DE10045831A1 - Anticonvulsant, anxiolytic and especially analgesic medicaments, comprising new or known beta-thio-alpha-aminoacid compounds having strong affinity for gabapentin binding site - Google Patents

Abstract

The use of beta -thio- alpha -aminoacids (I) as anticonvulsants, analgesics or anxiolytics and in the treatment of a very wide range of specific disorders (mainly pain-related, psychiatric and neuropathological disorders) is new. Some compounds (I), i.e. (I'), are new. The use of beta -thio- alpha -aminoacids of formula (I) (in the form of racemates, enantiomers, diastereomers or enantiomer or diastereomer mixtures and as free aminoacids or acid or base addition salts) in: (A) the preparation of medicaments for treating: (i) pain (especially neuropathic, chronic or acute pain), epilepsy and/or migraine; (ii) hyperalgesia and allodynia (especially thermal hyperalgesia, mechanical hyperalgesia and allodynia and cold allodynia) or inflammatory or post-operative pain; or (iii) hot flushes, post-menopausal disorders, amyotropic lateral sclerosis, reflex sympathetic dystrophy, spastic paralysis, restless leg syndrome, acquired nystagmus, psychiatric or neuropathic disorders (e.g. bipolar disorders, anxiety, panic attacks, mood swings, manic or manic depressive behavior, depression, painful diabetic neuropathy, symptoms and pain caused by multiple sclerosis or Parkinson's disease or neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease or epilepsy), gastrointestinal damage, erythro-melalgic or post-poliomyelitic pain or trigeminal or post-herpetic neuralgia; or (B) as anticonvulsants, analgesics or anxiolytics. R1, R2 = H; or optionally unsaturated 1-10C alkyl, benzyl, aryl, 3-8C cycloalkyl or heteroaryl (all optionally mono- or polysubstituted); or R1 + R2 = (CH2)n (optionally- (i) unsaturated, (ii) branched, (iii) mono- or polysubstituted and/or (iv) having 1 or 2C replaced by S, O or NR4); n = 3-6; R3 = H, as R4, or -L-R'3; R'3 = 3-8C cycloalkyl, aryl or heteroaryl (all optionally mono- or polysubstituted); and R4 = optionally unsaturated 1-10C alkyl (optionally mono- or polysubstituted); and L = direct bond or optionally unsaturated 1-3C alkylene. Independent claims are also included for: (1) Thioaminoacid compounds of formula (I') (including enantiomers, salts etc) as new compounds; and (2) Preparation of (I'). One of R'1, R'2 = optionally unsaturated 1-6C alkyl (optionally mono- or polysubstituted); and the other is an optionally unsaturated 3-10C alkyl, phenyl, thiophenyl or 3-8C cycloalkyl (all optionally mono- or polysubstituted).

Description

The invention relates to selected thio-amino acids and methods for their manufacture, their use in the manufacture of medicinal products and drugs containing these compounds.

The cyclic GABA analog gabapentin is a clinically proven Antiepileptic. Gabapentin also shows antinociceptive Characteristics. But it does exist with the above Indications of further need for substances in their properties Show matches with gabapentin.

The object of the invention was therefore to find new structures which have affinity for the gabapentin binding site and / or have corresponding physiological activity. The task is selected by a thio amino acid from the following compounds:

rac-2-amino-3-mercapto-3-methyl-octanoic acid;
rac-2-amino-3-ethylsulfanyl-3-methyl-octanoic acid;
rac-2-amino-3-benzylsulfanyl-3-methyl-octanoic acid;

in the form of their racemates; Enantiomers, diastereomers, in particular Mixtures of their enantiomers or diastereomers or a single one Enantiomers or diastereomers; of their bases or salts physiologically compatible acids dissolved.

Under the term of having a physiologically acceptable acid formed salt is understood in the sense of this invention salts of respective active ingredient with inorganic or organic acids, the  physiological - especially when used in humans and / or Mammal - are tolerated. The hydrochloride is preferred.

The threo forms of the selected ones are also more preferred Compounds, especially rac-threo-2-amino-3-mercapto-3-methyl octanoic acid, rac-threo-2-amino-3-benzylsulfanyl-3-methyl-octanoic acid. The erythro forms of the selected ones are also preferred Links.

The pharmaceuticals according to the invention contain at least one thioamino acid carrier materials, fillers, Solvents, diluents, dyes and / or binders and can be used as liquid dosage forms in the form of solutions for injection, drops or juices, as semi-solid dosage forms in the form of granules, tablets, Pellets, patches, capsules, plasters or aerosols can be administered. The Selection of the auxiliaries and the amounts to be used depends on them whether the drug is oral, oral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or locally, for example on infections on the skin, mucous membranes and on the eyes to be applied. Are suitable for oral administration Preparations in the form of tablets, dragees, capsules, granules, Drops, juices and syrups, for parenteral, topical and inhalation Application solutions, suspensions, easily reconstitutable Dry preparations and sprays. invention Thioamino acids in a depot in dissolved form or in a patch, if necessary with the addition of agents promoting skin penetration, are suitable, percutaneous application preparations. Oral or percutaneous Applicable preparation forms can the thio- Release amino acids with a delay. The to the patient too amount of active ingredient varies depending on the weight of the Patients, on the type of application, the indication and the severity  the disease. Usually 50 to 1000 mg / kg will be at least one applied thio-amino acid according to the invention.

Another subject is the use of a Thioamino acid according to the invention for the preparation of a Medicines used to treat pain or epilepsy.

The substituted ones according to the invention are preferably used Thioamino acids used for pain treatment. Beyond that the compounds useful for the treatment of epilepsy.

The invention also relates to a process for the preparation of a thioamino acid according to the invention, which proceeds according to the following scheme, R1 being selected from benzyl, ethyl or H:

The more precise conditions of the reaction are one of the following Take examples.  

The following examples are intended to illustrate the invention without limiting it restrict:

Examples

example 1

rac-2-amino-3-mercapto-3-methyl-octanoic acid hydrochloride as 1: 1 threo / erythro mixture

Example 2

rac-threo-2-amino-3-mercapto-3-methyl-octanoic acid hydrochloride

Example 3

rac-2-amino-3-ethylsulfanyl-3-methyl-octanoic acid hydrochloride as 1: 1 threo / erythro mixture

Example 4

rac-threo-2-amino-3-benzylsulfanyl-3-methyl-octanoic acid hydrochloride

Example 5 binding studies

In the binding assay, gabapentin is used to bind and Check affinities of the selected compounds. The affinity of the Compounds according to the invention is based on the displacement of Gabapentin measured from its binding site. If the selected Compounds can displace gabapentin from its binding site, one can expect it to be comparable to gabapentin  pharmacological properties develop z. B. as an agent against pain or epilepsy. The compounds of the invention show good ones Affinities in this assay. Gabapentin shows a binding of 60 nM.

Table 0

Example 6 Pharmacological examinations (pain relevance) 6.1 Writhing test mouse

The antinociceptive activity of the compounds according to the invention was modified in the phenylquinone-induced writhing test, modified according to I.C. Hendershot, J. Forsaith, "J. Pharmacol. Exp. Ther.", 125, 237-240 (1959) examined the mouse. Male NMRI mice with a Weight of 25-30 g used. Groups of 10 animals each Substance dose was 10 minutes after intravenous administration compound according to the invention 0.3 ml / mouse of a 0.02% aqueous solution Solution of phenylquinone (phenylbenzoquinone, Sigma, Deisenhofen; Preparation of the solution with the addition of 5% ethanol and storage applied intraperitoneally in a water bath at 45 ° C). The animals were individually placed in observation cages. Using a push button counter was the number of pain-induced stretching movements  (so-called writhing reactions = pushing the body through with Stretching the hind limbs) 5-20 minutes after the phenylquinone Gift counted. Animals were carried as a control physiological saline i. v. and phenylquinone i. v. received.

All substances were tested in the standard dose of 10 mg / kg. The percentage inhibition (% inhibition) of the writhing reactions by a substance was calculated using the following formula:

% Inhibition = 100 - [WR treated animals / WR control × 100].

Table 1

Analgesia test in the writhing test on the mouse

6.2. Formalin test mouse

The studies to determine the antinociceptive effect of Compounds according to the invention were in the formalin test male albino mice (NMRI, 25-35 g, Iffa Credo, Belgium) carried out.

In the formalin test, the first (early) phase (0-15 min after Formalin injection) and the second (late) phase (15-60 min after Formalin injection) (D. Dubuisson er al. "Pain", Vol. 4, pp. 161 -174 (1977)). The early phase is a direct reaction to the formalin  Injection represents a model for acute pain during the late phase Model for persistent (chronic) pain is considered (T. J. Coderre et al. "Pain", vol. 52, pp. 259-285 (1993)).

The compounds of the invention were in the second phase of Formalin tests examined to make statements about substance effects in the to get chronic / inflammatory pain.

By a single, subcutaneous formalin injection (20 µl, 1% aqueous Solution) in the dorsal side of the right hind paw was at freely moving experimental animals induced a nociceptive response that manifests itself in clear licking and biting of the affected paw. For the investigation period in the second (late) phase of Formalin tests were performed by observing the nociceptive behavior Animals recorded continuously. The quantification of pain behavior was done by summing the seconds in which the animals in the Investigation period showed licking and biting of the affected paw. After injection of substances that are antinociceptive in the formalin test the behavior of the animals described are effective reduced, possibly even canceled. According to the substance tests, in which the animals had been injected with test substance before formalin, The control animals were vehicle, i. H. Solvents (e.g. 0.9% NaCl Solution), injected before the formalin application. Animal behavior after administration of substance (n = 10 per substance dosage) with a Control group (n = 10 compared).

Based on the quantification of pain behavior, the substance effect in the formalin test was determined as a change in the control in percent. The ED ₅₀ calculations were carried out using regression analysis.

Depending on the type of application of the compounds according to the invention the time of application before the formalin injection was chosen (intraperitoneal: 15 min, intravenous: 5 min).  

The compound according to the invention according to Example 1 showed an inhibition of the formalin-induced nociception. The corresponding results in the formalin test on the mouse are summarized in Table 2 below. Gabapentin shows an ED ₅₀ of 79 mg / kg.

Table 2

Analgesia test in the formalin mouse test

6.3 Bennett Neuropathic pain in the rat

The investigation for efficacy in neuropathic pain was carried out in Bennett model (chronic constriction injury; Bennett and Xie, 1988, "Pain", 33: 87-107).

Sprague-Dawley rats weighing 140-160 g are under Nembutal anesthesia with 4 loose ligatures of the right ischiatic nerve Mistake. The animals develop on the innervated by the damaged nerve Paw a hypersensitivity after a recovery period from 1 week over about 4 weeks using a 4 ° C cold metal plate is quantified (cold allodynia). The animals are for a period of time from 2 min. observed on this plate, and the number of Pull-away reactions of the damaged paw are measured. Related to the effect before substance application is the substance effect over a Period of 1 hour at 4 times (15, 30, 45, 60 minutes after Application) and the resulting area under the curve (AUD) as well as the inhibition of the cold allodynia to the individual measuring points in Percent effect on vehicle control (AUD) or baseline  (Single measuring points). The group size is n = 10; the The significance of an anti-allodyne effect is based on the AUD values via a paired t-test (* 0.05 ≧ p <0.01; ** 0.01 ≧ p <0.001; *** p ≦ 0001; Armitage and Berry, 1987, "Stat. Methods in Medical Research", London: Blackwell Scientific-Publications).

The investigated compound according to the invention according to Example 1 showed an anti-allodyne effect. The results are compared to Gabapentin is summarized in Table 3 below.

Table 3

Examination of inhibition in neuropathic pain in the rat

Example 7 General procedure for displaying the selected Thio-amino acids

For the synthetic work are described in the literature Reactions applied Service.  

The subject of the invention is also a method for producing one of the Compounds according to the invention according to scheme 1:

Scheme 1

Deprotonation of the isocyanacetic acid ethyl ester with bases such as butyllithium, sodium hydride or potassium tert-butoxide and subsequent reaction with heptanone in tetrahydrofuran leads to ethyl (E, Z) -2-formylaminooctenoate. By reacting (E, Z) -2- formylaminooctenoic acid ethyl esters with P ₄ S ₁₀ in toluene or with mercaptans of the general formula R ₁ SH with R1, selected from benzyl, ethyl or H in the presence of butyllithium in toluene, formylamino-ethyl ester is obtained general formula 4. The reaction of the formylamino-ethyl esters of the general formula 4 with hydrochloric acid leads to the thio-amino acids of the formula 1 according to the invention with R1, selected from benzyl, ethyl or H. The diastereomers are separated at a suitable stage by means of HPLC, column chromatography or crystallization. The enantiomer separation is also carried out on the final stage by means of HPLC, column chromatography or crystallization. The amino acids according to the invention from Example 1-4 are obtained as hydrochlorides by this process. By releasing the base or reprecipitation by conventional methods, further salt forms are obtained.

Example 9 Preparation of the compounds according to one of Examples 1-4

The following examples serve to explain the inventive method.

The yields of the compounds produced are not optimized.

All temperatures are uncorrected.

Silica gel 60 was used as the stationary phase for column chromatography (0.040-0.063 mm) from E. Merck, Darmstadt.

The thin layer chromatographic investigations were carried out with HPTLC prefabricated plates, silica gel 60 F 254, from E. Merck, Darmstadt, carried out.

The mixing ratios of the solvents for all chromatographic Examinations are always given in volume / volume.

The indication ether means diethyl ether.

Unless otherwise stated, petroleum ether was used with the boiling range from 50 ° C-70 ° C.

Regulation 1

Representation of example 1

rac-2-amino-3-mercapto-3-methyl-octanoic acid hydrochloride as a threo / erythro mixture of 1: 1 (1)

1. Glycine ethyl ester hydrochloride (2)

247.3 g thionyl chloride and 130 g glycine were at -10 ° C in 1000 ml Given ethanol. After removing the ice bath there was another Equivalent glycine added in portions. The mixture was then stirred under reflux for 2 h. After cooling down The excess was at room temperature on the rotary evaporator Alcohol and the thionyl chloride removed. The white solid obtained was mixed twice with ethanol and this again on Rotary evaporator removed to completely adhere to thionyl chloride to remove. After recrystallization from ethanol, 218.6 g were obtained (90.4% of theory) of the title compound 2.

2. ethyl formylaminoacetate (3)

218 g of glycine ethyl ester hydrochloride (2) were in 1340 ml of ethyl formate suspended. 223 mg of toluenesulfonic acid were added and the mixture was heated to reflux. Now 178 g of triethylamine became the boiled solution was added dropwise, and the reaction solution was left overnight stirred under reflux. After cooling to RT, the precipitated Filtered off ammonium chloride salt; the filtrate was reduced to approx. 20% of the The original volume was concentrated and cooled to -5 ° C. That again precipitated ammonium chloride salt was filtered off; the filtrate again concentrated and distilled at 1 mbar. This gave 184 g (90.3% of theory) the title compound 3.

3. ethyl isocyanacetate (4)

50 g of ethyl formylaminoacetate (3) and 104 g of diisopropylamine were placed in 400 ml of dichloromethane and cooled to -3 ° C. Then 70.1 g of phosphoryl chloride in 400 ml of dichloromethane were added dropwise, and the mixture was then stirred at this temperature for a further hour. After the ice bath was removed and room temperature was reached, it was carefully hydrolyzed with 400 ml of 20% sodium carbonate solution. After stirring at RT for 60 minutes, 400 ml of water and then 200 ml of dichloromethane were added. The phases were separated and the organic phase was washed twice with 100 ml of 5% Na ₂ CO ₃ solution and dried over MgSO ₄ . The solvent was evaporated on a rotary evaporator and the remaining brown oil was distilled. This gave 34.16 g (79.3% of theory) of the title compound 4.

4. (E) - and (Z) -2-formylamino-3-methyloct-2-enoic acid ethyl ester (5)

A solution of 22 g of ethyl isocyanate in 49 ml of THF was added dropwise to a suspension of 23 g of potassium tert-butoxide in 148 ml of THF at -70 ° C. to -60 ° C. with stirring. The mixture was allowed to stir for 20 minutes; then 27.7 g of 2-heptanone in 24 ml of THF were added dropwise at this temperature. After warming to RT, 11.7 ml of glacial acetic acid were added. 15 min after the addition of glacial acetic acid (TLC control: ether: hexane 4: 1), the solvent was evaporated. The residue was mixed with 300 ml of diethyl ether and 200 ml of water. The organic phase was separated and the aqueous phase was washed twice with 120 ml of ether each time. The combined organic phases were washed with 80 ml of 2N NaHCO ₃ solution and dried over MgSO ₄ . The solvent was then evaporated. The crude product thus obtained was digested with 200 n-hexane. The solid was filtered off, washed four times with 80 ml of hexane each time and dried in an oil pump vacuum. This gave 34.8 g (69.9% of theory) of (E) - and (Z) -2-formylamino-3-methyloct-2-enoic acid ethyl ester (5) (E / Z ratio: 1: 1) as white solid.

5. 2-Formylamino-3-mercapto-3-methyl-octanoic acid ethyl ester as a threo / erythro mixture of 1: 1 (6)

34.8 g of (E) - and (Z) -2-formylamino-3-methyloct-2-enoic acid ethyl ester (5) (E / Z ratio: 1: 1) were dissolved in 273 ml of toluene at RT and then with 6.06 g P ₄ S ₁₀ added. The mixture was stirred with exclusion of moisture at 80 ° C. for 2 h (TLC control: ethyl acetate: hexane 1: 1). The resulting solution was then cooled to RT and the organic phase was freed from the solvent. The crude product obtained was taken up in 300 ml of diethyl ether and 5 ml of water were added. The mixture was stirred overnight. The water was separated and the organic phase was dried over MgSO ₄ and then the solvent was evaporated in vacuo. This gave 43 g of 2-formylamino-3-mercapto-3-methyl-octanoic acid ethyl ester as a threo / erythro mixture of 6: 4 (6) as a yellow oil. This was chromatographed on silica gel with diisopropyl ether containing 1% 25% ammonia. This gave 30 g (76% of theory) of 2-formylamino-3-mercapto-3-methyl-octanoic acid ethyl ester as a threo / erythro mixture of 6: 4 (6) in the form of a colorless oil.

6. rac-2-amino-3-mercapto-3-methyl-octanoic acid hydrochloride as a threo / erythro mixture of 6: 4 (1)

16.7 g of ethyl 2-formylamino-3-mercapto-3-methyl-octanoate as threo / erythro mixture of 6: 4 (6) were at RT to 606 ml of 6 N hydrochloric acid and then stirred under reflux for 24 h (TLC control: Dichloromethane: methanol: glacial acetic acid: 35: 5: 3). After cooling to RT was further stirred under ice cooling. The failed, white solid was suction filtered, washed with ether and then in vacuo dried. This gave 13.3 g (94.9% of theory) of rac-2-amino-3-mercapto-3- methyl octanoic acid hydrochloride as a threo / erythro mixture of 6: 4 (1).

Regulation 2 Representation of example 2 threo-diastereomer to Example 1 rac-threo-2-amino-3-mercapto-3-methyl-octanoic acid hydrochloride (7)

Rac-threo-2-amino-3-mercapto-3-methyl-octanoic acid was obtained Hydrochloride (7), by working analogously as in regulation 1; Parts 1, 2, 3 and 4. Changes occurred from part 5.

5. threo-2-formylamino-3-mercapto-3-methyl-octanoic acid ethyl ester (9)

34.8 g of (E) - and (Z) -2-formylamino-3-methyloct-2-enoic acid ethyl ester (5) (E / Z ratio: 1: 1) were dissolved in 273 ml of toluene at RT and then with 6.06 g P ₄ S ₁₀ added. The mixture was stirred with exclusion of moisture at 80 ° C. for 2 h (TLC control: ethyl acetate: hexane 1: 1). The resulting solution was then cooled to RT and the organic phase was freed from the solvent. The crude product obtained was taken up in 300 ml of diethyl ether and 5 ml of water were added. The mixture was stirred overnight. The water was separated and the organic phase was dried over MgSO ₄ and then the solvent was evaporated in vacuo. This gave 43 g of 2-formylamino-3-mercapto-3-methyl-octanoic acid ethyl ester as a threo / erythro mixture of 6: 4 (6) as a yellow oil. This was chromatographed on silica gel with diisopropyl ether containing 1% 25% ammonia. This gave 30 g (76% of theory) of 2-formylamino-3-mercapto-3-methyl-octanoic acid ethyl ester as a threo / erythro mixture of 6: 4 (6) in the form of a colorless oil. This mixed fraction was again chromatographed on silica gel with diisopropyl ether containing 1% 25% ammonia solution. This gave 5 g (12.7% of theory) of threo-2-formylamino-3-mercapto-3-methyl-octanoic acid ethyl ester (9) and 3.6 g (9.2% of theory) of erythro-2-formylamino-3- ethyl mercapto-3-methyl-octanoate (10).

6. rac-threo-2-amino-3-mercapto-3-methyl-octanoic acid hydrochloride (7)

5 g of ethyl threo-2-formylamino-3-mercapto-3-methyl-octanoate (9) was added to 183 ml of 6N hydrochloric acid at RT. It was then 24 h stirred under reflux (TLC control: dichloromethane: methanol: glacial acetic acid: 35: 5: 3). After cooling to RT, the mixture was cooled with ice further stirred. The precipitated, white solid was filtered off with Washed ether and then dried in vacuo. You got that 4.2 g (94.9% of theory) of rac-threo-2-amino-3-mercapto-3-methyl-octanoic acid Hydrochloride (7).

Regulation 3

Representation of example 3

rac-2-amino-3-ethylsulfanyl-3-methyl-octanoic acid hydrochloride as a threo / erythro mixture of 1: 1 (11)

The procedure is identical to that in regulation 1; Part 1; 2 and 3, 4. From part 5 there were differences.

5. Ethyl 3-ethylsulfanyl-2-formylamino-3-methyl-octanoate as a threo / erythro mixture of 1: 1 (12)

0.28 ml of butyllithium was added to 40 m absolute THF and the mixture was cooled to 0 ° C. 2.73 g of ethyl mercaptan were then added dropwise. After stirring for 20 minutes, the solution was cooled to a temperature between -40 and 0 ° C and a solution of 1 g of (E) and (Z) -2-formylamino-3-methyloct-2-enoic acid ethyl ester ( E / Z ratio: 1: 1) slowly added. The mixture was stirred at that temperature for 2 h and then warmed to 0 ° C., and the mixture was then hydrolyzed with 100 ml of a 5% sodium hydroxide solution. The phases were separated and the aqueous phase was extracted twice with 100 ml dichloromethane each time. The combined organic phases were dried over MgSO ₄ and the solvent was removed on a rotary evaporator. The mercaptan used in excess could be separated off by chromatography on silica gel with dichloromethane / diethyl ether (6: 1) as the eluent. The title compound 12 was thus obtained as a colorless oil in a yield of 1.05 g (82% of theory).

6. rac-2-amino-3-ethylsulfanyl-3-methyl-octanoic acid hydrochloride as a threo / erythro mixture of 1: 1 (11)

1.05 g of 3-ethylsulfanyl-2-formylamino-3-methyl-octanoic acid ethyl ester as threo / erythro mixture of 1: 1 were at RT to 40 ml of 6 N hydrochloric acid and then stirred under reflux for 24 h (TLC control: Dichloromethane: methanol: glacial acetic acid: 35: 5: 3). After cooling to RT was further stirred under ice cooling. The failed, white solid was suction filtered, washed with ether and then in vacuo dried. This gave 0.8 g (94.9% of theory) of rac-2-amino-3-ethylsulfanyl 3-methyl-octanoic acid hydrochloride as a threo / erythro mixture of 1: 1 (11).

Regulation 4

Representation of example 4

rac-threo-2-amino-benzylsulfanyl-methyl-octanoic acid hydrochloride (13)

The procedure is identical to that in regulation 15; Part 1, 2, 3 and 4. Differences appear from part 5.

5. ethyl threo-3-benzylsulfanyl-2-formylamino-3-methyl-octanoate (14)

0.28 ml of n-butyllithium was added to 40 ml of absolute THF and the mixture was cooled to 0 ° C. Now 5.5 g of benzyl mercaptan were added dropwise. After stirring for 20 minutes, the solution was cooled to a temperature between -40 and 0 ° C and a solution of 1 g of (E) and (Z) -2-formylamino-3-methyloct-2-enoic acid ethyl ester ( E / Z ratio: 1: 1) slowly added. The mixture was stirred at the temperature for 2 h and then warmed to 0 ° C. and was then hydrolyzed with 100 ml of a 5% sodium hydroxide solution. The phases were separated and the aqueous phase was extracted twice with 100 ml dichloromethane each time. The combined organic phases were dried over MgSO ₄ and the solvent was removed on a rotary evaporator. The mercaptan used in excess could be separated off by chromatography on silica gel with dichloromethane / diethyl ether (6: 1) as the eluent. Crystallization from pentane / ethanol (10: 1) gave the title compound 14 as a white solid in a yield of 1.51 g (98% of theory).

6. rac-threo-2-amino-benzylsulfanyl-methyl-octanoic acid hydrochloride (13)

1.51 g of threo-3-benzylsulfanyl-2-formylamino-3-methyl-octanoic acid ethyl ester (14) was added to 40 ml of 6N hydrochloric acid at RT and then stirred under reflux for 24 h (TLC control: dichloromethane: methanol: glacial acetic acid: 35: 5: 3). After cooling to RT, was under Ice cooling continued to stir. The precipitated white solid became suction filtered, washed with ether and then dried in vacuo. This gave 0.9 g (94.9% of theory) of rac-threo-2-amino-benzylsulfanyl methyl octanoic acid hydrochloride (13).

Claims (8)

1. Thioamino acid selected from the following compounds:

• rac-2-amino-3-mercapto-3-methyl-octanoic acid,
• rac-2-amino-3-ethylsulfanyl-3-methyl-octanoic acid,
• - rac-2-amino-3-benzylsulfanyl-3-methyl-octanoic acid

in the form of their racemates; Enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or of a single enantiomer or diastereomer; their bases or salts of physiologically acceptable acids. 2. thioamino acid according to claim 1, characterized in that it the threo forms of the selected compounds, especially rac-threo-2-amino-3-mercapto-3-methyl-octanoic acid or rac-threo-2-amino-3-benzylsulfanyl-3-methyl-octanoic acid is. 3. thioamino acid according to claim 1, characterized in that it the erythro forms of the selected ones Connections. 4. thioamino acid according to any one of claims 1 to 3, characterized marked that the salt is a hydrochloride. 5. Medicament containing at least one of the thioamino acids according to one of claims 1-4 and optionally additional and / or auxiliary substances.   6. Use of a thioamino acid according to one of the claims 1-4 for the manufacture of a medicament for the treatment of Pain. 7. Use of a thioamino acid according to one of the claims 1-4 for the manufacture of a medicament for the treatment of Epilepsy. 8. A process for the preparation of a thioamino acid according to any one of claims 1-4, characterized in that it proceeds according to the following scheme, wherein R1 is selected from benzyl, ethyl or H: