62 (dt, J = 10.6 / 6.9 Hz, 1 H, NCH ₂ ), 3.92 (d, J 11.1 Hz, 1 H, CH _{2 °} C = O), 4.17 (dd, J = 11.1 / 2.0 Hz, 1H, CH ₂ OC = O), 4.60-4.67 (m, 1 H, NCHC).

Production Example 4

(S) -2-pyrrolidine acetic acid (S-18-HCl)

325 mg (0.87 mmol) 16 were in 4 ml conc. Acetic acid dissolved, with 6 ml HCl conc. added and heated to 160 ° C. in the pressure tube for 24 h. The reaction mixture was then carefully poured onto 15 ml of ice water and extracted several times with CH ₂ Cl ₂ . The combined CH ₂ C ₁₂ extracts were dried (MgSO ₄ ) and i. Vac. constricted. The yield of auxiliary was 131 mg (71%). The aqueous phase was i. Vac. concentrated and brought to dryness under high vacuum. The yield of pyrrolidine acetic acid hydrochloride was 102 mg (70.8%). To determine the rotation value and melting point, the product was recrystallized from acetone / methanol / Et ₂ O. Colorless crystals, mp: 173-175 ° C, [α] 23 | D = + 19.1
(c = 1.2, H ₂ O) Lit .: [T. Govindachari, T. Rajagopalan, N. Viswanathan, J Chem. Soc. Perkin Trans. 1.1974, 1161-1165.] 175-176 ° C, [α] 28 | D = + 19.3 (c = 1.74, H ₂ O). - ¹ H NMR (CD ₃ OD, 20 ° C): δ = 1.66-1.79 (m, 1 H, NCH ₂ CH ₂ CH ₂ ), 1.92-2.16 (m, 2 H, NCH ₂ CH ₂ CH ₂ ), 2.21-2.32 (m, 1 H, NCH ₂ CH ₂ CH ₂ ), 2.74-2.92 (m, 2 H, CH ₂ COO), 3.26-3.34 (m, 2 H, NCH ₂ ), 3.79-3.89 (m, 1 H, NCHC).

Production Example 5 (S) -pyrrolidin-2-ylacetic acid methyl ester hydrochloride (S-19-HCl)

1.2 ml of methanol was added dropwise at 0 ° C with 0.3 ml (4.2 mmol) of thionyl chloride. Then 173 mg (I.05 mmol) of (S) -homoproline hydrochloride (S-18-HCl, see preparation example 4) were added. The mixture was slowly warmed to room temperature and stirred at room temperature for 24 h. The mixture was then concentrated under a water jet vacuum and the residue was dried in a high vacuum. Yield 176 mg (93.8%) of colorless crystals.
Mp: 53 ° C.
[α] 20 | D = + 3.3 (c = 1.2, CHCl ₃ ) Lit .: [T. Govindachari, T. Rajagopalan, N. Viswanathan, J. Chem. Soc. Perkin Trans. 1 1974, 1161-1165.] [Α] 20 | D = + 3.4 (c = 2.0, CHCl ₃ )]. - MS (70 eV); m / z (%): 143 (33) [M ⁺ ], 128 (29), 115 (53), 110 (100).

Production Example 6 (R) -1-benzyloxycarbonylpyrrolidin-2-ylacetic acid methyl ester (R-21)

The representation was made according to Ref. (J.-M. Casal, A. Fürst, W. Meier, Helv. Chim. Acta 1976, 59, 1917-1924.) Starting from 249 mg (1 mmol) (R) -1- Benzyloxycarbonylproline (R-20) over (R) -2-diazoacetylpyrrolidine-1-carboxylic acid benzyl ester.
Yield: 113 mg (40.8%); colorless oil.

Production Example 7 (S) -N-benzyloxycarbonylproline methyl ester (S-22)

The presentation was based on Lit .: R. Nurdinov, E. Liepiri sh, I. Kalvin'sh, Chem. Heterocycl. Compd. 1993, 29, 1352-1357. Batch size: 15 mmol (2.48 g); Yield: 3.79 g (96%); colorless oil.

Production Example 8 (R) -N-benzyloxycarbonylproline methyl ester (R-22)

The presentation followed the working instructions for S-22. Batch size: 9.17 mmol (1.52 g); Yield: 2.31 g (96%); colorless oil.

Production Example 9 (2E) -3 - [(2S) -1- (benzyloxycarbonyl) pyrrolidin-2-yl] methyl acrylate and (2Z) -3 - [(2S) -1- (benzyloxycarbonyl) pyrrolidin-2-yl] methyl acrylate (S-24)

The presentation was made according to Ref. [R. Grote, A. Zeeck, J. Stümpfel, H. Zahnner, Liebigs Ann. Chem. 1990, 29, 525-530; T. Sato, K. Tsujimoto, K. Matsubayashi, H. Ishibashi, M. Ikeda, Chem. Pharm. Bull. 1992, 40, 2308-2312.]

A solution of 2,346 g (8.92 mmol) of S-22 in 50 ml of toluene was added to 18 ml of DIBAH solution at -60 ° C. over 15 min. (1 M in hexane) was added dropwise and the reaction mixture was stirred at -60 ° C. for 1 h. The reaction was then stopped by dropwise addition of 2 ml of methanol, warmed to RT and taken up in 1N HCl and Et ₂ O. The aqueous phase was extracted three times with Et ₂ O, the combined organic phases were dried (MgSO ₄ ) and i. Vac. constricted. The oily residue (2.07 g) was dissolved in 35 ml of acetonitrile and 454 mg (10.7 mmol, 1.2 equiv.) Of LiCl and 1.86 ml (10.7 mmol, 1.2 equiv.) Of DIPEA were added. 1.73 ml (10.7 mmol, 1.2 equiv.) Of trimethylphosphonoacetate were then added dropwise. The reaction mixture was stirred at RT for 16 h, then i. Vac. concentrated, taken up in Et ₂ O and water and the aqueous phase extracted three times with Et ₂ O. The combined organic phases were dried (MgSO ₄ ) and i. Vac. constricted. SC (petroleum ether / ethyl acetate = 7/3) gave 1.88 g (72.9%) of a colorless oil.

Production Example 10 (2E) -3 - [(2R) -1- (benzyloxycarbonyl) pyrrolidin-2-yl] acrylic acid methyl ester and (2Z) -3 - [(2R) -1- (benzyloxycarbonyl) pyrro1idin-2-yl] methyl acrylate (R-24)

The presentation followed the working instructions for S-24. Batch size: 7.03 mmol (1.85 g); Yield: 1.48 g (72.8%); colorless oil.

Production Example 11 (S) -proline methyl ester hydrochloride (S-25-HCl)

The illustration is based on Lit .: D. Hoogwater, M. Peereboom, Tetrahedron 1990, 46, 5325- 5332; J. Pastuszak, J. Gardener, J. Singh and D. Rich, J. Org. Chem. 1982, 47, 2982-2987. Batch size: 43.5 mmol (5.02 g); Yield: 6.8 g (94%); Mp: 72 ° C (lit .: 73 ° C).

Production Example 12 (R) -proline methyl ester hydrochloride (R-25-HCl)

The illustration is based on Lit .: D. Hoogwater, M. Peereboom, Tetrahedron 1990, 46, 5325- 5332; J. Pastuszak, J. Gardener, J. Singh and D. Rich, J. Org. Chem. 1982, 47, 2982-2987. Batch size: 43.5 mmol (5.02 g); Yield: 7.0 g (97%); Mp: 71 ° C (Lit. 73 ° C).  

Production Example 13

2 - [(trismethoxyphenyl) methoxy] ethyl bromide (R-Br c)

A solution of 1.05 g (3 mmol) of tris (4-methoxyphenyl) methanol in 5 ml of benzene was 50 ul H ₂ SO ₄ conc. added dropwise and the reaction mixture heated to 65 ° C for 5 min. After adding 318 μl (4.5 mmol) of bromoethanol, the reaction mixture was stirred for a further 60 min at RT. It was then taken up in Et ₂ O and water, the aqueous phase was extracted three times with Et ₂ O, dried (MgSO ₄ ) and i. Vac. constricted. SC (petroleum ether / Et ₂ O = 9/1) of the oily residue gave 464 mg (33.8%) of a colorless oil. In addition, 564 mg (53.7%) of tris (4-methoxyphenyl) methanol could be recovered.
¹ H NMR (CDCl ₃ , 20 ° C): δ = 3.37-3.46 (m, 4 H, NCH ₂ CH ₂ O), 3.79 (s, 9 H, OCH ₃ ), 6.81-6.86 (m, 6 H, aromat. H), 7.32-7.37 (m, 6 H, aromat. H).

example 1 (a) N-Alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters General working instructions A

A suspension of the hydrochloride of the specified pyrrolidinylalkane carbonate (1 equiv.), 0.1 equiv. Potassium iodide and 2 equiv. Potassium carbonate in acetone (1.5 ml / mmol) became 1 equiv. of the specified bromide dissolved in acetone (1 ml / mmol) was added dropwise. The mixture was stirred at room temperature for the time indicated, taken up in water and CH ₂ Cl ₂ , extracted three times with CH ₂ Cl ₂ , dried (MgSO ₄ ) and i. Vac. constricted. The residue obtained was treated as indicated.

General working instructions B

A solution of the specified Cbz-protected amino acid alkyl ester (= 1 equiv.) In MeOH (0.1 M) was mixed with a spatula tip Pd / C and stirred at normal pressure (balloon) under an H ₂ atmosphere at RT for 1 h. After filtering off the catalyst, i. Vac. concentrated and the residue obtained with 1 equiv. Potassium carbonate and 0.1 equiv.

Potassium iodide suspended in acetone (1.5 ml / mmol). Then 1 equiv. of the specified bromide dissolved in acetone (1 ml / mmol) was added dropwise. The mixture was stirred at room temperature for the time indicated, taken up in water and CH ₂ Cl ₂ , extracted three times with CH ₂ Cl ₂ , dried (MgSO ₄ ) and i. Vac. constricted. The residue obtained was treated as indicated.

(b) (S) -N- (4,4-Diphenylbut-3-en-1-yl) pyrrolidin-2-carboxylic acid methyl ester (S-27a)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General procedure A: 497 mg (3 mmol) L-proline methyl ester hydrochloride (S-25-HCl, see preparation example 11), 49.8 mg (0.3 mmol) potassium iodide, 829 mg (6 mmol) potassium carbonate, 861 mg (3 mmol) 4.4 -Diphenylbut-3-en-1-yl bromide. Response time: 46 h. Purification by column chromatography (petroleum ether / ethyl acetate = 7/3) gave 527 mg (52.4%) of a colorless oil.
[α] 20 | D = -35.7 (c = 2.79, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.70-1.85 (m, 1 H, NCH ₂ CH ₂ ), 1.85-1.96 (m, 2H, NCH ₂ CH ₂ CH ₂ ), 2.02-2.14 ( m, 1 H, NCHCCH ₂ ), 2.27-2.37 (m, 3 H, NCH ₂ , = CCH ₂ CH ₂ N), 2.49-2.57 (m, 1 H, = CCH ₂ CH ₂ N), 2.81 (dt, J = 11.5 / 8.1 Hz, 1 H, = CCH ₂ CH ₂ N), 3.11 (td, J = 8.1 / 3.0 Hz, 1 H, NCH ₂ ), 3.16 (dd, J = 8.7 / 5.9 Hz, 1 H, NCHCOO), 3.68 (s, 3 H, OCH ₃ ), 6.08 (t, J = 7.4 Hz, 1 H, = CH), 7.15-7.40 (m, 10 H, aromatic H).

(c) (X) -N- (4,4-Diphenylbut-3-en-1-yl) pyrrolidin-2-carboxylic acid methyl ester (R-27a)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General procedure A: 359 mg (2.17 mmol) D-proline methyl ester hydrochloride (R-25-HCl, see preparation example 12), 36 mg (0.217 mmol) potassium iodide, 600 mg (4.34 mmol) potassium carbonate, 623 mg (2.17 mmol) 4.4 -Diphenylbut-3-en-1-yl bromide. Response time: 48 h. Purification by column chromatography (petroleum ether / ethyl acetate = 7/3) gave 350 mg (48.1%) of a colorless oil. The analytical data of the compound agree with that of the (5) enantiomer S-27a. [α] 20 | D = +34.9 (c = 1.72, CHCl ₃ ).

(d) (S) -N- {2- [Tris (4-methoxyphenyl) methoxy] ethyl} pyrrolidine-2-carboxylic acid methyl ester (S-27c)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General procedure A: 248 mg (1.5 mmol) L-proline methyl ester hydrochloride (S-25-HCl, see preparation example 11), 24.9 mg (0.15 mmol) potassium iodide, 415 mg (3 mmol) potassium carbonate, 686 mg (1.5 mmol) R-Br c (see preparation example 13). Response time: 40 h. Purification by column chromatography (ether / petroleum ether = 7/3) gave 285 mg (37.6%) of a colorless oil. [α] 20 | D = -29.6 (c = 1.05, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.73-1.81 (m, 1 H, NCH ₂ CH ₂ ), 1.81-1.93 (m, 2 H, NCH ₂ CH ₂ CH ₂ ), 2.02-2.14 (m, 1 H, NCHCCH ₂ ), 2.43 (q, J = 8.7 Hz, 1 H, NCH ₂ ), 2.73 (dt, J = 12.6 / 6.3 Hz, 1 H, OCH ₂ CH ₂ N), 2.95 (German , J = 12.6 / 6.3 Hz, 1 H, OCH ₂ CH ₂ N), 3.09-3.16 (m, 1 H, NCH ₂ ), 3.21 (t, J = 6.3 Hz, 2 H, OCH ₂ CH ₂ N), 3.26 (dd, J = 8.9 / 5.8 Hz, 1 H, NCHCOO), 3.65 (s, 3 H, COOCH ₃ ), 3.78 (s, 9 H, OCH ₃ ), 6.79-6.83 (m, 6 H, aromat. H), 7.29-7.34 (m, 6 H, aromatic H).

(e) (R) -N- {2- [Tris (4-methoxyphenyl) methoxy] ethyl) pyrrolidine-2-carboxylic acid methyl ester (R-27c)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General procedure A: 331 mg (2.0 mmol) D-proline methyl ester hydrochloride (R-25-HCl, see preparation example 12), 33.2 mg (0.2 mmol) potassium iodide, 553 mg (4.0 mmol) potassium carbonate, 914 mg (2.0 mmol) R-Br c (see preparation example 13). Response time: 40 h. Purification by column chromatography (ether / petroleum ether = 7/3) gave 395 mg (39.1%) of a colorless oil. The analytical data ( ¹ H NMR, IR, MS) of the compound agree with that of the (5) enantiomer S-27c. [α] 20 | D = + 30.5 (c = 1.75, CHCl ₃ ).

(f) (S) - (1- (4,4-Diphenylbut-3-en-1-yl) pyrrolidin-2-yl] methyl acetate (S-28a)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General procedure A: 176 mg (0.983 mmol) (S) -pyrrolidin-2-ylacetic acid methyl ester hydrochloride (S-19-HCl, see preparation example 5), 16.6 mg (0.1 mmol) potassium iodide, 304 mg (2.2 mmol) potassium carbonate, 287 mg (1 mmol) 4,4-diphenylbut-3-en-1-yl bromide. Response time: 46 h. Purification by column chromatography (petroleum ether / ethyl acetate = 7/3) gave 218 mg (63.5%) of a colorless oil.
[α] 20 | D = -62.5 (c = 3.35, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.49-1.59 (m, 1 H, NCHCCH ₂ ), I.62-1.80 (m, 2 H, NCH ₂ CH ₂ ), 1.94-2.05 (m , 1 H, NCHCCH ₂ ), 2.11 (dt, J = 8.2 / 9.0 Hz, 1 H, NCH ₂ ), 2.26 (dd, J = 14.9 / 9.0 Hz, 1 H, CH ₂ COO), 2.28-2.35 (m , 3 H, = CCH ₂ CH ₂ N), 2.60 (dd, J = 14.9 / 4.3 Hz, 1 H, CH ₂ COO), 2.70-2.79 (m, 1 H, NCHC), 2.80-2.88 (m, 1 H, = CCH ₂ CH ₂ N), 3.02 (ddd, J = 9.3 / 7.5 / 3.1 Hz, 1 H, NCH ₂ ), 3.64 (s, 3 H, OCH ₃ ), 6.10 (t, J = 7.0 Hz, 1 H, = CH), 7.16-7.40 (m, 10 H, aromatic H).

(g) (R) - (1- (4,4-Diphenylbut-3-en-1-yl) pyrrolidin-2-yl] methyl acetate (R-28a)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General procedure B: 227 mg (0.82 mmol) (R) -1-benzyloxycarbonylpyrrolidin-2-ylacetic acid methyl ester (R-21, see preparation example 6), 13.6 mg (0.082 mmol) potassium iodide, 113 mg (0.82 mmol) potassium carbonate, 235 mg ( 0.82 mmol) 4,4-diphenylbut-3-en-1-yl bromide. Response time: 47 h. Purification by column chromatography (petroleum ether / ethyl acetate = 7/3) gave 175 mg (61.1%) of a colorless oil. The analytical data of the compound agree with that of the (S) -enantiomer S-28a. [α] 20 | D = + 61.2 (c = 1.49, CHCl ₃ ).

(h) (S) - {1- [4,4-bis (3-methyl-2-thienyl) but-3-en-1-yl] pyrrolidin-2-yl} methyl acetate (S-28b)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General procedure A: 179 mg (1.0 mmol) (S) -pyrrolidin-2-ylacetic acid methyl ester hydrochloride (S-19-HCl, see preparation example 5), 16.6 mg (0.1 mmol) potassium iodide, 276 mg (2.0 mmol) potassium carbonate, 327 mg (1.0 mmol) 4,4-bis (3-methyl-2-thienyl) but-3-en-1-yl bromide. Response time: 46 h. Purification by column chromatography (petroleum ether / ethyl acetate = 7/3) gave 159 mg (40.8%) of a colorless oil.
[α] 20 | D = -60.2 (c = 0.99, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.49-1.57 (m, 1 H, NCH ₂ CH ₂ ), 1.67-1.76 (m, 2 H, NCH ₂ CH ₂ CH ₂ ), 1.96-2.03 (m, 1 H, NCHCCH ₂ ), 2.02 (s, 3 H, -CH ₃ ), 2.04 (s, 3 H, -CH ₃ ), 2.13 (td, J = 8.7 / 8.4 Hz, 1 H, NCH ₂ ), 2.25 (dd, J = 14.8 / 8.8 Hz, 1 H, CH ₂ COO), 2.28-2.36 (m, 3 H, = CCH ₂ CH ₂ N), 2.62 (dd, J = 14.8 / 4.4 Hz, 1 H, CH ₂ COO), 2.70-2.78 (m, 1 H, NCHC), 2.81-2.89 (m, 1 H, = CCH ₂ CH ₂ N), 3.04 (ddd, J = 10.0 / 7.4 / 3.3 Hz, 1 H, NCH ₂ ), 3.66 (s, 3 H, -OCH ₃ ), 6.06 (t, J = 7.0 Hz, 1 H, = CH), 6.77 (d, J = 5.2 Hz, 1 H, SC = CH) , 6.84 (d, J = 5.2 Hz, 1 H, SC = CH), 7.06 (d, J = 5.2 Hz, 1 H, SCH =), 7.21 (d, J = 5.2 Hz, 1 H, SCH =).

(i) (R) - {1- [4,4-bis (3-methyl-2-thienyl) but-3-en-1-yl] pyrrolidin-2-yl} methyl acetate (R-28b)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General procedure B: 277 mg (1.0 mmol) (R) -1-benzyloxycarbonylpyrrolidin-2-ylacetic acid methyl ester (R-21, see preparation example 6), 16.6 mg (1.0 mmol) potassium iodide, 138 mg (1.0 mmol) potassium carbonate, 327 mg ( 1 mmol) 4,4-bis (3-methyl-2-thienyl) but-3-en-1-yl bromide. Response time: 46 h. Purification by column chromatography (petroleum ether / ethyl acetate = 7/3) gave 161 mg (41.3%) of a colorless oil. The analytical data of the compound agree with that of the (S) -enantiomer S-28b.
[α] 20 | D = + 61.3 (c = 1.04, CHCl ₃ ).

(j) (S) - (1- {2- (Tris (4-methoxyphenyl) methoxyl) ethyl} pyrrolidin-2-yl) methyl acetate (S-28c)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General working procedure A: 215 mg (1.2 mmol) (S) -pyrrolidin-2-ylacetic acid emmethyl ester hydrochloride (S-19-HCl, see preparation example 5), 19.9 mg (0.12 mmol) potassium iodide, 332 mg (2.4 mmol) potassium carbonate, 548 mg (1 mmol) R-Br c (see preparation example 13). Response time: 46 h. Purification by column chromatography (petroleum ether / ethyl acetate = 20/80) gave 220 mg (35.2%) of a colorless oil.
[α] 20 | D = - 27.6 (c = 1.77, CHCl). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.49-1.59 (m, 1 H, NCH ₂ CH ₂ ), 1.68-1.80 (m, 2 H, NCH ₂ CH ₂ CH ₂ ), 1.97-2.07 (m, 1 H, NCHCCH ₂ ), 2.21-2.31 (m, 2 H, CH ₂ COO, NCH ₂ ), 2.51 (dt, J = 12.5 / 6.5 Hz, 1 H, OCH ₂ CH ₂ N), 2.65 ( dd, J = 15.1 / 4.0 Hz, 1 H, CH ₂ COO), 2.79-2.87 (m, 1 H, NCHC), 2.97 (dt, J = 12.5 / 6.5 Hz, 1 H, OCH ₂ CH ₂ N), 3.06 (ddd, J = 10.4 / 7.1 / 3.5 Hz, 1 H, NCH ₂ ), 3.20 (m, 2 H, OCH ₂ CH ₂ N), 3.67 (s, 3 H, COOCH ₃ ), 3.81 (s, 9 H, -OCH ₃ ), 6.81-6.87 (m, 6 H, aromat. H), 7.34-7.39 (m, 6 H, aromat. 11).

(k) (R) - (1- {2- [Tris (4-methoxyphenyl) methoxy] ethyl} pyrrolidin-2-yl) methyl acetate (R-28c)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General procedure B: 227 mg (0.82 mmol) (R) -1-benzyloxycarbonylpyrrolidin-2-ylacetic acid methyl ester (R-21, see preparation example 6), 13.6 mg (0.082 mmol) potassium iodide, 113 mg (0.82 mmol) potassium carbonate, 375 mg ( 0.82 mmol) R-Br c (see preparation example 13). Response time: 45 h. The analytical data of the compound agree with that of the (S) -enantiomer S-28c. Purification by column chromatography (petroleum ether / ethyl acetate = 20/80) gave 175 mg (41.1%) of a colorless oil. [α] 20 | D = + 26.7 (c = 1.5, CHCl ₃ ).

(I) 3 - [(S) -1- (4,4-diphenylbut-3-en-1-yl) pyrrolidin-2-yl] methyl propionate (S-29a)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General procedure B: 269 mg (0.93 mmol) S-24 (see preparation example 9), 15.4 mg (0.093 mmol) potassium iodide, 128 mg (0.93 mmol) potassium carbonate, 267 mg (0.93 mmol) 4,4-diphenylbut-3-ene -1-yl bromide. Response time: 48 h. Purification by column chromatography (n-hexane / ether = 7/3) gave 142 mg (42.0%) of a colorless oil. [α] 20 | D = - 63.9 (c = 1.1, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.30-1.39 (m, 1 H, NCHCCH ₂ ), 1.47-1.70 (m, 3 H, CH ₂ CH ₂ COO, NCH ₂ CH ₂ ), 1.75 -1..83 (m, 1 H, NCHCCH ₂ ), 1.83-1.93 (m, 1 H, CH ₂ CH ₂ COO), 1.99 (td, J = 9.0 / 8.2 Hz, 1 H, NCH ₂ ), 2.11 -2.28 (m, 5 H, = CCH ₂ CH ₂ N, CH ₂ OO, NCHC), 2.33 (ddd, J = 15.6 / 9.S / 5.9 Hz, 1 H, CH ₂ COO), 2.84 (ddd, J = 15.3 / 8.5 / 6.1 Hz, 1 H, = CCH ₂ CH ₂ N), 2.97 (ddd, J = 9.0 / 7.4 / 2.9 Hz, 1 H, NCH ₂ ), 3.59 (s, 3 H, OCH ₃ ), 6.05 (t, J = 7.3 Hz, 1 H, = CH), 7.10-7.33 (m, 10 H, aromatic H).

(m) 3 - [(R) -1- (4,4-diphenylbut-3-en-1-yl) pyrrolidin-2-yl] methyl propionate (R-29a)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General procedure B: 231 mg (0.8 mmol) R-24 (see preparation example 10), 13.3 mg (0.08 mmol) potassium iodide, 111 mg (0.8 mmol) potassium carbonate, 230 mg (0.8 mmol) 4,4-diphenylbut-3-ene -1-yl bromide. Response time: 46 h. Purification by column chromatography (n-hexane 1 ether = 3/7) gave 131 mg (45.0%) of a colorless oil. The analytical data of the compound agree with that of the (S) -enantiomer S-29a. [α] 20 | D = + 63.55 (c 1.07, CHCl ₃ ).

(n) 3 - {(S) -1- (4,4-bis (3-methyl-2-thienyl) but-3-en-1-yl] pyrrolidin-2-yl) methyl propionate (S-29b)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General procedure B: 289 mg (1.0 mmol) S-24 (see preparation example 9), 16.6 mg (0.1 mmol) potassium iodide, 138 mg (1.0 mmol) potassium carbonate, 327 mg (1.0 mmol) 4,4-bis (3-methyl -2-thienyl) but-3-en-1-yl bromide. Response time: 46 h. Purification by column chromatography (petroleum ether / ethyl acetate = 5/5) gave 165 mg (40.9%) of a colorless oil. [α] 20 | D = - 6.2 (c = 1.05, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.37-1.47 (m, 1 H, NCHCCH ₂ ), 1.53- 1.78 (m, 3 H, CH ₂ CH ₂ COO, NCH ₂ CH ₂ ), 1.82 -1.90 (m, 1 H, NCHCCH ₂ ), 1.91-2.01 (m, 1 H, CH ₂ CH ₂ COO), 2.03 (s, 3 H, CH ₃ ), 2.05 (s, 3 H, CH ₃ ), 2.07 (q, J = 8.9 Hz, 1 H, NCH ₂ ), 2.18-2.35 (m, 5 H, = CCH ₂ CH ₂ N, CH ₂ COO, NCHC), 2.40 (ddd, J = 15.6 / 9.5 / 5.9 Hz, 1 H, CH ₂ COO), 2.91 (dt, J = I 1.4 / 8.1 Hz, IH, = CCH ₂ CH ₂ N), 3.07 (ddd, J = 9.5 / 7.5 / 3.0 Hz, 1 H, NCH ₂ ), 3.68 (s, 3 H, OCH ₃ ), 6.09 (t, J = 7.3 Hz, 1 H, = CH), 6.77 (d, J = 5.2 Hz, 1 H, SC = CH), 6.85 (d, J = 5.2 Hz, 1 H, SC = CH), 7.06 (d, J = 5.2 Hz, 1 H, SCH =), 7.21 (d, J = 5.2 Hz, 1 H, SCH =).

(o) 3 - {(R) -1- [4,4-bis (3-methyl-2-thienyl) but-3-en-1-yl] pyrrolidin-2-yl} methyl propionate (R-29b)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General procedure B: 474 mg (1.64 mmol) R-24 (see preparation example 10), 27.2 mg (0.16 mmol) potassium iodide, 227 mg (1.64 mmol) potassium carbonate, 536 mg (1.64 mmol) 4,4-bis (3-methyl -2-thienyl) but-3-en-1-yl bromide. Response time: 47 h. Purification by column chromatography (petroleum ether / ethyl acetate = 5/5) gave 260 mg (39.4%) of a colorless oil. The analytical data of the compound agree with that of the (S) -enantiomer S-29b. [α] 20 | D = + 6.3 (c = 1.18, CHCl ₃ ).

(p) 3 - [(S) -1- {2- (Tris (4-methoxyphenyl) methoxy] ethyl} pyrrolidin-2-yl] propionic acid methyl ester (S-29c)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General working procedure B: 289 mg (1.0 mmol) S-24 (see preparation example 9), 16.6 mg (0.1 mmol) potassium iodide, 138 mg (1.0 mmol) potassium carbonate, 457 mg (1.0 mmol) R-Br c (see preparation example 13) . Response time: 48 h. Purification by column chromatography (petroleum ether / ethyl acetate = 2/8) gave 117 mg (21.9%) of a colorless oil. [α] 20 | D = - 29.5 (c = 1.27, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.36-1.46 (m, 1 H, NCH ₂ CH ₂ ), 1.56-1.64 (m, 1 H, CH ₂ CH ₂ COO), 1.64-1.73 ( m, 2 H, NCH ₂ CH ₂ CH ₂ ), 1.81-1.89 (m, 1 H, NCHCCH ₂ ), 1.90-2.00 (m, 1 H, CH ₂ CH ₂ COO), 2.15 (q, J = 9.0 Hz , 1 H, NCH ₂ ), 2.21-2.47 (m, 4 H, CH ₂ CO, OCH ₂ CH ₂ N, NCHC), 2.98-3.10 (m, 2 H, OCH ₂ CH ₂ N, NCH ₂ ), 3.12 -3.25 (m, 2 H, OCH ₂ CH ₂ N), 3.67 (s, 3 H, COOCH ₃ ), 3.80 (s, 9 H, OCH ₃ ), 6.80-6.85 (m, 6 H, aromatic H) , 7.33-7.37 (m, 6H, aromatic H).

(q) 3 - [(R) -1- {2- [tris (4-methoxyphenyl) methoxy] ethyl} pyrrolidin-2-yl] propionic acid methyl ester (R-29c)

N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters:
General procedure B: 289 mg (1.0 mmol) R-24 (see preparation example 10), 16.6 mg (0.1 mmol) potassium iodide, 138 mg (1.0 mmol) potassium carbonate, 457 mg (1.0 mmol) R-Br c (see preparation example 13) ,. Response time: 48 h. Purification by column chromatography (petroleum ether / ethyl acetate = 2/8) gave 239 mg (44.8%) of a colorless oil. The analytical data of the compound agree with that of the (S) -enantiomer S-29c. [α] 20 | D = + 29.5 (c = 1.05, CHCl ₃ ).

Example 2 (α) Saponification of the methyl esters, general working instructions

The methyl esters (= 1 equiv.) Were each dissolved in ethanol (approx. 2 ml / mmol). The solution was cooled to 0 ° C and 12N NaOH (2 equiv) was added dropwise. The cooling bath was then removed and the mixture was stirred at RT for the time indicated in each case. The mixture was cooled again to 0 ° C. and, unless otherwise stated, acidified dropwise to pH ≈ 6 with 0.25 N HCl. The reaction mixture was taken up in CH ₂ Cl ₂ and water and extracted five times with CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), i. Vac. concentrated and the residue obtained further treated as indicated.

(b) (S) -N- (4,4-diphenylbut-3-en-1-yl) pyrrolidin-2-carboxylic acid hydrochloride (S-30a)

Saponification methyl ester, general working instructions: 265 mg (0.79 mmol) S-27a (see Example 1 (b)), 132 µl 12 M NaOH, reaction time S h. In contrast to the general working procedure, the work-up was carried out by acidifying dropwise with cooling with 4 M HCl to pH ≈ 1 and extraction five times with CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), i. Vac. concentrated and the hydrochloride obtained crystallized from ethanol. Yield: 231 mg (81.9%); colorless crystals, mp: 220 ° C. - [α] 20 | D = - 21.0 (c = 1.00, CH ₃ OH). - ¹ H NMR (CD ₃ OD, 20 ° C): δ = 1.88-2.00 (m, 1 H, NCH ₂ CH ₂ ), 2.08-2.21 (m, 2 H, NCH ₂ CH ₂ CH ₂ ), 2.43- 2.53 (m, 1 H, NCHCCH ₂ ), 2.54-2.62 (m, 2 H, = CHCH ₂ ), 3.05-3.14 (m, 1 H, NCH ₂ ), 3.20-3.30 (m, 1 H, = CHCH ₂ CH ₂ ), 3.45 (td, J = 12.4 / 8.0 Hz, 1 H, = CHCH ₂ CH ₂ ), 3.62 (ddd, J = 12.4 / 7.5 / 4.0 Hz, 1 H, NCH ₂ ), 4.08 (dd, J = 9.6 / 6.8 Hz, 1 H, NCHC), 6.11 (t, J = 7.3 Hz, 1 H, = CH), 7.19-7.49 (m, 10 H, aromatic H).

(c) (R) -N- (4,4-diphenylbut-3-en-1-yl) pyrrolidin-2-carboxylic acid hydrochloride (R-30a)

Saponification methyl ester, general working instructions: 210 mg (0.63 mmol) R-27a (see Example 1 (c)), 105 µl 12 M NaOH, reaction time 5 h. In contrast to the general working procedure, the work-up was carried out by acidifying dropwise with cooling with 4 M HCl to pH ≈ 1 and extraction five times with CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), i. Vac. concentrated and the hydrochloride obtained crystallized from ethanol. Yield: 184 mg (82.1%); colorless crystals, m.p .: 218 ° C. The analytical data of the compound agree with that of the (S) -enantiomer S-30a. - [α] 20 | D = + 21.9 (c = 0.71, CH ₃ OH).

(d) (S) -N- {2- [Tris (4-methoxyphenyl) methoxy] ethyl} pyrrolidine-2-carboxylic acid (S-30c)

Saponification methyl ester, general working instructions: 289 mg (0.63 mmol) S-27c (see Example 1 (d)), 95 µl 12 M NaOH, reaction time 4 h. Recrystallization from ether / n-pentane (1/1) gave 225 mg (80.1%) colorless crystals, mp: 69-75 ° C (decomposition). - [α] 20 | D = - 8.2 (c = 4.92, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.85-1.95 (m, 2 H, NCH ₂ CH ₂ ), 2.22 (q, J = 7.3 Hz, 2 H, NCHCCH ₂ ), 2.77 (dt, J = 9.8 / 8.8 Hz, 1 H, NCH ₂ ), 2.93-3.01 (m, 1 H, OCH ₂ CH ₂ N), 3.27-3.36 (m, 2 H, OCH ₂ CH ₂ N), 3.39-3.47 ( m, 1 H, OCH ₂ CH ₂ N), 3.54 (dt, J = 9.8 / 5.5 Hz, 1 H, NCH ₂ ), 3.68-3.76 (m, 1 H, NCHC), 3.80 (s, 9 H, OCH ₃ ), 6.80-6.86 (m, 6 H, aromatic H), 7.28-7.33 (m, 6 H, aromatic H).

(e) (R) -N- {2- [tris (4-methoxyphenyl) methoxy] ethyl} pyrrolidine-2-carboxylic acid (R-30c)

Saponification methyl ester, general working instructions: 243 mg (0.48 mmol) R-27c (see Example 1 (e)), 80 µl 12 M NaOH, reaction time 4 h. Recrystallization from ether / n-pentane (1/1) gave 186 mg (78.8%); colorless crystals, mp: 69-75 ° C (decomposition). The analytical data of the compound agree with that of the (S) -enantiomer S-30c. [α] 20 | D = + 8.1 (c = 2.73, CHCl ₃ ).

(f) (S) - [1- (4,4-Diphenylbut-3-en-1-yl) pyrrolidin-2-yl] acetic acid (S-31a)

Saponification methyl ester, general working instructions: 139 mg (0.398 mmol) S-28a (see Example 1 (f)), 66 µl 12 M NaOH, reaction time 5 h. SC (CH ₂ Cl ₂ / ethanol = 8/2) gave 110 mg (82.5%) colorless crystals, mp: 130-137 ° C (decomposition). - [α] 20 | D = - 85.4 (c = 1.30, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.67-1.94 (m, 3 H, NCH ₂ CH ₂ CH ₂ ), 2.05-2.15 (m, 1 H, NCHCCH ₂ ), 2.35 (td, J = 10.5 / 8.5 Hz, 1 H, NCH ₂ ), 2.42-2.54 (m, 4 H, = CCH ₂ CH ₂ N, CH ₂ COO), 2.65 (dd, J = 17.1 / 5.1 Hz, 1 H, CH ₂ COO), 2.95-3.04 (m, 1 H, NCHC), 3.06-3.16 (m, 1 H, = CCH ₂ CH ₂ N), 3.19 (ddd, J = 10.5 / 7.1 / 3.9 Hz, 1 H, NCH ₂ ), 6.02 (t, J = 7.3 Hz, 1 H, = CH), 7.14-7.44 (m, 10 H, aromatic H).

(g) (R) - [1- (4,4-Diphenylbut-3-en-1-yl) pyrrolidin-2-yl] acetic acid (R-31a)

Saponification methyl ester, general working instructions: 136 mg (0.389 mmol) R-28a (see Example 1 (g)), 65 µl 12 M NaOH, reaction time 5 h. SC (ethanol) provided 105 mg (80.4%) colorless crystals, mp: 129-135 ° C (decomposition). The analytical data of the compound agree with that of the (5) enantiomer S-31a. - [α] 20 | D = + 86.5 (c = 0.47, CHCl ₃ ).

(h) (S) - {1- [4,4-bis (3-methyl-2-thienyl) but-3-en-1-yl] pyrrolidin-2-yl} acetic acid (S-31b)

Saponification methyl ester, general working instructions: 85 mg (0.218 mmol) S-28b (see Example 1 (h)), 36 µl 12 M NaOH, reaction time 5 h. SC (ethanol) provided 57 mg (69.6%) colorless oil. -
[α] 20 | D = - 64.9 (c = 0.85, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.66-1.79 (m, 1 H, NCH ₂ CH ₂ ), 1.79-1.95 (m, 2 H, NCH ₂ CH ₂ CH ₂ ), 1.98 (see , 3 H, CH ₃ ), 2.03 (s, 3 H, CH ₃ ), 2.04-2.17 (m, 1 H, NCHCCH ₂ ), 2.38-2.55 (m, 5 H, = CCH ₂ CH ₂ N, CH ₂ COO, NCH ₂ ), 2.63 (dd, J = 16.9 / 5.3 Hz, 1 H, CH ₂ COO), 2.93-3.01 (m, 1 H, NCHC), 3.03-3.12 (m, 1 H, = CCH ₂ CH ₂ N), 3.29 (ddd, J = 11.0 / 7.5 / 4.0 Hz, 1 H, NCH ₂ ), 6.01 (t, J = 7.3 Hz, 1 H, = CH), 6.76 (d, J = 5.1 Hz, 1 H, SC = CH), 6.87 (d, J = 5.1 Hz, 1 H, SC = CH), 7.06 (d, J = 5.1 Hz, 1 H, SCH =), 7.24 (d, J = 5.1 Hz, 1 H, SCH =).

(i) (R) - {1- [4,4-bis (3-methyl-2-thienyl) but-3-en-1-yl] pyrrolidin-2-yl} acetic acid (R-31b)

Saponification methyl ester, general working instructions: 105 mg (0.27 mmol) R-28b (see Example 1 (j)), 45 µl 12 M NaOH, reaction time 5 h. SC (ethanol) provided 69 mg (68.1%) colorless oil. The analytical data of the compound agree with that of the (S) - enantiomer S-31b. [α] 20 | D = + 65.2 (c = 1.02, CHCl ₃ ).

(j) (S) - (1- {2- (Tris (4-methoxyphenyl) methoxy] ethyl} pyrrolidin-2-yl) acetic acid (S-31c)

Saponification methyl ester, general working instructions: 220 mg (0.423 mmol) S-28c (see Example 1 (j)), 70 µl 12 M NaOH, reaction time 5 h. Recrystallization from ether / n-pentane (1/1) gave 176 mg (82.2%); colorless crystals, mp: 68-73 ° C (decomposition). [α] 20 | D = - 32.0 (c = 0.66, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.69-1.97 (m, 3 H, NCH ₂ CH ₂ CH ₂ ), 2.04-2.15 (m, 1 H, NCHCCH ₂ ), 2.44-2.59 (m , 3 H, OCH ₂ CH ₂ N, NCH ₂ , CH ₂ COO), 2.68 (dd, J = 17.2 / 4.3 Hz, 1 H, CH ₂ COO), 2.98-3.07 (m, 1 H, NCHC), 3.07 -3.17 (m, 1 H, OCH ₂ CH ₂ N), 3.26-3.44 (m, 3 H, OCH ₂ CH ₂ N, NCH ₂ ), 3.79 (s, 9 H, OCH ₃ ), 6.84-6.86 (m , 6 H, aromatic H), 7.28-7.34 (m, 6 H, aromatic H).

(k) (R) - (1- {2- [Tris (4-methoxyphenyl) methoxy] ethyl} pyrrolidin-2-yl) acetic acid (R-31c)

Saponification methyl ester, general working instructions: 135 mg (0.26 mmol) R-28c (see Example 1 (k)), 43 µl 12 M NaOH, reaction time 5 h. Recrystallization from ether / n-pentane (1/1) gave 109 mg (83.0%); colorless crystals, mp: 68-73 ° C (decomposition). The analytical data of the compound agree with that of the (S) -enantiomer S-31c. [α] 20 | D = + 32.7 (c = 1.02, CHCl ₃ ).

(l) 3 - [(S) -1- (4,4-diphenylbut-3-en-1-yl) pyrrolidin-2-yl] propionic acid (S-32a)

Saponification methyl ester, general working instructions: 122 mg (0.336 mmol) S-29a (see Example 1 (l)), 56 µl 12 M NaOH, reaction time 5 h. SC (ethanol) provided 88 mg (75.0%) colorless oil. -
[α] 20 | D = - 20.4 (c = 1.10, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.61-1.72 (m, 1 H, NCH ₂ CH ₂ ), 1.72-1.90 (m, 4 H, CH ₂ CH ₂ COO, NCH ₂ CH ₂ CH ₂ ), 1.90-2.02 (m, 1 H, NCHCCH ₂ ), 2.32-2.59 (m, 6 H, = CCH ₂ CH ₂ N, NCH ₂ , CH ₂ COO), 2.85-2.94 (m, 1 H, NCHC ), 3.05 (td, J = 11.0 / 5.0 Hz, 1 H, = CCH ₂ CH ₂ N), 3.18-3.25 (m, 1 H, NCH ₂ ), 6.03 (t, J = 7.0 Hz, 1 H, = CH), 7.12-7.40 (m, 10 H, aromatic H).

(m) 3 - [(R) -1- (4,4-diphenylbut-3-en-1-yl) pyrrolidin-2-yl] propionic acid (R-32a)

Saponification methyl ester, general working instructions: 107 mg (0.336 mmol) R-29a (see Example 1 (m)), 49 µl 12 M NaOH, reaction time 5 h. SC (ethanol) provided 76 mg (73.9%) colorless oil. The analytical data of the compound agree with that of the (8) enantiomer S-32a. [α] 20 | D = + 19.5 (c = 0.87, CHCl ₃ ).

(n) 3 - {(S) -1- [4,4-bis (3-methyl-2-thienyl) -3-butenyl] pyrrolidin-2-yl} propionic acid (S-32b)

Saponification methyl ester, general working instructions: 100 mg (0.248 mmol) S-29b (see Example 1 (n)), 41 µl 12 M NaOH, reaction time 5 h. SC (ethanol) provided 68 mg (70.5%) colorless oil. -
[α] 20 | D = - 17.0 (c = 0.73, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.70-1.85 (m, 2 H, NCH ₂ CH ₂ CH ₂ ), 1.85-2.10 (m, 4 H, CH ₂ CH ₂ COO, NCH ₂ CH ₂ CH ₂ ), 1.96 (s, 3 H, CH ₃ ), 2.00 (s, 3 H, CH ₃ ), 2.40-2.75 (m, 5 H, = CCH ₂ CH ₂ N, NCH ₂ , CH ₂ COO) , 2.69 (td, J = 11.3 / 5.0 Hz, 1 H, = CCH ₂ CH ₂ N), 3.03-3.15 (m, 2 H, = CCH ₂ CH ₂ N, NCHC), 3.28-3.38 (m, 1 H , NCH ₂ ), 5.96 (t, J = 7.3 Hz, 1 H, = CH), 6.74 (d, J = 4.4 Hz, 1 H, SC = CH), 6.85 (d, J = 4.4 Hz, 1 H, SC = CH), 7.05 (d, J = 4.4 Hz, 1 H, SCH =), 7.22 (d, J = 4.4 Hz, 1 H, SCH =).

(o) 3 - {(R) -1- [4,4-bis (3-methyl-2-thienyl) -3-butenyl] pyrrolidin-2-yl} propionic acid (R-32b)

Saponification methyl ester, general working instructions: 170 mg (0.421 mmol) R-296 (see Example 1 (o)), 70 µl 12 M NaOH, reaction time 5 h. SC (ethanol) provided 112 mg (68.3%) colorless oil. The analytical data of the compound agree with that of the (8) enantiomer S-32b. [α] 20 | D = + 17.3 (c = 0.91, CHCl ₃ ).

(p) 3 - [(S) -1- {2- [Tris (4-methoxyphenyl) methoxy] ethyl} pyrrolidin-2-yl] propionic acid (S-32c)

Saponification methyl ester, general working instructions: 93 mg (0.174 mmol) S-29c (see Example 1 (p)), 29 µl 12 M NaOH, reaction time 5 h. Recrystallization from ether / n-pentane (1/1) gave 73 mg (80.6%); colorless crystals, mp: 65-73 ° C (decomposition). - [α] 20 | D = - 4.4 (c = 0.51, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.73-2.07 (m, 6 H, CH ₂ CH ₂ COO, NCH ₂ CH ₂ CH ₂ ), 2.36- 2.46 (m, 1 H, CH ₂ COO ), 2.50-2.60 (m, 1 H, CH ₂ COO), 2.72-3.81 (m, 2 H, OCH ₂ CH ₂ N, NCH ₂ ), 3.03-3.12 (m, 1 H, NCHC), 3.18-3.28 (m, 1 H, OCH ₂ CH ₂ N), 3.40-3.50 (m, 1 H, NCH ₂ ), 3.49-3.61 (m, 2 H, OCH ₂ CH ₂ N), 3.70 (s, 9 H, OCH ₃ ), 6.78-6.86 (m, 6 H, aromatic H), 7.23-7.35 (m, 6 H, aromatic H).

(q) 3 - [(R) -1- {2- [tris (4-methoxyphenyl) methoxy] ethyl] pyrrolidin-2-yl] propionic acid (R-32c)

Saponification methyl ester, general working instructions: 143 mg (0.268 mmol) R-29c (see example 1 (q)), 45 μl 12 M NaOH, reaction time 5 h. Recrystallization from ether / n-pentane (1/1) yielded 115 mg (82.6%) colorless crystals, mp: 64-72 ° C (decomposition). The analytical data of the compound agree with that of the (S) -enantiomer S-32c. [α] 20 | D = + 4.1 (c = 0.50, CHCl ₃ ).

Example 3

(a) (E) -3 - [(2S) -1- {2- [tris- (4-methoxyphenyl) methoxy) ethyl} pyrrolidin-2-yl] acrylic acid methyl ester (S-34)

A solution of 295 mg (0.584 mmol) of S-27c (see Example 1 (d)) in 4 ml of toluene was admixed with 1.4 ml (2.4 equiv.) Of DIBAH solution at -60 ° C. over a period of 10 min. (1 M in n-hexane) was added dropwise and the reaction mixture was stirred at -60 ° C. for 2 h. The reaction was then stopped by dropwise addition of 0.5 ml of methanol, warmed to RT and taken up in water and Et ₂ O. The aqueous phase was extracted three times with Et ₂ O, the combined organic phases were dried (MgSO ₄ ) and i. Vac. constricted. The oily residue (275 mg) was dissolved in 2.5 ml of acetonitrile and admixed with 30 mg (0.7 mmol, 1.2 equiv.) LiCl and with 123 μl (0.7 mmol, 1.2 equiv.) DIPEA. Then 113 μl (0.7 mmol, 1.2 equiv.) Trimethylphosphonoacetate were added dropwise. The reaction mixture was stirred at RT for 16 h, then i. Vac. concentrated, taken up in Et ₂ O and water and the aqueous phase extracted three times with Et ₂ O. The combined organic phases were dried (MgSO ₄ ) and i. Vac. constricted. Twice SC (n-hexane / ether = 1/1) provided 180 mg (58.0%) of a colorless oil.
[α] 20 | D = - 32.9 (c = 0.99, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.53-1.66 (m, 1 H, NCHCCH ₂ ), 1.69-1.87 (m, 2 H, NCH ₂ CH ₂ ), 1.90-2.02 (m, 1 H, NCHCCH ₂ ), 2.25 (q, J = 8.6 Hz, 1 H, NCH ₂ ), 2.41 (dt, J = 12.9 / 5.8 Hz, 1 H, OCH ₂ CH ₂ N), 2.86-3.02 (m, 2 H, OCH ₂ CH ₂ N, NCHC), 3.07-3.24 (m, 3 H, OCH ₂ CH ₂ N, NCH ₂ ), 3.74 (s, 3 H, COOCH ₃ ), 3.78 (s, 9 H, OCH ₃ ), 5.98 (d, J = 15.6 Hz, 1 H, = CHCOO), 6.78-6.87 (m, 7 H, CH =, aromatic H), 7.31-7.37 (m, 6 H, aromatic H).

(b) (E) -3 - [(2R) -1- {2- (tris- (4-methoxyphenyl) methoxy] ethyl} pyrrolidin-2-yl] acrylic acid methyl ester (R-34)

The connection was shown in the same way as the instructions for S-34.

Batch size: 308 mg (0.594 mmol) R-27c (see Example 1 (e)); 1.43 ml DIBAH solution. (1 M in n-hexane); 30 mg (0.7 mmol, 1.2 equiv.) LiCl; 125 µl (0.71 mmol, 1.2 equiv.) DIPEA; 115 µl (0.71 mmol, 1.2 equiv.) Trimethylphosphonoacetate. Yield: 181 mg (59.5%); colorless oil. The analytical data of the compound agree with that of the (S) -enantiomer S-34. [α] 20 | D = + 33.6 (c = 1.0, CHCl ₃ ).

Example 4

(α) (Z) -3 - [(2S) -1- {2- [tris- (4-methoxyphenyl) methoxy] ethyl) pyrrolidin-2-yl] acrylic acid methyl ester (S-35)

A solution of 437 mg (0.865 mmol) of S-27c (see Example 1 (d)) in 6 ml of toluene was admixed with 2.1 ml (2.4 equiv.) Of DIBAH solution at -60 ° C over a period of 10 min. (1 M in n-hexane) was added dropwise and the reaction mixture was stirred at -60 ° C. for 2 h. The reaction was then stopped by dropwise addition of 0.5 ml of methanol, warmed to RT and taken up in water and Et ₂ O. The aqueous phase was extracted three times with Et ₂ O, the combined organic phases were dried (MgSO ₄ ) and i. Vac. constricted. The oily residue (410 mg) was dissolved in 5 ml of THF and a solution of 1143 g (5 equiv.) Of crown ether (18-crown-6), 183 μl (1 equiv.) Bis (3. 3,3-trifluoroethoxy) phosphonic acid methyl ester and 1.15 ml (1 equiv.) KN (TMS) 2 (15% solution in toluene) in 5 ml THF were added dropwise at -78 ° C. The reaction mixture was stirred at RT for 1 h, the reaction by adding 1 ml of saturated NH ₄ Cl solution. terminated, taken up in CH ₂ Cl ₂ and water and the aqueous phase extracted three times with CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ) and i. Vac. constricted. Repeated SC (n-hexane / ether = 1/1) gave 197 mg (43.0%) S-35 as a colorless oil. In addition, 66 mg (14.3%) S-34 could be isolated as a colorless oil.
[α] 20 | D = + 9.6 (c = 0.54, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.42-1.55 (m, 1 H, NCHCCH ₂ ), 1.73-1.88 (m, 2 H, NCH ₂ CH ₂ ), 2.05-2.16 (m, 1 H, NCHCCH ₂ ), 2.25 (q, J = 8.9 Hz, 1 H, NCH ₂ ), 2.49 (dt, J = 12.6 / 6.3 Hz, 1 H, OCH ₂ CH ₂ N), 2.87 (dt, J = 12.6 /6.3 Hz, 1 H, OCH ₂ CH ₂ N), 3.10-3.24 (m, 3 H, OCH ₂ CH ₂ N, NCH ₂ ), 3.70 (s, 3 H, COOCH ₃ ), 3.78 (s, 9 H , OCH ₃ ), 4.01 (q, J = 8.0 Hz, 1 H, NCHC), 5.80 (d, J = 11.6 Hz, 1 H, = CHCOO), 6.18 (dd, J = 11.6 / 8.0 Hz, 1 H, CH =), 6.76-6.85 (m, 6 H, aromatic H), 7.29-7.38 (m, 6 H, aromatic H).

(b) (Z) -3 - [(2R) -1- {2- [tris- (4-methoxyphenyl) methoxy] ethyl} pyrrolidin-2-yl] acrylic acid methyl ester (R-35)

The connection was shown in the same way as the instructions for S-35.

Batch size: 259 mg (0.513 mmol) R-27c (see Example 1 (e)); 1.23 ml DIBAH solution. (1 M in n-hexane); 678 mg (5 equiv.) Crown ether (18-crown-6), 108 µl (1 equiv.) Bis (3,3,3-trifluoroethoxy) phosphoric acid methyl ester and 682 µl (1 equiv.) KN (TMS) 2 (15% solution in toluene).
Yield: 116 mg (42.2%) R-35 as a colorless oil, and 39 mg (14.3%) R-34. The analytical data of the compound agree with that of the (S) -enantiomers. [α] 20 | D = - 9.1 (c = 0.50, CHCl ₃ ).

Example 5

(a) (E) -3 - [(2S) -1- {2- [tris- (4-methoxyphenyl) methoxy] ethyl} pyrrolidin-2-yl] acrylic acid (S- 36)

Saponification methyl ester, general working instructions: 157 mg (0.296 mmol) S-34 (see Example 3 (α)), 49 µl 12 M NaOH, reaction time 5 h. Recrystallization from ether / n-pentane (1 / l) yielded 120 mg (78.5%) colorless crystals, mp: 78-86 ° C (decomposition). [α] 20 | D = - 15.6 (c 0.82, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.67-1.80 (m, 2 H, NCH ₂ CH ₂ CH ₂ ), 1.85-1.98 (m, 2 H, NCH ₂ CH ₂ CH ₂ ), 2.49 -2.59 (m, 2 H, OCH ₂ CH ₂ N, NCH ₂ ), 3.04-3.18 (m, 2 H, OCH ₂ CH ₂ N, NCH ₂ ), 3.23-3.37 (m, 2 H, OCH ₂ CH ₂ N), 3.60-3.68 (m, 1 H, NCHC), 3.70 (s, 9 H, OCH ₃ ), 5.85 (d, J = 15.2 Hz, 1 H, = CHCOO), 6.67 (dd, J = 15.2 / 8.9 Hz, 1 H, CH = CHCOO), 6.71-6.76 (m, 6 H, aromatic H), 7.21-7.25 (m, 6 H, aromatic H).

(b) (E) -3 - [(2R) -1- {2- [tris- (4-methoxyphenyl) methoxy] ethyl} pyrrolidin-2-yl) acrylic acid (R- 36)

Saponification methyl ester, general working instructions: 202 mg (0.38 mmol) R-34 (see Example 3 (α)), 63 µl 12 M NaOH, reaction time 5 h. Recrystallization from ether / n-pentane (1/1) gave 156 mg (79.3%); colorless crystals, mp: 78-86 ° C (decomposition). The analytical data of the compound agree with that of the (S) -enantiomer S-36. [α] 20 | D = + 16.2 (c = 3.31, CHCl ₃ ).

Example 6

(a) (Z) -3 - [(2S) -1- {2- [tris- (4-methoxyphenyl) methoxy] ethyl} pyrrolidin-2-yl) acrylic acid (S- 37)

Saponification methyl ester, general working instructions: 85 mg (0.16 mmol) S-35 (see Example 4 (α)), 27 µl 12 M NaOH, reaction time 23 h. Recrystallization from ether J n-pentane (1/1) gave 61 mg (73.7%); colorless crystals, mp: 100-105 ° C (decomposition). - [α] 20 | D = - 12.7 (c = 1.30, CHCl ₃ ). - ¹ H NMR (CDCl ₃ , 20 ° C): δ = 1.82-1.95 (m, 2 H, NCH ₂ CH ₂ CH ₂ ), 1.98-2.10 (m, 1 H, NCH ₂ CH ₂ ), 2.18-2.27 (m, 1 H, NCHCCH ₂ ), 2.59-2.71 (m, 2 H, NCH ₂ , OCH ₂ CH ₂ N), 3.06 (German, J = 13.2 / 5.5 Hz, 1 H, NCH ₂ ), 3.39-3.50 (m, 4 H, OCH ₂ CH ₂ N, NCH ₂ , NCHC), 3.79 (s, 9 H, OCH ₃ ), 5.99-6.09 (m, 2 H, CH = CH), 6.78-6.85 (m, 6 H, aromatic H), 7.24-7.32 (m, 6 H, aromatic H).

(b) (Z) -3 - [(2R) -1- {2- (tris- (4-methoxyphenyl) methoxy] ethyl} pyrrolidin-2-yl] acrylic acid (R- 37)

Saponification methyl ester, general working instructions: 91 mg (0.17 mmol) R-35 (see Example 4 (b)), 29 µl 12 M NaOH, reaction time 23 h. Recrystallization from ether / n-pentane (1/1) gave 65 mg (73.4%); colorless crystals, mp: 100-105 ° C (decomposition). The analytical data of the compound agree with that of the (S) -enantiomer S-37 - [α] 20 | D = + 13.4 (c = 1.57, CHCl ₃ ).

Claims (15)

1. Compounds of the general formula (I)
wherein
R ¹ to R ^{7 are} independently selected from H, optionally substituted C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, optionally substituted aryl or heteroaryl; OH, halogen, CN, OR ¹² , SR ¹² , COR ¹² , COOR ¹² , SOR ¹² , SO ₂ R ¹² , NR ¹³ R ¹⁴ , CONR ¹³ R ¹⁴ , SO ₂ NR ¹³ R ¹⁴ , where R ¹³ and R ^{14 are} independent are selected from H and C _1-3 alkyl and R ^{12 is} C _1-6 alkyl; in each case two of R ¹ to R ⁷ can be combined to form a 3- to 6-membered ring system which can also contain one or more heteroatoms; R ¹ and R ² and / or R ³ and R ⁴ and / or R ⁵ and R ^{6 can be} replaced by an optionally substituted alkylidene group or = O; and in each case two of R ¹ to R ¹ , which are located on adjacent C atoms, can be replaced by a CC bond;
A ¹ (-CR ⁸ R ⁹ -) _n , optionally substituted C _3-6 cycloalkylene or a combination of these groups, where Re and R ⁹ independently from H, C _1-6 alkyl, halogen, OH, OR ¹² and NR ¹³ R ^{14 are} selected and for n ≧ 2 R ⁸ and R ⁹ can be different in each grouping and two groups of R ⁸ and R ⁹ on adjacent C atoms can be replaced by a CC bond and between two be neighboring groupings can be a grouping -O- or -CO-; and wherein one of R ⁸ and R ^{9 can be combined} with one of R ¹ to R ⁷ to form a 5- to 7-membered ring structure; and n = 0, 1, 2, 3 or 4;
X represents COOM or a group that can be converted to COOM under physiological conditions, where MH represents a pharmaceutically acceptable cation;
A ^{2 represents} (-CR ¹⁰ R ¹¹ -) _m , where R ¹⁰ and R ^{11 are} independently selected from H, C _1-2 - alkyl and halogen; where for m ≧ 2 the groups R ¹⁰ and R ¹¹ can be different in each grouping, there can be a grouping -O- or -S- between two neighboring groups and two groups of R ¹⁰ and R ¹¹ each on adjacent C atoms can be replaced by a CC bond; and wherein one of R ¹⁰ and R ^{11 may be combined} with one of R ¹ to R ⁹ to form a 5- to 7-membered ring structure; and m is 1, 2, 3, or 4;
Z is selected from Y ₃ CO, Y ₂ C = CR ¹⁵ and Y ₂ C = NO, where R ^{15 represents} H, C _1-3 alkyl or halogen and the groups Y independently of one another are optionally substituted C _6-12 aryl or optionally substituted C _2-5 heteroaryl with up to three heteroatoms selected from N, O and S, and the groups Y by a covalent bond or by groupings selected from -O-, -S-, -NH-, -CO- , - CH = CH-, -CH = N-, -CH ₂ and -CH ₂ CH _{2 can be connected} between atoms belonging to different groups Y;
as well as the individual stereoisomers of these compounds. 2. Compounds according to claim 1, in which R ^{7 is} hydrogen and R ¹ to R ^{6 are} independently selected from optionally substituted C _1-3 alkyl, halogen, OH, CN, optionally substituted phenyl and optionally substituted heteroaryl with 5 to 10 Ring members and one or two heteroatoms selected from O, N and S, and in particular hydrogen, C _1-3 alkyl and phenyl. 3. Compounds according to any one of claims 1 and 2, in which R ¹ to R ^{7 are} all hydrogen. 4. Compounds according to any one of claims 1 to 3, in which A ^{1 represents} (-CR ⁸ R ⁹ -) n, wherein R ⁸ and R ^{9 are} independently selected from H and C _1-3 alkyl and in particular are hydrogen and n has the value 0, 1 or 2, in particular 1 or 2. 5. Compounds according to any one of claims 1 to 4, in which X is COOM, where M = H, Na, K, NH ₄ , Ca _0.5 or Mg _0.5 and preferably H or Na. 6. Compounds according to any one of claims 1 to 5, in which R ¹⁰ and R ¹¹ are independently selected from H and C _1-2 alkyl and preferably both represent H and m is 2 or 3, in particular 2. 7. Compounds according to any one of claims 1 to 6, in which Z represents Y ₂ CO and the groups Y, which are preferably identical, are phenyl optionally substituted by one or two substituents, the substituents consisting of C _1-3 alkoxy, C _1-3 alkyl, halogen, OH, NO ₂ , CN and NR ¹³ R ^{14 are} selected and R ¹³ and R ^{14 are} as defined in claim 1. 8. Compounds according to claim 7, in which the phenyl radicals are mono- or disubstituted and the substituents are preferably selected from C _1-2 alkoxy, in particular methoxy, and C _1-2 alkyl, in particular methyl. 9. Compounds according to any one of claims 1 to 6, in which Z represents Y ₂ C = CR ¹⁵ or Y ₂ C = NO, wherein the groups Y are preferably identical and for optionally substituted phenyl or optionally substituted heteroaryl with 5 or 6 Ring members and one or two heteroatoms selected from O, N and S and R ^{15 is} H or CH ₃ , preferably H. 10. Compounds according to claim 9, in which the radicals Y carry 0, 1 or 2 substituents, the substituents consisting of C _1-3 alkyl, C _1-3 alkoxy, halogen, OH, NO ₂ , CN and NR ¹³ R ¹⁴ as defined in claim 1 are selected. 11. Compounds according to any one of claims 1-10, in which the substituents Y are identical and selected from phenyl, 4-methoxyphenyl and 3-methyl-2-thienyl are. 12. A process for the preparation of a compound of the general formula (I) according to claim 1, in which a compound of the general formula (II)
in which R ¹ to R ⁷ , A ¹ and X are as defined in claim 1, with a compound of the general formula (III):
DA ² -Z (III)
wherein A ² and Z are as defined in claim 1 and D represents a group which can react with the NH group of the compound of general formula (II) to form HD, especially halogen. 13. A pharmaceutical composition comprising at least one pharma acceptable carrier or excipient and at least one compound of general formula (I) as defined in any of claims 1 to 11. 14. Compounds according to any one of claims 1 to 11 for use in one Process for the treatment of the human or animal body. 15. Use of the compounds according to any one of claims 1 to 11 for Manufacture of a medication for the treatment of diseases caused by a GABAergic neurotransmission enhancement can be alleviated or cured.