DE10049484A1 - 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 present invention relates to β-thio-α-amino acids, processes for their Manufacture, drugs containing these compounds and the use of Thioamino acids for the manufacture of medicinal products.

Cyclic GABA analog gabapentin is a clinically proven antiepileptic. Gabapentin also shows other interesting, medically relevant Properties, especially as an analgesic. New ones are therefore interesting Structural classes that have affinity for the gabapentin binding site. It exists for the indications mentioned further need for substances contained in their Properties Show similarities with gabapentin, for example in the analgesic effect.

The treatment of chronic and non-chronic pain conditions has in the Medicine is of great importance. There is a worldwide need for effective ones Pain therapies. The urgent need for action for a patient-friendly and goal-oriented treatment of chronic and non-chronic pain conditions, including the successful and satisfactory pain treatment for the Understanding patients is documented in the large number of knowledge scientific work in the field of applied analgesics or Basic research on nociception has appeared recently.

Classic opioids such as morphine are stronger or stronger in therapy Pain well effective. However, their use is well known Side effects e.g. B. respiratory depression, vomiting, sedation, constipation and Tolerance development limited. They are also neuropathic or  incidental pain, in particular from tumor patients, less effective.

The object of the invention was therefore to develop new structures, the affinity for gabapentin Binding site and / or corresponding physiological effects, for example with regard to analgesia.

The invention therefore relates to β-thio-α-amino acids of the general formula I,

, in which
R ¹ and R ^{2 are} each independently selected from H; C _1-10 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Aryl, C _1-10 cycloalkyl or heteroaryl, each unsubstituted or substituted one or more times; or
R1 and R2 together form a (CH ₂ ) _3-6 ring, saturated or unsaturated, substituted or unsubstituted, in which 0-2 C atoms can be replaced by S, O or NR ⁴ ,
with R ⁴ selected from: H; C _1-10 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
R _{3 is} selected from H; C _1-10 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C _3-9 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or aryl, C _3-9 cycloalkyl or heteroaryl bound via saturated or unsaturated C _1-3 alkyl, in each case unsubstituted or mono- or polysubstituted;
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 and / or physiologically compatible acidic and basic salts.

The substances according to the invention bind to the gabapentin binding site and show a pronounced analgesic effect.

Compounds of general formula I are not part of this invention if
R ¹ and R ^{2 are} simultaneously H or R ¹ and R ^{2 are} simultaneously CH ₃ and R ³ corresponds to hydrogen.

For the purposes of this invention, alkyl or cycloalkyl radicals are taken to mean saturated and unsaturated, branched, unbranched and cyclic hydrocarbons, which can also be substituted at least once. With regard to cycloalkyl, the term also includes cycloalkyls in which one or two carbon atoms have been replaced by a hetero atom, S, N or O. The alkyl or cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, Pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, CHF ₂ , CF ₃ or CH ₂ OH.

In connection with alkyl and cycloalkyl, the term substituted in the sense of this invention means the substitution of a hydrogen radical by F, Cl, Br, I, NH ₂ , SH or OH, where “multiply substituted” radicals are understood to mean that the substitution is carried out both on different and on the same atom several times with the same or different substituents, for example three times on the same C atom as in the case of CF ₃ or at different points as in the case of -CH (OH) -CH = CH- CHCl ₂ . Particularly preferred substituents here are F, Cl and hydroxy.

An aryl residue is understood to mean phenyl or naphthyl residues, which also can be substituted at least once. The phenyl radicals can also with other rings are condensed.

A heteroaryl radical contains 5- or 6-membered unsaturated, optionally provided with a fused-on aryl system, heterocyclic Compounds understood that one or more heteroatoms from the group of Contain nitrogen, oxygen and / or sulfur and also one or more times can be substituted. Examples from the group of heteroaryls furan, Benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, quinoline, Isoquinoline, phthalazine and quinazoline listed.

In connection with aryl and heteroaryl, this is understood to mean the substitution of aryl or heteroaryl with OR ²² , a halogen, preferably F and / or Cl, a CF ₃ , a CN, a NO ₂ , an NR ²³ R ²⁴ , a C. _1-6 alkyl (saturated), a C _1-6 alkoxy, a C _3-8 cycloalkoxy, a C _3-8 cycloalkyl or a C _2-6 alkylene.

The radical R ^{22 here stands} for H, a C _1-10 alkyl, preferably a C _1-6 alkyl, an unsubstituted aryl, an unsubstituted heteroaryl or for a via a C _1-3 alkylene group bound unsubstituted aryl or heteroaryl radical, the radicals R ²³ and R ²⁴ , identical or different, for H, a C _1-10 alkyl, preferably a C _1-6 alkyl, an unsubstituted aryl, an unsubstituted Heteroaryl or an unsubstituted aryl or heteroaryl radical bonded via a C _1-3 alkylene group,
or the radicals R ²³ and R ²⁴ together mean CH ₂ CH ₂ OCH ₂ CH ₂ , CH ₂ CH ₂ NR ²⁵ CH ₂ CH ₂ or (CH ₂ ) _3-6 , and
the radical R ²⁵ stands for H, a C _1-10 alkyl, preferably a C _1-6 alkyl, an unsubstituted aryl, an unsubstituted heteroaryl or for a bond via a C _1-3 alkylene group unsubstituted aryl or heteroaryl radical.

For the purposes of this invention, the term “physiologically tolerated acid salt” means salts of the respective active ingredient with inorganic or organic acids that are physiologically tolerated — in particular when used in humans and / or mammals. The hydrochloride is particularly preferred. Examples of physiologically acceptable acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro1λ ⁶ - benzo [ d] isothiazol-3-one (saccharic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, α-lipoic acid , Acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid. In the case of basic salts, a salt with a metal ion, e.g. E.g .: Alkali or alkaline earth ion formed.

In one embodiment of the invention, the thioamino acids of the formula I according to the invention
R ¹ and R ^{2 are} each independently selected from H; C _1-10 - alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; preferably one of the radicals R ¹ and R ^{2 is} C _1-2 alkyl and the other C _2-10 alkyl, preferably unsubstituted, unbranched and saturated, or
R1 and R2 together form cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.

In a further embodiment of the invention, the thioamino acids of the formula I according to the invention
R ₃ selected from H; C _1-6 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Phenyl, unsubstituted or mono- or polysubstituted; or via saturated or unsaturated CH ₃ -bound phenyl, unsubstituted or mono- or polysubstituted;
, where R3 is preferably H.

In a preferred embodiment of the invention, the thioamino acids according to the invention are selected from the following group:

• - 2-amino-3-mercapto-3-methyl-pentanoic acid
• - 2-amino-3-mercapto-3-methyl-hexanoic acid
• - 2-amino-3-mercapto-3-methyl-heptanoic acid
• - 2-amino-3-mercapto-3-methyl-octanoic acid
• - 2-amino-3-mercapto-3-methyl-nonanoic acid
• - 2-amino-3-mercapto-3-methyl-decanoic acid
• - 2-amino-3-ethyl-3-mercapto-pentanoic acid
• - amino- (1-mercapto-cyclopentyl) acetic acid
• - amino-3-ethyl-3-mercapto-hexanoic acid
• - 2-amino-3-mercapto-3-methyl-decanoic acid
• - 2-amino-3-mercapto-3-methyl-nonanoic acid  
• - 2-amino-3-mercapto-3-methyl-octanoic acid
• - 2-amino-3-ethylsulfanyl-3-methyl-octanoic acid
• - 2-amino-3-benzylsulfanyl-3-methyl-octanoic acid
• - 2-amino-3-mercapto-3-propyl-3-hexanoic acid
• - amino- (1-mercapto-cycloheptyl) acetic 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 and / or physiologically compatible acidic and basic salts.

The substances according to the invention are toxicologically harmless, so that they are suitable as active pharmaceutical ingredients in pharmaceuticals. Another The invention therefore relates to medicaments containing at least one thioamino acid according to the invention and, if appropriate, suitable additional and / or auxiliary substances and / or optionally further active substances.

The pharmaceuticals according to the invention contain at least one Substituted thioamino acid according to the invention optionally suitable Additives and / or auxiliaries, including 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, patches or aerosols can be administered. The selection of excipients etc. and the amounts to be used depend on whether the Oral, oral, parenteral, intravenous, intraperitoneal, intradermal, intramuscularly, intranasally, buccally, rectally or locally, for example on the skin that Mucous membranes or in the eyes. For oral application preparations in the form of tablets, coated tablets, capsules, granules, Drops, juices and syrups for parenteral, topical and inhalation application Solutions, suspensions, easily reconstitutable dry preparations as well Sprays. Thioamino acids according to the invention in a depot, in dissolved form or in a plaster, if necessary with the addition of skin penetration promoting  Appropriate percutaneous application preparations. Oral or percutaneous The thioamino acids according to the invention can be used as preparation forms release with delay. In principle, the pharmaceuticals according to the invention other active ingredients known to the person skilled in the art can be added.

The amount of active ingredient to be administered to the patient varies depending on on the weight of the patient, on the type of application, the indication and the Severity of the disease. Usually 0.005 to 1000 mg / kg, preferably 0.05 to 5 mg / kg of at least one thioamino acid according to the invention applied.

In a preferred form of the medicament there is an inventive one Thioamino acid as a pure diastereomer and / or enantiomer, as a racemate or as non-equimolar or equimolar mixture of the diastereomers and / or Enantiomers.

Gabapentin is a well-known antiepileptic with an anticonvulsant effect. Next this is used by gabapentin in various other indications, among other things by doctors treating migraines and bipolar disorders as well as hot flashes (e.g. during postmenopause) (M. Schrope, Modern Drug Discovery, September 2000, p. 11). Other indications in which Gabapentin has shown therapeutic potential during human studies and identified in clinical use (J. S. Bryans, D. J. Wustrow; "3-Substituted GABA Analogs with Central Nervous System Activity: A Review "in Med. Res. Rev. (1999), pp. 149-177). This review article details the effects of Gabapentin listed. So gabapentin is more effective in treating chronic Pain and behavioral disorders. In particular, the following are listed: anticonvulsants and anti-epileptic effects, the use against chronic, neuropathic Pain, especially thermal hyperalgesia, mechanical allodynia, cold Allodynia. It also acts against nerve damage Neuropathy, especially neuropathic pain, as well inflammatory and postoperative pain successful. Gabapentin is too successful with antipsychotic effects, especially as an anxiolytic. Further  verified indications include: amyotropic lateral sclerosis (ALS), reflex Sympasthetic Dystrophy (RSD), Spastic Paralysis, Restless Leg Syndrome, Treatment of symptoms and pain due to multiple sclerosis, acquired nystagmus, treatment of symptoms of Parkinson's disease, painful diabetic neuropathy and psychiatric disorders, e.g. B. bipolar disorders, mood swings, manic behavior. Further Gabapentin was successfully used for erythromelalgic pain, postpoliomyelitis pain, trigeminal neuralgia and postherpetic neuralgia (Bryans and Wustrow (1999), op. Cit.). Well known and also the one mentioned The general article can also be seen from the examples Efficacy in neurodegenerative diseases. Such neurodegeneratives Diseases are e.g. B. Alzheimer's disease, Huntington's disease, Parkinson's disease and epilepsy. The effectiveness of gabapentin is also known gastrointestinal damage.

All substances according to the invention displace gabapentin from its - also in the hitherto unknown of science - binding site. But that implies that the substances according to the invention bind at the same binding site and they will have a physiological effect, presumably with the same effect profile like gabapentin. That this assumption has the same effect with the same Binding site also applies, is proven by the analgesic effect. So The compounds according to the invention not only displace gabapentin from its Binding site but also - like gabapentin - have a clearly analgesic effect.

Another object of the invention is therefore the use of a Thioamino acid according to the invention for the manufacture of a medicament for Treatment of pain, especially neuropathic, chronic or acute pain, epilepsy and / or migraine.

The substances according to the invention are also particularly suitable for treatment with symptoms related to neuropathic pain but also other related symptoms Indications can be used. Another object of the invention is therefore Use of a thioamino acid according to the invention for the preparation of a  Medicament for the treatment of hyperalgesia and allodynia, in particular thermal hyperalgesia, mechanical hyperalgesia and allodynia and cold Allodynia, or inflammatory or postoperative pain.

The compounds according to the invention are also in other indications used. Another object of the invention is therefore the use of a Thioamino acid according to the invention for the manufacture of a medicament for Treatment of hot flashes, postmenopausal symptoms, Amyotropic Lateral Sclerosis (ALS), Reflex Sympasthetic Dystrophy (RSD), Spastic paralysis, restless leg syndrome, acquired nystagmus; psychiatric or neuropathological disorders, such as bipolar disorders, Anxiety, panic attacks, mood swings, manic behavior, Depression, manic-depressive behavior; painful diabetic Neuropathy, symptoms and pain due to multiple sclerosis or Parkinson's disease, neurodegenerative diseases, such as disease Alzheimer's, Huntington's disease, Parkinson's disease and epilepsy; gastrointestinal Damage; of erythromelalgic or postpoliomyelitic pain, trigeminal or post-herpetic neuralgia; or as an anticonvulsant, analgesic or anxiolytic.

It may be preferred if a thioamino acid used is used according to a of claims 1 to 11, as a pure diastereomer and / or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and / or Enantiomer is present.

Another object of the invention is a method for treating a non-human mammal or human, the one or the one treatment medically relevant symptoms required by administering a therapeutic Wiksamen dose of a thioamino acid according to the invention, or one drug according to the invention. The invention relates in particular corresponding methods for the treatment of pain, in particular of neuropathic, chronic or acute pain; Migraines, hyperalgesia and Allodynia, especially thermal hyperalgesia, mechanical hyperalgesia and  Allodynia and cold allodynia, or of inflammatory or postoperative Pain; Epilepsy, hot flashes, postmenopausal symptoms, Amyotropic Lateral Sclerosis (ALS), Reflex Sympasthetic Dystrophy (RSD), Spastic paralysis, restless leg syndrome, acquired nystagmus; psychiatric or neuropathological disorders, such as bipolar disorders, Anxiety, panic attacks, mood swings, manic behavior, Depression, manic-depressive behavior; painful diabetic Neuropathy, symptoms and pain due to multiple sclerosis or Parkinson's disease, neurodegenerative diseases such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease and Epilepsy; of erythromelalgic or postpoliomyelitic pain, trigeminal or post-herpetic neuralgia

Another object of the invention is a method for producing a Thioamino acid according to the invention in a form as described below.

General procedure for the preparation of the substituted β-thio α-amino acids

The reactions described in the literature are for synthetic work applied, as well as in-house experience.

The subject of the invention is also a method for producing a connection of the Formula 1 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 ketones of the general formula 2 in tetrahydrofuran leads to (E, Z) -2-formylaminoacrylic acid ethyl esters of the general formula 3. By reacting (E, Z) -2-formylaminoacrylic acid ethyl esters of the general formula 3 with P ₄ S ₁₀ in toluene or with mercaptans of the general formula R ₃ SH in the presence of butyllithium in toluene, formylamino-ethyl esters of the general formula 4 are obtained. Reaction of the formylamino-ethyl ester of the general formula 4 with hydrochloric acid leads to the thio-amino acids of the general formula 1. 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 of the general formula 1 are obtained as hydrochlorides by this process. By releasing the base or reprecipitation by conventional methods, further salt forms are obtained.

salt formation

The compounds of formula I can be combined with physiologically acceptable acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2 -dihydro1λ ⁶ -benzo [d] isothiazol-3-one (saccharic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl -benzoic acid, α-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid, convert into their salts in a known manner. Salt formation is preferably carried out in a solvent, for example diethyl ether, diisopropyl ether, alkyl acetate, acetone and / or 2-butanone or else water. Trimethylchlorosilane in aqueous solution is also suitable for the preparation of the hydrochlorides. It is also possible to convert them into basic salts using metal ions, e.g. E.g .: alkali and alkaline earth ions.

In the following the invention is further illustrated by examples, without being directed thereto restrict.

Examples

The following examples show compounds according to the invention and their Presentation and effectiveness studies carried out with these.

The following information generally applies:
The chemicals and solvents used were purchased commercially from conventional suppliers (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCl etc. or synthesized).

The analysis was carried out using ESI mass spectrometry or HPLC.

Synthesized examples

Representative examples of the above claim are:  

1)

rac-2-amino-3-mercapto-3-methyl-pentanoic acid hydrochloride as threo / erythro- Mixture of 7: 3

2)

rac-2-amino-3-mercapto-3-methyl-hexanoic acid hydrochloride as threo / erythro- Mixture of 7: 3

3)

rac-2-amino-3mercapto-3-methyl-heptanoic acid hydrochloride as threo / erythro- Mixture of 6: 4

4)

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

5)

rac-2-amino-3mercapto-3-methyl-nonanoic acid hydrochloride as threo / erythro- Mixture of 6: 4

6)

rac-2-amino-3mercapto-3-methyl-decanoic acid hydrochloride as threo / erythro- Mixture of 6: 4

7)

rac-2-amino-3-ethyl-3-mercapto-pentanoic acid hydrochloride

8th)

rac-amino- (1-mercapto-cyclopentyl) acetic acid hydrochloride

9)

rac-Amino-3-ethyl-3-mercaptohexanoic acid hydrochloride as a threo / erythro mixture of 1: 1

10)

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

11)

rac-erythro-2-amino-3-mercapto-3-methyl-decanoic acid hydrochloride

12)

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

13)

rac-erythro-2-amino-3-mercapto-3-methyl-nonanoic acid hydrochloride

14)

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

15)

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

16)

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

17)

rac-2-amino-3-mercapto-3-propyl-3-hexanoic acid hydrochloride

18)

rac-amino- (1-mercapto-cycloheptyl) acetic acid hydrochloride

method

The following examples serve to explain the invention in more detail Process.

The yields of the compounds produced are not optimized.

All temperatures are uncorrected.

As a stationary phase for column chromatography, silica gel 60 (0.040- 0.063 mm) from E. Merck, Darmstadt.  

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

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 with a boiling range of 50 ° C. 70 ° C used.

Regulation 1

Representation of example 6

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

1. Glycine ethyl ester hydrochloride (2)

247.3 g of thionyl chloride and 130 g of glycine were at -10 ° C in 1000 ml of ethanol given. After removing the ice bath, another equivalent of glycine added in portions. The mixture was then refluxed for 2 hours touched. After cooling to room temperature, the excess alcohol and the thionyl chloride removed. The preserved white Solid was mixed twice with ethanol and this again on Rotary evaporator removed to completely remove adhering thionyl chloride remove. After recrystallization from ethanol, 218.6 g (90.4% of theory) of Title link 2.

2. ethyl formylaminoacetate (3)

218 g of glycine ethyl ester hydrochloride (2) was suspended in 1340 ml of ethyl formate. 223 mg of toluenesulfonic acid were added and the mixture became reflux heated. Now 178 g of triethylamine were added dropwise to the boiling solution and the Reaction solution was stirred under reflux overnight. After cooling to RT the precipitated ammonium chloride salt was filtered off, the filtrate was brought to approx. Concentrated 20% of the original volume and cooled to -5 ° C. That again precipitated ammonium chloride salt was filtered off, the filtrate was concentrated again and distilled at 1 mbar. This gave 184 g (90.3% of theory) of 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 for a further hour at this temperature. 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. 34.16 g (79.3% of theory) of the title compound 4 are thus obtained.

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

A solution of 22 g of isocyanacetic acid ethyl ester 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. while stirring. The mixture was allowed to stir for 20 minutes; then 27.7 g of 2-nonanone 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 rocked 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-methyldec-2-enoic acid ethyl ester (5) (E / Z ratio: 1: 1) as white solid.

5. 2-Formylamino-3-mercapto-3-methyl-decanoic acid ethyl ester as a threo / erythro mixture of 6: 4 (6)

34.8 g of (E) - and (Z) -2-formylamino-3-methyldec-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 decanoic 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-decanoic acid ethyl ester as a threo / erythro mixture of 6: 4 (6) in the form of a colorless oil.

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

16.7 g of ethyl 2-formylamino-3-mercapto-3-methyl-decanoate as threo / erythro- Mixture of 6: 4 (6) was added at RT to 606 ml of 6N hydrochloric acid and then stirred under reflux for 24 h (TLC control: dichloromethane: methanol: glacial acetic acid: 35: 5: 3). After cooling to RT, stirring was continued with ice cooling. The precipitated white solid was filtered off, washed with ether and then dried in vacuo. This gave 13.3 g (94.9% of theory) of rac-2- Amino-3mercapto-3-methyl-decanoic acid hydrochloride as a threo / erythro mixture of 6: 4 (1).

Regulation 2 Representation of example 10 and Representation of example 11 rac-threo-2-amino-3-mercapto-3-methyl-decanoic acid hydrochloride (7) and rac- erythro-2-amino-3-mercapto-3-methyl-decanoic acid hydrochloride (8)

Rac-threo-2-amino-3-mercapto-3-methyl-decanoic acid hydrochloride was obtained (7) or erythro-2-amino-3-mercapto-3-methyl-decanoic acid hydrochloride (8), by working analogously to regulation 1; Parts 1, 2, 3 and 4. Changes occurred from part 5 on.

5. threo-2-formylamino-3-mercapto-3-methyl-decanoic acid ethyl ester (9) and erythro-2-formylamino-3-mercapto-3-methyl-decanoic acid ethyl ester (10)

34.8 g of (E) - and (Z) -2-formylamino-3-methyldec-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-decanoic 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-decanoic 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-decanoic acid ethyl ester (9) and 3.6 g (9.2% of theory) of erythro-2-formylamino-3- ethyl mercapto-3-methyl-decanoate (10).

6. rac-threo-2-amino-3-mercapto-3-methyl-decanoic acid hydrochloride (7) and rac-erythro-2-amino-3-mercapto-3-methyl-decanoic acid hydrochloride (8)

5 g of threo-2-formylamino-3-mercapto-3-methyl-decanoic acid ethyl ester (9) was added to RT added to 183 ml of 6 N hydrochloric acid or 3.6 g of erythro-2-formylamino-3-mercapto- Ethyl 3-methyl-decanoate (10) was added to 132 ml of 6 N hydrochloric acid at RT. The rest of the procedure was identical. It was then under 24 h Reflux stirred (TLC control: dichloromethane: methanol: glacial acetic acid: 35: 5: 3). After cooling to RT, stirring was continued with ice cooling. The fancy white solid was filtered off, washed with ether and then in Vacuum dried. This gave 4.2 g (94.9% of theory) of rac-threo-2-amino-3- mercapto-3-methyl-decanoic acid hydrochloride (7) or 3 g (94.9% of theory) rac-erythro- 2-Amino-3-mercapto-3-methyl-decanoic acid hydrochloride (8).  

Regulation 3

Representation of example 1

rac-2-amino-3-mercapto-3-methyl-pentanoic acid hydrochloride as a threo / erythro mixture of 7: 3 (11)

By using 2-butanone instead of 2-nonanone in procedure 1, rac- 2-Amino-3-mercapto-3-methyl-pentanoic acid hydrochloride as a threo / erythro mixture from 7: 3 (11).

Regulation 4

Representation of example 2

rac-2-amino-3-mercapto-3-methyl-hexanoic acid hydrochloride as a threo / erythro mixture of 7: 3 (12)

By using 2-pentanone instead of 2-nonanone in regulation 1, one obtained rac-2-amino-3-mercapto-3-methyl-hexanoic acid hydrochloride as threo / erythro- Mixture of 7: 3 (12)

Regulation 5

Representation of example 3

rac-2-amino-3mercapto-3-methyl-heptanoic acid hydrochloride as a threo / erythro mixture of 6: 4 (13)

By using 2-hexanone instead of 2-nonanone in procedure 1, one obtained rac-2-amino-3-mercapto-3-methyl-heptanoic acid hydrochloride as threo / erythro- Mixture of 6: 4 (13)

Regulation 6

Representation of example 4

rac-2-amino-3mercapto-3-methyl-octanoic acid hydrochloride as a threo / erythro mixture of 1: 1 (14)

By using 2-heptanone instead of 2-nonanone in procedure 1, one obtained rac-2-amino-3mercapto-3-methyl-octanoic acid hydrochloride as threo / erythro- Mixture of 1: 1 (14)

Regulation 7 Representation of example 14 rac-threo-2-amino-3mercapto-3-methyl-octanoic acid hydrochloride (15)

By using 2-heptanone instead of 2-nonanone in protocol 2, one obtained rac-threo-2-amino-3mercapto-3-methyl-octanoic acid hydrochloride (15)  

Regulation 8

Representation of example 5

rac-2-amino-3mercapto-3-methyl-nonanoic acid hydrochloride as a threo / erythro mixture of 6: 4 (16)

By using 2-octanone instead of 2-nonanone in regulation 1, one obtained rac-2-amino-3mercapto-3-methyl-nonanoic acid hydrochloride as threo / erythro- Mixture of 6: 4 (16).

Regulation 9 Representation of example 12 and example 13 rac-threo-2-amino-3-mercapto-3-methyl-nonanoic acid hydrochloride (17) and rac- erythro-2-amino-3-mercapto-3-methyl-nonanoic acid hydrochloride (18)

By using 2-octanone instead of 2-nonanone in regulation 2, one obtained rac-threo-2-amino-3-mercapto-3-methyl-nonanoic acid hydrochloride (17) and rac- erythro-2-amino-3-mercapto-3-methyl-nonanoic acid hydrochloride (18).

Regulation 10

Representation of example 7

rac-2-amino-3-ethyl-3-mercapto-pentanoic acid hydrochloride (19)

By using 3-pentanone instead of 2-nonanone in regulation 1, one obtained rac-2-amino-3-ethyl-3-mercapto-pentanoic acid hydrochloride (19).

Regulation 11

Representation of example 8

rac-amino- (1-mercapto-cyclopentyl) acetic acid hydrochloride (20)

By using cyclopentanone of 2-nonanone in procedure 1, rac- Amino- (1-mercapto-cyclopentyl) acetic acid hydrochloride (20).

Regulation 12

Representation of example 9

rac-Amino-3-ethyl-3-mercaptohexanoic acid hydrochloride as a threo / erythro mixture of 1: 1 (21)

By using 3-hexanone instead of 2-nonanone in procedure 1, one obtained rac-Amino-3-ethyl-3-mercaptohexanoic acid hydrochloride as a threo / erythro mixture of 1: 1 (21).  

Regulation 13

Representation of example 17

rac-2-amino-3-mercapto-3-propyl-3-hexanoic acid hydrochloride (22)

By using 4-heptanone instead of 2-nonanone in procedure 1, one obtained rac-2-amino-3-mercapto-3-propyl-3-hexanoic acid hydrochloride (22).

Regulation 14

Representation of example 18

rac-amino- (1-mercapto-cycloheptyl) acetic acid hydrochloride (23)

Obtained by using cycloheptanone instead of 2-nonanone in regulation 1 rac-amino- (1-mercapto-cycloheptyl) acetic acid hydrochloride (23).

Regulation 15

Representation of example 15

rac-2-amino-3-ethylsulfanyl-3-methyl-octanoic acid hydrochloride as a threo / erythro mixture of 1: 1 (24)

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

4. (E) and (Z) -2-formylamino-3-methyl-oct-2-enoic acid ethyl ester (25)

A solution of 22 g of isocyanacetic acid ethyl ester 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. while 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 rocked 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-methyldec-2-enoic acid ethyl ester (5) (E / Z ratio: 1: 1) as white solid.

5. 3-ethylsulfanyl-2-formylamino-3-methyl-octanoic acid ethyl ester as a threo / erythro mixture of 1: 1 (26)

0.28 ml of butyllithium was added to 40 ml of 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 the temperature for 2 h and then warmed to 0 ° C. and then was 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 26 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 (24)

1.05 g of 3-ethylsulfanyl-2-formylamino-3-methyl-octanoic acid ethyl ester as threo / erythro mixture of 1: 1 (26) were added to 40 ml of 6 N 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, the mixture was cooled with ice further stirred. The precipitated white solid was filtered off with ether washed and then dried in vacuo. This gave 0.8 g (94.9% d. Th.) Rac-2-amino-3-ethylsulfanyl-3-methyl-octanoic acid hydrochloride as threo / erythro mixture of 1: 1 (24).

Regulation 16

Representation of example 16

rac-threo-2-amino-benzylsulfanyl-methyl-octanoic acid hydrochloride (27)

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

5. threo-3-benzylsulfanyl-2-formylamino-3-methyl-octaic acid ethyl ester (28)

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 then was 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 28 as a white solid in a yield of 1.51 g (98% of theory).

6. rac-threo-2-amino-benzylsulfanyl-methyl-octanoic acid hydrochloride (27)

1.51 g ethyl threo-3-benzylsulfanyl-2-formylamino-3-methyl-octanoate (28) were added at RT to 40 ml of 6N hydrochloric acid and then for 24 h Reflux stirred (TLC control: dichloromethane: methanol: glacial acetic acid: 35: 5: 3). After cooling to RT, stirring was continued with ice cooling. The fancy white solid was filtered off, washed with ether and then in Vacuum dried. This gave 0.9 g (94.9% of theory) of rac-threo-2-amino benzylsulfanyl methyl octanoic acid hydrochloride (27).

Pharmacological examinations binding assay

In the binding assay, gabapentin is used to determine the binding and affinities of the check selected connections. The affinity of the invention Connections are made by displacing gabapentin from its binding site measured. If the selected compounds gabapentin from its Can displace binding site, it can be expected that the gabapentin comparable pharmacological properties develop z. B. as an agent against Pain or epilepsy. The compounds according to the invention show a good one Inhibition / displacement of gabapentin in this assay. The examined Compounds therefore have an affinity for this biochemical assay previously unknown gabapentin binding site.  

Analgesia test in the writhing test on the mouse

The antinociceptive activity of the compounds according to the invention was in the Phenylquinone-induced writhing test, modified from I.C. Hendershot, J. Forsaith, J. Pharmacol. Exp. Ther. 125, 237-240 (1959) on the mouse. Male NMRI mice weighing 25-30 g were used for this. Groups of 10 animals per substance dose were administered 10 minutes after intravenous Administration of a 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 in Water bath at 45 ° C) applied intraperitoneally. The animals were singled in Observation cages set. The number of Pain-induced stretching movements (so-called writhing reactions) Pushing through the body with stretching the hind limbs) 5-20 minutes counted after administration of phenylquinone. Animals were carried as a control physiological saline i. v. and phenyylquinone 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]

All investigated compounds according to the invention showed an effect in Writhing test.

The results of selected writhing tests are summarized in Table 1. Gabapentin shows an ED ₅₀ of 38 mg / kg.

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 tested in the formalin test on male albino Mice (NMRI, 25-35 g, Iffa Credo, Belgium) performed.

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) distinguished (D. Dubuisson er al. Pain, Vol. 4, pp. 161-174 (1977)). The early one Phase provides a model for, in direct response to formalin injection Acute pain presents during the late phase as a 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 the 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) the dorsal side of the right hind paw was moved freely Experimental animals induced a nociceptive response that resulted in marked licking and biting the affected paw.

For the investigation period in the second (late) phase of the formalin test the nociceptive behavior was continuously recorded by observing the animals. Pain behavior was quantified by summing the Seconds in which the animals lick and bite during the study period affected paw showed. After injection of substances in the formalin test antinociceptive effects are the behavior of the animals described reduced, possibly even canceled. According to the substance tests in which the animals had been injected with the test substance before formalin Control vehicle, d. H. Solvent (e.g. 0.9% NaCl solution) before Formalin application sprayed. Animal behavior after administration of substance (n = 10 per substance dose) was compared with a control group (n = 10).

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 selected (intraperitoneal: 15 min, intravenous: 5 min).

The compounds of the invention showed inhibition by formalin induced nociception. The corresponding results in the formalin test at the Mouse are summarized in Table 2 below. Gabapentin shows one ED50 of 79 mg / kg

Table 2

Analgesia test in the formalin test mouse

6.3 Bennett Neuropathic pain in the rat

The investigation of efficacy in neuropathic pain was carried out in the Bennett Model (chronic constriction injury; Bennett and Xie, 1988, Pain 33: 87-107) examined.

Sprague-Dawley rats weighing 140-160 g are treated with nembutal Anesthesia is provided with four loose ligatures of the right ischiatic nerve. The animals develop a on the paw innervated by the damaged nerve Hypersensitivity that occurs after a recovery period of about a week is quantified for four weeks using a 4 ° C cold metal plate (cold allodynia). The animals are kept for a period of 2 min. observed on this plate and the The number of pull-away reactions of the damaged paw is measured. Related to the pre-value before substance application is the substance effect over a period of time determined from one hour at four points in time (15, 30, 45, 60 min. 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 for vehicle control (AUD) or to the initial value (single measuring points). The group size is n = 10, the significance of an anti-allodynic effect is based on the AUD values via a paired t-test (* 0.05 ≧ p <0.01; ** 0.01 ≧ p <0.001; *** p ≦ 0.001; Armitage and Berry, 1987, stat. Methods in Medical Research, London: Blackwell Scientific Publications).

The investigated compounds according to the invention showed an anti-allodynic Effect. The results are compared to gabapentin in the following Table 3 summarized.

Table 3

Examination of inhibition in neuropathic pain in the rat

Claims (10)

1. Use of a thioamino acid of the general formula I,
, in which
R ¹ and R ^{2 are} each independently selected from H; C _1-10 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Aryl, C _1-10 cycloalkyl or heteroaryl, each unsubstituted or substituted one or more times; or
R1 and R2 together form a (CH ₂ ) _3-6 ring, saturated or unsaturated, substituted or unsubstituted, in which 0-2 C atoms can be replaced by S, O or NR ⁴ ,
with R ⁴ selected from: H; C _1-10 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
R _{3 is} selected from H; C _1-10 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C _3-9 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or aryl, C _3-9 cycloalkyl or heteroaryl bound via saturated or unsaturated C _1-3 alkyl, in each case unsubstituted or mono- or polysubstituted; with the exception of compounds in which R1 and R2 are simultaneously H or R ¹ and R ^{2 are} simultaneously CH ₃ and R3 corresponds to hydrogen;
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 and / or physiologically compatible acidic and basic salts
with the exception of compounds in which R1 and R2 are simultaneously H or R ¹ and R ^{2 are} simultaneously CH ₃ and R3 corresponds to hydrogen;
for the manufacture of a medicament for the treatment of pain, in particular acute, neuropathic or chronic pain, epilepsy and / or migraine. 2. β-thio-α-amino acids of the general formula I,
, in which
R ¹ and R ^{2 are} each independently selected from H; C _1-10 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Aryl, C _1-10 cycloalkyl or heteroaryl, each unsubstituted or substituted one or more times; or
R1 and R2 together form a (CH ₂ ) _3-6 ring, saturated or unsaturated, substituted or unsubstituted, in which 0-2 C atoms can be replaced by S, O or NR ⁴ ,
with R ⁴ selected from: H; C _1-10 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
R _{3 is} selected from H; C _1-10 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C _3-9 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or aryl, C _3-9 cycloalkyl or heteroaryl bound via saturated or unsaturated C _1-3 alkyl, in each case unsubstituted or mono- or polysubstituted;
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 and / or physiologically acceptable acidic and basic salts;
with the exception of compounds in which R ¹ and R ^{2 are} simultaneously H or R ¹ and R ^{2 are} simultaneously CH ₃ and R ³ corresponds to hydrogen. 3. Thioamino acids according to claim 2, characterized in that
R ¹ and R ^{2 are} each independently selected from H; C _1-10 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; preferably one of the radicals R ¹ and R ^{2 is} C _1-2 alkyl and the other C _2-10 alkyl, preferably unsubstituted, unbranched and saturated, or
R1 and R2 together form cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl. 4. thioamino acids according to one of claims 2 or 3, characterized in that
R _{3 is} selected from H; C _1-6 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Phenyl, unsubstituted or mono- or polysubstituted; or via saturated or unsaturated CH ₃ -bound phenyl, unsubstituted or mono- or polysubstituted;
preferably R ³ H. 5. thioamino acids according to one of claims 2 to 4, characterized in that they are selected from the following group:

• - 2-Amino-3-mercapto-3-methyl-pentanoic acid
• - 2-Amino-3-mercapto-3-methyl-hexanoic acid
• - 2-Amino-3-mercapto-3-methyl-heptanoic acid
• - 2-Amino-3-mercapto-3-methyl-octanoic acid
• - 2-Amino-3-mercapto-3-methyl-nonanoic acid
• - 2-Amino-3-mercapto-3-methyl-decanoic acid
• - 2-Amino-3-ethyl-3-mercapto-pentanoic acid
• - Amino- (1-mercapto-cyclopentyl) acetic acid
• - Amino-3-ethyl-3-mercapto-hexanoic acid
• - 2-Amino-3-mercapto-3-methyl-decanoic acid
• - 2-Amino-3-mercapto-3-methyl-nonanoic acid
• - 2-Amino-3-mercapto-3-methyl-octanoic acid
• - 2-Amino-3-ethylsulfanyl-3-methyl-octanoic acid
• - 2-Amino-3-benzylsulfanyl-3-methyl-octanoic acid
• - 2-Amino-3-mercapto-3-propyl-3-hexanoic acid
• - Amino- (1-mercapto-cycloheptyl) acetic 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 and / or and / or physiologically compatible acidic and basic salts. 6. Medicament containing at least one thioamino acid according to one of the Claims 2 to 5, and optionally suitable additives and / or auxiliaries and / or optionally further active ingredients. 7. Medicament according to claim 6, characterized in that a contained Thioamino acid according to one of claims 2 to 5, as a pure diastereomer and / or enantiomer, as racemate or as non-equimolar or equimolar Mixture of the diastereomers and / or enantiomers is present. 8. Use of a thioamino acid according to one of claims 2 to 5 for Manufacture of a medicament for the treatment of hyperalgesia and allodynia, especially thermal hyperalgesia, mechanical hyperalgesia and Allodynia and cold allodynia, or of inflammatory or postoperative Pain. 9. Use of a thioamino acid according to one of claims 2 to 5 for Manufacture of a medicinal product for the treatment of hot flashes, Postmenopausal complaints, amyotropic lateral sclerosis (ALS), Reflex Sympasthetic Dystrophy (RSD), Spastic Paralysis, Restless Leg Syndrome, acquired nystagmus; psychiatric or neuropathological Disorders such as bipolar disorders, anxiety, panic attacks, Mood swings, manic behavior, depression, manic depressed behavior; painful diabetic neuropathy, symptoms and pain due to multiple sclerosis or Parkinson's Disease, neurodegenerative diseases, such as Alzheimer's disease, disease Huntington's, Parkinson's disease and epilepsy; gastrointestinal damage; of erythromelalgic or postpoliomyelitic pain, trigeminal or  post-herpetic neuralgia; or as an anticonvulsant, analgesic or Anxiolytic. 10. Use according to one of claims 1, 8 or 9, characterized in that that a thioamino acid used according to any one of claims 2 to 5, as pure diastereomer and / or enantiomer, as a racemate or as a non- equimolar or equimolar mixture of the diastereomers and / or enantiomers is present.