WO2004022542A2 - Substituted 1,2,3,4-tetrahydroquinoline derivatives - Google Patents

Abstract

The invention relates to substituted 1,2,3,4-tetrahydroquinoline derivatives, to methods for the production thereof, to their use for producing medicaments, and to medicaments containing these compounds.

Description

 Patent application of Grünenthal GmbH, D-52078 Aachen (own mark GRA 3029)

Substituted 1, 2,3,4-tetrahvdroquinoline derivatives

The present invention relates to substituted 1, 2,3,4-tetrahydroquinoline derivatives, and to processes for their preparation, their use in the preparation of medicaments and medicaments containing these compounds.

The treatment of chronic and non-chronic pain conditions is of great importance in medicine. There is a worldwide need for effective pain therapies for a patient-oriented and goal-oriented treatment of chronic and non-chronic pain conditions, which means the successful and satisfactory pain treatment for the patient. This can be seen in the large number of scientific papers that have recently appeared in the field of applied analgesics or basic research on nociception.

Classic opioids such as morphine are effective in treating severe to severe pain. However, their use is limited by the known side effects, for example ^" respiratory depression, vomiting, sedation, constipation and development of tolerance. In addition, they are less effective in neuropathic or incidental pain, from which tumor patients in particular suffer.

Opioids exert their analgesic effect by binding to membrane-bound receptors, which belong to the family of so-called G-protein-coupled receptors. The biochemical and pharmacological characterization of subtypes of these receptors has now raised hope that subtype-specific opioids have a different activity / side effect profile than, for example, morphine. Further pharmacological studies have meanwhile made the existence of several subtypes of these opioid receptors (μi, μ ₂ , κ κ ₂ , κ ₃ , δi and δ ₂ ) probable. There are also other receptors and ion channels that are significantly involved in the system of pain development and pain transmission. Particularly noteworthy in this context are compounds with affinity for binding site 2 of the sodium channel (BTX binding).

Knowledge of the physiological importance of ion channel-selective substances has been gained through the development of the patch clamp technique. It is important that the mechanism of action is different from, for example, opiates.

The object on which the invention was based was to provide analgesically active substances, in particular BTX-binding substances, which are suitable for pain therapy - in particular also chronic and neuropathic pain. In addition, these substances should have as few side effects as possible, e.g. Have nausea, vomiting, addiction, respiratory depression or constipation. Another associated task was to find active ingredients which are also suitable for use as a local anesthetic and / or antiarrhythmic and / or antiemetic and / or nootropic (neurotropic) and / or for the treatment of cardiovascular diseases and / or urinary incontinence and / or Diarrhea and / or pruritus and / or alcohol and / or drug and / or drug addiction and / or inflammation are suitable.

The invention accordingly relates to substituted 1,2,3,4-tetrahydroquinoline derivatives of the general formula I

, gegebenenfalls in Form ihrer Racemate, ihrer reinen Ster-eoisomeren, insbesondere Enantiomeren oder Diastereomeren, oder in Form von Mischungen der Stereoisomeren, insbesondere der Enantiomeren oder Diastereomeren, in einem beliebigen Mischungsverhältnis; in dargestellter Form oder in Form ihrer Säuren oder ihrer Baseη oder in Form ihrer Salze, insbesondere der physiologisch verträglichen Salze, oder in Form ihrer Solvate, insbesondere der Hydrate, ^•

, optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the prepared form or in the form of their acids or their Baseη or in the form of their salts, in particular physiologically acceptable salts, or in the form of their solvates, especially the hydrates, ^•

wherein

either

R ^tf and R ² together are each mono- or polysubstituted or unsubstituted,

- (CH ₂ ) _n - with n = 3-10,

-CH = CH-CH ₂ -, -CH ₂ -CH = CH-,

-CH = CH-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH = CH-

-CH ₂ -CH ⁼ CH-CH ₂ -,

-CH ₂ -CH = CH-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH = CH-CH ₂ -

-O-CH ₂ -CH ₂ -, -CH2-CH2-O-

-O-CH ₂ -CH -CH2-, -CH ₂ -CH ₂ -CH ₂ -O-

-CH ₂ -O-CH ₂ -,

-CH ₂ -CH ₂ -O-CH ₂ -, -CH2-O-CH2-CH2-

form,

and R ^1a means H,

R ³ H, C 1 -C ₈ -alkyl (branched or unbranched), C ₃ -C ₈ cycloalkyl, C (O) R ^3a , optionally substituted phenyl, optionally substituted 1-naphthyl,

2-naphthyl, quinoline, anthracene, indole, phenanthrene, benzbthiophene, benzofurfuryl, optionally substituted pyrrole, 2-pyridyl, 3-pyridyl, 4-pyridyl, optionally substituted furfuryl or optionally substituted thiophene or imidazolyl,

with R ^3a selected from alkyl (branched / unbranched) (in each case 1-8 C), cycloalkyl (3-8 C), unsubst. or subst. Phenyl group, unsubst. or subst. Benzyl group, unsubst. or subst. Phenethyl group here in particular: 2-fluorophenethyl, 2-chlorophenethyl, 2-methoxyphenethyl, 2-hydroxyphenethyl, 3-chlorophenethyl, 3-methoxyphenethyl, 3,4-

Dimethoxyphenethyl, 3-hydroxyphenethyl, 3-methylphenethyl, 4-bromophenethyl, 4-fluorophenethyl, 4-chlorophenethyl, 4-methoxyphenethyl, 4-hydroxyphenethyl, 4-methylphenethyl, 2- (trifluoromethyl) phenethyl, 2-nitrophenethyl, 2-amino- phenethyl, 4-aminophenethyl, 3- (trifluoromethyl) phenethyl, 4-nitrophenethyl, 3-

Nitrophenethyl, 4-benzyloxyphenethyl, 2,4,6-trimethylphenethyl, 2,5-dimethylphenethyl, 2-methylphenethyl, 3-fluorophenethyl, 4- Cyanophenethyl, 4-tert. Butyl-2,6-dimethylphenyl, 2-bromophenethyl, 3-bromophenethyl, 2,4-dichlorophenethyl,

is selected

R ^4a or ZR ^4a with Z = d-Ce-alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted, selected with R ^4a

H; C ₁ -C ₂ alkyl, C ₂ -C ₂ alkenyl or C ₂ -C ₂ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; Cs-Cs-cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted;

C (O) R ⁹ , C (O) OR ⁹ , C (S) R ⁹ , C (S) OR ⁹ or S (O ₂ ) R ⁹ with R ⁹ selected from H; dC-io-alkyl, C ₂ -Cι ₀ alkenyl or C ₂ -Cι ₀ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; Ca-Cs-cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; Alkylaryl or

Alkylheteroaryl, each mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted, in particular phenethyl, 1-adamantyl, 2-adamantyl, 1-naphthyl or 2-naphthyl 2-, 3- or 4-pyridyl; thiazolyl;

SR ¹⁰ with R ¹⁰ selected from

Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted, C (O) NR ¹¹ R ¹² , C (O) NR ¹¹ NR ¹² R ¹³ , C (NR ¹¹ ) NR ¹² R ¹³ , C (S) NR ¹¹ R ¹² or C (S) NR ¹¹ NR ¹² R ¹³ , wherein R ¹¹ , R ¹² and R ^{13 are} independently selected from H; Ci-Ciβ-alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₁₈ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C3-C ₈ -cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by S, O or N, alkylaryl or

Alkylheteroaryl, each mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted;

R ⁵ , R ⁶ , R ⁷ and R ^{8 are} independently selected from

H, F, Cl, Br, I, CN, NO ₂ ; -CC ₁₀ alkyl, C ₂ -C ₁₀ alkenyl or C ₂ -C ₁₀ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted;

OR ¹⁴ , OC (O) R ¹⁴ , OC (S) R ¹⁴ , C (O) R ¹⁴ , C (O) OR ¹⁴ , C (S) R ¹⁴ , C (S) OR ¹⁴ , SR ¹⁴ , S ( O) R ¹⁴ or S (O ₂ ) R ¹⁴ , where R ^{14 is} selected from

H; Ci-Cio-Aikyl, C ₂ -Cι ₀ alkenyl or C ₂ -Cιo alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one C atom in the ring is replaced by S, O or N; Alkylaryl or alkylheteroaryl, each mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted; NR ¹⁵ R ¹⁶ , NR ¹⁵ C (O) R ¹⁶ , C (NR ¹⁵ ) NR ¹⁶ R ¹⁷ NR ¹⁵ C (S) R ¹⁶ , C (S) NR ⁵ R ¹⁶ or C (S) NR ¹⁵ NR ¹⁶ R ¹⁷ or S (O ₂ ) NR ¹⁵ R ¹⁶ , where R ¹⁵ , R ¹⁶ and R ^{17 are} independently selected from one another

H, O; -CC ₁₈ alkyl, C ₂ -C ₁₈ -alkenyl or C ₂ -C ₈ -alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one C atom in the ring is replaced by S, O or N, alkylaryl or alkylheteroaryl, in each case simple or multiply substituted or unsubstituted; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted;

or

R ¹⁵ and R ¹⁶ or R ¹⁶ and R ¹⁷ together form a C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom passes through in the ring S, O or N is replaced; or

R ⁵ and R ⁶ , R ⁶ and R ⁷ or R ⁷ and R ⁸ together

= CR ¹⁸ form -CH = CH-CH = or = CH-CR ¹⁸ = CH-CH =, where R ¹⁸ is selected from H, F, Cl, Br, I, OH or C Cι ₀ alkyl, C ₂ -C ₁₀ alkenyl or C ₂ -C ₁₀ -

Alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted;

or

R ^{1a is} H or C-ι- ₄ alkyl, substituted or unsubstituted, branched or unbranched ,.

R, 1 ¹ b ^{D is} selected from Cι-Cι ₀ alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; C-3-C ₈ -cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one carbon atom in the

Ring is replaced by S, O or N; Alkylaryl, mono- or polysubstituted or unsubstituted; Aryl, mono- or polysubstituted or unsubstituted;

, OR ¹⁹ , SR ¹⁹ , SO ₂ R ¹⁹ with R ¹⁹ selected from.

Ci-C-io-alkyl, C ₂ -Cιo alkenyl or C ₂ -Cι ₀ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloakyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which a carbon atom in the ring through S,

O or N is replaced; Alkylaryl, aryl, alkylheteroaryl or heteroaryl, each mono- or polysubstituted or unsubstituted;

R ^{2 is} selected from H; Cι-Qιo-alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; Phenyl, mono- or polysubstituted or unsubstituted; where, when R ^{2 is} phenyl, R ^{1 must be} aryl, O-aryl or S-aryl,

R ³ H, C Cιo-alkyl (branched or unbranched), C ₃ -C ₈ cycloalkyl, C (O) R ^3a , optionally substituted phenyl, optionally substituted 1-naphthyl, 2-naphthyl, quinoline, anthracene, indole, phenanthrene , Benzothiophene, benzofurfuryl, optionally substituted pyrrole, 2-pyridyl, 3-pyridyl, 4-pyridyl, optionally substituted furfuryl or optionally substituted thiophene or imidazolyl,

with R ^3a selected from alkyl (branched / unbranched) (in each case 1-8 C), cycloalkyl (3-8 C), unsubst. or subst. Phenyl group, unsubst. or subst. Benzyl group, unsubst. or subst. Phenethyl group here especially: 2-fluorophenethyl, 2-chlorophenethyl, 2-methoxyphenethyl, 2-hydroxyphenethyl, 3-chlorophenethyl, 3-methoxyphenethyl, 3,4-dimethoxyphenethyl, 3-hydroxyphenethyl, 3-methylphenethyl, 4-bromophenethyl, 4-fluorophenethyl, 4- Chlorophenethyl, 4-methoxyphenethyl, 4-hydroxyphenethyl, 4-methylphenethyl, 2- (trifluoromethyl) phenethyl, 2-

Nitrophenethyl, 2-aminophenethyl, 4-aminophenethyl, 3- (trifluoromethyl) phenethyl, 4-nitrophenethyl, 3- ^•

Nitrophenethyl, 4-benzyloxyphenethyl, 2,4,6-trimethylphenethyl, 2,5-dimethylphenethyl, 2-methylphenethyl, 3-fluorophenethyl, 4- _. Cyanophenethyl, 4-tert. Butyl-2,6-dimethylphenethyl, 2-bromophenethyl, 3-

Bromophenethyl, 2,4-dichlorophenethyl,

R ^{4 is} selected from

R ^4a or ZR ^4a with Z = Ci-Ce-alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted, with R selected from

H; C ₁ -C ₂ alkyl, C ₂ -C ₂ alkenyl or C ₂ -C ₂ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one C atom in the ring is replaced by S, O or N; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted;

C (O) R ⁹ , C (O) OR ⁹ , C (S) R ⁹ , C (S) OR ⁹ or S (O ₂ ) R ⁹ with R ⁹ selected from

H; CrCio-alkyl, C ₂ -C ₁₀ alkenyl or C ₂ -C ₁₀ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one C atom in the ring is replaced by S, O or N; Alkylaryl or Alkylheteroaryl, each mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted, in particular phenethyl, 1-adamantyli, 2-adamantyl, 1-naphthyl or 2-naphthyl 2-, 3- or 4-pyridyl; thiazolyl;

SR ¹⁰ with R ¹⁰ selected from

Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted,

C (O) NR ¹¹ R ¹² , C (O) NR- ¹ NR ¹² R ¹³ , C (NR ¹¹ ) NR ¹² R ¹³ , C (S) NR ¹¹ R ¹² or C (S) NR ¹¹ NR ¹² R ¹³ , wherein R ¹¹ , R ¹² and R ^{13 are} independently selected from

H; Ci-Ciβ-alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one

C atom in the ring is replaced by S, O or N, alkylaryl or alkylheteroaryl, in each case mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted;

R ⁵ , R ⁶ , R ⁷ and R ^{8 are} independently selected from

H, F, Cl, Br, I, CN, NO ₂ ; -CC ₁₀ alkyl, C ₂ -C ₁₀ alkenyl or C ₂ -C ₁₀ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted;

OR ¹⁴ , OC (O) R ¹⁴ , OC (S) R ¹⁴ , C (O) R ¹⁴ , C (O) OR ¹⁴ , C (S) R ¹⁴ , C (S) OR ¹⁴ ,

SR ¹⁴ , S (O) R ¹⁴ or S (O ₂ ) R ¹⁴ , where R ^{14 is} selected from

H; C -C-alkyl, C ₂ -Cιo-alkenyl or C ₂ -Cιo-alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, simple or substituted or unsubstituted, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; Alkylaryl or alkylheteroaryl, each mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted;

NR ¹⁵ R ¹⁶ , NR ¹⁵ C (O) R ¹⁶ , C (NR ¹⁵ ) NR ¹⁶ R ¹⁷ NR ¹⁵ C (S) R ¹⁶ , C (S) NR ¹⁵ R ¹⁶ or C (S) NR ¹⁵ NR ¹⁶ R ¹⁷ or S (O ₂ ) NR ¹⁵ R ¹⁶ , where R ¹⁵ , R ¹⁶ and R ^{17 are} independently selected from

H, O; C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₈ -alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C3-C ₈ -cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one carbon atom in the

Ring is replaced by S, O or N, alkylaryl or alkylheteroaryl, in each case mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted;

or

R ¹⁵ and R ¹⁶ or R ¹⁶ and R ¹⁷ together are a C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted.biiden, or a corresponding heterocycle, in which at least one carbon atom passes through in the ring S, O or N is replaced; or

R ⁵ and R ⁶ , R ⁶ and R ⁷ or R ⁷ and R ⁸ together = CR ¹⁸ -CH = CH-CH = or = CH-CR ¹⁸ = CH-CH = form, with R ¹⁸ selected from

H, F, Cl, Br, I, OH or CτC-10-alkyl, C ₂ -C ₁₀ aikenyl or C2-C-10-alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; The 1, 2,3,4-tetrahydroquinoline derivatives according to the invention show a clear analgesic effect. The compounds of general formula I show strong affinity for binding site 2 of the sodium channel (BTX binding). Accordingly, the compounds of the general formula I according to the invention are also suitable for use as a local anesthetic and / or antiarrhythmic and / or anti-emetic and / or nootropic (neurotropic) and / or for the treatment / therapy of cardiovascular diseases and / or urinary incontinence and / or diarrhea and / or pruritus and / or alcohol and / or drug and / or drug addiction and / or inflammation, as this property of BTX-binding substances is known from the literature. The compounds of general formula I according to the invention are therefore also suitable for increasing vigilance and / or increasing libido and / or for treating depression. The compounds of the invention also bind to other binding sites and receptors.

In _. For the purposes of this invention, alkyl or cycloalkyl radicals are understood to mean saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted. Here d- ₂ -alkyl is C1- or C2-alkyl, d- ₃ -alkyl is C1-, C2- or C3-alkyl, C- _M -alkyl is C1-, C2-, C3- or C4-alkyl, d_ ₅ alkyl for C1, C2, C3, C4 or C5 alkyl, d. ₆ -alkyl for C1-, C2-, C3-, C4-, C5- or C6- alkyl, C. ₇ -alkyl for C1-, C2-, C3-, C4-, C5-, C6- or C7- Alkyl, i.e. ₈ alkyl for C1, C2, C3, C4, C5, C6, C7 or C8 alkyl, i.e. ₁₀ alkyl for C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl and d_ ₁₈ alkyl for C1, C2, C3, C4 -, C5-, C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl. Next is C ₃ . -Cycloalkyl for C3- or C4-cycloalkyl, C ₃ . _5- cycloalkyl for C3-, C4- or C5-cycloalkyl, C ₃ . ₆ -cycloalkyl for C3-, C4-, C5- or C6-cycloalkyl, C ₃ . _7- cycloalkyl for C3-, C4-, C5-, C6- or C7-cycloalkyl, C ₃ . _8- cycloalkyl for C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl, C ₄ . ₅ - cycloalkyl for C4 or C5 cycloalkyl, C ₄ . ₆ -cycloalkyl for C4-, C5- or C6-

Cycloalkyl, C ₄ . For ₇ -cycloalkyl C4-, C5-, C6- or C7-cycloalkyl, C ₅ - ₆ cycloalkyl of C5 or C6 cycloalkyl, and C. ₅ -Cycloalkyl for C5-, C6- or C7-cycloalkyl. With regard to cycloalkyl, the term also includes saturated cycloalkyls in which one or two carbon atoms have been replaced by a hetero atom, S, N or O. Under the term However, cycloalkyl in particular also falls one or more times, preferably mono, unsaturated cycloalkyls without a hetero atom in the ring, as long as the cycloalkyl is not an aromatic system. 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, cyclopentyimethyl, cyclohexyl, cycloheptyl, cyclooctyl, but also adamantyl, CHF2, CF3 or CH2OH as well as pyrazolinone, oxopyrazolinone, [1, 4] dioxane or dioxolane.

In connection with alkyl and cycloalkyl - unless otherwise expressly defined - the term substituted in the sense of this invention means the substitution of at least one (possibly also several) hydrogen radicals by F, Cl, Br, I, NH ₂ , SH or OH, where “multiply substituted” or “substituted” in the case of multiple substitution is to be understood to mean that the substitution takes place both on different and on the same atoms several times with the same or different substituents, for example three times on the same carbon atom as in the case of CF ₃ or in different places as in the case of -CH (OH) -CH = CH-CHCI ₂ . F, Cl and OH are particularly preferred substituents here. With regard to cycloalkyl, the hydrogen radical can also be OCι-3-alkyl or Cι. ₃ -alkyl (in each case mono- or polysubstituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF3, methoxy or ethoxy, can be replaced.

Under the term (CH ₂ ) ₃ -6 is -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ - CH ₂ -CH ₂ - and CH ₂ -CH ₂ -CH2-CH ₂ -CH ₂ -CH2- to understand, under (CH ₂ ) ι- ₄ is -CH ₂ -, - CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ - and -CH ₂ -CH ₂ -CH ₂ -CH ₂ - to understand, (CH ₂ ) ₄ -5 is - CH ₂ -CH ₂ -CH ₂ -CH ₂ - and -CH2-CH2-CH2 -CH2-CH2- to understand, etc.

An aryl radical is understood to mean ring systems with at least one aromatic ring but without heteroatoms in even one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or mono- or polysubstituted. A heteroaryl radical is understood to mean heterocyclic ring systems with at least one unsaturated ring which contain one or more heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur and can also be mono- or polysubstituted. Examples include from the group of the heteroaryls furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzό [1; 2.5] thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, Benzodioxane, carbazole, indole and quinazoline are listed.

In connection with aryl and heteroaryl, this is understood to mean the substitution of aryl or heteroaryl with R ⁸² , OR ^82, a halogen, preferably F and / or Cl, a CF3, a CN, a NO2, an NR ⁸³ R ⁸⁴ , a C. ^ .g- alkyl (saturated), a C ^ .ρ-alkoxy, a C3_8-cycloalkoxy, a C3_s-cycloalkyl or a C2_g-Alkyleη.

In this case, the radical R ⁸² represents H, a C ^ - _j Q-alkyl, preferably a C ^ alkyl, an aryl or heteroaryl, or for a about C ^ alkyl, saturated or unsaturated, or a C ^ Alkylene group-bonded aryl or heteroaryl radical, these aryl and heteroaryl radicals themselves may not be substituted with aryl or heteroaryl radicals,

the radicals R ⁸³ and R ⁸⁴ , identical or different, for H, a C ^ - _j Q-alkyl, preferably a C- _j .ρ-alkyl, an aryl, a heteroaryl or a via C-μ - Alkyl, saturated or unsaturated, or an aryl or heteroaryl radical bonded to a C 1-4 alkylene group, where these aryl and heteroaryl radicals themselves may not be substituted with aryl or heteroaryl radicals,

or the radicals R ⁸³ and R ⁸⁴ together denote CH ₂ CH2θCH ₂ CH2, CH 2 CH ₂ NR ⁸⁵ CH ₂ CH 2 or (CH ₂₎ 3_6> and

vorzugsweise einen C-_j_₆-Alkyl-, einen Aryl-, oder Heteroaryl- Rest oder für einen über C^-Alkyl, gesättigt oder ungesättigt, oder eine C<_|_3-Alkylen-Gruppe gebundenen Aryl- oder Heteroaryl-Rest, wobei diese Aryl und Heteroarylreste nicht selbst mit Aryl- oder Heteroaryl-Resten substituiert sein dürfen.the rest R ⁸⁵ for H, one

preferably a C- _j _ ₆ alkyl, an aryl or heteroaryl radical or an about C ^ alkyl, saturated or unsaturated, or a C _<| _3-alkylene group bound aryl or heteroaryl radical, these aryl and heteroaryl residues must not themselves be substituted with aryl or heteroaryl residues.

The term salt is to be understood to mean any form of the active ingredient according to the invention in which it takes on an ionic form or is charged and is coupled to a counterion (a cation or anioη) or is in solution. This also includes complexes of the active ingredient with other molecules and ions, in particular complexes that are complexed via ionic interactions. In particular, this means (and this is also a preferred embodiment of this invention) physiologically compatible salts, in particular physiologically compatible salts with cations or bases and physiologically compatible salts with anions or acids or else a salt formed with a physiologically compatible acid or a physiologically compatible cation ,

Physiologically compatible is understood to mean that the substance, in particular the salt as such, is compatible when used in humans or mammals, that is to say, for example, it does not have an unphysiological (e.g. toxic) effect.

For the purposes of this invention, the term “physiologically compatible salt with anions or acids” is understood to mean salts of at least one of the compounds according to the invention - mostly, for example, protonated on nitrogen - as. Cation with at least one anion that are physiologically compatible - especially when used in humans and / or mammals. In the sense of this invention, this is understood in particular to mean the salt formed with a physiologically compatible acid, namely salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible - in particular when used in humans and / or mammals. Examples of physiologically acceptable salts of certain acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid,

Acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1, 1-dioxo-1, 2-dihydro1b6-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, a-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid. The hydrochloride salt is particularly preferred.

For the purposes of this invention, the term salt formed with a physiologically compatible acid is understood to mean salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals. The hydrochloride is particularly preferred. Examples of physiologically compatible acids are: hydrochloric acid, Bromwasserstqffsäure, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1, 1-dioxo- 1, 2-dihydro1λ ⁶ - benzo [cf] 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 -Liponic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid.

For the purposes of this invention, the term “physiologically compatible salt with cations or bases” is understood to mean salts of at least one of the compounds according to the invention - usually one (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiological, in particular when used in humans and / or mammal - are compatible. Particularly preferred are the salts of the alkali and alkaline earth metals but also with NH ₄ ⁺ , but especially (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts.

For the purposes of this invention, the term salt formed with a physiologically compatible cation is understood to mean salts of at least one of the respective compounds as an anion with at least one inorganic cation which is physiologically compatible, in particular when used in humans and / or mammals. The salts of the alkali and alkaline earth metals but also NH ₄ ⁺ are particularly preferred, but in particular (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts. Next means -C (O) -

O

II - c -

which also applies to -C (S) - or -S (O) - or -S (O ₂ ) -.

In a preferred embodiment, for substituted 1, 2,3,4-tetrahydroquinoline derivatives according to the invention, R ^{4 is} selected from

H; C ₁ -C ₁₀ alkyl, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted;

is preferably selected from H, CH ₃ or C ₂ H ₅ ,

is particularly selected from H.

In a preferred embodiment, for substituted 1, 2,3,4-tetrahydroquinoline derivatives according to the invention, R ^{3 is} selected from

H; CrC ₄ alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; Phenyl, benzyl, or phenethyl, mono- or polysubstituted or unsubstituted, preferably H, CH ₃ or

C ₂ H _δ .

In a particularly preferred embodiment, for substituted 1,2,3,4-tetrahydroquinoline derivatives according to the invention, R ^1b and R ² together

oder insbesondere-CH = CH-CH ₂ -, -CH = CH-CH ₂ -CH ₂ -,

or in particular

-CH = CH-CH ₂ -, form.

In another preferred embodiment, for substituted 1, 2,3,4-tetrahydroquinoline derivatives according to the invention, R ^{1b is} selected from Phenyl, pyridinyl, in particular 2-pyridinyl or 4-pyridinyl, naphthyl or imidazole, unsubstituted or mono- or polysubstituted; preferably 1-imidazole, 2-naphthyl or in particular phenyl, unsubstituted or substituted one or more times, in particular phenyl unsubstituted, 2-chlorophenyl, 3-

Chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,6-dichlorophenyl, 4-carboxyphenyl,. 3-nitrophenyl, 2,4,6-trimethylphenyl, 2,5-dimethylphenyl, 3,4-dimethoxyphenyl, 4-benzyloxy-3-methoxyphenyl,. 3-methylphenyl, 4-

Methoxyphenyl, 4-biphenyl, 4-methylphenyl, 4-ethoxyphenyl, 2-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 4-hydroxy-3-methoxyphenyl, 4-methylhydroxyphenyl, 4-hydroxyphenyl, 4-phenoxyphenyl, 4-nitrophenyl, 4-chloromethylphenyl, 4-tert-butylphenyl, 3,5-bis (trifluoromethyl) phenyl,

4-acetoxyphenyl, 4-cyanophenyl, 2-methoxyphenyl, 2,6-

, Difluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-

Trifluoromethylphenyl, 3-methoxyphenyl, 2-, 3- or 4-

Benzyloxyphenyl, preferably phenyl unsubstituted, 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-

Bromophenyl or 3-bromophenyl.

In a further preferred embodiment, the present invention applies to ^• substituted 1, 2,3,4-tetrahydroquinoline that R ^5, R ^6, R ⁷ and R ⁸ are independently selected from

H, F, Cl, Br, I, CN, NO ₂ ; C.-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted;

OR ¹⁴ , C (O) R ¹⁴ , C (O) OR ¹⁴ or SR ¹⁴ , where R ^{14 is} selected from H; -CC ₄ alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, mono- or polysubstituted or unsubstituted, preferably R ⁵ , R ⁶ , R ⁷ and R ^{8 are} independently selected from

H, F, Cl, Br, I, CN; -CC alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted;

OR ¹⁴ or SR ¹⁴ , with R ¹⁴ selected from

-CC alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, mono- or polysubstituted or unsubstituted,

in particular R ⁵ , R ⁶ , R ⁷ and R ⁸ are selected independently of one another

H, F, Cl, Br, I, CN; CH ₃ , CF ₃ , t-butyl, i-butyl, -OCH ₃ , -OCF ₃ , -SCH ₃ , -O-phenyl.

In a further very preferred embodiment, the following applies to substituted 1,2,3,4-tetrahydroquinoline derivatives according to the invention:

R ⁵ , R ⁶ and R ⁸ H and R ⁷ Cl or

R ⁵ and R ^{7 are} H and R ⁶ and R ^{8 are} Cl.

In a preferred embodiment, the substituted ones according to the invention

1, 2,3,4-tetrahydroquinoline derivatives in the form of their hydrochloride salts.

In the literature there are various methods for the representation of

Tetrahydroquinolines described:

A solid phase approach (WO 98/34111),

• multi-stage process control (WO 98/42673; Bioorganic and Medicinal Chemistry Lettetters Vol. 2, p. 371, 1992; Journal of Heterocyclic Chemistry Vol.

25, p. 1831, 1988; Journal of the Chemical Society, Perkin Transactions I (1989), page 2245) or A Lewis acid catalyzed "one-pot" process (Journal of the Chemical Society, Chemical Communications, 1999, p. 651; Journal of the American Chemical Society, vol. 118, p. 8977, 1996).

In principle, all of these processes are suitable for producing the substances according to the invention, and the cited literature references are therefore fully part of these

Description.

Notwithstanding these is the so-called basic method described here a trifluoroacetic acid mediated -. Preferably "pot ¹ - process, depending on an aromatic amine, aldehyde and electron-rich olefin component to react with each other at the.

First, substituted 1,2,3,4-tetrahydroquinoline derivatives according to formula I with R ⁴ = H, while the other radicals have one of the meanings already mentioned, are produced in the Gruhd process. Anilines according to formula II in which R ⁵ , R ⁶ , R ⁷ and R ^{8 have} one of the meanings already given are

with glyoxalic acid esters according to formula III and olefins according to IV, in which R ^1a , R ^1b ,

R _2a have one of the meanings already given, are reacted with trifluoroacetic acid between 0 ° C. and 100 ° C. It is preferred that the reaction time is 0.25-12 h, preferably a maximum of 2 h, the reaction is preferably carried out at a temperature between 20 and 40 ° C., preferably room temperature, and / or the reaction is a one-pot reaction. A decisive advantage of the process according to the invention is that the process leads, according to a domino reaction (imine formation and subsequent aza-Diels-Alder reaction) very selectively with good yields to the desired systems.

Without having to carry out a knotting or splitting step, as in the case of the solid phase approach, and also without purifying the intermediate stages - as in the case of the solution chemistry described - the method according to the invention also differs in addition to its simple feasibility by its purification method. By repeated. Washing with non-polar solvents, such as n-hexane, for the most part allows the products to be obtained in high purity. Otherwise, they can be purified by means of column chromatography. In particular, compounds of the formula I can be obtained in a diastereomerically pure manner by washing processes with non-polar solvents - such as, for example, /.hexane - or by crystallizing their salts, for example the hydrochlorides.

Most of the reagents used here, in particular according to formulas II, III and IV, are commercially available or can be prepared by simple synthesis steps known to the person skilled in the art.

Subsequent to the basic process, in subsequent reactions the products obtained according to the basic process can be converted into secondary products according to the invention according to formula I according to the procedure known to the person skilled in the art, the hydrogen being initially substituted on R ⁴ .

Thus, if the product is to be substituted 1,2,3,4-tetrahydroquinoline derivatives according to formula I with R ⁴ = alkylformyl, acyl, sulfenyl and sulfonyl, the reaction product with the corresponding chloroformates or fluoroformates, acid chlorides, sulfenyl chlorides and Sulfonyl chlorides are reacted in the presence of a base, preferably triethylamine, pyridine or NaOH in water, dioxane-water or THF-water mixtures at a temperature between 0-20 ° C. (J. Org. Chem. 1989, 54, 5574-5580 ). Likewise, if the product is to be substituted 1, 2,3,4-tetrahydroquinoline derivatives according to formula I with R ⁴ = CSNR ¹⁷ , the reaction product with a thionating reagent, preferably Lawesson's reagent (2,4-bis (4- methoxyphenyl) -2,4-dithioxo-1, 3,2,4-dithiaphosph-etane), in organic solvents, preferably THF or toluene at a temperature of 30-50 ° C.

Or, if the product is to be substituted 1, 2,3,4-tetrahydroquinoline derivatives according to formula I with R ⁴ = C (O) N ¹³ R ¹⁴ or C (S) N ¹³ N ¹⁴ , the reaction product can be run after the basic reaction with potassium cyanate or potassium isothiocyanate in water at temperatures up to 100 ° C or with organic isocyanates or isothiocyanates in alcohols, preferably methanol, ethanol or isopropanol at temperatures up to the boiling point.

Furthermore, if the product should be substituted 1, 2,3,4-tetrahydroquinoline derivatives according to formula I with R ⁴ = C (NR ¹³ ) NR ¹⁴ R ¹⁵ , the reaction product under alkaline conditions with O-methylisoureas or S -Methylisothio-urstoffe be implemented at temperatures of 20-50 ° C, preferably ethanolic or methanolic NaOH or KOH.

Furthermore, if the product should be substituted 1, 2,3,4-tetrahydroquinoline derivatives according to formula I with R ⁴ = C (O) NR ¹³ R ¹⁴ , the reaction product in water / glacial acetic acid at 30-60 ° after the basic reaction has ended C are reacted with propanone-2-semicarbazone.

Similarly, if the product is to be substituted 1, 2,3,4-tetrahydroquinoline derivatives according to formula I with R ⁴ = C (S) NR ¹³ R ¹⁴ , the reaction product in water / NaOH at 30-60 ° C. after the basic reaction has ended be implemented with CS ₂ and hydrazines.

As the last option to be mentioned here, if the product is to be substituted 1, 2,3,4-tetrahydroquinoline derivatives according to formula I with R ⁴ = alkyl, benzyl or phenethyl, the reaction product with a corresponding alkylation halide, benzyl halide or Phenethyl halide and a suitable base, preferably sodium hydride or potassium tert-butoxide, in a solvent, for example ethanol, between 0 and 100 ° C. (J. Org. Chem. 1947, 12, 760; Zh. Obshch. Khim 1942, 12 , 418.

It may also be advantageous to use starting products according to formula III for the preparation of substituted 1, 2,3,4-tetrahydroquinoline derivatives according to formula I with R ³ = H for the basic process, in which R ³ ≠ H and R ^{3 are} preferably alkyl, in particular CH ₃ and C-2H ₅ are to be used. After the basic process and possibly the subsequent reactions, the reaction product is saponified with an appropriate base, preferably with 6N NaOH in ethanol, at temperatures between 0-100 ° C (Organikum, 1990, p. 418).

Under many of the reaction conditions mentioned, OH-SH and NH ₂ groups can possibly undergo undesirable side reactions. It is therefore preferred to provide these with protective groups or, in the case of NH _2, to replace them with NO ₂ and to split off the protective group prior to purification of the end product, or to reduce the Nθ ₂ group. Another object of the application is therefore a modification of the method described above, in which in the starting compounds at least one OH group by an OSi (Ph) ₂ tert-butyl group, at least one SH group by an Sp-methoxybenzyl group and / or at least one NH ₂ group has been replaced by a NO ₂ group and, before purification of the end product, at least one - preferably all - OSi (Ph) ₂ tert-butyl group / s, with tetrabutylammonium fluoride in tetrahydrofuran and / or at least one - preferably all - p-methoxybenzyl group / s with a metal amine, preferably sodium amine, split off and / or at least one - preferably all - NO ₂ group / s is reduced to NH ₂ .

Furthermore, carboxylic acid or thiocarboxylic acid groups may not be stable under the reaction conditions mentioned, so that it is preferred to use their methyl esters in the reactions and then to process the process product with KOH solution or NaOH solution in methanol at 40 ° C.-60 ° C to saponify. Another object of the invention is therefore a modification of Process described above, in which, prior to the purification of the end product, a process product with at least one C (O) OCH - OC (O) OCH - and / or C (S) OCH ₃ group with KOH solution or NaOH solution in methanol is saponified at 40 ° C - 60 ° C.

The substituted 1, 2,3,4-tetrahydroquinoline derivatives according to the invention are toxicologically harmless, so that they are suitable as active pharmaceutical ingredients in pharmaceuticals.

Another object of the invention is therefore also a medicament containing as active ingredient at least one substituted 1, 2,3,4-tetrahydroquinoline derivative according to the invention in the form shown or in the form of the acid or base or in the form of its salts, in particular the physiologically tolerable salts, or in Form of its solvates, especially hydrates; in particular in the form of its physiologically tolerable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; and optionally containing suitable additives and / or auxiliaries and / or optionally further active ingredients.

Preference is given to pharmaceuticals which contain at least one substituted 1, 2,3,4-tetrahydroquinoline-2-carboxylic acid derivative according to formula I as the active ingredient, wherein R ⁵ , R ⁶ and R ⁸ H and R ⁷ Cl or R ⁵ and R ⁷ H and R ⁶ and R ⁸ Cl mean.

The medicaments according to the invention can be administered as liquid dosage forms in the form of injection solutions, drops or juices, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols and, if appropriate, contain, in addition to at least one substituted tetrahydroquinoline derivative according to the invention, depending on the galenic form Carrier materials fillers, solvents, diluents, dyes and / or binders. The choice of excipients and the amounts to be used depends on whether the drug is oral, oral, parenteral, intravenous, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example to infections on the skin, mucous membranes and on the eyes. Preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative administration. Substituted tetrahydroquinoline derivatives according to the invention in a depot in dissolved form or in a plaster, optionally with the addition of agents which promote skin penetration, are suitable percutaneous application preparations. Formulations which can be used orally or percutaneously can release the substituted tetrahydroquinoline derivatives according to the invention with a delay. The amount of active ingredient to be administered to the patient varies depending on the weight of the patient, the type of application, the indication and the severity of the disease. 2 to 500 mg / kg of at least one substituted tetrahydroquinoline derivative of the formula I according to the invention are usually applied.

The substituted 1, 2,3,4-tetrahydroquinoline derivatives according to the invention are preferably used for pain treatment, in particular chronic and neuropathic pain, but also for migraines, so that a further subject of the invention is the use of at least one substituted 1,2,3,4-tetrahydroquinoline derivative according to the invention Formula I including its diastereomers or enantiomers in the form of its free base or a salt formed with a physiologically compatible acid, in particular the hydrochloride salt, for the manufacture of a medicament for the treatment of pain, in particular neuropathic and / or chronic pain, and / or for the treatment of Is migraine.

Since this is known from the literature, the BTX bond gives rise to further fields of application, so that a further subject of the invention is the use of at least one 1,2,3,4-tetrahydroquinoline derivative according to the invention in the form shown or in the form of the acid or base or in Form of its salts, in particular the physiologically tolerable salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically tolerable salts with cations or bases or with anions or acids; where appropriate in Form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; for the manufacture of a medicament for the treatment of urinary incontinence, itching, tinnitus aurium and / or diarrhea; for use as a local anesthetic and / or antiarrhythmic and / or antiemetic and / or nootropic (neurotropic) and / or for the treatment / therapy of cardiovascular diseases and / or alcohol and / or drug and / or drug addiction and / or inflammation; as well as to increase vigilance and / or libido and / or to treat depression; is.

The compounds of the invention also bind to other binding sites and receptors. Another subject is therefore the use of at least one 1, 2,3,4-tetrahydroquinoline derivative according to the invention in the form shown or in the form of the acid or base or in the form of its salts, in particular the physiologically tolerable salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically tolerable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; for the manufacture of a medicament for the treatment / prophylaxis of / for epilepsy, Parkinson's disease, Huntington's disease, glaucoma, osteoporosis, ototoxicity, withdrawal symptoms from alcohol and / or drug abuse, stroke, cerebral ischemia, cerebral infarction, cerebral edema, hypoxia, anoxia and / or for anxiolysis and / or anesthesia; for the treatment / prophylaxis of / in schizophrenia, Alzheimer's disease, psychoses due to increased amino acid levels, AIDS dementia, encephalomyelitis, Tourette syndrome, perinatal asphyxia, inflammatory and allergic reactions, drug and / or alcohol abuse, gastritis, diabetes, respiratory diseases, cough and / or mental illness. Another object of the invention are corresponding treatment methods using the compounds according to the invention for the treatment of the above-mentioned clinical pictures.

In the following the invention is further illustrated by examples and illustrations, without being limited thereto.

Examples

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

The following information generally applies:

The chemicals and solvents used were purchased commercially from conventional suppliers (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI etc. or synthesized).

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

The yields of the compounds produced are not optimized.

The analysis was carried out using ESI mass spectroscopy.

The connections are numbered.

Example 1: Preparation of the example compounds

The sample connections were made according to the following procedure: A round bottom tube made of glass (diameter 16 mm, length 125 mm) with thread was provided with a stirrer and with a screw cap Closed septum. The tube was placed in the stirring block heated to 20 ° C. The following reagents were then pipetted in successively:

1 ml of a solution of trifluoroacetic acid, 0.1 M, and aniline component, 0.1 M, in acetonitrile;

1 ml of a 0.11 M solution of the aldehyde in acetonitrile; 1 ml of a 0.3 M solution of the olefin in acetonitrile.

The reaction mixture was stirred at 20 ° C in one of the stirring blocks for 10 hours. The reaction solution was then filtered off. The tube was rinsed twice with 1.5 ml of a 7.5% NaHCO ₃ solution.

The reaction mixture was mixed on a vortex mixer with 2 ml of ethyl acetate and shaken. To form the phase boundary, centrifugation was carried out briefly in the centrifuge. The phase boundary was optically detected and the organic phase was pipetted off. In the next step, the aqueous phase was again mixed with 2 ml of ethyl acetate, shaken, centrifuged and the organic phase was pipetted off. The combined organic phases were dried over 2.4 g of MgSO 4 (granulated). The solvent was removed in a vacuum centrifuge.

The compounds were characterized for each of the compounds listed below by ESI mass spectrometry.

For the illustration of the example compounds given in Table 1 below with “Name” (numbered under Vbdg. (Compound)), the starting materials listed in each case as the reagents were added in the course of the above-described reaction as aniline component (“aniline”), aldehyde and olefin.

Table 1 :

Example 2:

Binding studies on the sodium channel

Binding site 2 (BTX binding):

Binding site 2 of the sodium channel is the so-called batrachotoxin (BTX) binding site. [ ³ H] -Batrachotoxinin A20 α-benzoate was used as the ligand _. (10 nM in the approach) used. These ion channel particles (synaptosomes) were enriched from the rat cerebrocortex according to Gray and Whittaker (EG Gray and VP Whittaker (1962) J. Anat. 76, 79-88). Radioactivity is defined as non-specific binding, which is measured in the presence of veratridine (0.3 mM in the batch). Incubate at 25 ° C for 120 min. The assay conditions were carried out after the publication by Pauwels, Leysen and Laduron (PJ Pauwels, JE Leysen and PM Laduron (1986) Eur. J. Pharmacol. 124, 291-298). The K _D value for this binding site is 24.63 ± 1.56 nM. (N = 3, ie mean values ± SEM from 3 independent test series which were carried out in triple parallel tests).

EVALUATION

In addition to the percentage inhibition of the test systems at fixed test substance concentrations (NA uptake: 1 μM in the approach; ion channel assays: 10 μM in the approach), dose dependencies were checked. This gives ICsQ values which can be converted into inhibitor constants (Kj) according to the "Cheng-Prusoff equation" (YC Cheng and WH Prusoff (1973) Biochem. Pharmacol. 22, 3099-3108). The IC50 values were calculated with the aid of the computer program "Figure P" (Version 6.0, Biosoft, Cambridge, England). Km values were calculated according to Lineweaver and Burk (H. Lineweaver and D. Burk (1934) J. Am. Chem. Soc. 56, 658-666). The computer program "Ligand" (Version 4, Biosoft, England) has been used to represent Kp values.

The results of the biochemical tests are summarized in Table 2 together with the names of the compounds according to the invention. The compounds according to the invention (Vbdg.) Were prepared according to the processes described above (see Example 1).

Table 2:

Example 3:

Parenteral solution of a substituted invention

Tetrahydrochinolinderivats

38 g of one of the substituted tetrahydroquinoline derivatives according to the invention, here compound 1, is dissolved in 1 l of water for injection purposes at room temperature and then by adding. anhydrous glucose set for isotonic conditions for injections.

Claims

claims 1. Substituted 1, 2,3,4-tetrahydroquinoline derivatives of the general formula I

, optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, in particular the physiologically tolerable salts, or in the form of their solvates, in particular the hydrates, wherein either R ^1b and R ² together are each mono- or polysubstituted or unsubstituted, - (CH ₂ ) _n - with n = 3-10, -CH = CH-CH ₂ -, -CH ₂ -CH = CH-, -CH = CH-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH = CH- -CH ₂ -CH = CH-CH ₂ -, -CH ₂ -CH = CH-CH ₂ -CH ₂ -, -CH2-CH ₂ -CH = CH-CH ₂ - -CH ₂ -CH ₂ -CH = CH-CH ₂ -CH2-, -O-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -O- -0-CH ₂ -CH2-CH2-, -CH2-CH ₂ -CH ₂ -O- -CH ₂ -O-CH ₂ -, -CH2-CH2-O-CH2-, -CH2-O-CH2-CH2-

form, and R »1 ^, a ^d H means R ³ H, dC ₁₀ alkyl (branched or unbranched), C ₃ -C ₈ cycloalkyl, C (O) R ^3a , optionally substituted phenyl, optionally substituted 1-naphtyl, 2-naphthyl, quinoline, anthracene, indole, phenanthrene , Benzothiophene, benzofurfuryl, optionally substituted pyrrole, 2-pyridyl, 3-pyridyl, 4-pyridyl, optionally substituted furfuryl or optionally substituted thiophene or imidazolyl, with R ^3a selected from alkyl (branched / unbranched) (in each case 1-8 C), cycloalkyl (3-8 C), unsubst. or subst. Phenyl group, unsubst. or subst. Benzyl group, unsubst. or subst. Phenethyl group here in particular: 2-fluorophenethyl, 2-chlorophenethyl, 2-methoxyphenethyl, 5 2-hydroxyphenethyl, 3-chlorophenethyl, 3-methoxyphenethyl,. 3,4- Dimethoxyphenethyl, 3-hydroxyphenethyl, 3-methylphenethyl, 4-bromophenethyl, 4-fluorophenethyl, 4-chlorophenethyl, 4-methoxyphenethyl, 4-hydroxyphenethyl, 4-methylphenethyl, 2- (trifluoromethyl) phenethyl, 2-nitrophenethyl, 2-amino- phenethyl, 4-aminophenethyl, 3- (trifluoro 10 methyl) phenethyl, 4-nitrophenethyl, 3- Nitrophenethyl, 4-benzyloxyphenethyl, 2,4,6-trimethylphenethyl, 2,5-dimethylphenethyl, 2-methylphenethyl, 3-fluorophenethyl, 4-cyanophenethyl, 4-tert. Butyl-2,6-dimethylphenethyl, 2-bromophenethyl, 3-bromophenethyl, 2,4-dichlorophenethyl, 15 R _4 is selected from R ^4a or ZR ^4a with Z = d-cer alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, each branched or unbranched, mono- or polysubstituted 20 _. or unsubstituted, selected from R ^4a H; CrC ₁₂ alkyl, C ₂ -Ci ₂ aikenyl or C ₂ d ₂ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, simple 25 or multiply substituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by S, O or N; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted; 30 C (O) R ⁹ , C (0) OR ⁹ , C (S) R ⁹ , C (S) OR ⁹ or S (O ₂ ) R ⁹ with R ⁹ selected from H; d-do-alkyl, C ₂ -Cι ₀ -alkenyl or C ₂ -Cι ₀ -alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; Alkylaryl or alkylheteroaryl, each mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, each simple. or substituted or unsubstituted, in particular phenethyl, 1-adamantyl, 2-adamantyl, 1-naphthyl or 2-naphthyl 2-, 3- or 4-pyridyl; thiazolyl; SR ¹⁰ with R ¹⁰ selected from Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted, C (0) NR ¹¹ R ¹² , C (O) NR ¹¹ NR ¹² R ¹³ , C (NR ¹¹ ) NR ¹² R ¹³ , C (S) NR ¹¹ R ¹² or C (S) NR ¹¹ NR ¹² R ¹³ , wherein R ¹¹ , R ¹² and R ^{13 are} independently selected from , H; -CC ₈ alkyl, C ₂ -C ₈ alkenyl or Cz-dβ-alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one C atom in the ring is replaced by S, O or N, alkylaryl or alkylheteroaryl, in each case simple or multiply substituted or unsubstituted; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted; R ⁵ , R ⁶ , R ⁷ and R ^{8 are} independently selected from H, F, Cl, Br, I, CN, NO ₂ ; d-Cio-alkyl, C ₂ -C ₁₀ alkenyl or C ₂ -Cι ₀ -alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; OR ¹⁴ , OC (O) R ¹⁴ , OC (S) R ¹⁴ , C (O) R ¹⁴ , C (O) OR ¹⁴ , C (S) R ¹⁴ , C (S) OR ¹⁴ , SR ¹⁴ , S ( O) R ¹⁴ or S (O ₂ ) R ¹⁴ , where R ^{14 is} selected from H; -C-Cιo-alkyl, C ₂ -C ₁₀ alkenyl or C ₂ -Cιo-alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one C atom in the ring is replaced by S, O or N; Alkylaryl or alkylheteroaryl, each mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted; NR ¹⁵ R ¹⁶ , NR ¹⁵ C (O) R ¹⁶ , C (NR ¹⁵ ) NR ¹⁶ R ¹⁷ NR ¹⁵ C (S) R ¹⁶ , C (S) NR ¹⁵ R ¹⁶ or C (S) NR ¹⁵ NR ¹⁶ R ¹⁷ or S (0 ₂ ) NR ¹⁵ R ¹⁶ , where R ¹⁵ , R ¹⁶ and R ^{17 are} independently selected from H, O; d-dβ-alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₈ -alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one C atom in the ring is replaced by S, O or N, alkylaryl or alkylheteroaryl, in each case simple or substituted or unsubstituted; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted; or R ¹⁵ and R ¹⁶ or R ¹⁶ and R ¹⁷ together form a C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one C atom in the ring is formed by S, O or N is replaced; or R ⁵ and R ⁶ , R ⁶ and R ⁷ or R ⁷ and R ⁸ together = CR ¹⁸ -CH = CH-CH = or = CH-CR ¹⁸ = CH-CH = form, with R ¹⁸ selected from H, F, Cl, Br, I, OH or d-Cio-alkyl, C ₂ -C ₁₀ alkenyl or ^' C ₂ -C ₁₀ alkynyl, each branched or unbranched, - mono- or polysubstituted or unsubstituted; or R ^{1a is} H or C- alkyl, substituted or unsubstituted, branched or unbranched ,. R ^{1b is} selected from CrCio-alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one carbon atom in the Ring is replaced by S, O or N; Alkylaryl, mono- or polysubstituted or unsubstituted; Aryl, mono- or polysubstituted or unsubstituted; OR ¹⁹ , SR ¹⁹ , SO ₂ R ¹⁹ with R ¹⁹ selected from d-do-alkyl, C2-Cιo-alkenyl or C2-Cιo-alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; d-Cs-cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which a carbon atom in the ring is represented by S, O or N is replaced; Alkylaryl, aryl, alkylheteroaryl or heteroaryl, each mono- or polysubstituted or unsubstituted; R ^{2 is} selected from H; Cι-Cιo-alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; Phenyl, mono- or polysubstituted or unsubstituted; where, when R ^{2 is} phenyl, R ^{1 must be} aryl, O-aryl or S-aryl, R ³ H d-do-alkyl, (branched or unbranched), C ₃ -C ₈ cycloalkyl, ^'C (O) R ^3a, optionally substituted phenyl, optionally substituted 1-naphthyl, 2-naphthyl, quinoline, anthracene, indole Phenanthrene, benzothiophene, benzofurfuryl, optionally substituted pyrrole, 2-pyridyl, 3-pyridyl, 4-pyridyi, optionally substituted furfuryl or optionally substituted thiophene or imidazqlyl, with R ^3a selected from alkyl (branched / unbranched) (in each case 1-8 C), cycloalkyl (3-8. C), unsubst. or subst. Phenyl group, unsubst. or subst. Benzyl group, unsubst. or subst. Phenethyl group here in particular: 2-fluorophenethyl, 2-chlorophenethyl, 2-methoxyphenethyl, 2-hydroxyphenethyl, 3-chlorophenethyl, 3-methoxyphenethyl, 3,4-dimethoxyphenethyl, 3-hydroxyphenethyl, 3-methylphenethyl, 4-bromophenethyl, 4-fluorophenethyl, 4-chlorophenethyl, 4-methoxyphenethyl, 4-hydroxyphenethyl, 4-methylphenethyl, 2- (trifluoromethyl) phenethyl, 2- Nitrophenethyl, 2-amino-phenethyl, 4-aminophenethyl, 3- (trifluoromethyl) phenethyl, 4-nitrophenethyl, 3- Nitrophenethyl, 4-benzyloxyphenethyl, 2,4,6-trimethylphenethyl, 2,5-dimethylphenethyl, 2-methylphenethyl, 3-fluorophenethyl, 4-cyanophenethyl, 4-tert. Butyl-2,6-dimethylphenethyl, 2-bromophenethyl, 3- Bromophenethyl, 2,4-dichlorophenethyl, R ^{4 is} selected from R ^4a or ZR ^4a with Z = -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted, with R selected from H; Cι-d ₂ alkyl, C ₂ -C ₁₂ alkenyl or C ₂ -C. ₂ -alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one carbon atom in the Ring is replaced by S, O or N; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted; C (O) R ⁹ , C (0) OR ⁹ , C (S) R ⁹ , C (S) OR ⁹ or S (O ₂ ) R ⁹ with R ⁹ selected from H; Cι-Cιo-alkyl, C ₂ -Cι ₀ alkenyl or C ₂ -C ₁₀ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one C atom in the ring is replaced by S, O or l; Alkylaryl or alkylheteroaryl, each mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted, in particular phenethyl, 1-adamantyl, 2-adamantyl, 1-naphthyl or 2- Naphthyl 2-, 3- or 4-pyridyl; thiazolyl; SR ¹⁰ with R ¹⁰ selected from Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted, C (O) NR ¹¹ R ¹² , C (O) NR ¹¹ NR ¹² R ¹³ , C (NR ¹¹ ) NR ¹² R ¹³ , C (S) NR ¹¹ R ¹² or C (S) NR ¹¹ NR ¹² R ¹³ , wherein R ¹¹ , R ¹² and R ^{13 are} independently selected from H; Cι-C. _8- alkyl, C ₂ -d ₈ -alkenyl or C ₂ -C ₁₈ -alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one C atom in the ring is replaced by S, O or N, alkylaryl or Alkylheteroaryl, each mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted; R ⁵ , R ⁶ , R ⁷ and R ^{8 are} independently selected from H, F, Cl, Br, I, CN, NO ₂ ; dC.o-alkyl, C ₂ -Cι ₀ -alkenyl or C ₂ -Cι ₀ -alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; OR ¹⁴ , OC (0) R ¹⁴ , OC (S) R ¹⁴ , C (O) R ¹⁴ , C (O) OR ¹⁴ , C (S) R ¹⁴ , C (S) OR ¹⁴ , SR ¹⁴ , S ( O) R ¹⁴ or S (O ₂ ) R ¹⁴ , where R ^{14 is} selected from H; -C-Cιo-alkyl, C ₂ -Cιo-alkenyl or C ₂ -Cι ₀ -alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one C atom in the ring is replaced by S, O or N; Alkylaryl or alkylheteroaryl, each mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted; NR ¹⁵ R ¹⁶ , NR ¹⁵ C (O) R ¹⁶ , C (NR ¹⁵ ) NR ¹⁶ R ¹⁷ NR ¹⁵ C (S) R ¹⁶ , C (S) NR ¹⁵ R ¹⁶ or C (S) NR ¹⁵ NR ¹⁶ R ¹⁷ or S (O ₂ ) NR ¹⁵ R ¹⁶ , where R ¹⁵ , R ¹⁶ and R ^{17 are} independently selected from H, O; -C ₈ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₁₈ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one C atom in the ring is replaced by S, O or N, alkylaryl or alkylheteroaryl, in each case simple or multiply substituted or unsubstituted; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted; or R ¹⁵ and R ¹⁶ or R ¹⁶ and R ¹⁷ together form a C ₃ -C ₈ cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom passes through in the ring S, O or N is replaced; or R ⁵ and R ⁶ , R ⁶ and R ⁷ or R ⁷ and R ⁸ together = CR ¹⁸ -CH = CH-CH = or = CH-CR ¹⁸ = CH-CH = form, with R ¹⁸ selected from H, F, Cl, Br, I, OH or d-Cio-alkyl ,. C ₂ -Cιo alkenyl or C ₂ -C ₁₀ - Alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; 2. Substituted 1, 2,3,4-tetrahydroquinoline derivatives according to claim 1, characterized in that R ^{4 is} selected from H; C ₁ -C ₁₀ alkyl, unsubstituted or mono- or polysubstituted; Phenyl, unsubstituted or mono- or polysubstituted; is preferably selected from H, CH ₃ or C ₂ H ₅ , is particularly selected from H. 3. Substituted 1, 2,3,4-tetrahydroquinoline derivatives according to one of claims 1 or 2, characterized in that R ^{3 is} selected from H; -CC ₄ alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; Phenyl, benzyl, or phenethyl, mono- or polysubstituted or unsubstituted, preferably H, CH3 or C ₂ H _δ . 4. Substituted 1, 2,3,4-tetrahydroquinoline derivatives according to any one of claims 1-3, characterized in that R ^1b and R ² together

in particular -CH = CH-CH ₂ -, form, 5. Substituted 1, 2,3,4-tetrahydroquinoline derivatives according to any one of claims 1-3, characterized in that R ^{1b is} selected from Phenyl, pyridinyl, in particular 2-pyridinyl or 4-pyridinyl, naphthyl or imidazole, unsubstituted or mono- or polysubstituted; preferably 1-imidazole, 2-naphthyl or in particular phenyl, unsubstituted or substituted one or more times, in particular phenyl unsubstituted, 2-chlorophenyl, 3- Chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4- Fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,6-. Dichlorophenyl, 4-carb.oxyphenyl, 3-nitrophenyl, 2,4,6- Trimethylphenyl, 2,5-dimethylphenyl, 3,4-dimethoxyphenyl, 4-benzyloxy-3-methoxyphenyl, 3-methylphenyl, 4- Methoxyphenyl, 4-biphenyl, 4-methylphenyl, 4-ethoxyphenyl, 2-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 4-hydroxy-3-methoxyphenyl, 4-methylhydroxyphenyl, 4- Hydroxyphenyl, 4-phenoxyphenyl, 4-nitrophenyl, 4-chloromethylphenyl, 4-tert-butylphenyl, 3,5-bis (trifluoromethyl) phenyl, 4-acetoxy-phenyl, 4-cyanophenyl, 2-methoxyphenyl, 2,6- Difluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-methoxyphenyl, 2-, 3- or 4- Benzyloxyphenyl, preferably phenyl unsubstituted, 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-bromophenyl or 3-bromophenyl. 6. Salts according to one of claims 1 to 5, characterized in that R ⁵ , R ⁶ , R ⁷ and R ⁸ are selected independently of one another H, F, Cl, Br, I, CN, N0 ₂ ; dC ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, each branched or unbranched, mono- or polysubstituted or unsubstituted; OR ¹⁴ , C (O) R ¹⁴ , C (O) OR ¹⁴ or SR ¹⁴ , where R ^{14 is} selected from H; d-C -alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, mono- or polysubstituted or unsubstituted, preferably R ⁵ , R ⁶ , R ⁷ and R ^{δ are} independently selected from H, F, Cl, Br, I, CN; -CC ₄ alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; OR ¹⁴ or SR ¹⁴ , with R ¹⁴ selected from dC ₄ alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, mono- or polysubstituted or unsubstituted, in particular R ⁵ , R ⁶ , R ⁷ and R ⁸ are selected independently of one another H, F, Cl, Br, I, CN; CH ₃₎ CF ₃₎ t-butyl, i-butyl, -OCH ₃ , -OCF ₃ , -SCH ₃ , - O-phenyl. 7. Substituted 1, 2,3,4-tetrahydroquinoline derivatives according to any one of claims 1-6, characterized in that R ⁵ , R ⁶ and R ⁸ H and R ⁷ Cl or R ⁵ and R ^{7 are} H and R ⁶ and R ^{8 are} Cl. 8. Substituted 1, 2,3,4-tetrahydro ocl .inolinder iva te according to any one of claims 1 to 7 in the form of their hydrochloride salts. 9. Medicament containing as active ingredient at least one substituted 1, 2,3,4-tetrahydroquinoline derivative according to claim 1, in the form shown or in the form the acid or base or in the form of its salts, in particular the physiologically acceptable salts, or in the form of its solvates, in particular the hydrates; especially in the form of its physiologically acceptable salts. with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; and optionally containing suitable additives and / or auxiliaries and / or optionally further active ingredients. 10. Medicament according to claim 9, containing at least one substituted 1, 2,3,4-tetrahydroquinoline derivative according to formula I as active ingredient, wherein R ⁵ , R ⁶ and R ⁸ H and R ⁷ Cl or R ⁵ and R ⁷ H and R ⁶ and R ⁸ Cl mean. 11. Use of at least one substituted 1, 2,3,4-tetrahydroquinoline derivative according to claim 1, in the form shown or in the form of the acid or base or in the form of its salts, in particular the physiologically tolerable salts, or in the form of its solvates, in particular the hydrates ; in particular in the form of its physiologically tolerable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; for the manufacture of a medicinal product Treatment of pain, in particular neuropathic and / or chronic pain and / or for the treatment of migraines; for the treatment of urinary incontinence, itching, tinnitus aurium and / or diarrhea; for use as a local anesthetic and / or antiarrhythmic and / or anti-emetic and / or nootropic (neurotropic) and / or for the treatment / therapy of cardiovascular diseases and / or urinary incontinence and / or diarrhea and / or pruritus and / or alcohol and / or drug and / or drug addiction and / or inflammation; as well as Increase vigilance and / or libido and / or to treat depression.