PIPERIDINE AND PYRROLIDINE DERIVATIVES DISPLAYING NEURONAL ACTIVITY

Abstract: The invention relates to the compounds of Formula (I), as well as the process for their production and their use as pharmaceutical agents.

Description: PIPERIDINE AND PYRROLIDINE DERIVATIVES DISPLAYING NEURONAL ACTIVITY This application claims the benefit of the filing date of U.S. Provisional Application Serial No. 60/150,568 filed August 25, 1999. The invention relates to piperidine and pyrrolidine derivatives, the process for their production and their use in pharmaceutical agents. It has been reported that compounds with an affinity for the FK506 binding protein (FKBP) that inhibit that protein's rotamase activity also possess nerve growth stimulatory activity. [Lyons et al., PNAS. 91, pp. 3191-3195 (1994)] . Many of these such compounds also have immunosuppressive activity. FK506 (Tacrolimus) , an immunosuppressive drug, has been demonstrated to act synergistically with NGF in stimulating neurite outgrowth in PC12 cells as well as sensory ganglia [Lyons et al . (1994)] . This compound has also been shown to be neuroprotective in focal cerebral ischemia [J. Sharkey and S. P. Butcher, Nature. 371, pp. 336-339 (1994)] and to increase the rate of axonal regeneration in injured sciatic nerve [B . Gold et al . , J. Neurosci .. 15, pp. 7509-16 (1995)] . The use of immunosuppressive compounds, however, has obvious drawbacks. In addition to compromising immune function, prolonged treatment with these compounds can cause nephrocoxicity [Kopp et al . , J. Am. Soc. Nephrol . , 1, p. 162 (1991)], neurological deficits [P. C. DeGroen et al . , N. Enσ . J . Med . , 317, p. 861 (1987)] and vascular hypertension [Kahan et al . , N. Enα. J. Med.. 321, p. 1725 (1989)]. More recently, sub-classes of FKBP binding compounds which inhibit rotamase activity, but which purportedly lack immunosuppressive activity have been disclosed for use in stimulating nerve growth [see United States patents 5,614,547; 5,696,135; WO 96/40633; WO 96/40140; WO 97/16190; J. P. Steiner et al . , Proc. Natl. Acad. Sci. USA r 94, pp. 2019-23 (1997); and G.S. Hamilton et al . , Bioorg. Med. Chem. Lett.. 7, pp. 1785-90 (1997)] . While these compounds supposedly avoid certain unwanted side effects of immunosuppressive FKBP binding compounds, they still bind to FKBP and inhibit its rotamase activity. This latter property may still lead to undesirable side effects due to other roles FKBP may play in mammals. Surprisingly, it is now known that binding to FKBP is not necessary for neuronal activity. Co-pending United States patent application Serial Nos. 08/748,447, 08/748,448 and 08/749,114, each of which is incorporated by reference in its entirety, each describe the use of non-FKBP binding, non- immunosuppressive compounds for stimulating nerve growth and preventing neurodegeneration. Due to their lack of affinity for FKBP, these compounds advantageously avoid any potential interference with FKBP-associated biochemical pathways. These compounds do, however, inhibit multi-drug resistance ("MDR") through inhibition of the p-glycoprotein and MRP. While it appears that the dosages of those compounds necessary to stimulate nerve growth and prevent neurodegeneration are lower than those that effect MDR, it would still be desirable to obtain compounds which are specific for neuronal activity, without other significant mechanisms of action. It is known that piperidine and pyrrolidine derivatives have immunosuppressive and non- immunosuppressive properties. For example, WO 96/40633 describes that N-glyoxyl-propylester compounds, which have an affinity to FKBP receptors, have a neurotrophic action and stimulate neuronal regeneration as inhibitors of the FKBP-rotamase . The stimulation of neurite growth in nerve cells with piperidine derivatives is described in WO 96/41609. The clinical use of the previously known piperidine and pyrrolidine derivatives for stimulation of neurite growth does not increase the chances of success, since the compounds are unstable in plasma and do not pass through the blood-brain barriers in sufficient amounts. WO 99/10340 also discloses compounds having neuronal activity. Its entire disclosure is also incorporated by reference herein. Applicants have identified several subclasses of compounds that have potent neuronal activity. The term "neuronal activity," as used herein, includes stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of a neurological disorder. The compounds of this invention have activity in both peripheral nerves and the central nervous system. Applicants have discovered diverse genera of compound with neuronal activity which do not bind to FKBP, and which do not have multi-drug resistance reversal activity. Without being bound by theory, applicants believe that the compounds disclosed m this application exert their neuronal activity by increasing cytoplasmic Ca 2+ concentrations. This is likely achieved by interaction, either direct or indirect, with a calcium release channel, such as the ryanodine receptor or the inositol 1,4,5- trisphosphate receptor, in the endoplasmic reticulum of the nerve cell. Thus, according to one embodiment, the invention provides a method of stimulating nerve growth or preventing neurodegeneration by contacting nerve cells with a compound that : a. increases cytoplasmic Ca 2+ concentration or binds to the ryanodine receptor; b. does not bind to FKBP; and c. does not possess MDR reversal activity. According to a related embodiment, the present invention provides a compounds that : a. has neuronal activity; b. increases cytoplasmic Ca 2+ concentration or bind to the ryanodine receptor; c. does not bind to FKBP; and d. does not possess MDR reversal activity. The term "increases cytoplasmic Ca concentration," as used herein means a detectable increase m channel current recorded m the single channel recording assay described below m the presence of such a compound as compared to an appropriate control. Alternatively, the term "increases cytoplasmic Ca 2+ concentration," as used herein means a detectable shift in the fluorescence spectrum in the cell assay described herein. The term "binds to the ryanodine receptor," as used herein, means that the compound specifically competes with ryanodine for binding to microsomes in the assay described below. The term "does not bind FKBP," as used herein means that the compound demonstrates a Ki of 10 μM or greater in at least one of the rotamase inhibitory assays described below. The term "does not possess MDR reversal activity," as used herein means that at a concentration of 2.5 μM, the compound has an MDR ratio of less than 7.0, and preferably less than 3.0 in at least one of the MDR assays described below. Single-channel recording experiments are useful to determine if the compounds of this invention cause the requisite increase in cytoplasmic Ca 2+ concentration. These experiments are conducted as described in E. Kaftan et al . , Circulation Research, 78, pp. 990-997 (1996), the disclosure of which is herein incorporated by reference. Single channel recordings are conducted under voltage clamp conditions with a pair of Ag/AgCl electrodes contacting the solutions via CsCl junctions. Vesicles are added to the cis chamber and fused with planar lipid bilayers composed of phosphatidylethanolamine/phosphatidylcholine (3:1, 30 mg/ml m decane, Avanti Polar Lipids) . The trans chamber contains 250 mM HEPES and 53 mM B(OH)_, pH 7.35; the ci s chamber contains 250 mM HEPES-Tris pH 7.35. Compounds dissolved in methanol are added to the ci s chamber. Channel currents are amplified using a bilayer clamp amplifier (BC-525A, Warner Instruments) and recorded on VHS tape (Dagen Corp.) . Data are filtered to an eight-pole Bessel filter (Frequency Devices) to 500 Hz, digitized at 2 kHz, transferred to a personal computer, and analyzed with pClamp version 6.0 (Axon Instruments) . Single channel recordings are done at least 3 times for each compound condition . Ryanodine binding may be measured by incubating microsomal protein with 3 H-ryanodine in buffer containing 36 mM Tris pH 7.2 and 50 mM KC1 in the absence or presence of test compounds. Controls for maximum binding were done in the presence of 0.72 mM ATP and 36 μM CaCl 2 . Nonspecific binding was measured in the presence of 25 μM unlabeled ryanodine. Binding reactions were incubated for 2 hours at room temperature, and then centrifuged for 15 minutes at 30,000 x g. The pellets were solubilized and the radioactivity was measured by scintillation counting. Alternatively, the flux of cytoplasmic Ca 2 ' into the cell can be followed fluorescently. For example, neuronal cells can be incubated with NGF and a calcium binding fluorescent dye, such as Fura-2, m a calcium-containing buffer. Cells are imaged continuously both before and after the addition of a test compound of this invention The difference m fluorescent intensity before and after the addition of compounds is then plotted as a ratio of fluorescence units at 340 nm and 380 n . Testing a compound of this invention to confirm that it binds to FKBP12 with a Ki of 10 μM or higher may be achieved using several assays known in the art. In particular, those compounds may be assayed for their ability (or lack thereof) to inhibit rotamase. Examples of assays that measure inhibition of FKBP12 rotamase activity are those in which the isomerization of an artificial substrate -- N-succinyl-Ala-Ala-Pro-Phe-p- nitroanilide -- is followed spectrophotometrically [M. W. Harding et al., Nature. 341, pp. 758-60 (1989); by J. J. Siekierka et al., Nature. 341, pp. 755-57 (1989); and S. T. Park et al . , J. Biol . Chem. , 267, pp. 3316-24 (1992)]. The assay includes the cis form of the substrate, FKBP12, the compound to be tested and chymotrypsin. Chymotrypsin is able to cleave p-nitroanilide from the trans form of the substrate, but not the cis form. Release of p-nitronilide is measured. Other FKBP binding assays include a competitive LH20 binding assay using labeled FK-506 as a reporting ligand. These have been described by M. W. Harding et al . , Nature , 341, pp. 758-60 (1989) and by J. J. Siekierka et al . , Nature . 341, pp. 755-57 (1989) . To determine whether a compound according to this invention has the requisite MDR ratio below 7.0, any of the assays described m United States patents 5,543,423, 5,717,092, 5,726,184 or 5,744,485, the disclosures of which are herein incorporated by reference m their entireties, may be utilized. In particular, cell lines which are known to be resistant to particular drug are employed. These cell lines include, but are not limited to, the L1210, P388D, HL60 and MCF7 cell lines. Alternatively, resistant cell lines may be developed. The cell line is exposed to the drug to which it is resistant, or to the test compound; cell viability is then measured and compared to the viability of cells which are exposed to the drug in the presence of the test compound ("MDR ratio") . The compounds of Formula I are metabolically stable and pass through the blood-brain barriers and stimulate the neurite growth by itself or in combination with neuronal growth factors. Since the new compounds also do not show any significant side effects, they are suitable for treatment of the various neuropathological diseases, which are affected by neuronal regeneration and growth, such as, e.g., peripheral nervous disturbances, which are caused by physical damages or diseases such as diabetes; physical damages of the central nervous system (e.g., of the brain or spinal cord); strokes; neurological disorders by neurodegenerations such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. The invention relates to the compounds of Formula I and their physiologically compatible salts ich R 1 means hydrogen, Ar, straight-chain or branched C^C, alkyl, which can be substituted with Ar or E, straight- chain or branched C 2 -C 7 alkenyl, which can be substituted with Ar or E, C 3 -C 7 cycloalkyl, which can be substituted with Ar or E, or C 5 -C 7 cycloalkenyl , which can be substituted with Ar or E, Y means - (C=0) - (C=0) - , -S0 2 - , -(C=0) H-, -(C=S)NH-, - (C=0) - (C=0) -0-, - (C=0) - (C=0)NH-, - (C=0) -O- or -S0 2 -NH, R 2 means straight -chain or branched Cj-Cg alkyl, which can be substituted with phenyl or halogenated phenyl, R 3 means straight-chain or branched Ci-Cg alkyl, straight- chain or branched C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, cyclohexylmethyl , whereby the alkyl, alkenyl, cycloalkyl and cycloalkenyl radical can be substituted by the same or a different component in one to two places with Ar, or R 2 and R 3 together with the N atom form a 5- to 7-membered heterocycle, which can be saturated or unsaturated and can be substituted with C}-^ alkyl and OH, X means -S-, -SO-, -S0 2 -, -NH- or -NR 5 -, R 4 and R 5 are the same or different and, independently of one another, mean Ar, straight -chain or branched Cj-Cq alkyl, straight-chain or branched C -C q alkenyl, C<-C cycloalkyl, C -C cycloalkenyl, whereby the alkyl and the alkenyl radicals can be substituted in one to two places with the same or a different component with Ar, C 3 -C cycloalkyl and C 5 -C 7 cycloalkenyl, and wherein the alkyl radical can be substituted by halogen, and Ar is a C 6 -C 12 monocyclic or bicyclic aromatic compound, which can contain 0 to 4 N, S or O atoms and which is optionally partially hydrogenated and which can be substituted in one to three places with E, and E is halogen, hydroxy, nitro, CF 3 , CN, 0CF 3 , amino, phenyl, methylenedioxy, phenoxy, benzyloxy, C 1 -C 4 alkoxy or C^ alkyl, whereby, if Y = S0 2 , R 1 does not mean hydrogen, and, if X = NR 5 and YR 1 = tosyl , R 2 , R 3 , R 4 and R 5 do not mean methyl simultaneously, and if X = SO, Y = (C=0)NH, R 1 and R 2 mean benzyl and R 3 means -CH=CH 2 , R 4 is not n-butyl, and, if X = NR 5 and YR 1 = tosyl, and R 2 and R 3 together with the N atom form a 6- or 7-membered saturated heterocycle, R 4 and R 5 do not mean n-propyl simultaneously, and, if X = NR , Y = (C=S)NH, R 1 means 4 -methylphenyl and R 3 = phenyl , and R 2 , R 4 and R 5 do not mean methyl simultaneously. The compounds of Formula I can be present as stereoisomers, geometric isomers or stable tautomers . The invention comprises all possible isomers, such as E- and Z-isomers, S- and R- enantiomers, diastereomers , racemates and mixtures thereof. The stereochemistry of the CH group, which carries substituent R 3 , can be R or preferably S. The physiologically compatible salts can be formed with inorganic and organic acids, such as, for example, oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, HCl, HBr, sulfuric acid, p- toluenesulfonic acid, methanesulfonic acid, i.a. In each case, alkyl means a straight -chain or branched alkyl group, such as, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl, neopentyl , n-hexyl, sec-hexyl, heptyl , octyl , nonyl . The alkenyl substituents contain at least one double bond, such as, for example, the following radicals: vinyl, 2 -propenyl, 1-propenyl, 2-butenyl, 1-butenyl, 1-methyl -1-propenyl , 2 -methyl - 2 -propenyl, 3 -methyl -2 -propenyl , l-penten-3 -yl , n-hexenyl, 1- hepten-4-yl . Cycloalkyl is defined in each case as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl . Cycloalkenyl means, e.g., cyclopentenyl , cyclohexenyl and cycloheptenyl . In each case, halogen means fluorine, chlorine, bromine or iodine . In the case the alkyl radical is halogenated, one or more hydrogens can be replaced with halogen, e.g., 2 , 2 , 2- trifluorethyl as especially 4 , 4 , 5 , 5 , 5-pentafluoropentyl . In each case, in the embodiment that does not contain heteroatoms, Ar is defined as 1- and 2-naphthyl, biphenyl, indenyl and preferably phenyl . In the embodiment that contains the heteroatoms, Ar is a monocyclic or bicyclic heteroaromatic compound, which in each ring contains 5 to 6 ring links and 1 to 4 heteroatoms and which can be partially hydrogenated; Ar preferably means a 5- or 6- ring, which contains 1 to 3 heteroatoms, and which can have a benzene ring annelated, whereby the bonding generally takes place with carbon atoms . For example, the following heteroaromatic compounds can be mentioned: furyl , thienyl , pyridyl , pyrrolyl, oxazolyl, thiazolyl, isothiazolyl , imidazolyl , pyrazolyl, isoxazolyl, triazolyl, oxadiazolyl, pyrimidinyl , pyrazinyl, indolyl, benzimidazolyl , benzothiophenyl , quinolinyl, isoquinolinyl , quinoxalinyl , 1 , 2 , 3 , 4-tetrahydroquinolinyl , and benzothiazolyl . Preferred are pyridinyl , thienyl, furyl , thiazolyl, indolyl, quinolinyl, and isoquinolinyl. Especially preferred are 2-, 3- and 4 -pyridyl, 2- and 3 -thienyl, 2- and 3 -indolyl and 2-, 4- and 5 -thiazolyl . Preferred embodiments of R 1 are Ar, straight-chain or branched Cj-C-, alkyl, which can be substituted with Ar or E, and C 3 -C cycloalkyl, which can be substituted with Ar or E, whereby in the case of cycloalkyl E, it especially means C--C, alkyl. Especially preferred are phenyl that is optionally substituted with E and straigh -chain or branched C :- ,-, preferably, C 3 -C 7 alkyl that is optionally substituted with E. Preferred embodiments of Y are - (C=0) - (C=0) - , -S0 2 -, -(C=0)NH-, -(C=S)NH-, -S0 2 -NH and especially -CO-CO-, -S0 2 - and -CS-NH 2 - . A preferred embodiment of R 2 is methyl, ethyl and optionally benzyl that is substituted with halogen in the aromatic compound in one to three places . A preferred embodiment of R 3 is straight -chain or branched Ci-Cg alkyl, which can be substituted in one to two places with Ar, whereby Ar can be substituted in one to three places with E. If R 2 and R 3 together with the nitrogen atom form a heterocycle, the latter is preferably saturated and has 5 to 7 ring links; pyrrolidine and piperidine are especially preferred. In each case, E preferably means halogen, hydroxy, nitro, CF 3 , CN, C : -C 4 alkoxy and Cχ-C 4 alkyl. Preferred embodiments of R are straight-chain or branched alkyl, which optionally is substituted in one to four places with Ar or Ar optionally substituted with E. Especially preferred is R 4 in the meaning of a straight - chain or branched alkyl radical, which is substituted in one to two places with Ar . Especially preferred is R 4 with the structure in which Ar has the above-mentioned meaning, and o and p mean 0, 1, 2 or 3 , and n is 1 or 2. The invention also relates to the use of the compounds of Formula I for the production of a pharmaceutical agent for the stimulation of neuronal activity. The compounds of Formula I are suitable for stimulation of neurite growth in nerve cells, for promotion of neuronal regeneration, for prevention of neurodegeneration, for treatment of neurological diseases such as neurodegeneration and for treatment of peripheral neuropathies. With the compounds of Formula I, the prevention and treatment of neuron cell death, which is triggered by a variety of diseases or physical trauma, is made possible. The methods of stimulating nerve growth and preventing neurodegeneration disclosed herein employ the above compounds either alone or in combination with a neuronal growth factor. The methods are useful in treating or preventing nerve damage caused by various neurological diseases and physical traumas and also in ex vivo nerve regeneration. Diseases, which can be treated according to the invention with the compounds of Formula I or can be prevented with them, are especially trigeminal neuralgia, Collet-Sicard syndrome, Bell's palsy, myasthenia gravis, muscular dystrophy, muscle damage, progressive muscular atrophy, peripheral neurophathies , peripheral myelin disorders, Alzheimer's disease, Guillain- Barre syndrome, Parkinson's disease, amyotrophic lateral sclerosis, Tourette ' s syndrome, multiple sclerosis, central myelin disorders, stroke, ischemia, neural degenerative diseases, trauma and Huntington's disease. The invention also relates to the use of compounds of Formula IA and their physiologically compatible salts (IA), in which R 1 , R 2 , R 3 , R 4 and X have the meaning that is mentioned above , and Y 2 means - (C=0) - (C=0) - , -S0 2 -, -(C=0)NH-, (C=S)NH-, - (C=0) - (C=0)-0-, - (C=0) - (C=0)NH-, -(C=0)-0-, -S0 2 -NH-, -C=0- or a bond, for the production of a pharmaceutical agent for stimulation of neuronal activity and for prevention and treatment of diseases and physical trauma, which are triggered by neuron cell death, such as for stimulation of neurite growth in nerve cells, for promotion of neuronal regeneration, for prevention of neurodegeneration, for treatment of neurological diseases such as neurodegeneration and for treatment of peripheral neuropathies. All diseases that are mentioned above can be prevented or the latter can be treated. The compounds of Formulas I and IA can be administered m one formulation or m separate formulations m combination with a neurotrophic factor or alone. The term "neurotrophic factor" relates to compounds that stimulate the growth and the proliferation of nerve cells. Numerous neurotrophic factors are known, such as, for example, NGF, BNDF, aFGF, bFGF, PDGF, BDNF, GDNF, CNTF, NT- 3, NT-4/5 and IGF-1 and its derivatives, such as glGF-1 and Des (1-3 ) IGF-1. Especially preferred for a combined For use of the compounds according to the invention as pharmaceutical agents, the latter are brought into the form of a pharmaceutical preparation, which in addition to the active ingredient contains vehicles, adjuvants and/or additives that are suitable for enteral or parenteral administration. The administration can be done orally or sublingually as a solid m the form of capsules or tablets or as a liquid m the form of solutions, suspensions, elixirs, aerosols or emulsions or rectally in the form of suppositories or m the form of injection solutions that optionally also can be admmsitered subcutaneously, intramuscularly or intravenously, or topically or mtrathecally . As adjuvants for the desired pharmaceutical agent formulation, the inert organic and inorganic carrier materials that are known to one skilled m the art are suitable, such as, e.g., water, gelatin, gum arable, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc In addition, preservatives, stabilizers, wetting agents, emulsifiers or salts for changing the osmotic pressure or buffers can optionally be contained. For parenteral administration, especially injection solutions or suspensions, especially aqueous solutions of active compounds m polyhydroxyethoxylated castor oil, are suitable Topical application is defined as transdermal patches, ophthalmic preparations, and aerosols for inhalation. As vehicle systems, surface-active adjuvants, such as salts of bile acids or animal or plant phospholipids, but also mixtures thereof as well as liposomes or components thereof can also be used. For oral administration, especially tablets, coated tablets or capsules with talc and/or hydrocarbon vehicles or binders, such as, for example, lactose, corn or potato starch, are suitable. The administration can also be done in liquid form, such as, for example, as a juice, to which a sweetener is optionally added. The dosage of the active ingredients can vary based on the method of administration, age and weight of the patient, type and severity of the disease that is to be treated and similar factors. The daily dose is 0.01-100 mg/kg of body weight/day, whereby the dose can be given as a single dose that is to be administered once or divided into two or more daily doses. If a combination therapy is performed, the dose can be reduced due to the synergistic action of the active ingredients. The neurotrophic factor is preferably administered m a dose of 0.01 μg - 100 mg/kg/day together with the above-mentioned dose of the active ingredients. The neurotrophic action of the compounds of Formula I and their physiologically compatible salts can be determined according to methods by W. E. Lyons et al . , Proc. Natl. Acad. Sci. USA, 91, pages 3191-95 (1994) . The production of the compounds of Formula I is characterized in that a compound of Formula II in which P is a protective group, R 2 and R 3 have the above- mentioned meanings, and A means a reactive leaving group, a) is reacted with H-XR 4 , in which X is S, NH or NR 6 , and R 4 and R 5 have the above-mentioned meaning, and then is optionally oxidized to sulfoxide or sulfone, b) amino protective group P is cleaved off, c) Y-R 1 is introduced and optionally the isomers are separated, and the salts are formed. As an alternative, the production is carried out by a compound of Formula III m which R , R ^ and P have the above-mentioned meaning, a) being reacted with A-R', b) R 4 optionally being further modified by, e.g., C-C- linking reactions, such as, e.g., Heck reaction and/or hydrogenation, c) amino protective group P being cleaved off, d) Y-R 1 being introduced and optionally the isomers being separated and the salts being formed. A compound of Formula III can also, however, be reacted with, for example, a ketone, ketal or enol ether, to a compound of Formula IV in which R 2 , R 3 and P have the above-mentioned meaning, and R and R' are selected such that the desired radical R 4 is formed in the above-mentioned meaning, and then b) optionally the double bond is hydrogenated, c) amino protective group P is cleaved off, d) Y-R 1 is introduced, and optionally the isomers are separated, and the salts are formed . As protective group P, all known amino protective groups are suitable, such as alkoxycarbonyl groups, such as BOC, and trimethylsilylalkoxycarbonyl groups, such as TeOC, i.a. The thiolation, animation and alkylation are carried out m the usual way in the presence of bases, such as sodium hydride in polar solvents or in substances at room temperature or elevated temperature . As active group A, for example, tosylate, mesylate, halogen or triflate is suitable. The cleavage of the amino protective group and the subsequent introduction of Y-R 1 is carried out according to known methods, which are described in, for example, US 5,721,256 and WO 98/29117 and WO 98/13355. The oxidation to sulfones or sulfoxides can be carried out according to the methods that are known to one skilled in the art, which are described in, for example, Methoden der Organichen Chemie [Methods of Organic Chemistry] (Houben-Weyl) , Editors D. Klamann, Thieme Stuttgart New York 1985, Volume Ell (Organic Sulfur Compounds) 702 ff and 1194 ff. The Heck reaction is carried out according to methods that are known to one skilled m the art, such as, e.g., in Tetrahedron Letters Vol. 34, 8329 (1993). The production of the enol ether can be carried out, for example, according to the process that is described in Methoden der Organischen Chemie (Houben-Weyl), Thieme Stuttgart 1965, Volume Vl/3 (Oxygen Compounds) 90 ff . The optically active compounds of Formula I can be obtained with optically active starting materials or by separation according to commonly used methods, such as, for example, crystallization, chromatography or salt formation m the enantiomers or E/Z-isomers in the intermediate or final stages. If the production of the starting compounds is not described, the latter are known or can be produced analogously to the processes that are known or described here. The compounds of Formula IA are also obtained according to known processes or analogously to the processes that are described. Below, the production of some precursors, intermediate products and products are described by way of example. The presently disclosed compounds advantageously possess neuronal activity, without interfering with other pathways known to be affected by structurally similar compounds. The nerve growth activity of the compounds of this invention may be initially assayed using several cell culture assays known in the art. For example, the compounds of this invention may be tested m neurite outgrowth assay using pheochromocytoma PC12 cells as described by Lyons et al . , PNAS , 91, pp. 3191-3195 (1994) . A similar assay may be carried out m SH-SY5Y human neuroblastoma cells. Alternatively, the chick dorsal root ganglia assay described m United States patent 5,614,547 or m G. S. Hamilton et al . , Bioorg. Med. Chem. Lett., (1997) and references cited therein, may be utilized. The compounds of this invention may also be assayed for nerve growth activity m vivo using a mouse model of Parkinson's disease [J. P. Sterner et al . , Proc. Natl. Acad Sci. USA, 94, pp. 2019-23 (1997), United States patent 5,721,256] or following surgical sciatic nerve crush in rats. Diseases which are treatable include, but are not limited to, trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, myasthenia gravis, muscular dystrophy, muscle injury, progressive muscular atrophy, progressive bulbar inherited muscular trophy, herniated, ruptured or prolapsed invertebrae disk syndrome's, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neuropathies, such as those caused by lead, dapsone, ticks, or porphyria, other peripheral myelin disorders, Alzheimer's disease, Gullain-Barre syndrome, Parkinson's disease and other Parkmsonian disorders, ALS, multiple sclerosis, other central myelin disorders, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic crush, neuropathy associated with diabetes, spinal cord injuries, facial nerve crush and other trauma, chemotherapy- and other medication- induced neuropathies and Huntmgton's disease. In another aspect, the method is used to stimulate nerve growth ex vivo . For this aspect, the compounds or compositions described above can be applied directly to the nerve cells m culture. This aspect of the invention is useful for ex vivo nerve regeneration. According to an alternate embodiment, the method of stimulating neurite outgrowth or preventing neurodegeneration comprises the additional step of treating a patient or ex vivo nerve cells in culture with a neurotrophic factor, such as those contained in the compositions of this invention described above. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight . The entire disclosures of all applications, patents and publications, cited above, and of corresponding German application No. 199 39 707.4, filed August 18, 1999, and U.S. Provisional Application Serial No. 60/150,568, filed August 25, 1999, are hereby incorporated by reference. Example 1 a) (2S) -1, l-Dimethylethyl-2- (phenylethylthiomethyl) -pyrrolidine- 1-carboxylate 1 Tosylation: 10.0 g (50 mmol) of boc-prolinol is dissolved in 50 ml of CH 2 C1 2 , and 30 ml of pyridine is added. It is cooled to 0°C, and then a solution of 11.4 g (60 mmol) of p-tolylsulfonyl chloride in 60 ml of CH 2 C1 2 is added. The reaction is heated to room temperature and stirred overnigh . The mixture is poured into water and extracted several times with CH 2 C1_. The organic phases are dried on MgSO and concentrated by evaporation in a vacuum. After chromatography (hexane → hexane/ethyl acetate 4:1), 14.1 g (79%) of clear oil is obtained. Thioether Formation; 0.30 ml (2.1 mmol) of 2-phenethylmercaptan is dissolved in 10 ml of THF, and 155 mg of NaH (65% in paraffin, 1.4 mmol) is added. After 5 minutes of stirring at room temperature, a solution of 820 mg (2.3 mmol) of tosylate in 20 ml of THF is added, and the reaction mixture is refluxed for 3.5 hours. Then, it is poured into 2N NaOH and extracted with CH 2 C1 2 . The combined extracts are dried on MgS0 4 , dried, and concentrated by evaporation in a vacuum. Chromatography of the residue (hexane - hexane/ethyl acetate 7:3) produces 620 mg (53%) of the title compound as a clear oil . 13 C-NMR (75 MHz, CDCl 3 ) : δ = 22.7T (23.6T) (C-3 ) , 28.6Q (1C- 3), 30. IT (29.4T) (C-4) , 34. IT (2C-3), 36.2T (35. T) (2C- 1) , 36.5T (2C-2) , 46.6T (47.1T) (C-5) , 57. ID (C-2), 79.5S ( 79.2S) ( 1C-2 ) , 126.4D (2C-7) , 128.4D (2C-5), 128.4D (2C-6), 140.4S (140.6S) (2C- 4) , 154.3S ppm (1C1) . Mixture of rotamers, displacement of the underfeed-rotamer in () if observed. b) (2S) -1, l-Dimethylethyl-2- (phenylethylsulfonylme hyl) - pyrrolidine-1-carboxylate 2 337 mg (1.04 mmol) of the compound that is obtained according to method a) is dissolved in 20 ml of CH,C1 , and 540 mg (2.2 mmol) of m-chloroperbenzoic acid (70% active oxidant) is added. After stirring at room temperature overnight, the mixture is added to 2N NaOH, and CH 2 C1 2 is extracted. The combined extracts are dried, concentrated by evaporation and chromatographed (hexane → hexane/ethyl acetate 1:2) . 325 mg (89%) of the title compound is obtained. After recrystallization from hexane, 269 mg (73%) is obtained. Melting point 78.5-79.5°C. 13 C-NMR (75 MHz, CDCl 3 ) : δ = 23. OT (C-3), 28. OT (C-4), 28.5Q (1C-3), 30.7T (2C-3), 46.4T (C-5), 52.6D (C-2), 54.9T (2C-2), 55.4T (2C-1) , 80.8S (1C-2), 126.9D (2C7), 128.7D (2C-6), 128.8D (2C-5) , 137.95 (2C-4), 154.3S ppm (IC-l). c) N-Cyclohexyl ( (2S) -2 - (phenylethylsulfonylmethyl) - pyrrolidine) -1-thiocarbamide 3 Boc-Cleavage : 225 mg (0.72 mmol) of the compound that is obtained according to b) is dissolved in 10 ml of CH 2 C1 , and 1.10 ml (14 mmol) of TFA is added. After 2.5 hours at room temperature, the solvent is drawn off, made basic with 2N NaOH, and extracted with CH 2 C1.. The combined extracts are dried on Na-,SO, and concentrated by evaporation m a vacuum. 175 mg (96%) is obtained . Reaction with isothiocyanate : The product that is obtained is dissolved m 10 ml of 1,2- dichloroethane and 0.11 ml (0.80 mmol) of triethylamine, mixed with 113 mg (0.80 mmol) of cyclohexylisothiocyanate and heated at 80°C for 26 hours. After cooling, it is dispersed between 2N NaOH and CH 2 C1 2 , the aqueous phase is extracted again, the combined extracts are dried on Na 2 S0 4 , and concentrated by evaporation in a vacuum. The solvent is drawn off, and the residue is chromatographed (hexane - hexane/ethyl acetate 6:4) . 222 mg (78%) of the title compound is obtained as a solid foam. Melting point 106-107°C, [ ] p = -3° (0.5 in chloroform) 13 C-NMR (75 MHz, CDCl 3 ) : δ = 23.2T (C-4), 24.9T (1C-7), 25. OT (1C-4) , 25.5T (1C-5), 28.4T (2C-3), 30. OT b (C-3), 33. IT (1C-6) , 33.2T (1C-3), 47.3T b (C-5), 53.9D (C-2), 54.3T b (2C-1), 55.0T (2C-2) , 57.0T b (1C-2), 126.9D (2C-7), 128.6D (2C-6), 128.8D (2C-5) , 137.7S (2C-4), 177.6S ppm (lC-1). Example 2 (2S)-2-(4,4,5,5, 5-Pentafluoropentylthiomethyl) -1- ( (3,4, 5- trimethoxyphenyl) -glyoxyloyl) -pyrrolidine 4 a) 865 mg (3.6 mmol) of 3 , 4 , 5 - trimethoxyphenylglyoxylic acid is dissolved in 5 ml of toluene, and 0.33 ml of 1,1- dichloromethyl ether is added. The mixture is heated for 3 hours to 60°C, concentrated by evaporation, and the corresponding glyoxyloyl chloride is obtained. b) 300 mg (1.08 mmol) of (2S) -2- (4 , 4 , 5 , 5 , 5- pentafluoropentylthiomethyl) -pyrrolidine (WO 98/07740) is dissolved in 2 ml of CH 2 C1 2 , and 0.64 ml of triethylamine and a solution of glyoxyloyl chloride in 2 ml of CH 2 C1 2 is added at 0°C. The mixture is stirred for 5 days at room temperature. After working-up and chromatography on silica gel (CH 2 C1 2 - CH 2 Cl 2 /EtOH 8:2), 301 mg (56%) of title compound is obtained. (2S)-2-(4,4,5,5, 5-Pentafluoropentylsulfonylmethyl) -1- ( (3,4,5- trimethoxyphenyl) glyoxyoyl) -pyrrolidine 5 280 mg (0.56 mmol) of (2S) -2- (4 , 4 , 5 , 5 , 5 - pentafluoropentylthiomethyl) -1- ( (3,4, 5- trimethoxyphenyl) - glyoxyloyl) -pyrrolidine is dissolved in 10 ml of CH 2 C1 2 and mixed with 542 mg (2.2 mmol) of m-chloroperbenzoic acid (70% active oxidant) . It is stirred for 3 hours at room temperature, another 542 mg of oxidizing agent is added, stirred for 2 more hours, poured into 2N NaOH and extracted with CH 2 C1 . . After working-up, the product is filtered on a short silica gel column (CH 2 Cl 2 ) , and 200 mg (67%) of title compound is obtained. Melting point = 98"C (diisopropylether/hexane) 13 C-NMR (75 MHz, CDC1 3 ) : δ = 24. IT ( 20.9T) ( C- 3 ) , 29.2T (t22) (2C-4) , 30.4T (30.9T) (C-4) , 47. IT (45. IT) (C- 5 ) , 52.4T (52.8T) (2C- 2), 52.6D (53.1D) (C-2) , 54.5T (53.5T) (2C-1) , 56.3D ( 56.3D) (1C-7) , 61.0D (1C-8) , 107.3D (107.5D), (1C-4), 115.3S ( t253/q38 ) ( 2C-5 ) , 118.9S (q285/t35) (2C-6) , 127.4S ( 127.7S) (1C-6 ) , 13.8T (2C-3), 144.4S (144.6S) (1C-3) , 153.4S ( 153.4S) (1C-5 ) , 165.6S (164.4S) ) (lC-1) , 189.4S (190. OS) ppm (1C-2) . Both rotamers are seen in the ratio 5.6:1, and the displacement of the underfeed rotamer is in (), if necessary. J^ P and J 2 CF are indicated in Hz . Produced analogously are : (2S) -2- (3- (3 -Pyridyl) propylsulfonylmethyl) -1- ( (1,1- dimethylpropyl) glyoxyloyl) -pyrrolidine 6 (2S) -2- (1, 5-bιs (4 -pyridyl) -3 -pentylsulfonylmethyl ) -1- ((1,1- dimethylpropyl) -glyoxyloyl) -pyrrolidine 9 (2S)-2(l,5-bιs (4 -pyridyl) -3 -pentylsulfonylmethyl) -1- ( (3,4,5- trimethoxyphenyl) -glyoxyloyl) -pyrrolidine 10 (2S) -2- (1,5-bιs- (phenyl -3 -pentylsulfonylmethyl) -1- ( (3- pyridyl) glyoxyloyl) -pyrrolidine 11 (2S) -2- ( (4R) -7-phenyl-l- (3-pyridyl) -4-heptylsulfonylmethyl) ■ 1- ( (1 , 1 -dimethyl -propyl) -glyoxyloyl) -pyrrolidine 12a (2S) -2- ( (4S) -7-phenyl-l- (3-pyridyl) -4-heptylsulfonylmethyl) ■ 1- ( (1 , 1 -dimethyl -propyl) glyoxyloyl) -pyrrolidine 12b (2S) -2- ( (4R) -7-phenyl-l- (3-pyridyl) -4 -heptysulfonylmethyl) - 1- ( (3 , 4 , 5- tπmethoxy-phenyl) -glyoxyloyl) -pyrrolidine 13a (2S) -2- ( (4S) -7-phenyl-l- (3-pyridyl) -4-heptylsulfonylmethyl) 1- ( (3,4, 5 -tπmethoxy-phenyl) -glyoxyloyl) -pyrrolidine 13b (2S)-2(l,5-bιs (3 -pyridyl) -3 -pentylsulfonylmethyl) -1- ( (1,1- dimethylpropyl ) -glyoxyloyl) -pyrrolidine 14 (2S) -2- ( (4R) -6 -phenyl -1- (3 -pyridyl) -4 -hexylsulfonylmethyl ) - 1 - ( (1 , 1 -dimethyl -propyl ) glyoxyloyl ) -pyrrolidine 15a (2S) -2- ( (4S) -6 -phenyl -1- (3 -pyridyl) -4 -hexylsulfonylmethyl ) - 1- ( (1 , 1-dιmethylpropyl) glyoxyloyl ) -pyrrolidine 15b (2S) -2- ( (4R) -6 -phenyl- 1- (3 -pyridyl) -4 -hexylsulfonylmethyl ) - 1- ( (3 , 4 , 5- trimethoxy phenyl ) -glyoxyloyl ) -pyrrolidine 16a (2S) -2- ( (4S) -6 -phenyl -1- (3 -pyridyl) -4 -hexylsulfonylmethyl ) - 1 ( (3 , 4 , 5- tπmethoxy-phenyl) -glyoxyloyl) -pyrrolidine 16b (2S) -2- (1, 5-bis (3-pyridyl) -3 -pentylsulfonylmethyl ) -1- ( (3,4, 5-trimethoxyphenyl) -glyoxyloyl) -pyrrolidine 17 Example 3 a) (2S) -1, l-Dimethylethyl-2- (N-allyl-N-methyl aminomethyl) - pyrrolidine-1-carboxylate 18 15.55 g (43.8 mmol) of boc-prolinol-tosylate and 12.5 ml (130 mmol) of allylmethylamine are stirred at room temperature overnight. Then, the excess amine is drawn off in a vacuum, and the reaction product is chromatographed (hexane → hexane/ethyl acetate 2:1) . 5.79 g (52%) of the title compound is obtained as a clear oil . 13 C-NMR (75 MHz, CDC1 3 ) : δ = 55.5D (C-2), 22.5T (23.4T) (C- 3), 29.6T (28.3T) (C-4) , 46. IT (46.6T) (C-5) , 154.5S (lC-1), 79. IS (1C-2) , 28.5T (1C-3) , 59.6T (58.8T) (2C-1) , 42.9Q (2C-2), 61.7T (2C-3) , 135.9D (2C-4), 117.4T ppm (2C-5). Displacement of the underfeed-rotamer in 0 if observed. b) (2S) -1, l-Dimethylethyl-2- (N- (3- (3-pyridyl) -2-propenyl) -N- methyl aminomethyl) -pyrrolidine- 1-carboxylate 19 766 g (3.0 mmol) of the component that is obtained according to process a) is dissolved m 2 ml of DMF and 40 μl of triethylamine. 471 mg (3.0 mmol) of 3 -bromo-pyridme, 254 mg (3.0 mmol) of sodium bicarbonate, 25 mg (0.10 mmol) of triphenylphosphme and 8 mg (30 μmol) of palladium (II) acetate are added, and the mixture is held for 26 hours at 120°C. The black mixture is filtered, concentrated by evaporation, and the residue is chromatographed (hexane/ethyl acetate 1:1, ethyl acetate, methanol) 767 mg (77% ) of the title compound is obtained c) (2S) -1, l-Dimethylethyl-2- (N- (3- (3 -pyridyl) propyl] -N-methyl aminomethyl) -pyrrolidine-1-carboxylate 20 767 mg (2 3 mmol) of the compound that is obtained according to b) is dissolved m 20 ml of ethanol and mixed with 30 mg of Pd/C (10%) and hydrogenated at room temperature After the necessary amount of hydrogen is taken up, it is filtered on Celite After workmg-up, 725 g (94%) of orange oil is obtained. Alternatively, the compound of example 3c can be produced as follows : (2S) -1- (1,1-Dimethylethoxycarbonyl) - 2 - (N-methyl-N- (3- (3- pyridyl) propyl-aminomethyl) -pyrrolidine 3.55 g (10 mmol) boc-prolinol tosylate and 1.90 g (12.6 mmol) methyl- (3- (3 -pyridyl) propyl -amine [1] (whose preparation is described in WO 99/10340) were mixed without solvent and a catalytic quantity potassium iodide was added. After 144h at ambient temperature, the mixture was taken up in CH 2 C1 2 and washed with IN NaOH. The organic phase was dried over MgS0 4 and evaporated. Chromatography (CH 2 C1 2 -4 CH 2 C1 2 / MeOH/ TEA 90:9:1) of the residue gave 1.08 g (33%) of the ittle compound as an oil. 13C-NMR (75 MHz, CDC13): δ=22.6Tb (C3 ) , 28.5T (1C3), 28.8Tb (2C4), 29.6Tb(C4), 30.5T(2C5), 43. OQb (2C2 ) , 46.1Tb(C5), 55.5D(C2), 57.7Tb(2C3), 60.5Tb(2Cl), 79.2Sb(lC2), 123.3D(2C9), 135.8D(2C8), 137.4Sb(2C7) , 147.3D(2C10) , 149.9D(2C6), 154.5Sb ppm (1C1) . b denotes broadened signals. d) ( (2S) -2- (N-Methyl-N- (3- (3 -pyridyl) propyl) -aminomethyl) -1- (3 , 4 , 5- trimethoxyphenylglyoxyloyl) -pyrrolidine 21 Boc - Cleavage : 700 mg (2.1 mmol) of the compound that is obtained according to c) is taken up in 18 ml of dichioromethane, cooled and mixed at 0°C with 3.0 ml of trifluoroacetic acid. The mixture is brought to room temperature and stirred for 2 more hours. By carefully adding 2N NaOH, it is made basic and then extracted with dichioromethane. After working-up, 437 mg (90%) of yellow oil is obtained. Acylation : 1: 1.73 mg (7.2 mmol) of 3,4,5 trimethoxyphenylglyoxylic acid is dissolved in 10 ml of toluene, and 0.65 ml of 1,1- dichloromethyl ether is added. The mixture is heated for 3 hours to 60°C, the solvent is drawn off, and the corresponding glyoxyloyl chloride is obtained. 2: 4.37 mg (1.89 mmol) of the amine is dissolved in 5 ml of CH 2 C1 2 , and 1.2 ml of triethylamine and a solution of glyoxyloyl chloride in 4 ml of CH 2 C1 2 are added at 0°C. The mixture is stirred for 2 days at room temperature, and then is dispersed between 2N NaOH and CH-C1 2 . The organic phase is washed with brine, dried on Na 2 S0 4 , the solvent is drawn off, and the residue is chromatographed on silica gel. 531 mg (62%) of the title compound is obtained. The following compounds are obtained analogously: (2S) -2- (N-Methyl-N-3- ( 3 -pyridyl ) propyl -aminomethyl ) -1- ( (1,1- dimethylpropyl) -glyoxyloyl) -pyrrolidine 22 (2S) -2- (N-methyl-N-3- ( 3 -pyridyl ) propyl -aminomethyl ) -1- (4- methylphenylsul onyl) -pyrrolidine 23 (2S) -2- (N-methyl-N-3-phenylpropyl-aminomethyl) -1- ((1,1- dimethylpropyl) -glyoxyloyl) -pyrrolidine 24 (2S) -2- (N-methyl-N- ( (4R) -7-phenyl-l- (3-pyridyl) -4-heptyl) - aminomethyl) -1- ( (1 , 1-dimethylpropyl) glyoxyloyl) -pyrrolidine 25a (2S) -2- (N-methyl-N- ( (4S) -7-phenyl-l- (3-pyridyl) -4-heptyl) - aminomethyl) -1- ( (1 , 1-dimethylpropyl) -glyoxyloyl) -pyrrolidine 26a (2S) -2- (N- (1, 5-bis (4 - fluorophenyl ) -3-phenyl) -N-methyl- aminomethyl) -1- ( (3 , 4 , 5-trimethoxyphenyl) glyoxyloyl) -pyrrolidine 26 (2S) -2- (N- (1, 5-bis (4-pyridyl) -3-pentyl) -N- (4- fluorophenylmethyl) -aminomethyl) -1- ( (3 , 4 , 5-trimethoxyphenyl) - glyoxyloyl) -pyrrolidine 27 (2S) -2- (N-methyl-N- ( (4R) -7-phenyl-l- (3 -pyridyl) -4-heptyl) - aminomethyl) -1- ( (3 , 4 , 5-trimethoxyphenyl) -glyoxyloyl) -pyrrolidine 28a (2S) -2- (N-methyl-N- ( (4S) -7-phenyl-l- (3-pyridyl) -4-heptyl) - aminomethyl) -1- ( (3 , , 5-trimethoxyphenyl) -glyoxyloyl) -pyrrolidine 28b (2S) -2- (N- (1,5-bιs (4 -fluorophenyl) -3-pentyl) -N-methyl - aminomethyl) -1- ( (1 , 1-dimethylpropyl) glyoxyloyl) -pyrrolidine 29 (2S) -2- (N-methyl-N- 3 -phenylpropyl -aminomethyl) -1- ( (3 , 4 , 5- trimethoxyphenyl) -glyoxyloyl) -pyrrolidine 30 (2S) -2- (N-benzyl-N- (1,5 bis (4 -pyridyl) -3-pentyl) - aminomethyl) -1- ( (3,4, 5 - tri -methoxyphenyl ) glyoxyloyl) -pyrrolidine 31 N-methyl-N- ( (2S) -1- (N-benzyl-N- (1, 5-bis (4-pyridyl) -3- pentyl) amino) -3 -phenyl -prop-2 -yl) -3,4, 5-trimethoxyphenyl) glyoxyl amide 32 N-methyl-N- ( (2S) -1- (N-benzyl-N- (1, 5-bis (4-pyridyl) -3- pentyl) amino) -3 - (4-chlorophenyl) -prop-2-yl) -3,4,5- trimethoxyphenyl) glyoxyl amide 33 (2S) -2- (N-methyl-N- 3 -phenylpropyl-aminomethyl) -1- (cyclohexyl -thiocarbamoyl) -pyrrolidine 34 O 01/12622 38 Synthesis of sulfones Example 4 S-(3-(3-pyrldyl)propyl)-acetate 57.4 g (0.22 mol) Triphenylphosphme are dissolved in 1.2 I THF and 34.5 ml (0.22 mol) DEAD are added dropwise at 0 °C. Then 25.0 g (0.18 mol) 3-(3- pyridyl)propanol and 16.5 ml (0.22 mol) thioacetic acid are added sequentially and the mixture stirred at room temperature for 18h. The mixture is concentrated on the rotary evaporator and the solids removed by filtration. The filtrate is further concentrated and purified by chromatography (hexane ■ => hexane/ethyl acetate 1 :2). The resulting product (35.5 g, 99%) is rechromatographed (hexane ■=> hexane/ethyl acetate 2:1 ) to give 26.8 g (75%) pure title compound as an oil. 13 C-NMR (75 MHz, CDCI 3 ): δ = 28.3T (Pr-2), 30.3Q (C-2), 30.6T (Pr-3), 31.9T (Pr-1 ), 123.4D (Py-5), 135.8D (Py-4), 136.4S (Py-3), 147.5S (Py-6), 149.8S (Py- 2), 195.6S ppm (C-1 ). (2S)-1 ,1 -Dimethylethyl-2-(3-(3-pyridyl)propylthiomethyl)-pyrrolidine-1 - carboxylate 11.25g (57.6 mmol) of S-(3-(3-pyridyl)propyl)-acetate are dissolved in 576 ml ethanol containing 1 M sodium ethylate (576 mmol) and stirred overnight at room temperature. Then 34.83g (98 mmol) boc-prolinol tosylate in 50 ml ethanol and a catalytic quantity potassium iodide are added and the mixture brought to reflux for 2.5h. It is then allowed to cool and left over night at RT. The ethanol is removed and the residue partitioned between dichioromethane and 1 M NaOH. After several extractions with dichioromethane, the combined organic phases are dried over MgS0 and concentrated. Chromatography (hexane/ethyl acetate 1 :1 < => ethyl acetate) gives 13.3g (69%) of the title compound as an oil. 13 C-NMR (75 MHz, CDCI 3 ): δ = 23.6T(22.7T) (C 4), 28.5T (1 C3), 30.1T(29.4T) (C 3), 30.9T (2C2), 31.7T (2C3), 31.7T (2C4), 36.0T35.2T) (2C1 ), 46.6T(47.0T) (C 5), 57.0D (C 2), 79.5S(79.2S (1 C2), 123.3D (2C8), 135.9D (2C7), 136.6S (136.9S) (2C6), 147.5D(147.4S (2C9), 149.9D (2C5), 154.4S ppm (1C1 ). ,,„ O 01/126 3 g A 1.1 : 1 mixture of rotomers is observed, shifts of the minor rotomer in () if observed. (2S)-1,1-Dimethylethyl-2.(3-(3-pyridyl)propylsulfonylmethyl)-pyrrolidlne-1- carboxylate 13.3 g (40 mmol) of (2S)-1 ,1-Dimethylethy!-2-(3-(3-pyridyl)propylthiomethyl)- pyrrolidine-1 -carboxylate are dissolved in 400 ml CH2CI 2 and 19.5g (79 mmol) mCPBA (70% active ingredient) added at 0 °C. The reaction is stirred over night at ambient temperature. The mixture is then extracted with 1 M NaOH and the aqueous phase reextracted with dichioromethane. The combined organic phases are dried over MgSU4 and concentrated. Chromatography (ethyl acetate) gives 11.7g (80%) of the title compound. 13 C-NMR (75 MHz, CDCI 3 ): δ = 23.3T(22.8T) (C 4), 23.5T(2C3), 28.4Q(1C3), 30.7T(31.1T) (C 3), 31.4T(2C4), 46.4T(46.0T) (C 5), 52.4T(52.9T) (2C2), 52.6D (52.0D) (C 2), 55.5T(56.1T) (2C1), 80.0S (80.5S) (1C2), 123.5D(2C8), 135.6S (2C6), 136.0D(2C7), 147.9D(148.0D) (2C9), 149.8D(2C5), 154.4S ppm (1C1 ). A 4.1 : 1 mixture of rotomers is observed, shifts of the minor rotomer in () if observed. (2S)-2-(3-(3-pyridyl)propylsulfonylmethyl)-1-(trimethoxyphenylglyoxyloyl)- pyrrolldine i 1 . 4.91 g (13.3 mmol) (2S)-1 ,1-Dimethylethyl-2.(3-(3-pyridyl)propylsulfonyl- methyl)-pyrrolidine-1 -carboxylate are dissolved in 169 ml CH 2 CI 2 and 28.9 ml trifluoroacetic acid added at 0 °C. After 3h at this temperature, some water is added and the pH adjusted to 11 by addition of K 2 C0 3 and stirred for a while. The organic phase is separated. The aqueous phase is saturated with NaCl, the pH readjusted to 1 1 and reextracted with CH 2 CI 2 . Finally the aqueous phase is made basic with 2N NaOH and extracted a third time. The combined organic phases are dried over Na 2 S0 4 and concentrated in vacuo. 3.66 g (>100%) raw product is obtained. 2. The material obtained above is dissolved in 33 ml dichioromethane and cooled to 0 °C. 3.64 ml (16.8 mmol) triethylamine are added and after 20 in O 01/12622 4 0 a solution of 1.76 ml (19 mmol) methyloxalylchloride in 21 ml dichioromethane is added dropwise. After stirring at 0 °C for 3h, the reaction is poured into water. The mixture is made basic (K 2 CO 3 ) and saturated with NaCl and then extracted with dichoromethane. The combined organic phases are washed with brine and dried over MgS0 . After evaporation of the solvent 5.62 (>100%) g oil is obtained. 3. The material is redissolved in 50 ml dry THF and cooled to -70 °C. 10.4 ml (10.4 mmol) of a commercial solution of 1 ,1-dimethylpropylmagnesium- chloride (1M in ether) is added dropwise and stirring is continued at that temperature for 2h. The reaction is allowed to warm to ambient temperature and left over night. After quench with sat. NH 4 CI (under ice cooling) the mixture is saturated with NaCl and extracted with ethyl acetate three times. The combined organic phases are washed with brine and dried over MgSCλt. The residue (2.78 g) is chromatographed (CH 2 CI 2 ■ = CH 2 Cl 2 /ethanol 92:8) to give 2.16 g of a clear oil. Rechromatography (ethyl acetate) gives 1.63 g (31 %) of the title compound as a clear oil. 13 C-NMR (75 MHz, CDCI 3 ): δ = 8.9Q(1C5), 23.3Q(23.9Q) (1C6), 23.3T(23.2T) (2C3), 23.6Q(22.9Q) (1C7), 24.2T(20.7T) (C 4), 30.1T(30.8T) C 3), 31.4T (2C4), 32.3T(32.4T) (1C4), 46.7S(46.9S) (1C3), 47.0T(44.6T) (C 5), 52.4D(52.9D) (C 2), 52.7T(53.6T) (2C2), 54.4T(55.1T) (2C1 ), 123.6D (2C8), 135.5S (2C6), 136.0D (135.9D) (2C7), 147.9D (148.1D) (2C9), 149.8D (2C5), 165.7S (1C1), 206.8S ppm (1 C2). A 6.4 : 1 mixture of rotomers is observed, shifts of the minor rotomer in () if observed. Example 5 (2S)-1 ,1 -Dimethylethyl-2-(3-phenylpropylthiomethyl)-pyrrolidlne-1 - carboxylate 9.1 ml (60 mmol) 3-phenyl-propylmercaptan is added to a suspension of 2.16 g (45 mmol) NaH (50% in paraffin) in 200 ml THF. After the gas evolution O 0 41 subsedes, 23.5 g (66 mmol) boc-prolinol tosylate are added and the mixture refluxed for 6.5h and left at ambient temperature over the weekend. Then 1 N NaOH and CH 2 CI 2 are added. The organic layer is separated and the aqueous phase extracted with CH 2 CI 2 . The combined organic phase is washed with 1 N NaOH and brine and dried over MgS0 4 . Solvent evaporation gives a residue, which is chromatographed (hexane ■ => ethyl acetate) to give 13.2 g (76%) of the title compound and 5.24 g of boc-prolinol tosylate. 13 C-NMR (75 MHz, CDCI 3 ): δ = 23.1T (C 4), 28.8Q (1C3), 30.1T (C 3), 31. T (2C4), 31.7T (2C3), 34.7T (2C2), 35.6T (2C1)b, 45.8T (C 5), 57.1 D (C 2), 79.3S (1 C2), 125.9D (2C8), 128.4D (2C7), 128.5D (2C6), 141.5S (2C5), 154.4S ppm (1C1). (2S)-1 ,1 -Dimethylethyl-2-(3-phenylpropylsulfonylmethyl)-pyrrolidlne-1 - carboxylate 13.1 g (39 mmol) of (2S)-1 , 1 -Dimethylethyl-2-(3-phθnylpropylthiomethyl)- pyrrolidine-1 -carboxylate are dissolved in 300 ml CH 2 CI 2 and 21.2g (86 mmol) mCPBA (70% active ingredient) added at 0 °C and the reaction stirred over night at ambient temperature. The mixture is then extracted with 1M NaOH and the aqueous phase reextracted with dichioromethane. The combined organic phases are dried over MgSO 4 and concentrated. Chromatography (hexane/ ethyl acetate 2:1) gives 12.8 g (90%) of the title compound which is recrystallised from hexane/diisopropylether (10 g, 70%). 13 C-NMR (75 MHz, d 6 DMSO): δ = 22.6T (2C3), 23.1T (C 4), 28.2Q (1C3), 30.4T (C 3), 33.6T (2C4), 45.8T (C 5), 52.0D (C 2), 53.3T (2C2), 55.5T (2C1), 79.1 S (1C2), 125.9D (2C8), 128.1 D (2C7), 128.2D (2C6), 140.8S (2C5), 153.4S ppm (1 C1). (2S)-2-((3-Phenyl-propyIsulfonylmethyl)-1-(3-pyridyl-glyoxyloyl)-pyrrolidine i 1 1 70 g (4 60 mmol) (2S)-1 ,1-Dιmethylethyl-2-(3-pheπylpropylsulfoπylmethyl)- pyrrolιdιπe-1 -carboxylate are dissolved in 15 ml CH 2 CI 2 and 3.5 ml trifluoroacetic acid added at 0 °C. The mixture is stirred over night at ambient temperature, made then basic with 2N NaOH and extracted with CH 2 CI 2 . The combined organic phase are dried over MgSO 4 and concentrated in vacuo 1.14 g (92%) raw product is obtained. 2. 968 mg (6.38 mmol) 3-pyridylglyoxylic acid are dissolved in 100 ml THF and 0.2 ml DMF and cooled to 0 °C. 0.55 ml (6.38 mmol) oxalylchloride are added dropwise and the reaction stirred for 5.5h at 0 °C. 3. The amine obtained in 1. is dissolved in 20 ml THF and 1.77 ml (12.8 mmol) triethylamine added. This solution is added to the reaction mixture obtained 2. at 0 °C and the resulting mixture stirred at ambient temperature over night. The reaction is made basic with 2N NaOH and extracted with CH 2 CI 2 . The combined organic phases are washed with 2N NaOH and brine and dried over MgS0 4 . After evaporation of solvent 1.94 g material is obtained, which is subjected to chromatography (ethyl acetate) to give 1.58 g (86%) of the title compound, which was recrystallised from CH 2 CI 2 /Diisopropylether (1.50 g, 81 %). m.p. 95 - 96 °C, [α] D = 46° (C = 0.5, CHCI3), 13 C-NMR (75 MHz, CDCI 3 ): δ = 23.5T(23.4T) (2C3), 24.2T(20.9T) (C 4), 30.1T(31.0T) (C 3), 34.2T (2C4), 47.3T(45.3T) (C 5), 53.0D (C 2), 53.3T(53.7T) (2C2), 53.9T(55.2T) (2C1 ), 123.9D(123.8D) (1C5), 126.5D(126.6D) (2C8), 128.5D(128.5D) (2C7), 128.6D (128.7D) (2C6), 137.1 D(137.3D) (1 C4), 139.9S(139.7S) (2C5), 151.5D(151.7D) (1 C6), 154.8D (1C3), 163.9S(163.2S) (1C1 ), 188.9S(189.6S) ppm (1C2). A 4.6 : 1 mixture of rotomers is observed, shifts of the minor rotomer in () if observed. Example 6 (2S)-1 ,1 -Dimethylethyl-2-(2-(2-pyridyl)ethylthiomethyl)-pyrrolidine-1 - carboxylate 10.0 ml (71.8 mmol) 2-(2-ρyridyl)ethylmercaptan is added at 0 °C to a suspension of 5.17 g (107 mmol) NaH (50% in paraffin) in 500 ml THF. After the gas evolution subsedes, 27.5 g (77.4 mmol) boc-prolinol tosylate is added at ambient temperature and heated at 60 °C for 18h. Then 1 N NaOH and CH 2 CI 2 is added. The organic layer is separated and the aqueous phase extracted with CH 2 CI 2 . The combined organic phase is washed with 1N NaOH and brine and dried over MgS0 . Solvent evaporation gives a residue, which is chromatographed (hexane/ethyl acetate 1 :1 ) to give 10.6 g (46%) of the title compound as an oil. 13 C-NMR (75 MHz, CDCI3): δ = 22.7T(23.6T) (C 4), 28.5Q (1C3), 30.1T(29.4T) (C 3), 32.1T (2C2), 36.2T(35.2T) (2C1 ), 38.4T(38.3T) (2C3), 46.5T(47.0T) (C 5), 57.0D (C 2), 79.5S(79.1) (1C2), 121.5D (2C7), 123.2D(123.4D) (2C5), 136.5D (2C6), 149.2D(148.9D) (2C8), 154.3S (1 C1 ), 159.7S ppm (2C4). A 1.2 : 1 mixture of rotomers is observed, shifts of the minor rotomer in () if observed. (2S)-1 ,1 -Dimethylethyl-2-(2-(2-pyridyI)ethylsulfonylmethyl)-pyrrolidinβ-1 ■ carboxylate 3.22 g (10 mmol) of (2S)-1 ,1-Dimethylethyl-2-(2-(2-pyridyl)ethylthiomethyl)- pyrrolidine-1 -carboxylate are dissolved in 70 ml CH 2 CI 2 and 4.93g (20 mmol) mCPBA (70% active ingredient) added at 0 °C and the reaction stirred over night at ambient temperature. 1 NaOH is then added and the mixture extracted with CH 2 CI 2 and the aqueous phase reextracted with dichioromethane. The combi- ned organic phases are dried over MgS0 4 and concentrated. Chromatography (hexane/ethyl acetate 1 :2) gave 2.78 g (79%) of the title compound which was recrystallised from CH 2 CI 2 /diisopropylether (1.36 g, 39%). m.p. = 96 °C, 13 C-NMR (75 MHz, CDCI 3 ): δ = 23.6T(22.7T) (C 4), 28.4Q (1C3), 29.8T(29.5T) (2C3), 30.4T(31.1T) (C 3), 46.4T(46.0T) (C 5), 52.4D.51.9D) (C 2), 52.7T(53.0T) (2C2), 55.3T(56.2T) (2C1 ), 79.8S(80.4S) (1 C2), 122.0D (2C7), 123.5D (2C5), 137.0D (2C6), 149.2D (2C8), 154.3S(153.7S) (1 C1 ), 157.4S (156.9S) ppm (2C4). A 1.9 : 1 mixture of rotomers is observed, shifts of the minor rotomer in () if observed. (ΣSJ^^-iZ-pyri y ethylsulfoπylmethy -I^S^^-trimethoxyphθnyl- glyoxyloyI)-pyrrolidiπe 1. 1.36 g (3.80 mmol) (2S)-1 , 1 -Dimethylethyl-2-(2-(2-pyridyl)ethylsulfonyl- methyl)-pyrroIidine-1 -carboxylate are dissolved in 20 ml CH 2 CI 2 and 6.0 ml trifluoroacetic acid added at 0 °C. The mixture is stirred over night at ambient temperature, made then basic with 2N NaOH and extracted with CH 2 CI 2 . The combined organic phase are dried over MgS0 4 and concentrated in vacuo. 783 mg (81 %) raw product is obtained. 2. 4.56 g (19 mmol) 3,4,5-trimethoxyphenylglyoxylic acid are dissolved in 50 ml THF and 0.2 ml DMF and cooled to 0 β C. 1.64 ml (19 mmol) oxalylchloride are added dropwise and the reaction stirred for 4h at 0 °C. 3. The amine obtained in 1. is dissolved in 10 ml CH 2 CI 2 and 1.28 ml (9.23 mmol) triethylamine added. To this solution is added the reaction mixture obtained 2. at 0 °C and the resulting mixture stirred 68h at ambient temperature. The reaction is made basic with 2N NaOH and extracted with CH2CI2. The combined organic phases are washed with 2N NaOH and brine and dried over MgS0 4 . After evaporation of solvent 1.72 g material is obtained, which is subjected to chromatography (CH 2 CI 2 => CH ∑ C /ethaπol 20:1 ) to give 1 .25 g (69%) of the title compound as an oil. 13 C-NMR (75 MHz, CDCI3): δ = 24.2T(21 .1T) (C 4), 30.0T(29.7T) (C 3), 30.1 T (30.8T) (2C3), 47.1 T (45.0T) (C 5), 52.7D(52.9D) (C 2), 53.1 T(53.2T) (2C2), 54.2T(55.4T) (2C1 ), 56.4Q(56.3Q) (1 C7), 61 .0Q (1 C8), 107.3D(107.5D) (1 C4), 122.1 D (2C7), 123.5D(123.4D) (2C5), 127.6S(127.7S) (1 C6), 136.9D (136.9D) (2C6), 144.3Sb (1 C3), 149.3D (2C8), 153.4S(153.3S) (1 C5), 157.1 S(157.0S) (2C4), 165.5S (164.7S) (1 C1 ), 189.5S(189.9S) ppm (1C2). A 4.3 : 1 mixture of rotomers is observed, shifts of the minor rotomer in () if observed. Example 7 Ethyl N-((2S)-3-(4-Ethoxyphenyl)-1-((3-pyridyl)propylsulfanyl)-2-propyl)- carbamate 4.8 g (24.6 mmol) of S-(3-(3-pyridyl)propyl)-acetate are dissolved in 245 ml ethanol containing 1 M sodium ethylate (245 mmol) and stirred overnight at room temperature. Then 5.00g (12.3 mmol) benzyl N-((2S)-3-(4-Ethoxyphenyl)-1 - (mesyloxy)-2-propyl)-N-methyl-carbamate is added and the mixture stirred at 60 °C for 7h. It is then allowed to cool and left over the weekend at RT. The ethanol is removed and the residue partitioned between dichioromethane and 1M NaOH. After several extractions with dichioromethane, the combined organic phases are dried over MgS0 4 and concentrated. Chromatography (hexane/ethyl acetate 2:1 1 :2) gave 1.49 g (30%) of the title compound as an oil. 13 C-NMR (75 MHz, CDCI 3 ): δ = 14.6Q (7C2), 14.9Q (2C3), 30.7T (1C2), 31.7T (1C3), 32.0T (C 3), 35.9Tb (1C1 ), 38.5Tb (C 1 ), 51.6Db (C 2), 60.8Tb (2C2), 63.4T (7C1 ), 114.5D (C 5), 123,4D (1C7), 129.2S (C 4), 130.3D (C 6), 136.0D (1C6), 136.7S (1C5), 147.4D (1C8), 149.8D (1C4), 156.0S (2C1 ), 157.7S ppm (0 7). Methyl-[((2S)-3-(4-Ethoxyphenyl)-1-((3-pyrldyl)ρropylsulfaπyl)-2-propyl)- amine 2.422 g (6.00 mmol) Ethyl N-((2S)-3-(4-Ethoxypheπyl)-1-((3-pyridyl)propyl- sulfaπyl)-2-propyl)-carbamate is dissolved in 40 ml THF and 2.28 g (60 mmol) LiAIH 4 is added portionwise. After completion of the addition, the mixture is refluxed for 7h and then left at ambient temperature over night. The excess hydride is destroyed by addition of ethyl acetate, then 2N NaOH was added and extracted with ethyl acetate. The combined organic phases are washed with brine, dried with MgSO 4 and evaporated in vacuo to give 1.85 g of the title compound which was used as such. 1 C-NMR (75 MHz, CDCI 3 ): δ = 14.9Q (7C2), 30.8T (1 C2), 31.7T (1 C3), 31.8T (C 3), 34.0Q (2C1 ), 35.8T (1C1 ), 38.7T (C 1 ), 60.5D (C 2), 63.4T (7C1 ), 114.5D (C 5), 123.3D (1C7), 130.2D (C 6), 130.5S (C 4), 135.9D (1 C6), 136.7S (1 C5), 147.5D (1 C8), 149.9D (1C4), 157.5S ppm (C 7). As described in example 2, N-Methyl-N-[((2S)-3-(4-Ethoxyphenyl)-1-((3- pyridyl)propylsulfoπyl)-2-propyl)]-3,4,5-trimethoxyphenylglyoxylamide is obtained. Produced analoguously are: 5 N-Methyl-N-[((2S)-3-(4-chloro-phenyl)-1-((3-pyridyl)propylsulfonyl)-2-propyl)]- 3,4,5-trimethoxyphenylglyoxylamide N-Methyl-N-[((2S)-3-phenyl-1-((3-pyridyl)propylsulfonyl)-2-propyl)]-3,4,5- trimethoxyphenylglyoxylamide The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims: Claims 1. Compounds of formula I and their physiologically compatible salts in which R 1 means hydrogen, Ar, straight-chain or branched C j -C, alkyl, which can be substituted with Ar or E, straight - chain or branched C 2 -C 7 alkenyl, which can be substituted with Ar or E, C 3 -C 7 cycloalkyl, which can be substituted with Ar or E, or C 5 -C 7 that cycloalkenyl, which can be substituted with Ar or E, Y means - (C=0) - (C=0) - , -S0 2 -, -(C=0)NH-, -(C=S)NH-, - (C=0) - (C=0) -0-, - (C=0) - (C=0)NH-, - (C=0) -0- or -S0 2 -NH, R 2 means straight-chain or branched C^-Cg alkyl, which can be substituted with phenyl or halogenated phenyl, R 3 means straight-chain or branched C 1 -C 6 alkyl, straight- chain or branched C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C,-C cycloalkenyl, cyclohexylmethyl , whereby the alkyl, alkenyl, cycloalkyl and cycloalkenyl radical can be substituted by the same or a different component in one to two places with Ar, or R 2 and R 3 together with the N atom form a 5- to 7-membered heterocycle, which can be saturated or unsaturated and which can be substituted with C^C alkyl and OH, X means -S-, -SO-, -S0 2 -, -NH- or -NR 5 -, R 4 and R 5 are the same or different and, independently of one another, mean Ar, straight-chain or branched C j -Cg alkyl, straight-chain or branched C 2 -C 9 alkenyl, C 3 -C, cycloalkyl, C 5 -C 7 cycloalkenyl, whereby the alkyl and the alkenyl radicals can be substituted in one to two places with the same or a different component with Ar, C 3 -C 7 cycloalkyl and C 5 -C 7 cycloalkenyl, or wherein the alkyl radical can be substituted by halogen, and Ar is a C 6 -C 12 monocyclic or bicyclic aromatic compound, which can contain 0 to 4 N, S or 0 atoms and which is optionally partially hydrogenated and which can be substituted in one to three places with E, and E is halogen, hydroxy, nitro, CF 3 , CN, OCF 3 , amino, phenyl, methylenedioxy, phenoxy, benzyloxy, Cj-C, alkoxy or Cj-C,, alkyl, whereby, if Y = S0 2 , R 1 does not mean hydrogen, and, if X = NR 5 and YR 1 = tosyl, R 2 , R 3 , R 4 and R J do not mean methyl simultaneously, and if X = SO, Y = (C=0)NH, R' and R 2 mean benzyl and R means -CH=CH-,, R 1 is not n-butyl, and, if X = NR 5 and YR 1 = tosyl, and R 2 and R together with the N atom form a 6 - or 7-membered saturated heterocycle, R 4 and R 5 do not mean n-propyl simultaneously, and, if X = NR 5 , Y = (C=S)NH, R 1 means 4-methylphenyl and R 3 = phenyl , and R 2 , R 4 and R 5 do not mean methyl simultaneously . 2. Compounds of Formula I according to claim 1, in which R means a straight -chain or branched alkyl radical, which is substituted with Ar in one to two places. 3. Compounds of Formula I according to claim 1, in which R 1 means Ci-C-, alkyl or Ar. 4. N-Cyclohexyl ( (2S) -2- (phenylethylsulfonylmethyl) - pyrrolidine) -1-thiocarbamide (2S) -2- (3- (3- pyridyl) propylsulfonylmethyl) -1- ( (1 , 1-dimethylpropyl) glyoxyloyl) - pyrrolidine (2S) -2- (4,4,5,5, 5 -pentafluoropentylthiomethyl) -1- ( (3 , 4 , 5- trimethoxyphenyl) -glyoxyloyl) -pyrrolidine (2S) -2- (4,4,5,5, 5 -pentafluoropentylsulfonylmethyl) -1- ( (3,4, 5-trιmethoxy-phenyl) glyoxyloyl) -pyrrolidine ( (2S) -2- (N-methyl-N- (3- (3 -pyridyl ) propyl ) -aminomethyl) -1- (3,4,5 - trimethoxy-phenylglyoxyloyl ) -pyrrolidine (2S) -2- (3- (3-pyridyl) propylsulfonylmethyl ) -1- ( (3,4,5- tπmethoxyphenyl ) -glyoxyloyl) -pyrrolidine (2S) -2- (3 -phenyl -propylsulfonylmethyl) -1- ( (3- pyridyl ) glyoxyloyl ) -pyrrolidine (2S)-2-(l,5-bιs (4 -pyridyl) - 3 -pentylsulfonylmethyl ) -1- ( (1 , 1- dimethylpropyl) -glyoxyloyl) -pyrrolidine (2S) -2- (1, 5-bis (4-pyridyl) -3 -pentylsulfonylmethyl) -1- ( (3,4, 5-trimethoxyphenyl) -glyoxyloyl) -pyrrolidine (2S) -2- (1, 5-bis-phenyl-3-pentylsulfonylmethyl) -1- ( (3- pyridyl) glyoxyloyl) -pyrrolidine (2S) -2- ( (4R) -7-phenyl-l- (3-pyridyl) -4-heptylsulfonylmethyl) - 1- ( (1 , 1-dimethyl-propyl) -glyoxyloyl) -pyrrolidine (2S) -2- ( (4S) -7-phenyl-l- (3-pyridyl) -4-heptysulfonylmethyl) - 1- ( (1 , 1-dimethyl -propyl) glyoxyloyl) -pyrrolidine (2S) -2- ( (4R) -7-phenyl-l- (3-pyridyl) -4-heptylsulfonylmethyl) - 1- ( (3 , 4 , 5-trimethoxy-phenyl) -glyoxyloyl) -pyrrolidine (2S) -2- ( (4S) -7-phenyl-l- (3-pyridyl) -4-heptylsulfonylmethyl) - 1- ( (3 , 4 , 5-trimethoxy-phenyl) -glyoxyloyl) -pyrrolidine (2S) -2- (1, 5-bis (3-pyridyl) -3 -pentylsulfonylmethyl) -1- ((1,1- dimethylpropyl) -glyoxyloyl) -pyrrolidine (2S) -2- ( (4R) -6-phenyl-l- (3-pyridyl) -4-hexylsulfonylmethyl) - 1- ( (1 , 1-dimethyl-propyl) glyoxyloyl) -pyrrolidine (2S) -2- ( (4S) -6-phenyl-l- (3-pyridyl) -4-hexylsulfonylmethyl) - 1- ( (1, 1-dimethyl -propyl) glyoxyloyl) -pyrrolidine (2S) -2- ( (4R) -6-phenyl-l- (3-pyridyl) -4-hexylsulfonylmethyl) - 1 ' - ( (3 , 4 , 5-trimethoxy-phenyl) -glyoxyloyl) -pyrrolidine (2S) -2- ( (4S) -6-phenyl-l- (3-pyridyl) -4-hexylsulfonylmethyl) - 1- ( (3 , 4 , 5-trimethoxy-phenyl) -glyoxyoyl) -pyrrolidine (2S) -2- (1, 5-bis (3-pyridyl) -3 -pentylsulfonylmethyl) -1- ( (3,4, 5-trimethoxyphenyl) -glyoxyloyl) -pyrrolidine (2S) -2- (N-methyl-N- 3- (3-pyridyl) propyl -aminomethyl) -1- ( (1,1- dimethylpropyl) -glyoxyloyl) -pyrrolidine (2S) -2- (N-methyl-N-3- (3 -pyridyl) propyl -aminomethyl ) -1- (4- methylphenylsulfonyl) -pyrrolidine (2S) -2- (N-methyl-N-3-phenylpropyl-aminomethyl) -1- ((1,1- dimethylpropyl) -glyoxyloyl) -pyrrolidine (2S) -2- (N-methyl-N- ( (4R) -7-phenyl-l- (3-pyridyl) -4-heptyl) - aminomethyl) -1- ( (1 , 1-dimethylpropyl) glyoxyloyl) -pyrrolidine (2S) -2- (N-methyl-N- ( (4S) -7-phenyl-l- (3-pyridyl) -4-heptyl) - aminomethyl) -1- ( (1, 1-dimethylpropyl) glyoxyloyl) -pyrrolidine (2S) -2- (N- (1, 5-bis (4 -fluorophenyl) -3-pentyl) -N-methyl- aminomethyl) -1- ( (3 , 4 , 5-trimethoxyphenyl) glyoxyloyl) -pyrrolidine (2S) -2- (N- (1, 5-bis (4-pyridyl) -3-pentyl) -N- (4- fluorophenylmethyl) -aminomethyl) -1- ( (3 , 4 , 5-trimethoxyphenyl) - glyoxyloyl] -pyrrolidine (2S) -2- (N-methyl-N- ( (4R) -7-phenyl-l- (3-pyridyl) -4-heptyl) - aminomethyl) -1- ( (3 , 4 , 5-trimethoxyphenyl) -glyoxyloyl) -pyrrolidine (2S) -2- (N-methyl-N- ( (4S) -7-phenyl-l- (3-pyridyl) -4-heptyl) - aminomethyl) -1- ( (3 , 4 , 5-dimethoxyphenyl) -glyoxyloyl) -pyrrolidine (2S) -2- (N- (1, 5-bis (4 -fluorophenyl ) -3-pentyl) -N-methyl- aminomethyl) -1- ( (1 , 1-dimethylpropyl) lyoxyloyl) -pyrrolidine (2S) -2- (N-methyl-N- 3 -phenylpropyl -aminomethyl) -1- ((3,4,5- trimethoxyphenyl) -glyoxyloyl) -pyrrolidine (2S) -2- (N-benzyl-N- (1, 5-bis (4-pyridyl) -3-pentyl) - aminomethyl) -1- ( (3 , 4 , 5-trimethoxyphenyl) glyoxyloyl) -pyrrolidine N-methyl-N- ( (2S) -1- (N-benzyl-N- (1, 5-bis (4-pyridyl) -3- pentyl) amino) -3 -phenyl -prop-2 -yl) -3,4, 5-trimethoxyphenyl) glyoxyl amide N-methyl-N- ( (2S) -1- (N-benzyl-N- (1, 5-bis (4-pyridyl) -3- pentyl) amino) -3 - (4-chlorophenyl) -prop-2-yl) -3,4,5- trimethoxyphenyl) glyoxyl amide (2S) -2- (N-methyl-N-3-phenylpropyl-aminomethyl) -1- (eyelohexyl -thiocarbamoyl) -pyrrolidine according to claim 1. 5. Pharmaceutical agent that contains a compound according to claims 1 to 4 and one or more pharmaceutically conventional vehicles and adjuvants. 6. Pharmaceutical agent according to claim 5 in combination with a neurotrophic factor. 7. Pharmaceutical agent according to claim 6, in which the neurotrophic factor is IGF-1, gIGF-1, Des (1-3 ) IGF-1 , aFGF, bFGF, PDGF, BDNF, CNTF, GDNF, TN-3, NT-4/5 or preferably NGF. 8. Use of a compound according to claims 1-4 for the production of a pharmaceutical agent. 9. Use of a compound according to claims 1-4 for the production of a pharmaceutical agent for stimulation of neuronal activity. 10. Use of a compound of Formula IA and its physiologically compatible salts ich R 1 means hydrogen, Ar, straight-chain or branched C^C, alkyl, which can be substituted with Ar or E, straight- chain or branched C 2 -C 7 alkenyl, which can be substituted with Ar or E, C 3 -C 7 cycloalkyl, which can be substituted with Ar or E, or C 5 -C 7 cycloalkenyl, which can be substituted with Ar or E, Y means - (C=0) - (C=0) - , -S0 2 -, -(C=0)NH-, -(C=S)NH-, - (C=0) - (C=0) -0-, - (C=0) - (C=0)NH-, -(C=0)-0-, -S0 2 -NH, -C=0- or a bond, R 2 means straight-chain or branched Ci-Cg alkyl, which can be substituted with phenyl or halogenated phenyl, R 3 means straight-chain or branched Cj-Cg alkyl, straight- chain or branched C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, cyclohexylmethyl , whereby the alkyl, alkenyl, cycloalkyl and cycloalkenyl radical can be substituted by the same or a different component in one to two places with Ar, or R 2 and R J together with the N atom form a 5- to 7-membered heterocycle, which can be saturated or unsaturated and can be substituted with C ! -C 4 alkyl and OH, X means -S-, -SO-, -S0 2 -, -NH- or -NR 5 - , R 4 and R are the same or different and, independently of one another, mean Ar, straigh -chain or branched C,-C, alkyl, straight-chain or branched C-.-C, alkenyl, C,-C- cycloalkyl, C 5 -C ^ cycloalkenyl, whereby the alkyl and the alkenyl radicals can be substituted in one to two places with the same or a different component with Ar, C 3 -C 7 cycloalkyl and C 5 -C 7 cycloalkenyl, or wherein the alkyl radical can be substituted by halogen, and Ar is a C 6 -C 12 monocyclic or bicyclic aromatic compound, which can contain 0 to 4 N, S or O atoms and which is optionally partially hydrogenated and which can be substituted in one to three places with E, and E is halogen, hydroxy, nitro, CF 3 , CN, OCF 3 , amino, phenyl, methylenedioxy, phenoxy, benzyloxy, C^C, alkoxy or C^C, alkyl, for the production of a pharmaceutical agent for stimulation of the neuronal activity. 11. Use according to claims 9 and 10 for treatment and prevention of neurodegeneration, for promotion of neuronal regeneration, for treatment of neurological diseases and for stimulation of neurite growth. 12. Use according to claim 11 for the treatment of Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, ischemia, strokes, multiple sclerosis, peripheral neuropathies, neuralgias, muscular atrophies and Guillain-Barre syndrome. 13. Production of the compounds of Formula I of Claim 1, characterized in that a compound of Formula II (ID, in which P is a protective group, R 2 and R 3 have the above- mentioned meanings, and A means a reactive leaving group, a) is reacted with H-XR 4 , in which X is S, NH or NR 6 , and R 4 and R 5 have the above-mentioned meaning, and then is optionally oxidized to sulfoxide or sulfone, b) amino protective group P is cleaved off, c) Y-R 1 is introduced and optionally the isomers are separated, and the salts are formed. 14. Process for the production of compounds of formula I of Claim 1, wherein a compound of Formula III in which R 2 , R" and P have the above-mentioned meaning, a) is reacted with A-R 4 , b) R 4 optionally is modified by C-C-linking reactions and/or hydrogenation, c) amino protective group P is cleaved off, d) Y-R 1 is introduced and optionally the isomers are separated and the salts are formed .

Inventors: BRUMBY THOMAS, MCDONALD FIONA, SCHNEIDER HERBERT, BRUMBY, THOMAS, MCDONALD, FIONA, SCHNEIDER, HERBERT
Applicants: SCHERING AG, VERTEX PHARMA, SCHERING AKTIENGESELLSCHAFT, VERTEX PHARMACEUTICALS, INC.
Application year: 2000
Main classification: C07D401
IPC codes: A61K31, A61K38, A61P21, A61P25, A61P41, A61P43, C07D207, C07D213, C07D401