EP2112993A1 - Substituted tetrahydropyrrolopyrazine compounds having affinity with the kcnq2/3 k+ channel and use thereof in medicaments - Google Patents

Abstract

The invention relates to substituted tetrahydropyrrolopyrazine compounds, to methods for the production thereof, medicaments containing said compounds and to the use of said compounds for producing medicaments.

Description

 SUBSTITUTED TETRAHYDROPYRROLOPYRAZIN COMPOUNDS WITH AFFINITY TO THE KCNQ2 / 3K + CHANNEL AND THEIR USE IN MEDICAMENTS

The present invention relates to substituted Tetrahydropyrrolopyrazin- compounds, processes for their preparation, medicaments containing these compounds and the use of these compounds for the preparation of medicaments.

The treatment of pain, especially of neuropathic pain, is of great importance in medicine. There is a worldwide need for effective pain therapies. The urgent need for a patient-oriented and goal-oriented treatment of chronic and non-chronic pain states, which is to be understood as the successful and satisfactory treatment of pain for the patient, is also documented in the large number of scientific papers in the field of applied analgesics Basic research on nociception have recently appeared.

One pathophysiological feature of chronic pain is the influx of neurons. The neuronal excitability is decisively influenced by the activity of K ⁺ channels, since these decisively determine the resting membrane potential of the cell and thus the excitability threshold. Heteromeric K ⁺ channels of the molecular subtype KCNQ2 / 3 (Kv7.2 / 7.3) are expressed in neurons of different regions of the central (hippocampus, amygdala) and peripheral (dorsal root ganglia) nervous system and regulate their excitability. Activation of KCNQ2 / 3 K ⁺ channels leads to hyperpolarization of the cell membrane and concomitant decrease in the electrical excitability of these neurons. KCNQ2 / 3-expressing neurons of the dorsal root ganglia are involved in the transmission of nociceptive excitations from the periphery to the spinal cord (Passmore et al., J Neurosci., 2003; 23 (18) 7227-36). Accordingly, for the KCNQ2 / 3 agonist retigabine, analgesic efficacy has been demonstrated in preclinical neuropathy and inflammatory pain models (Blackbum-Munro and Jensen, Eur J Pharmacol., 2003; 460 (2-3): 109-16; Dost et al., Naunyn Schmiedeberg's Arch Pharmacol 2004; 369 (4): 382-390). The KCNQ2 / 3K ⁺ channel thus provides a suitable starting point for the treatment of pain; in particular pain selected from the group consisting of chronic pain, neuropathic pain, inflammatory pain and muscular pain (Nielsen et al., Eur J Pharmacol. 2004; 487 (1-3): 93-103), especially neuropathic and inflammatory pain represents.

In addition, the KCNQ2 / 3 K ⁺ channel is a suitable target for the therapy of a variety of other diseases such as migraine (US2002 / 0128277), cognitive disorders (Gribkoff, Expert Opin Ther Targets 2003; 7 (6): 737-748), 2005, 14 (1): 282-92), epilepsy (Wickenden et al., Expert Opin Ther Pat 2004; 14 (4): 457-469), and urinary incontinence (Strictly et al., J Urol 2004; 172: 2054-2058).

It was therefore an object of the present invention to provide novel compounds which are particularly suitable as pharmacologically active substances in medicaments, preferably in medicaments for the treatment of disorders or diseases mediated at least in part by KCNQ2 / 3K ⁺ channels.

Surprisingly, it has now been found that substituted tetrahydropyrrolopyrazine compounds of the general formula I given below are suitable for the treatment of pain and also have an excellent affinity for the KCNQ2 / 3K ⁺ channel and are therefore suitable for the treatment of disorders or diseases which are at least partially KCNQ2 / 3 K ⁺ channels.

From the literature and from databases already substituted tetrahydropyrrolopyrazines are known. Thus, US Pat. No. 4,188,389 discloses tetrahydropyrrolopyrazines which are suitable for the treatment of depression. WO9429315 discloses tetrahydropyrrolopyrazines having anxiolytic properties which are unsubstituted on the piperazine ring except for the piperazine nitrogen. WO 2003024967 discloses tetrahydropyrrolopyrazines bearing a (C = Z) -NH ₂ substituent on R ³ and useful in the treatment of cancer. Furthermore, tetrahydropyrrolopyrazines are listed in databases without any indication of biological activity, for example in CAS. An object of the present invention are therefore substituted tetrahydropyrrolopyrazine compounds of general formula I _1st

wherein

R ^1, R ² and R ³ independently represent hydrogen, C ₆ alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; F, Cl, Br, I, CN, NH _2, NH-d-β-alkyl, NH-d-β-alkyl-OH, N (Ci _-6 alkyl) _2, N _{(Ci-6-alkyl-OH) 2} , NHAryl; NH-alkylaryl; NH-heteroaryl; NO _2, SH, SC _1-6 alkyl, OH, OC _1-6 alkyl, _{O-Ci-6-alkyl-OH,} C (= O) d _-6 alkyl, NHSO ₂ Ci _-6 alkyl, NHCOAryl ; NHCOC _1-6 alkyl, CO ₂ H, CH ₂ SO ₂ phenyl, CO ₂ -Ci. ₆ alkyl, OCF ₃ , SCF ₃ , CF ₃ , benzyloxy, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, phenoxy, phenyl, pyridyl, alkylaryl, thienyl or furyl; or the radicals R ¹ and R ² or R ² and R ^{3 is} a

Form ring and together

R ⁴ and R ⁵ independently of one another are H, F, Cl, Br, I ₁ -CN, NH ₂ , NH-de-alkyl, NH-d-β-alkyl-OH, C _1-6 -alkyl, N (Ci _-6 alkyl) _2, N _{(Ci-6-alkyl-OH) 2,} NO _2, SH, SC _1-6 alkyl, S- benzyl, Od-β-alkyl, OH, O-Ci _-6 alkyl -OH, O-benzyl, C (= O) Ci _-6- alkyl, CO ₂ H, CO ₂ - C ₆ -alkyl or benzyl;

R ⁶ is d- ₆ alkyl, branched or unbranched, unsubstituted or mono- or polysubstituted; Aryl or heteroaryl, unsubstituted or singly or multiply - A -

substituted in; or an aryl or heteroaryl radical linked via a C _1-3 -alkyl chain, unsubstituted or monosubstituted or polysubstituted;

R ^4a, R ^5a and R ^6a are independently H or Ci _-6 alkyl;

R ^{7 is} (CH ₂ ) _t C (= O) R ⁸ ; (C = O) (CH ₂ ) _m NR ¹¹ R ¹² ; C (= O) (CH ₂ ) _n (C = O) R ⁸ ; (CH ₂ ) _s NHC (= O) R ⁸ where m is 1, 2 or 3 n is 1, 2, 3 or 4 t is 1, 2, 3 or 4 s is 1, 2, 3 or 4 stands

R ⁸ Ci- ₆ alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; Aryl, heteroaryl, heterocyclyl or C 3-8 -cycloalkyl, each unsubstituted or monosubstituted or polysubstituted; or linked via a Ci _-5 alkyl aryl, heteroaryl, heterocyclyl or C _3-8 cycloalkyl, respectively unsubstituted or singly or multiply substituted, wherein the alkyl chain in each case saturated or unsaturated, may be branched or unbranched; NR ⁹ R ¹⁰ ; means;

R ⁹ and R ^{10 are} independently H; C 1 -C ₆ -alkyl in each case saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case unsubstituted or monosubstituted or polysubstituted; Heterocyclyl or C _3-8 -cycloalkyl, in each case saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; C (= O) R ²⁰ ; SO ₂ R ¹³ ; or Ci- ₃ alkyl-bound aryl, C _3-8 cycloalkyl, heterocyclyl or heteroaryl, in each case mono- or polysubstituted or unsubstituted, wherein the alkyl chain in each case saturated or unsaturated, may be branched or unbranched, are provided;

or the radicals R ⁹ and R ¹⁰ together are CH ₂ CH ₂ OCH ₂ CH ₂ , CH ₂ CH ₂ NR ¹⁴ CH ₂ CH ₂ or (CH ₂ ) _3-6 ,

R ¹¹ and R ^{12 are} independently H; C-ι _-6 alkyl in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Heterocyclyl or C _3-8 cycloalkyl, respectively saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; C (= O) R ²⁰ ; SO ₂ R ¹³ ; or aryl, C _3-8 -cycloalkyl, heterocyclyl or heteroaryl bonded via C _1-3 -alkyl, in each case monosubstituted or polysubstituted or unsubstituted, where the alkyl chain may in each case be saturated or unsaturated, branched or unbranched;

or the radicals R ¹¹ and R ¹² together represent CH ₂ CH ₂ OCH ₂ CH ₂ , CH ₂ CH ₂ NR ¹⁴ CH ₂ CH ₂ or (CH ₂ ) _3-6 ,

where R ^{14 is} H; d _-6- alkyl, in each case saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C _3-8 cycloalkyl, respectively saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; C (= O) R ¹³ ; or Ci _-3 alkyl-bound aryl, C _3-8 -cycloalkyl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;

R ¹³ Ci ₆ alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; Aryl, heteroaryl or C ₃ _ ₈ -cycloalkyl, each unsubstituted or mono- or polysubstituted; or linked via a C ₅ alkyl aryl, heteroaryl, or Cs-s-cycloalkyl can be unsubstituted or mono- or polysubstituted, wherein the alkyl chain in each case saturated or unsaturated, branched or unbranched, alkyl;

R ²⁰ Ci ₆ alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; Aryl, heteroaryl or C _3-8 -cycloalkyl, each unsubstituted or mono- or polysubstituted; NR ²¹ R ²² ; or a Ci _-5 - linked chain alkyl aryl, heteroaryl or _C3-8 cycloalkyl, each unsubstituted or mono- or polysubstituted, wherein the alkyl chain in each case saturated or unsaturated, may be branched or unbranched means;

R ²¹ and R ²² are each independently of one another d-β-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted; Aryl, heteroaryl or C _3-8 -cycloalkyl, each unsubstituted or mono- or polysubstituted; or via a Ci _-5 alkyl chain linked aryl, heteroaryl or C _3-8 - cycloalkyl, each unsubstituted or mono- or polysubstituted, wherein the Each alkyl chain may be saturated or unsaturated, branched or unbranched, means

in the form of the Razemats; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers, or a single enantiomer or diastereomer; the bases and / or salts of physiologically acceptable acids.

In connection with "phenyl", "phenyloxy", "benzyl", "benzyloxy", "aryl" the term in each case includes the unsubstituted structure as well as by F, Cl, OCH _3, CF _3, OCF _3, SCF ₃ and CH ₃ substituted structure.

Be the terms "Ci ₃ alkyl", "Ci _-5 alkyl" and "Ci ₆ alkyl" includes within the meaning of this invention acyclic saturated or unsaturated hydrocarbon radicals which have branched or straight chained and unsubstituted or mono- or polysubstituted can, with 1 to 3 C-atoms or 1 to 5 C-atoms or 1 to 6 C-atoms, ie Ci _-3- Alkanyle, C _2-3 alkenyls and C _2-3 alkynyls or Ci- ₅ -Alkanyle, C ₂ - ₅ alkenyls, and C ₂ - ₅ alkynyls or Ci _-6 -Alkanyle, C _2-6 alkenyls, and C ₂ - ₆ alkynyls alkenyls have at least one C-C double bond and alkynyls at least. Alkyl is advantageously selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso - pentyl, neo-pentyl, hexyl, ethylenyl (vinyl), ethynyl, propenyl (-CH ₂ CH = CH ₂ , -CH = CH-CH ₃ , -C (= CH ₂ ) -CH ₃ ), propynyl (-CH -C≡CH, -C≡C-CH ₃ ), butenyl, butynyl, pentenyl, pentynyl, hexenyl and hexynyl Of these, preference is given to methyl, ethyl, n-propyl and isopropyl.

For purposes of this invention, the term "cycloalkyl" or _"C3 _8 cycloalkyl" denotes cyclic hydrocarbons having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein the hydrocarbons may be saturated or unsaturated (but not aromatic), unsubstituted or - or may be substituted several times. Advantageously, C ₃ _s-cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. The term "heterocyclyl" includes saturated or unsaturated (but not aromatic) cycloalkyls having three to eight ring members in which one or two carbon atoms are replaced by a heteroatom S, N or O. Heterocyclyl radicals from the group of tetrahydropyranyl, dioxanyl, are advantageous. Dioxolanyl, morpholinyl, piperidinyl, piperazinyl, pyrazolinonyl and pyrrolidinyl.

The term "aryl" in the context of this invention means aromatic hydrocarbons having up to 14 ring members, i.a. Phenyle and naphthyls. The aryl radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems. Each aryl radical may be unsubstituted or monosubstituted or polysubstituted, wherein the aryl substituents may be the same or different and may be in any desired and possible position of the aryl. Advantageously, aryl is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, which may each be unsubstituted or mono- or polysubstituted.

The term "heteroaryl" represents a 5-, 6- or 7-membered cyclic aromatic radical containing at least 1, optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are the same or different and the heterocycle is unsubstituted or in the case of substitution on the heterocycle, the substituents may be the same or different and may be in any and possible position of the heteroaryl The heterocycle may also be part of a bi- or polycyclic system having up to 14 ring members Preferred heteroatoms are nitrogen, oxygen and sulfur It is preferred that the heteroaryl radical is selected from the group consisting of pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, Benzodioxolanyl, benzodioxanyl, phthalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxadiazolyl, isoxazoyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl , Indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, or oxadiazolyl, wherein the attachment to the compounds of general structure I can be via any and possible ring member of the heteroaryl radical. Particularly preferred are pyridyl, furyl and thienyl. The terms "about Ci- ₃ alkyl bound aryl, heteroaryl, heterocyclyl or cycloalkyl" and "on Ci _-5 alkyl-bound aryl, heteroaryl or cycloalkyl" mean for the purposes of the present invention is that or Ci- ₃ alkyl and aryl Heteroaryl or heterocyclyl or cycloalkyl have the meanings defined above and the aryl or heteroaryl or heterocyclyl or cycloalkyl radical via a Ci _-3 alkyl group or a Ci _-5 alkyl group to the Compound of the general structure I is bound. The alkyl chain can in all cases be saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted. It is advantageous if the alkyl chain is unsubstituted or substituted by a methyl group. Particularly advantageous for the purposes of this invention is phenyl, benzyl and phenethyl.

In connection with "alkyl", "heterocyclyl" and "cycloalkyl" is meant "substituted", the term for the purposes of this invention, the substitution of a hydrogen radical by F, Cl, Br, I ₁ is -CN, NH _2, NH-Ci _-6 alkyl, _{NH-Ci-6-alkyl-OH,} Ci _-6 - alkyl, N (Ci _-6 alkyl) _2, N (C _1-6 alkyl-OH) _2, NO _2, SH, SC _{1 6} alkyl, S-benzyl, O-Ci _-6 alkyl, OH, O-Ci- ₆ alkyl-OH, = 0, O-benzyl, C (= O) Ci _-6 alkyl, CO ₂ H, CO ₂ -C _-6 alkyl, phenyl or benzyl, where under polysubstituted radicals such radicals are to be understood which are several times, either on different or on the same atoms, eg two or three times substituted, for example three times on the same C atom as in the case of CF ₃ or -CH ₂ CF ₃ or at different positions as in the case of - CH (OH) -CH = CH-CHCl ₂ . Multiple substitution can be with the same or different substituents.

In the context of this invention, "aryl" and "heteroaryl" are understood as meaning "mono- or polysubstituted" the substitution of one or more, for example two, three or four times, substitution of one or more hydrogen atoms of the ring system by F, Cl , Br, I, CN, NH _{2, NH-Ci-6-alkyl,} NH-C _1-6 alkyl-OH, N (Ci _-6 alkyl) _2, N (Ci _-6 - alkyl-OH) _2, NO _2, SH, S-Ci _-6 alkyl, OH, _{O-Ci-6-alkyl, O-Ci-6-alkyl-OH,} C (= O) Ci _-6 alkyl, C (= O) NHCi _{- 6-} alkyl; C (= O) -aryl; C (= O) -N-morpholine; C (= O) -piperidine; (C = O) -

pyrrolidine; (C = O) piperazine; NHSO ₂ Ci _-6 alkyl, NHCOCi _-6 -alkyl, CO ₂ H, CH ₂ SO ₂ -

Phenyl, CO ₂ -C _1-6 alkyl, OCF ₃ , SCF ₃ , CF ₃ , , Ci _-6 alkyl, pyrrolidinyl,

Piperidinyl, morpholinyl, benzyloxy, phenoxy, phenyl, pyridyl, alkylaryl, thienyl or furyl; at one or possibly different atoms, where a substituent may be substituted in turn, but not with another aryl or heteroaryl ring. The multiple substitution takes place with the same or different substituents. For "aryl" or "heteroaryl", preferred substituents are F, Cl ₁ OCH ₃ , CF ₃ , OCF ₃ , SCF ₃ and CH ₃ .

For the purposes of the present invention, the term salt formed with a physiologically acceptable acid means salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals. Particularly preferred is the hydrochloride. Examples of physiologically tolerated acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic 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-trimethylbenzoic acid , α-lipoic acid, acetylglycine, hippuric acid, phosphoric acid and / or aspartic acid. Particularly preferred are citric acid and hydrochloric acid.

For the purposes of this invention, preference is given to substituted tetrahydropyrrolopyrazine

Compounds of general formula I ₁ wherein

R ¹ , R ² and R ³ independently of one another represent hydrogen, C 1 -C ₆ -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted; F, Cl, Br, I ₁ CN, NH _2, NH-Ci-β-alkyl, NH-d-β-alkyl-OH, N (Ci _-6 alkyl) _2, N (C _1-6 alkyl-OH ) ₂ , NHAryl; NH-alkylaryl; NH-heteroaryl; NO _2, SH, S-Ci _-6 alkyl, OH, O-Ci- ₆ alkyl, OC _1-6 alkyl-OH, C (= O) Ci _-6 alkyl, NHSO ₂ C _1-6 alkyl , NHCOAryl; NHCOCi _-6 -alkyl, CO ₂ H, CH ₂ SO ₂ -phenyl, CO ₂ -C _-6 alkyl, OCF _3, SCF _3, CF _3, benzyloxy, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, phenoxy, phenyl, pyridyl , Alkylaryl, thienyl or furyl; or the radicals R ¹ and R ² or R ² and

R form a ring and together R ⁴ and R ⁵ independently of one another are H, F, Cl, Br, I, -CN, NH ₂ , NH-C 1 _-6- alkyl, NH-C ₁ -6-alkyl-OH, C 1 _-6- alkyl, N ( Ci _-6 alkyl) _2, N (C _1-6 alkyl-OH) _2, NO _2, SH, _{S-Ci-6-alkyl,} S- benzyl, O-Ci _-6 alkyl, OH, O- Ci _-6- alkyl-OH, O-benzyl, C (= O) C _1-6 -alkyl, CO ₂ H, CO ₂ - C ₆ -alkyl or benzyl;

R ⁶ is d- ₆ alkyl, branched or unbranched, unsubstituted or mono- or polysubstituted; Aryl or heteroaryl, unsubstituted or substituted once or several times; or via a C _-3 alkyl chain linked aryl or heteroaryl, unsubstituted or mono- or polysubstituted group;

R ^4a, R ^5a and R ^6a are independently H or Ci _-6 alkyl;

R ^{7 is} (CH ₂ ), C (= O) R ⁸ ; (C = O) (CH ₂ ) _m NR ¹¹ R ¹² ; C (= O) (CH ₂ ) _n (C = O) R ⁸ ; (CH ₂ ) _s NHC (= O) R ⁸ where m is 1, 2 or 3 n is 1, 2, 3 or 4 t is 1, 2, 3 or 4 s is 1, 2, 3 or 4 stands

R ⁸ Ci- ₆ alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; Aryl, heteroaryl, heterocyclyl or C ₃ -β-cycloalkyl, each unsubstituted or monosubstituted or polysubstituted; or linked via a Ci _-5 alkyl aryl, heteroaryl, heterocyclyl or C _3-8 cycloalkyl, respectively unsubstituted or singly or multiply substituted, wherein the alkyl chain in each case saturated or unsaturated, may be branched or unbranched; NR ⁹ R ¹⁰ ; means;

R ⁹ and R ^{10 are} independently H; Ci- ₆ alkyl in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case unsubstituted or monosubstituted or polysubstituted; Heterocyclyl or C _3-8 -cycloalkyl, in each case saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; C (= O) R ²⁰ ; SO ₂ R ¹³ ; or Ci- ₃ alkyl-bound aryl, C _3-8 cycloalkyl, heterocyclyl or heteroaryl, each monosubstituted or polysubstituted or unsubstituted, where the alkyl chain may in each case be saturated or unsaturated, branched or unbranched;

or the radicals R ⁹ and R ¹⁰ together are CH ₂ CH ₂ OCH ₂ CH ₂ , CH ₂ CH ₂ NR ¹⁴ CH ₂ CH ₂ or (CH ₂ ) _3-6 ,

R ¹¹ and R ^{12 are} independently H; C-ι _-6 alkyl in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Heterocyclyl or C _3-8 -cycloalkyl, in each case saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; C (= O) R ²⁰ ; SO ₂ R ¹³ ; or aryl, C _3-8 -cycloalkyl, heterocyclyl or heteroaryl bonded via C _1-3 -alkyl, in each case monosubstituted or polysubstituted or unsubstituted, where the alkyl chain may in each case be saturated or unsaturated, branched or unbranched;

or the radicals R ¹¹ and R ¹² together represent CH ₂ CH ₂ OCH ₂ CH ₂ , CH ₂ CH ₂ NR ¹⁴ CH ₂ CH ₂ or (CH ₂ ) _3-6 ,

where R ^{14 is} H; C _1-6 -alkyl, in each case saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C _3-8 -cycloalkyl, in each case saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; C (= O) R ¹³ ; or Ci _-3 alkyl-bound aryl, C _3-8 cycloalkyl or heteroaryl, respectively singly or multiply substituted or unsubstituted;

R ¹³ C-ι- ₆ alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; Aryl, heteroaryl or C _3-8 -cycloalkyl, each unsubstituted or mono- or polysubstituted; or linked via a Ci _-5 alkyl aryl, heteroaryl or _C3-8 cycloalkyl, each unsubstituted or mono- or polysubstituted, wherein the alkyl chain in each case saturated or unsaturated, may be branched or unbranched means;

R ^{20 is} d- _6- alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted; Aryl, heteroaryl or C _3-8 -cycloalkyl, each unsubstituted or mono- or polysubstituted; NR ²¹ R ²² ; or a Ci _-5 - linked chain alkyl aryl, heteroaryl or _C3-8 cycloalkyl, each unsubstituted or monosubstituted or polysubstituted, where the alkyl chain can in each case be saturated or unsaturated, branched or unbranched;

R ²¹ and R ^{22 are} independently Ci _-6 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; aryl,

Heteroaryl, or C _3-8 cycloalkyl, each unsubstituted or mono- or polysubstituted; or linked via a Ci _-5 alkyl aryl, heteroaryl or C _3- β-

Cycloalkyl, each unsubstituted or monosubstituted or polysubstituted, wherein the

Each alkyl chain can be saturated or unsaturated, branched or unbranched, means

"Alkyl substituted", "heterocyclyl substituted" and "cycloalkyl substituted" for the substitution of a hydrogen radical by F, Cl ₁ Br, I ₁ -CN, NH ₂ , NH-Ci _-6 alkyl, NH-Ci-β-alkyl OH, Ci. ₆ alkyl, N (Ci _-6 alkyl) _2, N (C _1-6 alkyl-OH) _2, NO _2, SH, SD-β-alkyl, S-benzyl, OC _1-6 alkyl, OH , Od-β-alkyl-OH, = 0, O-benzyl, C (= O) Ci _-6 alkyl, CO ₂ H, CO ₂ -C _-6 alkyl, phenyl or benzyl

and "aryl substituted" and "heteroaryl substituted" for the one or more, for example two, three or four times, substitution of one or more hydrogen atoms of the ring system by F, Cl, Br, I ₁ CN, NH ₂ , NH de alkyl, NH-C _1-6 alkyl-OH, N (Ci ₆ alkyl) _2, N (C _1-6 alkyl-OH) _2, NO _2, SH, SC _1-6 alkyl, OH, od-β-alkyl, _{O-Ci-6-alkyl-OH,} C (= O) aryl; C (= O) Ci _-6 alkyl, C (= O) NHCi _-6 alkyl, C (= O) -N-morpholine; C (= 0) - piperidine; (C = O) -pyrrolidine; (C = O) piperazine; NHSO ₂ Ci _-6 alkyl, NHCOCi _-6 alkyl,

CO ₂ H, CH ₂ SO ₂ -phenyl, CO ₂ -Ci _-6- alkyl, OCF ₃ , SCF ₃ CF ₃ , , Ci _-6 alkyl, pyrrolidinyl, piperidinyl, morpholinyl, benzyloxy, phenoxy, phenyl, pyridyl, alkylaryl, thienyl or furyl;

in the form of the Razemats; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers, or a single enantiomer or diastereomer; the bases and / or salts of physiologically acceptable acids.

Preference is given to substituted tetrahydropyrrolopyrazine compounds of the formula I ₁ in which R ^{7 is} CH ₂ C (OO) R ⁸ ; (C =O) (CH ₂ ) _m NR ¹¹ R ¹² or C (OO) (CH ₂ ) _n (C =O) R ⁸ , where m is 1, 2 or 3 and n is 1, 2, 3 or 4.

And substituted tetrahydropyrrolopyrazines of the general formula I ₁ wherein R ^1, R ² and R ³ are preferably each independently hydrogen or Ci ₆ alkyl, branched or unbranched, are, in particular H.

Further preferably substituted tetrahydropyrrolopyrazines of the general formula I ₁ wherein R ⁴ and R ⁵ independently of one another are H or C ₆ alkyl, especially H.

Preference is also given to tetrahydropyrrolopyrazines of the general formula I ₁ in which R ^{6 is} phenyl, thienyl, furyl, pyridyl or benzyl, unsubstituted or mono- or disubstituted

substituted with OCH ₃ , F, Cl ₁ CH ₃ , isopropyl or * /; Methyl or te / t-butyl.

In addition, preference is given to substituted tetrahydropyrrolopyrazines of the general formula I ₁ in which R ^{7 is} CH ₂ CH ₂ C (OO) R ⁸ , CH ₂ CH ₂ CH ₂ C (OO) R ⁸ or CH ₂ CH ₂ CH ₂ CH ₂ C (= O) R ⁸ , in particular CH ₂ CH ₂ CH ₂ C (= O) R ⁸

Particular preference is given to substituted tetrahydropyrrolopyrazines of the general formula I ₁ in which R ^{7 is} C (OO) CH ₂ (C =O) R ⁸ , C (OO) CH ₂ CH ₂ (C =O) R ⁸ , C (OO ) CH ₂ CH ₂ CH ₂ (C = O) R ⁸ , especially C (= O) CH ₂ CH ₂ (C = O) R ⁸ .

Also preferred are tetrahydropyrrolopyrazines of the general formula I ₁ in which R ^{8 is} NR ⁹ R ¹⁰ , R ^{9 is} H and

R ¹⁰ aryl, heteroaryl, heterocyclyl or C _3-8 -cycloalkyl optionally bonded via a C _1-3 -alkyl chain, in each case unsubstituted or monosubstituted or polysubstituted, where the alkyl chain can in each case be saturated or unsaturated, branched or unbranched; C-ι _-6 alkyl, saturated, unsubstituted, branched or unbranched, means or the radicals R ⁹ and R ¹⁰ together represent CH ₂ CH ₂ OCH ₂ CH ₂ , CH ₂ CH ₂ NR ¹⁴ CH ₂ CH ₂₁ CH ₂ CH ₂ CH ₂ CH ₂ or CH ₂ CH ₂ CH ₂ CH ₂ CH ₂

where R ^{14 is} H; Benzyl or phenyl, each unsubstituted or monosubstituted or polysubstituted; C (= O) R ¹³ means.

Particular preference is given to substituted tetrahydropyrrolopyrazines of the general formula I embedded image in which

R ^{8 is} NR ⁹ R ¹⁰ , R ^{9 is} H and

R ^{10 is} phenyl, benzyl, phenethyl, methylthienyl, methylfuryl, methylpyridyl, ethylthienyl, ethylfuryl or ethylpyridyl, in each case monosubstituted or polysubstituted; Piperidyl, pyrrolidinyl, methylpiperidyl, methylpyrrolidinyl, ethylpiperidyl or ethylpyrrolidinyl, each singly or multiply substituted; Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Propyl, butyl or pentyl,

or

the radicals R ⁹ and R ¹⁰ together represent CH ₂ CH ₂ OCH ₂ CH ₂ , CH ₂ CH ₂ NR ¹⁴ CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ CH ₂ or CH ₂ CH ₂ CH ₂ CH ₂ CH ₂

where R ^{14 is} H; Benzyl or phenyl, each unsubstituted or monosubstituted or polysubstituted; C (= O) CH ₃ means.

Preference is also given to substituted tetrahydropyrrolopyrazine derivatives of the general formula I ₁ in which R ^{7 is} (C =O) CH ₂ NR ¹¹ R ¹² , (C =O) CH ₂ CH ₂ NR ¹¹ R ¹² or (C =O) CH ₂ CH ₂ CH ₂ NR ¹¹ R ¹² , and R ^{11 is} C (= O) R ²⁰ , and R ^{12 is} H; Ci _-6 -alkyl, branched or unbranched; C _3- 8 cycloalkyl, especially H; Methyl, ethyl, propyl, butyl or cyclopropyl, wherein R ^{20 is} NR ²¹ R ²² ; Phenyl, furyl, benzyl, phenethyl, propylphenyl or cyclopropyl, each unsubstituted or monosubstituted or polysubstituted; Methyl, ethyl, propyl or butyl, in particular NR ²¹ R ²² ; Phenyl, benzyl, phenethyl or propylphenyl, each unsubstituted or mono- or polysubstituted with CF ₃ , or CH ₃ ; Cyclopropyl, unsubstituted or substituted with phenyl; or Furyl, wherein R ²¹ and R ^{22 are} preferably independently of one another H or Ci- ₆ alkyl, preferably H, CH ₃ , tert-butyl or isopropyl.

Very particular preference is given to tetrahydropyrrolopyrazine derivatives from the group

1 4- [1- (4-chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -4-oxo-N- (3-trifluoromethylbenzyl) butyramide

2 4-Oxo-4- (1-phenyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -N- (3-trifluoromethyl-benzyl) -butyramide

3 N-sec-Butyl-2- [1- (2-methoxyphenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -acetamide

4 N-Cyclopropyl-3- [1- (3-fluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -3-oxo-propionamide

5 4-Oxo-4- (1-m-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -N- (3-trifluoromethyl-benzyl) -butyramide

6 3- {2- [1- (2-chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -2-oxo-ethyl} -1, 1-dimethylurea

7 4- [i - (4-Fluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -N-isobutyl-4-oxo-butyramide

8 2- [1 - (2,3-dihydro-benzo [1,4] dioxin-6-yl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] - N- (3-trifluoromethyl-benzyl) -acetamide:

9 2- [1- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] - np-tolyl-acetamide

10 3-tert-Butyl-1- {2- [1- (2,4-difluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -2- oxo-ethyl} -1-isopropylurea

11 2- [1- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] - N-isopropyl-acetamide

12 3-terf-butyl-1-isopropyl-1- [2-oxo-2- (1-m-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) ethyl] urea

13 N-Cyclopropyl-N- [2- (1-furan-3-yl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl) -2-oxo-ethyl] - 4-methyl-benzamide

14 Cyclopropanecarboxylic acid {2- [1- (3,4-dichlorophenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -2-oxo-ethyl} - isopropyl-amide 1-Cyclopropyl-1- {2- [1- (2,4-difluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -2-oxo-ethyl } -3-isopropylurea 1 - (4-acetyl-piperazin-1-yl) -2- [1- (2,4-difluorophenyl) -3,4-dihydro-1H-pyrrolo [1, 2 - a] pyrazin-2-yl] -ethanone furan-2-carboxylic acid-cyclopropyl {2- [1- (3,4-dichloro-phenyl) -3,4-dihydro-1 H-pyrrolo [1, 2] a] pyrazin-2-yl] -2-oxo-ethyl} -amide N-tert-butyl-N- [2-oxo-2- (1-p-tolyl-3,4-dihydric] -1 H-pyrrolo [1,2-a] pyrazin-2-yl) -ethyl] isobutyramide N-Cyclopropyl-N- {2- [1- (3,4-dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -2-oxo-ethyl} -isobutyramide 2- (1- (3-Methoxyphenyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1 H) -yl) -N- (3- (trifluoromethyl) benzyl) acetamide 1-ethyl-3,3-dimethyl-1- [2-oxo-2- (1-phenyl-3,4-dihydro-1H- pyrrolo [1,2-a] pyrazine-2-yl) -ethyl] -urea quinoline-8-sulfonic acid {2- [1- (2,4-difluoro-phenyl) -3,4-dihydro-1 H- pyrrolo [1,2 a-pyrazino-2-yl] -2-oxo-ethyl} -ethyl-amide

N-Cyclopropyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide Cyclopropanecarboxylic acid tert-butyl- [2-oxo-2 - (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl) -ethyl] -amide furan-2-carboxylic acid tert-butyl {2- [ 1- (3,4-dichloro-phenyl) -3,4-dihydro-1 H -pyrrolo [1,2-a] pyrazin-2-yl] -2-oxo-ethyl} -amide 2- [1- (1) 2-Chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazino-2-yl] -1-piperidin-1-yl-ethanone 2-phenylcyclopropanecarboxylic acid ethyl [2 -oxo-2- (1-phenyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -ethyl] -amide N- (4-fluoro-phenyl) -4- [1- (3-methoxyphenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -4-oxo-butyramide N-ethyl-N- [2-oxo -2- (1-phenyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -ethyl] -butyramide N- (1,2-dimethyl-propyl) -2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide

N-sec-butyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazino-2-yl) -acetamide N- {2- [1- (3 , 4-dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazino-2-yl] -2-oxo-ethyl} -N-ethyl-isobutyramide 4- [1- (2-yl) 3-Methoxy-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazino-2-yl] -4-oxo-N-pyridin-4-ylmethylbutyramide Furan-2-carboxylic acid isopropyl {2- [1- (4-isopropylphenyl) -3,4-dihydro-1 H -pyrrolo [1,2-a] pyrazin-2-yl] -2-oxo ethyl} -amide 1- [1- (3-methoxyphenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -3-morpholin-4-yl-propane 1,3-dione 2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -N- (3-trifluoromethyl-benzyl) -acetamide

N-pyridin-3-ylmethyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide 2- [1- (2, 4-difluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N-furan-2-ylmethyl-acetamide

N-Benzyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide N- (3,4-dimethylphenyl) - 3- [1- (3-methoxy-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -3-oxo-propionamide 4- [1 - (3 Chlorophenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N-isopropyl-4-oxobutyramide N- (1-benzyl-piperidin-4-yl ) -2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide 2- [1- (4-chloro-phenyl) -3 , 4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -1- [4- (2-chlorophenyl) -piperazin-1-yl] -ethanone N- (1-benzyl -piperidin-4-yl) -2- [1- (4-chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -acetamide 1- (4 Benzo [1,3] dioxol-5-ylmethyl-piperazin-1-yl) -2- [1- (4-chloro-phenyl) -3,4-dihydro-

1 H-pyrrolo [1,2-a] pyrazine-2-yl] -ethanone

N-phenethyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide 2- [1- (3,4-dichloro-2-yl) -acetamide phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N- (2-pyridin-2-yl-ethyl) -acetamide 1- (4-benzo [1 , 3] dioxol-5-ylmethylpiperazin-1-yl) -2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -ethanone 2- [1- (3,4-dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazino-2-yl] -N-pyridin-3-ylmethyl-acetamide 1 (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2- [1- (2-chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1, 2] a] pyrazin-2-yl] -ethanone 1- (4-benzylpiperazin-1-yl) -2- [1- (4-chlorophenyl) -3,4-dihydro-1H-pyrrolo [1, 2- [1- (4-Chloro-phenyl) -3,4-dihydro-1 H -pyrrolo [1,2-a] pyrazine-2-yl] -N-2-a] pyrazin-2-yl] -ethanone phenethylacetamide 2- [1- (2-Chloro-phenyl) -3,4-dihydro-1 H -pyrrolo [1,2-a] pyrazin-2-yl] -N-phenethyl-acetamide 2- [1- (3,4 Dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N- (4-fluoro-benzyl) -acetamide 1- (4-benzyl-piperazine- 1-yl) -2- [1- (2-chlorophenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -ethanone

N -Cyclohexyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl) -acetamide 1- (4-benzyl-piperazine-1-yl ) -2- (1 -p-tolyI-3, 4-d ihy d ro-1H-pyrrolo [1,2-a] pyrazin-2-yl) ethanone 2- [1- (4-chloro) phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N- (1,2-dimethyl-propyl) -acetamide N- (2-piperidin-1-yl -ethyl) -2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide

N- (4-fluoro-phenyl) -2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazino-2-yl) -acetamide furan-2-carboxylic acid ethyl [2-oxo-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl) -ethyl] -amide 2- [1- ( 4-fluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N-isopropyl-acetamide 2- [1- (3,4-dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N-isobutyl-acetamide 2- [1- (4-chloro-phenyl) -3,4-dihydro-1 H-pyrrolo [1,2-a] pyrazine-2-yl] -N- (2-pyrrolidin-1-yl-ethyl) -acetamide. N-Benzo [1,3] dioxol-5-ylmethyl-2- (1 -p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide 2- (1- (4-chlorophenyl) -3,4-dihydropyrrolo [1,2 -a] pyrazine-2 (1H) -yl) -N- (4-fluorobenzyl) acetamide 2- (1- (4-Chlorophenyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H ) -yl) -N- (3- (trifluoromethyl) benzyl) acetamide 2- (1- (4-chlorophenyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) - 1- (4- (4-methoxyphenyl) piperazin-1-yl) ethanone N- (2,4-dichlorophenethyl) -2- (1- (3,4-dichlorophenyl) -3,4-dihydropyrrolo [1, 2] a] pyrazine-2 (1H) -yl) acetamide 1- (4- (3-C hlorophenyl) piperazin-1-yl) -4- (1-m-tolyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -butane-1,4-dione 4-oxo -4- (1- (thiophen-2-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (3- (trifluoromethyl) benzyl) butanamide 77 4-Oxo-4- (1- (pyridin-2-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (3- (trifluoromethyl) benzyl ) butanamide

78 4- (1-tert-Butyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -4-oxo-N- (3- (trifluoromethyl) benzyl) butanamide

79 4-Oxo-4- (1 - (pyridin-4-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (3- (trifluoromethyl) benzyl ) butanamide

80 4- (1-Benzyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -4-oxo-N- (1- (3- (trifluoromethyl) phenyl) -ethyl) butanamide

81 4-Oxo-4- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (1- (3- (trifluoromethyl) -phenyl) -ethyl) butanamide

82 4-Oxo-4- (1 - (thiophen-2-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (1- (3- (3) trifluoromethyl) phenyl) ethyl) butanamide

83 4-Oxo-4- (1-phenyl-3 _l 4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (thiophen-2-ylmethyl) butanamide

84 4-Oxo-4- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (1- (3- (pyridin-3-yl) phenyl) ethyl) butanamide

85 N- (4-fluorobenzyl) -4- (1-methyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -4-oxobutanamide

86 4- (1-Methyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -4-oxo-N- (3- (trifluoromethyl) benzyl) butanamide

87 N- (2-Oxo-2- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1 H) -yl) ethyl) -3- (3- (trifluoromethyl) phenyl) propanamide

88 N- (2-Oxo-2- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) ethyl) -4-phenylbutanamide

89 3-Oxo-3- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (3- (trifluoromethyl) benzyl) propanamide

90 3-Oxo-3- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (3- (trifluoromethyl) phenyl) propanamide

91 2- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (3- (trifluoromethyl) benzyl) acetamide

92 (E) -3- (2-fluorophenyl) -N- (2-oxo-2- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) ethyl ) acrylamide

The substituted tetrahydropyrrolopyrazine compounds according to the invention and in each case the corresponding acids, bases, salts and solvates are suitable as pharmaceutical active ingredients in medicaments. Another object of the present invention is therefore a medicament containing at least one substituted according to the invention

Tetrahydropyrrolopyrazine compound of general formula I ₁ wherein the radicals R ¹ - R ^{7 have} the meaning given above, and optionally one or more pharmaceutically acceptable excipients.

These medicaments according to the invention are suitable for influencing KCNQ2 / 3 channels and exert an agonistic or antagonistic, in particular an agonistic action.

The medicaments according to the invention are preferably suitable for the treatment of disorders or diseases which are at least partially mediated by KCNQ2 / 3 channels.

The medicament of the invention is preferably suitable for the treatment of one or more diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain, migraine; Epilepsy, anxiety and urinary incontinence. The medicaments according to the invention are particularly preferably suitable for the treatment of pain, very particularly preferably of chronic pain, neuropathic pain, inflammatory pain and muscular pain. Furthermore, the compounds according to the invention are preferably suitable for the treatment of epilepsy.

Another object of the present invention is the use of at least one substituted tetrahydropyrrolopyrazine compound of the invention and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment of disorders or diseases that are mediated at least partially by KCNQ2 / 3 channels.

Preference is given to the use of at least one substituted tetrahydropyrrolopyrazine compound according to the invention and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain; Migraine; Epilepsy, anxiety and urinary incontinence.

Particularly preferred is the use of at least one substituted tetrahydropyrrolopyrazine compound of the invention and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment of pain, most preferably of chronic pain, neuropathic pain, inflammatory pain and muscular pain. Also particularly preferred is the use of at least one substituted tetrahydropyrrolopyrazine compound according to the invention and optionally one or more pharmaceutically acceptable auxiliaries for the preparation of a medicament for the treatment of epilepsy.

Efficacy against pain can be demonstrated, for example, in the Bennett and Chung models described below. Efficacy against epilepsy can be demonstrated, for example, in the DBA / 2 mouse model (De Sarro et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 2001, 363, 330-336).

A further subject of the present invention is a process for the preparation of the substituted tetrahydropyrrolopyrazine compounds according to the invention. The chemicals and reaction components used in the reactions described above are commercially available or can be prepared in each case by customary methods known to the person skilled in the art.

In this case, a solution of the optionally substituted 2- (1 H-pyrrol-1-yl) ethanamine and the aldehyde of the general formula R ⁶ C (= O) H a) in an organic acid, for example acetic acid, 6 - 48 h at room temperature stirred or b) in an alcohol, for example ethanol or methanol with the addition of an organic acid, for example acetic acid or citric acid at a temperature of 0-100 ⁰ C, preferably 2O ⁰ C to 78 ° C stirred for 2 - 48 h or c) in an organic solvent, for example toluene, benzene or DCM, with benzotriazole and an acid, for example p-toluenesulfonic acid are added and refluxed on a water.

After removal of the solvent, the residue in aqueous basic

Solution, for example, sodium carbonate solution, sodium bicarbonate solution, potassium carbonate solution, sodium hydroxide solution or potassium hydroxide solution and extracted with an organic solvent, for example, DCM, chloroform, ethyl acetate or diethyl ether. Alternatively, the residue may be dissolved in an organic solvent, for example ethyl acetate, DCM,

Chloroform or diethyl ether are added. The organic phase can be washed with aqueous basic solution, for example sodium carbonate solution, sodium bicarbonate solution, potassium carbonate solution, sodium hydroxide solution or potassium hydroxide solution.

Preparation of tetrahydropyrrolopyrazines with R ⁷ = C (OO) (CH ₂ ) _n (C =O) R ⁸

(CH ₂ ) n OC _1-6 alkyl

The corresponding tetrahydropyrrolopyrazine is reacted with an acid of the general formula HOOC (CH ₂ ) _n (C =O) OCi ₆ with addition of an organic base, for example triethylamine, diisopropylethylamine, diisopropylamine or pyridine, in an organic solvent, for example DCE or DCM. Alkyl, wherein Ci _-6- alkyl in this case preferably represents ethyl, methyl or tert-butyl, at a temperature of 30 - 100 ^c C, preferably 30-83 ⁰ C optionally using bases and optionally coupling reagents in solvents, such as methanol, DMF or DCM implemented. As bases, for example, sodium methoxide, TEA, DIEA or N-methylmorpholine can be used. Suitable coupling reagents are, for example, EDCI, HOBt, DCC, CDI, HBTU, DMAP or pentafluorophenyldiphenylphosphinate. The reaction time can vary between 1 h and 3 d. Acid chlorides or bromides of the general formula CI (O = C) (CH _{2) n} (C = O) Ci-6Alkyl or Br (O = C) (CH2) n (C = O) Ci- ₆ alkyl may in solvents such as DCM, benzene, toluene, THF, DMF, acetonitrile, pyridine, dioxane, water or 1-methylpyrrolidin-2-one or mixtures of these solvents, using bases such as pyridine, DIEA, TEA, N-methylmorpholine or

Sodium bicarbonate optionally be reacted with the addition of a coupling reagent, such as DCC.

The protective group D- _6- alkyl can with the aid of an acid, for example HCl, trifluoroacetic acid or p-toluenesulfonic acid, optionally in a suitable organic solvent, for example acetonitrile, diethyl ether, THF, DCM or toluene, at a temperature of -10-120 ⁰ C. be split off. In addition, the use of aqueous inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate in organic solvents such as methanol, ethanol, dioxane, DCM, THF, diethyl ether or in these solvents as mixtures is possible.

The corresponding tetrahydropyrolopyrazine can also be prepared by reacting the corresponding anhydride in solvents such as DCM, chloroform, 1, 2-dichloroethane, acetone, acetonitrile, dioxane, THF, DMF, diethyl ether, benzene, toluene, ethyl acetate, water, methanol, ethanol, propanol or i-propanol by adding bases such as triethylamine, diethylamine, diisopropylethylamine, pyridine, NaH, optionally with the addition of 18-crown-6, NaOH, KOH, sodium acetate, potassium acetate or potassium carbonate or by adding acids such as sulfuric acid, if appropriate be converted into the tetrahydropyrrolopyrazine acid derivative using coupling reagents such as DMAP, DCC or DIC.

The tetrahydropyrrolopyrazine acid derivative prepared is added with the addition of a base, for example sodium methoxide, N-methylmorpholine, diisopropylamine, triethylamine or diisopropylethylamine, and a coupling reagent, for example EDCI or CDI, DCC, HBTU, DMAP or pentafluorophenyldiphenylphosphinate and optionally hydroxybenzotriazole hydrate with the corresponding amine NHR ⁹ R ¹⁰ in an organic solvent, for example DMF, DCM or THF, at 0-100 ⁰ C, preferably 2O ⁰ C to 69 ° C converted to compounds in which R ⁷ = C (= O) (CH ₂ ) n (C = O) NR ⁹ R ¹⁰ .

For the preparation of compounds in which R ⁷ = C (OO) (CH ₂ ) _n (C =O) NH ₂ , the corresponding reaction with NH ₃ in dioxane is carried out.

NHR.R.0

Another possibility is to react the corresponding tetrahydropyrrolopyrazine with a building block of the general formula HOOC (CH ₂ ) _n (C =O) NR ⁹ R ¹⁰ . The said building block is obtained by reacting the corresponding amine of the formula NHR ⁹ R ¹⁰ with a monoalkyldicarboxylic acid ester or a Dicarbonsäurealkylesterchlorid or bromide or by reaction with the corresponding carboxylic acid anhydride.

The reaction of the Monoalkyldicarbonsäureesters with the corresponding amine is carried out using bases and optionally coupling reagents in solvents such as methanol, DMF or DCM reacted. As bases, for example, sodium methoxide, TEA, DIEA or N-methylmorpholine can be used. Suitable coupling reagents are, for example, EDCI, HOBt, DCC, CDI, HBTU, DMAP or pentafluorophenyldiphenylphosphinate. The reaction time can vary between 1 h and 3 d.

The Dicarbonsäurealkylesterchloride or bromides react in solvents such as DCM, benzene, toluene, THF, DMF, acetonitrile, pyridine, dioxane, water or 1-methyl-pyrrolidin-2-one or mixtures of these solvents Use of bases, for example pyridine, DIEA ₁ TEA, N-methylmorpholine or sodium bicarbonate optionally with addition of a coupling reagent, such as DCC.

The corresponding carboxylic anhydrides are dissolved in solvents such as DCM, chloroform, 1, 2-dichloroethane, acetone, acetonitrile, dioxane, THF, DMF, diethyl ether, benzene, toluene, ethyl acetate, water, methanol, ethanol, propanol or i-propanol by adding Bases such as triethylamine, diethylamine, diisopropylethylamine, pyridine, NaH optionally with the addition of 18-crown-6, NaOH, KOH, sodium acetate, potassium acetate or potassium carbonate or by adding acids such as sulfuric acid, optionally using coupling reagents such as DMAP, DCC or DIC transferred to the appropriate blocks.

The final coupling of the acid moiety and the tetrahydropyrrolopyrazine with addition of a base, for example, sodium, N-methylmorpholine, diisopropylamine, triethylamine or diisopropylethylamine, and optionally a coupling reagent, EDCI, CDI, DCC, HBTU, DMAP or Pentafluorophenyldiphenylphosphinat and optionally

Hydroxybenzotriazolhydrat in an organic solvent, for example DMF, DCM or THF, at 0-100 ⁰ C ₁ preferably 20 ⁰ C to 69 ° C to the compounds reacted.

Preparation of tetrahydropyrrolopyrazines in which R ^{7 is} (C = O) (CH ₂ ) _m NR ¹¹ R ¹²

The tetrahydropyrrolopyrazine is reacted with the addition of an organic base, for example triethylamine, diisopropylethylamine, diisopropylamine or pyridine, with chloroacetyl chloride at a temperature of 40-100 ⁰ C, preferably 40-83 ⁰ C. The resulting product is optionally with a primary or secondary amine in a reaction medium, preferably selected from the group consisting of ethanol, n-butanol, toluene or chloroform, with the addition of a basic salt, preferably Na ₂ CO ₃ or K ₂ CO ₃ , under Addition of an alkali metal halide, preferably potassium iodide or sodium iodide, optionally with the addition of a base, preferably selected from the group consisting of triethylamine, diisopropylethylamine and 4-dimethylamino-pyridine, more preferably triethylamine, at temperatures of 0-160 ⁰ C, preferably 20-120 ⁰ C implemented.

Acylation of the monoalkylated amines

At room temperature, the acid of general formula R ²⁰ COOH with the addition of a base, for example diisopropylamine, triethylamine or diisopropylethylamine, and one of a coupling reagent, for example EDCI or CDI, and optionally hydroxybenzotriazole hydrate with the corresponding tetrahydropyrrolopyrazine in an organic solvent, for example DCM or THF , reacted at 0-10O ⁰ C, preferably 20 ⁰ C to 69 ° C.

Alternatively, a tetrahydropyrrolopyrazine with the addition of a base, for example triethylamine, diisopropylethylamine or diisopropylamine, in an organic solvent, for example DCE or DCM, with an acid chloride of the general formula R ²⁰ (CO) Cl or R ¹³ SO ₂ Cl at a temperature of 0- 100 ⁰ C, preferably reacted 20 ⁰ C to 80 ° C.

Alkyl.

The products in which R ¹² = C (O) R ²⁰ may also be obtained by reacting the tetrahydropyrrolopyrazine with a glycine derivative. The glycine derivative is obtained by reacting the glycine alkyl ester with the corresponding acid of the general formula R ²⁰ (CO) OH using bases and optionally coupling reagents in solvents such as methanol, DMF or DCM. As bases, for example, sodium methoxide, TEA, DIEA or N-methylmorpholine can be used. Suitable coupling reagents are, for example, EDCI, HOBt, DCC, CDI, HBTU, DMAP or pentafluorophenyldiphenylphosphinate. The reaction time can vary between 1 h and 3 d.

The glycine alkyl ester can also be reacted with the corresponding acid chloride or bromide of the general formula R ²⁰ (CO) Cl or R ²⁰ (CO) Br. The carboxylic acid chlorides or bromides react in solvents such as DCM, benzene, toluene, THF, DMF, acetonitrile, pyridine, dioxane, water or 1-methylpyrrolidin-2-one or mixtures of these solvents, using bases such as pyridine. DIEA, TEA, N-methylmorpholine or sodium bicarbonate optionally with the addition of a coupling reagent, such as DCC. The alkyl ester is optionally cleaved off by means of an acid, for example HCl, trifluoroacetic acid or p-toluenesulfonic acid, in a suitable organic solvent, for example acetonitrile, diethyl ether, THF, DCM or toluene, at a temperature of -10-120 ⁰ C. In addition, the use of aqueous inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate in organic Solvents such as methanol, ethanol, dioxane, DCM, THF, diethyl ether or in this solvent as mixtures possible.

The coupling of the glycine derivative to the corresponding tetrahydropyrrolopyrazine is carried out using bases and optionally coupling reagents in solvents such as methanol, DMF or DCM. As bases, for example, sodium methoxide, TEA, DIEA or N-methylmorpholine can be used. Suitable coupling reagents are, for example, EDCI, HOBt, DCC, CDI, HBTU, DMAP or pentafluorophenyldiphenylphosphinate. The reaction time can vary between 1 h and 3 d.

Urea of the monoalkylated amines

The corresponding tetrahydropyrrolopyrazine (R ¹¹ = H) is dissolved in an organic solvent, for example DCE, DCM, chloroform, benzene, toluene, ethanol, acetone, diethyl ether, petroleum ether, dioxane or THF with an isocyanate of the general formula OCNR ²¹ at a temperature of 20 ⁰ C to 110 ⁰ C converted to compounds in which R ^{7 is} C (= O) CH ₂ NR ¹¹ (C = O) NHR ²¹ . The same products are obtained by reacting the corresponding tetrahydropyrrolopyrazine with a functionalized glycine building block. The glycine component is obtained by reacting glycine or N-alkylglycine with isocyanates of the general formula OCNR ²¹ in solvents such as dioxane, water, acetone, diethyl ether or acetonitrile, or mixtures of these solvents Addition of a base, such as triethylamine, NaOH, KOH or K ₂ CO ₃ obtained.

The coupling of the two components is accompanied by the addition of a base, for example

Sodium methoxide, N-methylmorpholine, diisopropylamine, triethylamine or diisopropylethylamine, and optionally a coupling reagent such as EDCI, CDI, DCC, HBTU, DMAP or

Pentafluorophenyldiphenylphosphinat and optionally

Hydroxybenzotriazole hydrate in an organic solvent, for example DMF,

DCM or THF, carried out at 0-100 ⁰ C, preferably 20 ⁰ C to 69 ° C.

Preparation of tetrahydropyrrolopyrazines in which R ^{7 is} CH ₂ C (= O) R ⁸

The tetrahydropyrrolopyrazine is dissolved in an organic solvent, for example acetonitrile, benzene, toluene, ethanol, DMF, THF or dioxane with addition of a base, for example potassium carbonate, NaOH, KOH, sodium amide, sodium ethoxide, potassium tert. Butylate, sodium amide, sodium hydride, triethylamine or diisopropylethylamine with ethyl bromoacetate at 20 ⁰ C to 160 ⁰ C reacted. The ester can by means of an acid, for example HCl, trifluoroacetic acid or p-toluenesulfonic acid, are optionally removed at a convenient organic solvent such as acetonitrile, diethyl ether, THF, DCM or toluene, at a temperature of -10-120 ⁰ C. In addition, the use of aqueous inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate in organic solvents such as methanol, dioxane, DCM ₁ THF, diethyl ether or in these solvents as mixtures is possible.

Preparation of tetrahydropyrrolopyrazines in which R ⁷ = CH ₂ (C = O) NR ⁹ R ¹⁰

The tetrahydropyrrolopyrazine acid derivative can be prepared by adding one of a base, for example diisopropylamine, thethylamine or diisopropylethylamine, and one of a coupling reagent, for example EDCI or CDI, and optionally hydroxybenzotriazole hydrate with the corresponding amine NHR ⁹ R ¹⁰ in an organic solvent, for example DCM or THF ₁ at 0-100 ⁰ C ₁ preferably 20 ⁰ C to 69 ° C are converted to compounds in which R ⁷ = CH ₂ (C = O) NR ⁹ R ¹⁰ .

For the preparation of compounds in which R ⁷ = CH ₂ (C = O) NH ₂ , the corresponding reaction with NH ₃ in dioxane is carried out.

The reactions described above can furthermore in each case be carried out under customary conditions known to the person skilled in the art, for example with regard to pressure, temperature, protective gas atmosphere or sequence of addition of the components. Possibly. can be determined under the respective conditions optimal process control by the skilled person by simple preliminary tests. All of the process steps described above, and in each case also the purification and / or isolation of intermediate or end products, can be carried out partly or completely under an inert gas atmosphere, preferably under a nitrogen atmosphere or argon atmosphere.

The substituted tetrahydropyrrolopyrazine compounds according to the invention can be isolated both in the form of their free bases, their free acids and in each case in the form of corresponding salts, in particular physiologically compatible salts.

The free bases of the respective substituted tetrahydropyrrolopyrazine compounds according to the invention can be prepared, for example, by reaction with an inorganic or organic acid, preferably with hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, carbonic, formic, acetic, oxalic, maleic, malic and succinic acids , Tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid, into the corresponding salts, preferably physiologically acceptable salts.

The free bases of the respective substituted tetrahydropyrrolopyrazine compounds of the present invention may also be reacted with the free acid or a salt of a sugar substitute, e.g. Saccharin, cyclamate or acesulfame, be converted into the corresponding physiologically acceptable salts.

Accordingly, the free acids of the substituted tetrahydropyrrolopyrazine compounds according to the invention can be converted by reaction with a suitable base into the corresponding physiologically tolerated salts. By way of example, the alkali metal salts, alkaline earth metal salts or ammonium salts [NH _x R _4-X ] ⁺ , wherein x is 0, 1, 2, 3 or 4 and R is a linear or branched C ₄ -alkyl radical, may be mentioned. If appropriate, the substituted tetrahydropyrrolopyrazine compounds according to the invention, as well as the corresponding acids, the corresponding bases or salts of these compounds, can also be obtained in the form of their solvates, preferably in the form of their hydrates, by customary methods known to the person skilled in the art.

If the substituted tetrahydropyrrolopyrazine compounds according to the invention are obtained after preparation in the form of a mixture of their stereoisomers, preferably in the form of their racemates or other mixtures of their various enantiomers and / or diastereomers, these can be separated and optionally isolated by conventional methods known to those skilled in the art , Examples which may be mentioned are chromatographic separation processes, in particular liquid chromatography processes under atmospheric pressure or under elevated pressure, preferably MPLC and HPLC processes, and also fractional crystallization processes. In particular, single enantiomers, e.g. by chiral stationary phase HPLC or diastereomeric salts formed by crystallization with chiral acids such as (+) - tartaric acid, (-) - tartaric acid or (+) - 10-camphorsulfonic acid.

The medicament according to the invention can be used as a liquid, semisolid or solid dosage form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, patches, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, optionally compressed into tablets, filled into capsules or suspended in a liquid, are present and as such also administered. In addition to at least one substituted tetrahydropyrrolopyrazine compound according to the invention, the pharmaceutical composition according to the invention usually contains further physiologically acceptable pharmaceutical excipients, which can preferably be selected from the group consisting of excipients, fillers, solvents, diluents, surfactants, dyes, preservatives, disintegrants, lubricants, lubricants, Flavors and binders. The choice of the physiologically acceptable excipients and the amounts to be used depend on whether the drug is administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example on infections of the skin, mucous membranes and on the eyes, to be applied. Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferred for oral administration, solutions, suspensions, readily reconstitutable dry preparations and sprays for parenteral, topical and inhalative administration.

The substituted tetrahydropyrrolopyrazine compounds used in the medicament according to the invention can be present in a depot, in dissolved form or in a plaster, optionally with the addition of skin penetration-promoting agents, as suitable percutaneous administration preparations. Orally or percutaneously applicable preparation forms can release the respective substituted tetrahydropyrrolopyrazine compound according to the invention also delayed.

The pharmaceutical compositions of the present invention are prepared by conventional means, devices, methods and methods known in the art, as described, for example, in "Remington's Pharmaceutical Sciences", by AR Gennaro, 17th Ed., Mack Publishing Company, Easton, Pa , 1985, especially in part 8, chapters 76 to 93. The corresponding description is hereby incorporated by reference and is considered part of the disclosure.

The amount of the respective substituted tetrahydropyrrolopyrazine compound according to the invention to be administered to the patient may vary and depends, for example, on the weight or age of the patient as well as on the mode of administration, the indication and the severity of the disease. Usually, 0.005 to 100 mg / kg, preferably 0.05 to 75 mg / kg of body weight of the patient of at least one such compound of the invention are administered.

In the following the invention will be explained with the help of some examples. These Explanations are merely exemplary and do not limit the general inventive concept.

Examples

In the examples, the radicals R ^4a , R ^5a and R ^{6a are} each H.

Synthesis of 2- (1H-pyrrol-1-yl) ethanamine To a solution of pyrrole (0.06 mol) in acetonitrile (33 ml) was added NaOH (9.4 g, 0.23 mol) and tetrabutylammonium hydrogensulfate (0, 8 g, 2.36 mmol) and stirred for 30 minutes at room temperature. After the addition of 2-chloroethylamine hydrochloride (8.2 g, 0.07 mol), the mixture was refluxed for 24 h. After cooling, the insoluble inorganic residue was filtered off and the solvent was removed under reduced pressure. The crude product was obtained which was used for further reactions without further purification.

Synthesis of 1-aryl-1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazines

Method A

A solution of 2- (1H-pyrrol-1-yl) ethanamine (0.1 mol) and the corresponding aldehyde (0.1 mol) in acetic acid (250 ml) was stirred at room temperature for 48 h. After the reaction was complete, the solvent was removed on a rotary evaporator and the residue taken up in aqueous sodium carbonate solution (10%) and extracted with DCM. Subsequently, the organic phase was dried over MgSO ₄ and concentrated in vacuo. The purification was carried out by column chromatography on neutral Al ₂ O ₃ or by washing with 2-propanol or by crystallization with 2-propanol / n-hexane.

Method B To a solution of 2- (1H-pyrrol-1-yl) ethanamine (0.05 mol) and the corresponding aldehyde (0.05 mol) in ethanol (25 ml) was added acetic acid (0.3 ml) and heated under reflux for 10 min. The mixture was then stirred for a further 1 h at room temperature. The reaction mixture was concentrated on a rotary evaporator and taken up in ethyl acetate. The organic phase was washed with NaHCO ₃ solution, dried over MgSO ₄ and concentrated.

The purification was carried out by column chromatography on neutral Al ₂ O ₃

Method C

A solution of the 2- (1H-pyrrol-1-yl) ethanamine (8.5 g, 77.2 mmol) in DCM (250 mL) was first treated with triethylamine (19.5 mL, 140 mmol) and O ² C cooled. Subsequently, the corresponding acid chloride (84.9 mmol) was added and stirred overnight at room temperature. The reaction was concentrated to dryness under reduced pressure. The residue was taken up in DCM (150 ml), washed with aqueous NaOH solution (1 M, 150 ml) and concentrated to dryness. The resulting amide was purified by column chromatography on silica gel (mobile phase DCM / MeOH, 95: 5). To POCl ₃ (50 mL) was added the appropriate amide (50.7 mmol) at room temperature and refluxed for 2 h. After cooling to room temperature, it was evaporated to dryness, the residue obtained was taken up in DCM (300 ml) and washed with aqueous NH ₄ OH solution (10%, 300 ml). The organic phase was dried üner sodium sulfate and then concentrated to dryness. The purification of the imine formed was carried out by column chromatography on silica gel (mobile phase: DCM / 7 M NH ₃ in MeOH, 95: 5).

To a solution of the imine (22.6 mmol) in MeOH / water (10: 1, 150 mL) was slowly added NaBH ₄ (2.57 g, 67.8 mmol) and stirred at room temperature overnight. As the reaction was still incomplete (TLC control) additional NaBH ₄ (0.86 g, 22.6 mmol) was added and stirred again overnight. The reaction was then concentrated and the residue taken up in NH 4 OH (10%, 450 mL) and extracted with DCM (450 mL). The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (eluent: DCM / 7 M NH ₃ in MeOH, 98: 2).

For the synthesis of the exemplified compounds, the following tetrahydropyrrolopyrazines were used:

N-acylation with malonic acid monoethyl ester chloride or succinic acid monoethyl ester chloride

In a round bottom flask equipped with CaCl ₂ dry tube was added the corresponding 1-aryl-tetrahydropyrrolopyrazine (12.0 mmol) and dissolved in DCE (40 ml). To this very well stirred solution TEA (1, 2 - 2 mol Äq., Based on the acid chloride) was added and then 1, 2 - 2 mol Äq. (relative to the 1-aryl-tetrahydropyrrolopyrazine) of the corresponding acid chloride, the round bottom flask is purged with nitrogen and the Reraktionsansatz for 2-4 h slightly heated (about 40 ⁰ C, TLC control). After completion of the reaction, the solution was diluted with DCE (about 25 ml) and extracted twice with water (2 x 10 ml). The aqueous phase was extracted twice more with DCE (2 × 10 ml) and the combined organic phases were dried over MgSO ₄ and concentrated in vacuo. The crude product was used without further purification for further reactions. Yield: 80 - 90%

10 mmol) was dissolved in a mixture of ethanol / water and NaOH (12 ml / 3 ml / 1.2 mol eq stirred until the reaction was complete (TLC control). The ethanol was removed in vacuo and the resulting oil was dissolved in water (about 20 ml) and washed with either ethyl acetate or diethyl ether. The basic aqueous phase was eliminated using the rotary evaporator of residues of the organic solvent and acidified to cool in an ice bath to below 10 ⁰ C with 3% aqueous HCl (about pH 4-6, depending calculated logD value) and extracted with DCM (2 x 25 ml). After drying over MgSO ₄ , the solvent was removed under reduced pressure. The purification was carried out either by column chromatography (silica gel, eluent chloroform) or by dissolving in chloroform, or the crude product was dissolved in chloroform, treated with silica gel, and then filtered. The residue was then recrystallized from 2-propanol / n-hexane. Yield: 35% - quantitative

Amidation of malonic or succinic acid derivatives

Automated synthesis In a reactor (6 × δ matrix) with the possibility of heating and stirring was first using a Cavro RSP 9000 robot system, a solution of the corresponding malonic acid or succinic acid derivative (250 .mu.mol, 0.1-0.2 M in DCE, 1, 25 - 2.5 ml) in a conical screw-top vial. The solution was prepared by the corresponding, in a vacuum drying oven dried malonic acid or succinic acid derivative with 1, 05 mol eq. 1, 1'-carbonyl-diimidazole mixed in DCE and then anhydrous at room temperature for 1.5 h was allowed to stand. The solution was then diluted to the extent that there was a 0.1-0.2 molar solution. This solution was treated with the appropriate amine (275 .mu.mol, 0.5 M, 0.55 ml) and the reaction vessel was sealed. The reaction was usually carried out at room temperature, only aromatic amines had to be heated to 60 ⁰ C.

For work-up, first of all K ₂ CO 3 solution (5% in water, 1 ml) and then with water (1 ml) were washed. Were used in the subsequent DC If traces of amine were detected, it was washed first with HCl solution (3% in water, 1 ml), then with K ₂ CO ₃ solution (5% in water, 1 ml) and then with water (1 ml).

The organic phase was diluted with ethanol (0.5 ml) and transferred to tared vials. The solvent was then stripped to constant weight in vacuo.

Synthesis of monoalkylated amines

In a round bottom flask equipped with CaCl ₂ -Totern tube, the corresponding 1-aryl-tetrahydropyrrolopyrazine (72 mmol) was added and dissolved in DCE (200 ml). TEA (2 mol eq., Based on the acid chloride) was added to this very well stirred solution and then 1.2 mol eq. (relative to the 1-aryl-tetrahydropyrrolopyrazine) added chloroacetic acid chloride, the round bottom flask purged with nitrogen and the Reraktionsansatz for 2-3 h slightly heated (about 40 ° C, TLC control).

After completion of the reaction, the solution was diluted with DCE (about 120 ml) and extracted twice with water (2 x 10 ml). The aqueous phase was extracted twice more with DCE (2 × 50 ml) and the combined organic phases were dried over MgSO ₄ and concentrated in vacuo. The crude product was used without further purification for further reactions.

Into a 100 ml round bottom flask equipped with CaCl ₂ -Totern tube, the corresponding 1-aryl-tetrahydropyrrolopyrazine (8 - 12 mmol) and the corresponding primary amine (20-30 ml, ca. 25-40 mol eq.). The reaction was stirred overnight at room temperature until complete reaction. The excess amine was removed in vacuo, the residual oil taken up in diethyl ether (50 ml) and extracted twice with acetic acid (3% in water, 50 ml each). The combined aqueous

Phases were cooled in an ice bath and adjusted to about pH 8-9 with Na ₂ CO ₃ solution (10% in water). The mixture was then extracted four times with 50 ml of DCM, the combined organic phases washed with water, dried over MgSO ₄ and concentrated in vacuo. In general, the product could be used without further purification. In some cases it was purified by column chromatography (silica gel, CHCb) Yield: 50 - 75%

Acylation of the monoalkylated amines

Automated synthesis

In a reactor (6 × δ matrix) with the possibility of heating and stirring, a solution of the corresponding monoalkylated amine (250 .mu.mol, 0, 1 - 0.2 M in DCE ₁ 1, 25 - 2.5 ml) was placed in a conical screw-top vial and then first with a solution of TEA (500 .mu.mol, 1 M in DCE, 0.5 ml) and then with a solution of the corresponding carboxylic acid chloride (275 .mu.mol, 0.5 M in DCE, 0.55 ml), sealed and stirred at room temperature until complete reaction (TLC check). The purification was carried out with the help of a Cavro RSP 9000 robot system. For purification, K ₂ CO ₃ solution (5% in water, 1 ml) was first pipetted in to remove residues of the carboxylic acids. Subsequently, the organic phase was washed with water (1 ml). Were after DC control still traces of Detected carboxylic acid, tris (aminoethyl) amine scavenger resin was used. To remove any traces of 1-aryl-tetrahydropyrrolopyrazine, the organic phase was washed with HCl solution (3% in water, 1 ml) and then with K ₂ CO ₃ solution (5% in water, 1 ml). The organic phase was diluted with ethanol (0.5 ml) and transferred to tared vials. The solvent was then stripped to constant weight in vacuo.

Sulfonylation of the monoalkylated amines

Automated synthesis

In a reactor (6 × δ matrix) with the possibility of heating and stirring was using a Cavro RSP 9000 robot system, first a solution of the corresponding monoalkylated amine (250 .mu.mol, 0.1-0.2 M in DCE, 1, 25 - 2.5 ml) was placed in a conical screw top glass and then first with a solution of TEA (500 .mu.mol, 1 M in DCE, 0.5 ml) and then with a solution of the corresponding sulfonyl chloride (275 .mu.mol, 0.5 M in DCE, 0.55 ml), sealed and stirred at room temperature until complete reaction (TLC check). The purification was carried out with the help of a Cavro RSP 9000 robot system. For purification, K ₂ CO ₃ solution (5% in water, 1 ml) was first pipetted in to remove residues of the sulfonic acids. Subsequently, the organic phase was washed with water (1 ml). When traces of the sulfonic acid were still detected after TLC control, tris (aminoethyl) amine scavenger resin was used. To remove any traces of 1-aryl-tetrahydropyrrolopyrazine, the organic phase was washed with HCl solution (3% in water, 1 ml) and then with K ₂ CO ₃ solution (5% in water, 1 ml). The organic phase was diluted with ethanol (0.5 ml) and transferred to tared vials. The solvent was then stripped to constant weight in vacuo. H arn substances of monoalkylated amines

In a reactor (6 × δ matrix) with the possibility of heating and stirring was using a Cavro RSP 9000 robot system, first a solution of the corresponding monoalkylated amine (250 .mu.mol, 0.1-0.2 M in DCE, 1, 25 2.5 ml) in a conical screw-top vial and then mixed with a solution of the corresponding isocyanate (250 .mu.mol, 0.5 M ₁ 0.5 ml), sealed and stirred at room temperature until complete reaction (TLC control), optionally, additional isocyanate solution was added. The purification was carried out with the help of a Cavro RSP 9000 robot system. For the separation of any traces of 1-aryl-tetrahydropyrrolopyrazine, the organic phase was washed with HCl solution (3% in water, 1 ml) and then first with K ₂ CO ₃ solution (5% in water, 1 ml) and then with Washed water (1 ml). The organic phase was diluted with ethanol (0.5 ml) and transferred to tared vials. The solvent was then stripped to constant weight in vacuo.

N-alkylation on the 1-aryltetrahydropyrrolopyrazine skeleton

A mixture of the pyrrolopyrazine (10 mmol), acetonitrile (10 ml), finely powdered K ₂ CO ₃ and the haloalkane was heated under stirring and nitrogen atmosphere until complete reaction of the pyrrolopyrazine under reflux (TLC control, about 1 - 2 h). Subsequently, the solvent was completely removed on a rotary evaporator. The residue was taken up in chloroform (about 10 ml) and washed with water (about 5 ml). The organic phase was dried over MgSO ₄ and concentrated in vacuo. The crude product was used without further purification for further reactions. Yield: 80 - 90%

Amidation of N-alkylated 1-aryltetrahydropyrrolopyrazines

Automated synthesis

In a reactor (6 × δ matrix) with the possibility of heating and stirring, using a Cavro RSP 9000 robot system, a solution of the corresponding malonic acid or succinic acid derivative (250 μmol, 0.1-0.2 M in DCE, 1, 25-2.5 ml) in a conical screw-top vial. The Solution was prepared by the corresponding, in a vacuum drying oven dried malonic acid or succinic acid derivative with 1, 05 mol eq. 1, 1'-carbonyl-diimidazole mixed in DCE and then anhydrous at room temperature for 1.5 h was allowed to stand. The solution was then diluted to the extent that there was a 0.1-0.2 molar solution.

This solution was treated with the appropriate amine (275 .mu.mol, 0.5 M, 0.55 ml) and the reaction vessel was sealed. The reaction was usually carried out at room temperature, only aromatic amines had to be heated to 60 ⁰ C. For work-up, first of all K ₂ CO 3 solution (5% in water, 1 ml) and then with water (1 ml) were washed. If traces of amine were detected in the subsequent TLC control, the reaction was initially with HCl solution (3% in water, 1 ml) followed by K ₂ CO ₃ solution (5% in water, 1 ml) and then with water (1 ml). The organic phase was diluted with ethanol (0.5 ml) and transferred to tared vials. The solvent was then stripped to constant weight in vacuo.

2- [1- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N - (3-trifluoromethyl-benzyl) -acetamide 8

1 H NMR (600 MHz, DMSO-d ₆ ) d ppm 2.69 - 2.96 (m, 2H) 2.96 - 3.16 (m, 2H) 3.86 - 4.09 (m, 1H) 4.14 - 4.28 (m, 5H) 4.35 (m, 2 H) 4.51 (s, 1 H) 5.17 (brs s., 1 H) 5.90 (t, J = 3.02 Hz, 1 H) 6.62 (br. S., 1 H) 6.77 (d, J = 8.31Hz, 1H) 6.86 (dd, J = 8.31, 1.51Hz, 1H) 6.92 (d, J = 2.27Hz, 1H) 7.49-7.63 (m, 4H) 8.62 (t, J = 6.04 Hz, 1H)

The following examples were synthesized according to the above instructions and purified by HPLC. The analysis was carried out by HPLC-MS. In all cases the mass was detected by ESI-MS; the purity was above 85%.

No name mass

1 4- [1- (4-chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -4-oxo 489.1

N- (3-trifluoromethyl-benzyl) -butyramide

2 4-Oxo-4- (1-phenyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -N- (3-455,2-trifluoromethyl-benzyl) -butyramide No name mass

3 N-sec-Butyl-2- [1- (2-methoxyphenyl) -3,4-dihydro-1H-pyrrolo [1,2- 341,2 a] pyrazine-2-yl] -acetamide

4 N-Cyclopropyl-3- [1- (3-fluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2- 341,2 a] pyrazin-2-yl] -3-oxo-propionamide

5 4-Oxo-4- (1-m-tolyl-3,4-dihydro-1 H -pyrrolo [1,2-a] pyrazin-2-yl) -N- (3-669,2-trifluoromethyl-benzyl) -butyramide

6 3- {2- [1 - (2-Chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazino-2-yl] -2-360.1-oxo-ethyl} -1 , 1-dimethyl-urea

7 4- [1 - (4-Fluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -N-371.2-isobutyl-4-oxo-butyramide

8 2- [1- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -3,4-dihydro-1H-pyrrolo [1,2,71,2a] pyrazine-2-yl] -N- (3-trifluoromethyl-benzyl) -acetamide:

9 2- [1- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -3,4-dihydro-1H-pyrrolo [1,2,3-a) pyrazine-2-yl] np-tolyl-acetamide

10 3-tert-Butyl-1- {2- [1- (2,4-difluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2,3,2,2a] pyrazin-2-yl] - 2-oxo-ethyl} -1-isopropyl-urea

11 2- [1- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -3,4-dihydro-1H-pyrrolo [1,2,35,2a] pyrazine-2-yl] -N-isopropyl-acetamide

12 3-tert-Butyl-1-isopropyl-1 - [2-oxo-2- (1-m-tolyl-3,4-dihydro-1H-410.3-pyrrolo [1,2-a] pyrazine-2-yl ) ethyl] urea

13 N-Cyclopropyl-N- [2- (1-furan-3-yl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine 403.2

2-yl) -2-oxo-ethyl] -4-methyl-benzamide

14 Cyclopropanecarboxylic acid {2- [1- (3,4-dichlorophenyl) -3,4-dihydro-1 H-433.1-pyrrolo [1,2-a] pyrazine-2-yl] -2-oxo-ethyl} isopropyl-amide

15 1-Cyclopropyl-1- {2- [1- (2,4-difluoro-phenyl) -3,4-dihydro-1 H -pyrrolo [1,2-4,16,2a] pyrazin-2-yl] -2-oxo ethyl} -3-isopropyl-urea

16 1- (4-acetylpiperazin-1-yl) -2- [1- (2,4-difluoro-phenyl) -3,4-dihydro-1H-402,2-pyrrolo [1,2-a] pyrazine 2-yl] -ethanone

17 furan-2-carboxylic acid-cyclopropyl {2- [1- (3,4-dichlorophenyl) -3,4- 457,1 dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] - 2-oxo-ethyl} -amide No name mass

18 N-tert-butyl-N- [2-oxo-2- (1 -p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine) 395.3

2-yl) -ethyl] -isobutyramide

19 N-Cyclopropyl-N- {2- [1- (3,4-dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2,33,1 a] pyrazine-2-yl] -2- oxo-ethyl} -isobutyramide

20 2- (1- (3-methoxyphenyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- 443.2

(3- (trifluoromethyl) benzyl) acetamide

21 1-Ethyl-3,3-dimethyl-1- [2-oxo-2- (1-phenyl-3,4-dihydro-1H-pyrrolo [1,2,34,2a] pyrazine-2-yl) - ethyl] urea

22 Quinoline-8-sulfonic acid {2- [1- (2,4-difluoro-phenyl) -3,4-dihydro-1 H-510.2-pyrrolo [1,2-a] pyrazin-2-yl] -2- oxo-ethyl} ethyl amide

23 N-Cyclopropyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) - 309.2 acetamide

24 Cyclopropanecarboxylic acid tert-butyl - ^ - oxo ^^ i -p-tolyl-S ^ -dihydro-I H-393.2-pyrrolo [1,2-a] pyrazin-2-yl) -ethyl] -amide

25 Furan-2-carboxylic acid tert-butyl {2- [1- (3,4-dichloro-phenyl) -3,4-dihydro-473.1

1 H-pyrrolo [1,2-a] pyrazine-2-yl] -2-oxo-ethyl} -amide

26 2- [1- (2-Chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazino-2-yl] -1- 357.2 -piperidine-1-yl-ethanone

27 2-phenylcyclopropanecarboxylic acid ethyl [2-oxo-2- (1-phenyl-3,4- 427,2-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -ethyl] -amide

29 N- (4-Fluoro-phenyl) -4- [1 - (3-methoxy-phenyl) -3,4-dihydro-1 H -pyrrolo [1,2- 421,2 a] pyrazin-2-yl] -4 oxo-butyramide

30 N-Ethyl-N- [2-oxo-2- (1-phenyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-353,2-yl) -ethyl] -butyramide

31 N- (1,2-Dimethyl-propyl) -2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2,39,2a] pyrazin-2-yl) -acetamide

32 N-sec-butyl-C1-C-p-tolyl-S-dihydro-1H-pyrroloti-ajpyrazine-1-yl) - 325.2 acetamide

33 N- {2- [1- (3,4-Dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] - 421.1

2-oxo-ethyl} -N-ethyl-isobutyramide No name mass

34 4- [1- (3-methoxyphenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -4- 418.2-oxo-N-pyridin-4-ylmethyl butyramide

35 furan-2-carboxylic acid isopropyl {2- [1- (4-isopropyl-phenyl) -3,4-dihydro-433.2

1 H-pyrrolo [1,2-a] pyrazine-2-yl] -2-oxo-ethyl} -amide

36 1 - [1 - (3-Methoxy-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -3- 383.2-morpholin-4-yl-propane-1 , 3-dione

37 2- (1-p-Tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -N- (3-427,2-trifluoromethyl-benzyl) -acetamide

38 N-Pyridin-3-ylmethyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine 360.2

2-yl) -acetamide

39 2- [1- (2,4-Difluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N-371.1-furan-2-ylmethyl-acetamide

41 N-Benzyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) - 359.2 acetamide

42 N- (3,4-dimethylphenyl) -3- [1- (3-methoxyphenyl) -3,4-dihydro-1H-417.2-pyrrolo [1,2-a] pyrazine-2-yl] -3-oxo-propionamide

43 4- [1- (3-chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N-373.2-isopropyl-4-oxo-butyramide

44 N- (1-Benzyl-piperidin-4-yl) -2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2,42,3a] pyrazine-2-yl) -acetamide

45 2- [1- (4-chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -1- [4- (2-468.1 chloro-phenyl ) piperazin-1-yl] -ethanone

46 N- (1-Benzyl-piperidin-4-yl) -2- [1- (4-chloro-phenyl) -3,4-dihydro-1H-462.2-pyrrolo [1,2-a] pyrazine-2-one yl] acetamide 8 1- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2- [1- (4-chloro-phenyl) -492.2

3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -ethanone 9 N-Phenethyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [ 1, 2-a] pyrazine-2-yl) - 373.2 acetamide

50 2- [1- (3,4-dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N-428.1

(2-pyridin-2-yl-ethyl) -acetamide No name mass

51 1- (4-Benzo [1,3-dioxol-5-ylmethyl-piperazin-1-yl) -2- (1-p-tolyl-3,4-47,2,2-dihydro-1H-pyrrolo [1, 2 a] pyrazin-2-yl) -ethanone

52 2- [1- (3,4-dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -N- 414.1 -pyridin-3-ylmethyl-acetamide

53 1- (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2- [1- (2-chloro-phenyl) -492.2

3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -ethanone

54 1- (4-benzyl-piperazin-1-yl) -2- [1- (4-chloro-phenyl) -3,4-dihydro-1H-448,2-pyrrolo [1,2-a] pyrazine-2-one yl] -ethanone

55 2- [1- (4-Chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -N- 393.2 -phenethyl-acetamide

56 2- [1- (2-Chloro-phenyl) -3,4-dihydro-1 H -pyrrolo [1,2-a] pyrazin-2-yl] -N- 393.2 -phenethyl-acetamide

57 2- [1- (3,4-dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N- 431.1

acetamide (4-fluoro-benzyl)

58 1- (4-Benzylpiperazin-1-yl) -2- [1- (2-chlorophenyl) -3,4-dihydro-1H-448,2-pyrrolo [1,2-a] pyrazine-2-yl ] ethanone

59 N-Cyclohexyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl) - 351.2 acetamide

60 1- (4-Benzyl-piperazin-1-yl) -2- (1-p-tolyl-3,4-dihydro-1 H -pyrrolo [1,2,3,4-a] pyrazin-2-yl) -ethanone

61 2- [1- (4-chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N- (1,2,329-dimethyl-propyl) -acetamide

62 N- (2-piperidin-1-yl-ethyl) -2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2,3,3,3,3] pyrazine-2-yl) -acetamide

65 N- (4-Fluoro-phenyl) -2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-363.2 yl) -acetamide

66 furan-2-carboxylic acid ethyl [2-oxo-2- (1-p-tolyl-3,4-dihydro-1 H-391.2-pyrrolo [1,2-a] pyrazine-2-yl) -ethyl] amide

67 2- [1- (4-fluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N-315.2-isopropyl-acetamide No name mass

68 2- [1- (3,4-dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -N-379.1-isobutyl-acetamide

69 2- [1- (4-chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N- (2-386.2 -pyrrolidin-1-yl-ethyl ) -acetamide

70 N-Benzo [1,3] dioxol-5-ylmethyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2,3-a) pyrazin-2-yl) -acetamide

71 2- (1- (4-Chlorophenyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (4-397.1 fluorobenzyl) acetamide

72 2- (1- (4-chlorophenyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (3-447.1

(Trifluoromethyl) benzyl) acetamide

73 2- (1- (4-Chlorophenyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -1- (4- (4-6,6,2-methoxyphenyl) -piperazine-1 yl) ethanone

74 N- (2,4-dichlorophenethyl) -2- (1- (3,4-dichlorophenyl) -3,4- 495,0-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -acetamide

75 1 - (4- (3-chlorophenyl) -piperazin-1-yl) -4- (1-m-tolyl-3,4-dihydropyrrolo [1,2,4- 4,00-a] pyrazine-2 (1H) -yl) butane-1, 4-dione

Synthesis of Exemplified Compounds 76 to 82. 87. 88 and 92 Synthesis of 4-oxo-4- (3- (trifluoromethyl) benzylamino) butanoic acid (S1)

To a suspension of 7.54 g (75.4 mmol) of succinic anhydride in ether (89 ml) was added a solution of 15.0 g (85.6 mmol) of (3- (trifluoromethyl) phenyl) methylamine in ether (18 ml). added dropwise within 30 min, then it was stirred at RT for 72 h. The resulting precipitate was filtered off with suction and washed with ether. The residue was dried and then crystallized from ether. SC (EE / MeOH 2: 1) of the crystallization product gave 13.2 g (47.9 mmol, 64%) of 4-oxo-4- (3- (trifluoromethyl) benzylamino) butanoic acid (S1).

Synthesis of 4-oxo-4- (1- (3- (trifluoromethyl) phenyl) ethylamino) butanoic acid (S2) To a suspension of 2.33 g (23.3 mmol) succinic anhydride in ether (28 ml) was added a solution of 5.0 g (26.5 mmol) of 1- (3- (trifluoromethyl) phenyl) ethylamine in ether (6 ml) was added dropwise over 30 min. The mixture was then stirred at RT for 72 h. Of the The resulting precipitate was filtered off with suction and dried at 40 ^° C. for 1 h in vacuo. SC (EE / MeOH 1: 4) of the residue afforded 3.68 g (12.7 mmol, 55%) of 4-oxo-4- (1- (3- (trifluoromethyl) phenyl) ethylamino) butanoic acid (S2).

Synthesis of (E) -2- (3- (2-fluorophenyl) acrylamido) acetic acid S7 a) Synthesis of (E) -2- (3- (2-fluorophenyl) acrylamido) acetic acid methyl ester

To a solution of (3.3 g, 20.0 mmol) 2'-fluorocinnamic acid in DCE (60 ml) was added (3.9 g, 24.0 mmol) CDI and the reaction solution was stirred at RT for 2 h. Then (2.76 g, 22.0 mmol) of glycine methyl ester hydrochloride and (4.37 mL, 25.0 mmol) of diisopropylethylamine were added and stirring was continued at RT for 5 h. It was then diluted with DCM (20 ml) and washed with water. The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. SC (DCE / ethanol 20: 1) with the residue gave 2.4 g (10.1 mmol, 51%) of methyl (E) -2- (3- (2-fluorophenyl) acrylamido) acetate.

b) Synthesis of (E) -2- (3- (2-fluorophenyl) acrylamido) acetic acid

A solution of (2.34g, 9.9mmol) (E) -2- (3- (2-fluorophenyl) acrylamido) acetic acid methyl ester in ethanol (50ml) was treated with a solution of (400mg, 10, 0 mmol) sodium hydroxide in water (2 ml). The reaction solution was stirred for 1 h at RT and then concentrated in vacuo. The residue was taken up in water and washed twice with ethyl acetate. Then, the aqueous phase was carefully adjusted to pH 4 with 3% hydrochloric acid and extracted with ethyl acetate. The organic phase was concentrated in vacuo to give, as residue, 1.22 g (5.5 mmol, 55%) of (E) -2- (3- (2-fluorophenyl) acrylamido) acetic acid (S7).

2-Amino-1- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) ethanone A23 a) Synthesis of tert-butyl 2-oxo-2- (1 phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) ethyl carbamate. To a solution of Boc-glycine (1.2 g, 6.7 mmol) in DCE (20 ml) was added ( 1, 1 g, 7.0 mmol) of CDI and it was stirred for 100 min at RT. Then (1, 3 g, 6.7 mmol) of 1-phenyl-1, 2,3,4-tetrahydropyrrolo [1, 2-a] pyrazine (A2) was added and stirred for a further 2 h at RT. Thereafter, it was heated to 50 ^° C. for 2 hours. Subsequently, (450 mg, 2 mmol) Boc-glycine imidazolide was added and it was allowed to stand for 2 h Reflux heated. After cooling to rt, it was washed successively with a 5% sodium bicarbonate solution, a 5% aq. Citric acid solution, water and brine. The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. By SC (DCE) with the residue, 1, 4 g (4.1 mmol, 61%) tert-butyl 2-oxo-2- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine- 2 (1H) -yl) ethylcarbamate.

b) Synthesis of 2-amino-1- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) ethanone A solution of (1.6 g, 4.6 mmol ) tert-Butyl 2-oxo-2- (1-phenyl-3,4-dihydropyrrolo)

[1,2-a] pyrazine-2 (1H) -yl) ethylcarbamate in DCM (20 ml) was added TFA (20 ml) and stirred at RT for 1 h. The mixture was then diluted with water while cooling (ice bath) and adjusted to pH 10 with 20% strength potassium carbonate solution. The aqueous phase was saturated with sodium chloride and then extracted with chloroform. The organic phase was dried over MgSO ₄ , filtered and concentrated

Vacuum concentrated. By SC (DCE / EtOH / conc. Aq. NH ₃ 5: 1: 0.06), 298 mg (1.2 mmol, 26%) of 2-amino-1- (1-phenyl-3,4-dihydropyrrolo [1, 2- a] pyrazine-2 (1H) -yl) ethanone (A23).

Acylation Reactions Method A

To a solution of the corresponding butanoic acid derivative (S1 or S2) (1.0 mmol) in THF (8 ml) was added the corresponding tetrahydropyrolopyrazine (1.1 mmol), NEt ₃ (263 μl, 1.9 mmol) and HATU (380 mg, 1.0 mmol). The reaction solution was stirred for 2 d at RT and then concentrated in vacuo. By SC (EE / DCM 1: 9 → 1: 1), the crude products were purified.

Method B

To a solution of (1.68 mmol) of the appropriate acid in DCM (27 ml) was added CDI (286 mg, 1.76 mmol) and stirred at RT for 1 h. Then the appropriate amine (1.68 mmol) was added and stirring was continued at RT for 16 h. Thereafter, a 4N aq. Ammonium chloride solution was added and the phases were separated. The aqueous phase was extracted twice more with DCM. The organic phases were combined and washed with a 1M Washed sodium bicarbonate solution, dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by SC (ethyl acetate).

Method C

To a solution of the appropriate amine moiety (0.7 mmol) in DCM (20 mL) was added the appropriate acid (1.05 mmol) and PS-diimide (1.18 g, ~ 1.4 mmol). It was then shaken for 2 h at RT. Thereafter, the resin was filtered off and washed several times with DCM and MeOH. The filtrate was concentrated in vacuo. SC (DCE / ethanol 20: 1) with the residue gave the corresponding product.

Synthesis of Exemplified Compounds 76 to 82

Synthesis of Exemplified Compounds 87 and 88

Synthesis of Exemplified Compound 92

Synthesis of Exemplified Compounds 83 to 86, 89 and 90

Synthesis of 4-oxo-4- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) butanoic acid (S3)

A suspension of succinic anhydride (176 mg, 1.76 mmol) in MeCN (28 mL) was treated with 1-phenyl-1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine (A2) (396 mg, 2 , 0 mmol) and NEt ₃ (277 .mu.l, 2.0 mmol) and stirred for 16 h at RT. It was then diluted with EA (30 ml) and washed with 2N hydrochloric acid (2 × 5 ml). The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue obtained was taken up in EA (50 ml) and redissolved with 2N hydrochloric acid (20 ml) followed by a sat. aq. sodium carbonate solution (2 x 30 ml). Again, the organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. By SC (EE / MeOH 3: 1) with the residue, 230 mg (0.77 mmol, 44%) of 4-oxo-4- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine) were added. 2 (1H) -yl) butanoic acid (S3).

Synthesis of 4- (1-methyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -4-oxobutanoic acid S4

To a suspension of (558 mg, 5.6 mmol) succinic anhydride in THF (10 mL) was added a solution of (190 mg, 1.4 mmol) 1-methyl-1,2,3,4-tetrahydropyrrolo [1, 2 -a] pyrazine (A21) in THF (10 ml) was added dropwise within 30 min. The mixture was then stirred at RT for 2 h and concentrated in vacuo. The residue was taken up with chloroform, washed with water and brine, dried over MgSO ₄ and concentrated Vacuum concentrated. This gave 257 mg (0.92 mmol, 54%) of 4- (1-methyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -4-oxobutanoic acid (S4) ,

Synthesis of 3-oxo-3- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) propanoic acid S5

a) Synthesis of methyl 3-oxo-3- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) propanoate

To a solution of (1.5 g, 7.6 mmol) 1-phenyl-1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine (A2) and (1.27 mL, 9.1 mmol) NEt ₃ in DCM (35 mL A solution of (852 μl, 7.9 mmol) methyl malonyl chloride in DCM (5 ml) was added dropwise with vigorous stirring and cooling (ice bath). The mixture was then stirred at RT for 60 min. It was then washed with water and brine and the organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. SC (chloroform / ethyl acetate 10: 1) gave 1.26 g (4.2 mmol, 55%) of 3-oxo-3- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) propanoic acid methyl ester.

b) Synthesis of

3-Oxo-3- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -propanoic acid

To a solution of (41.26 g, 55%) methyl 3-oxo-3- (1-phenyl-3,4-dihydro-pyrrolo [1,2-a] pyrazine-2 (1 H) -yl) propanoate in ethanol ( 20 ml) was added a solution of (260 mg, 4.6 mmol) potassium hydroxide in water (10 ml). The reaction solution was stirred at RT for 3 h and then concentrated in vacuo. The residue was taken up in water and washed twice with ethyl acetate. Then the aqueous phase was adjusted to pH 4 with 20% hydrochloric acid and extracted with dichloromethane. The organic phase was concentrated in vacuo, the residue being 1.03 g (3.8 mmol, 86%) of 3-oxo-3- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) propanoic acid (S5).

acylation

A solution of (1.68 mmol) of the corresponding acid S3, S4 or S5 in DCM (27 ml) was admixed with CDI (286 mg, 1.76 mmol) and stirred at RT for 1 h.

Then the appropriate amine (1.68 mmol) was added and stirring was continued at RT for 16 h. After that, with a 4N aq.

Ammonium chloride solution and the phases were separated. The watery

Phase was extracted 2 more times with DCM. The organic phases were combined and washed with a 1 M sodium bicarbonate solution, dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by SC (ethyl acetate).

Synthesis of Exemplified Compound 91 2- (1-Phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) acetic acid

a) Synthesis of 2- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -acetic acid methyl ester

A mixture of (1.0g, 5.0mmol) 1-phenyl-1,2,3,4-tetrahydropyrrolo [1,2a] pyrazine, 2-bromoacetic acid ethyl ester (587μl, 5.3mmol) and potassium carbonate (1.74 g, 12.6 mmol) in acetonitrile (20 mL) was heated at reflux for 2 h. Thereafter, water (10 ml) and EA (20 ml) were added, stirred for 15 minutes and the phases were separated. The organic phase was dried over MgSO ₄ , filtered and concentrated

Vacuum concentrated. The residue obtained was 1.38 g of 2- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -acetic acid methyl ester, which was used without further purification in the next step.

b) Synthesis of 2- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) acetic acid

To a solution of (1.38 g crude product, ~ 5.04 mmol) of 2- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -acetic acid methyl ester in ethanol (20 ml ) was added a solution of (300 mg, 5.3 mmol) potassium hydroxide in water (10 ml). The reaction solution was stirred at RT for 3 h and then concentrated in vacuo. The residue was taken up in water and washed twice with EA. Then the aqueous phase was adjusted to pH 4 with 20% hydrochloric acid and extracted with dichloromethane. The organic phase was concentrated in vacuo, the residue being 950 mg (3.7 mmol, 74%) of 2- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) acetic acid were obtained.

acylation

To a solution of (1.68 mmol) of the acid S6 in DCM (27 ml) was added CDI (286 mg, 1.76 mmol) and stirred at RT for 1 h. Then the appropriate amine (1.68 mmol) was added and stirring was continued at RT for 16 h. Thereafter, a 4N aq. Ammonium chloride solution was added and the phases were separated. The aqueous phase was extracted twice more with DCM. The organic phases were combined and washed with a 1M Washed sodium bicarbonate solution, dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by SC (ethyl acetate).

Biological data

Fluorescence assay using a voltage-sensitive ^dyes'

Human CHO-K1 cells expressing KCNQ2 / 3 channels are transfected into cell culture flasks (eg 80 cm ² TC flasks, Nunc) with MEM alpha medium (1x, liquid, Invitrogen, # 22571), 10% fetal calcium serum (FCS) (FCS). Invitrogen, # 10270-106, heat inactivated) and the necessary selection antibiotics are cultured adherently at 37 ° C, 5% CO ₂ and 95% humidity.

Before sowing for the measurements, the cells are washed with a 1 × DPBS buffer without Ca ² VMg ²⁺ (eg Invitrogen, # 14190-094) and detached from the bottom of the culture vessel by means of Accutase (PAA Laboratories, # L11-007) (incubation with Accutase for 15 min at 37 ° C). The number of cells then determined is determined using a CASY ™ cell counter (Model TCC, Schärfe System) to subsequently transfer 20,000 cells / well / 100 μl of the described nutrient medium to the 96 well Corning ™ CellBIND ™ (Fiat Clear Bottom Black Polystyrene Microplates, # 3340). This is followed by a one-hour incubation at room temperature without fumigation or humidity control, followed by a 24 hour incubation at 37 ° C, 5% CO ₂ and 95% humidity.

The voltage-sensitive fluorescent dye from the Membrane Potential Assay Kit (Red ™ BuIk format part R8123 for FLIPR, Molecular Devices ™) is prepared by adding the contents of one vessel of Membrane Potential Assay Kit Red Component A to 200 ml of Extracellular Buffer (ES buffer, 120 mM NaCl, 1mM KCl, 10mM HEPES, 2mM CaCl ₂ , 2mM MgCl ₂ , 10mM glucose, pH 7.4). After acceptance of the Nutrient media, the cells are washed with 200 ul ES buffer, then overlaid with 100 ul of the above dye solution and incubated for 45 min at room temperature under light.

The fluorescence measurements are performed with a BMG Labtech FLUOstar ™ or BMG Labtech POLARstar ™ instrument (525 nm Exation, 560 nm emission, bottom read mode). After the dye incubation, 50 .mu.l of the substances to be tested in the desired concentrations or 50 .mu.l of ES buffer are placed in separate wells of the measuring plate for control and incubated for 30 min at room temperature with the shielding of light. The fluorescence intensity of the dye is then measured for 5 minutes and the fluorescence value Fi of each well is determined at a fixed and constant point in time. Subsequently, 15 μl of a 100 mM KCl solution (final concentration 92 mM) is added to each well. The change in fluorescence is then measured until all relevant measured values have been obtained (primarily 5-30 min). At a fixed time after KCI application, a fluorescence value F _{2 is} determined, in this case at the time of the fluorescence peak.

For the calculation, the fluorescence intensity F _{2 is} compared with the fluorescence intensity Fi and from this the agonistic activity of the target compound on the potassium channel is determined. F ₂ and Fi are charged as follows:

^F ^ ^{~ F} "Mxlθθ = f-) (%)

.DELTA.F

To determine if a substance has agonistic activity, e.g. -

F with - are compared by control cells. - is determined by IF) _κ VF) _κ to the reaction mixture instead of the substance to be tested only the buffer solution is added, determines the value F _1K of the fluorescence intensity, adding the potassium ions as described above and a value F _2K measures the fluorescence intensity. Then F ₂ K and Fi «are calculated as follows: A substance has an agonistic activity on the potassium channel when

AF .... (AFλ. - greater than - is:

F \ F) _κ

AF_ (AFλ F [F) _K

AF (AFλ

Regardless of the comparison of - with - can also be on an agonistic

FKFJ _K

Close the activity of a target compound, if with increasing dosage of

AF target connection is an increase of - to observe.

Calculations of EC ₅ O and IC ₅ o values are made with the help of the software ^' Prism 4 ^'

(GraphPad Software ™).

By way of example, the following compounds were investigated:

Table 1: BMG AG% @ 10 μmol / EC50 values

Voltage-clam p measurements

To electrophysiologically confirm a KCNQ2 / 3 agonistic effect of the substances, patch-clamp measurements (Hamill et al., 1981) were performed in voltage-clamp mode on a stably transfected hKCNQ2 / 3 CHO-K1 cell line. After the formation of the Gigaseal, the cells were initially at a holding potential of -60 clamped in mV. Subsequently, depolarizing voltage jumps were applied up to a potential of +20 mV (increment: 20 mV, duration: 1 second) to confirm the functional expression of KCNQ2 / 3 typical currents. Substance testing was performed at a potential of -40 mV. At each cell, the retigabine (10 μM) induced current increase at -40 mV was first registered as a positive control. After complete washing out of the Retigabineffektes (duration: 80 s) the test substance was applied.

Hamill OP, Martv A, Neher E, Sakmann B. Siqworth FJ: Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pfluαer's Arch. 1981 Aug; 391 (2): 85-100. By way of example, the following compounds were investigated:

Table 2: MAN rel. Eff. @ 10 μmol

Bennett Model: Neuropathic pain in the mouse or rat

The study of efficacy in neuropathic pain was investigated in the Bennett model (chronic constriction injury, Bennett and Xie, 1988, Pain 33: 87-107).

Sprague-Dawley rats weighing 140-16Og are under Narcoren-

Anesthesia with four loose ligatures of the right nervus ischiaticus provided. NMRI

Mice weighing 16-18g are treated with three loose ligatures of the right nervus ischiaticus under Ketavet-Rompun anesthesia. The animals develop hypersensitivity to the paw innervated by the damaged nerve, which is quantified after a recovery period of one week for about four weeks using a 4 ° C cold metal plate (cold allodynia). The animals will be for one

Period of 2 min. observed on this plate and the number of pull-out reactions of the injured paw is measured. Based on the Preoperative value before substance application, the substance effect over a period of one hour at four time points (eg, 15, 30, 45, 60 minutes after application) determines and the resulting area under the curve (AUC) and the inhibition of cold allodynia to the individual Measurement points expressed in percent effect on vehicle control (AUC) or on the initial value (single measurement points). The group size is n = 10, the significance of an anti-allodynic effect (* = p <0.05) is determined by means of a repeated measures analysis of variance and a Bonferroni post hoc analysis.

By way of example, the activity of Example 2 was tested in the Bennett model (i.v.- application). At a dosage of 10 mg / kg, 40% MPE was measured.

Chung model: Mononeuropathy pain after spinal nerve ligation

Animals: Male Sprague Dawley rats (140-16Og) from a commercial breeder (Janvier, Genest St. Isle, France) were kept under a 12: 12h light-dark rhythm. The animals were kept ad libitum with food and tap water. Between the delivery of the animals and the operation a break of one week was kept. The animals were repeatedly tested after surgery for a period of 4-5 weeks, with a washout of at least one week was observed.

Model Description: Under pentobarbital anesthesia (Narcoren ^®, 60 mg / kg ip, Merial GmbH, Hallbergmoos, Germany), were left L5, exposed L6 spinal nerves by removing a piece of the paravertebral muscles and a part of the left spinal process of the L5 lumbar vertebra were. The spinal nerves L5 and L6 were carefully isolated and ligated with a solid ligature (NC-silk black.USP 5/0, metric 1, Braun Melsungen AG ₁ Melsungen, Germany) (Kim and Chung 1992). After ligature, muscle and adjacent tissues were sutured and the wound closed with metal clips. After a week of recovery time, the animals were placed in cages with a wire bottom to measure mechanical allodynia. On an ipsi- and / or contralateral hind paw, the withdrawal threshold was determined by means of an electronic von Frey filament (Somedic AB ₁ Malmö, Sweden). The median of five stimulations gave one measurement point. The animals were 30 min before and at various times after application of test substance or vehicle solution tested. The data were determined as% maximum possible effect (% MPE) from the pretests of the individual animals (= 0% MPE) and the test values of an independent sham control group (= 100% MPE). Alternatively, the withdrawal thresholds were displayed in grams. Statistical evaluation: EDsn values and 95% confidence intervals were determined by semilogarithmic regression analysis at the time of maximal effect. Data were analyzed by repeated measures analysis of variance and Bonferroni post hoc analysis. The group size was usually n = 10. References: Kim.SH and Chung.JM, An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat, Pain, 50 (1992) 355-363.

By way of example, the activity of Example 2 was tested in the Chung model (iv application). ED ₅₀ of 2.8 mg / kg was determined.

The stationary phase used for the column chromatography was silica gel 60 (particle size 0.040-0.063 mm) from E. Merck, Darmstadt.

Abbreviations: aq. Aqueous

Brine saturated, aqueous NaCl solution

CDI 1, 1'-carbonyldiimidazole d day (s)

DCC N.N'-dicyclohexylcarbodiimide

DCM dichloromethane

DCE 1, 2-dichloroethane

DIC diisopropylaminoethyl chloride hydrochloride

DMAP 4-dimethylaminopyridine

EE ethyl acetate

Ether diethyl ether sat. saturated h hour (s)

HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium

hexafluorophosphate

HBTU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium

hexafluorophosphate

Solution Solution m / z Ratio Mass to charge

MeCN acetonitrile

MeOH methanol min

MS mass spectroscopy

NEt ₃ triethylamine

PS diimide a polymer bound carbodiimide having the following structure Loading: 0.9-1.4 mmol / g particle size: 75-150 μm

RT room temperature 23 ± 7 ⁰ C

SC column chromatography on silica gel

TFA trifluoroacetic acid

THF tetrahydrofuran

Claims

Claims: 1. Substituted tetrahydropyrrolopyrazine compounds of the general formula I ₁ wherein R ^1, R ² and R ³ are each independently hydrogen, Ci _-6 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; F, Cl, Br, I ₁ CN, NH _{2, NH-Ci-6-alkyl, NH-Ci-6-alkyl-OH,} N (Ci. ₆ alkyl) _2, N _{(Ci-6-alkyl-OH) 2,} NHAryl; NH-alkylaryl; NH-heteroaryl; NO ₂ , SH, SC _1-6 alkyl, OH, OC _{t -6} alkyl, O-Ci- ₆ alkyl OH, C (= O) Ci _-6 alkyl, NHSO ₂ C _1-6 alkyl, NHCOAryl; NHCOC _1-6 alkyl, CO ₂ H, CH ₂ SO ₂ -phenyl, CO ₂ -C _-6 alkyl, OCF _3, CF _3, benzyloxy, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, phenoxy, phenyl, pyridyl, alkylaryl . Thienyl or furyl; or the radicals R ¹ and R ² or R ² and R ^{3 form} a ring and o ^ o P ^ o together mean ^ / or ^ /; R ⁴ and R ^{5 are} independently H, F, Cl, Br, I, -CN, NH _{2, NH-Ci-6-alkyl,} NH- Ci- ₆ alkyl-OH, C _1-6 alkyl, N (C _1-6 alkyl) _2, N _{(Ci-6-alkyl-OH) 2,} NO _2, SH, _{S-Ci-6-alkyl,} S- benzyl, OC _1-6 alkyl, OH, O- Ci _-6- alkyl-OH, O-benzyl, C (= O) Ci _-6- alkyl, CO ₂ H, CO ₂ - C ₆ -alkyl or benzyl; R ⁶ is C-ι- ₆ alkyl, branched or unbranched, unsubstituted or mono- or polysubstituted; Aryl or heteroaryl, unsubstituted or substituted once or several times; or an aryl or heteroaryl radical linked via a C _1-3 -alkyl chain, unsubstituted or monosubstituted or polysubstituted; R ^4a, R ^5a and R ^6a independently represent H or C ₆ alkyl; R ^{7 is} (CH ₂ ), C (= O) R ⁸ ; (C = O) (CH ₂ ) _m NR ¹¹ R ¹² ; C (= O) (CH ₂ ) _n (C = O) R ⁸ ; (CH ₂ ) _s NHC (= O) R ⁸ where m is 1, 2 or 3 n is 1, 2, 3 or 4 t is 1, 2, 3 or 4 s is 1, 2, 3 or 4 stands R ^{8 is} C 1-6 -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted; Aryl, heteroaryl, heterocyclyl or C _3-8 -cycloalkyl, each unsubstituted or monosubstituted or polysubstituted; or linked via a Ci _-5 alkyl aryl, heteroaryl, heterocyclyl or C _3-8 cycloalkyl, respectively unsubstituted or singly or multiply substituted, wherein the alkyl chain in each case saturated or unsaturated, may be branched or unbranched; NR ⁹ R ¹⁰ ; means; R ⁹ and R ^{10 are} independently H; Ci- ₆ alkyl in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case unsubstituted or monosubstituted or polysubstituted; Heterocyclyl or C _3-8 cycloalkyl, respectively saturated or unsaturated, mono- or polysubstituted or unsubstituted; C (= O) R ²⁰ ; SO ₂ R ¹³ ; or aryl, C _3-8 -cycloalkyl, heterocyclyl or heteroaryl bonded via C _1-3 -alkyl, in each case monosubstituted or polysubstituted or unsubstituted, where the alkyl chain may in each case be saturated or unsaturated, branched or unbranched; or the radicals R ⁹ and R ¹⁰ together represent CH ₂ CH ₂ OCH ₂ CH ₂ , CH ₂ CH ₂ NR ¹⁴ CH ₂ CH ₂ or (CH ₂ ) _3-6 , R ¹¹ and R ^{12 are} independently H; d-β-alkyl in each case saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; Heterocyclyl or C _3-8 cycloalkyl, respectively saturated or unsaturated, mono- or polysubstituted or unsubstituted; C (= O) R ²⁰ ; SO ₂ R ¹³ ; or aryl, C _3-8 -cycloalkyl, heterocyclyl or heteroaryl bonded via C _1-3 -alkyl, in each case monosubstituted or polysubstituted or unsubstituted, where the alkyl chain may in each case be saturated or unsaturated, branched or unbranched; or the radicals R ¹¹ and R ¹² together represent CH ₂ CH ₂ OCH ₂ CH ₂ , CH ₂ CH ₂ NR ¹⁴ CH ₂ CH ₂ or (CH ₂ ) _3-6 , where R ^{14 is} H; Ci _-6 alkyl, respectively saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C _3-8 -cycloalkyl, in each case saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; C (O) R ¹³ ; or aryl, C _3-8 -cycloalkyl or heteroaryl bonded via d _-3 -alkyl, in each case monosubstituted or polysubstituted or unsubstituted; R ¹³ Ci ₆ alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; Aryl, heteroaryl or C _3-8 -cycloalkyl, each unsubstituted or mono- or polysubstituted; or linked via a Ci _-5 alkyl aryl, heteroaryl or _C3-8 cycloalkyl, each unsubstituted or mono- or polysubstituted, wherein the alkyl chain in each case saturated or unsaturated, may be branched or unbranched means; R ²⁰ Ci ₆ alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; Aryl, heteroaryl or C _3-8 -cycloalkyl, each unsubstituted or mono- or polysubstituted; NR ²¹ R ²² ; or a Ci _-5 - linked chain alkyl aryl, heteroaryl or _C3-8 cycloalkyl, each unsubstituted or mono- or polysubstituted, wherein the alkyl chain in each case saturated or unsaturated, may be branched or unbranched means; R ²¹ and R ^{22 are} independently C 1-6 -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; Aryl, heteroaryl or C ₃ . ₈ -cycloalkyl, each unsubstituted or monosubstituted or polysubstituted; means or linked via a C-ι _-5 alkyl aryl, heteroaryl or C _3- β- cycloalkyl, each unsubstituted or substituted one or more times, wherein the alkyl chain in each case saturated or unsaturated, may be branched or unbranched in the form of the Razemats; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers, or a single enantiomer or diastereomer; the bases and / or salts of physiologically acceptable acids. 2. Substituted tetrahydropyrrolopyrazine compounds according to claim 1, wherein R ^{7 is} CH ₂ C (= O) R ⁸ ; (C =O) (CH ₂ ) _m NR ¹¹ R ¹² or C (= O) (CH ₂ ) _n (C =O) R ⁸ , where m is 1, 2 or 3 and n is 1, 2, 3 or 4 stands. 3. Substituted tetrahydropyrrolopyrazine compounds according to one of claims 1 or 2, wherein "Alkyl substituted", "heterocyclyl" and "cycloalkyl substituted" for the substitution of a hydrogen radical by F, Cl, Br, I, -CN, NH _2, NH-Ci _-6 alkyl, Ci _-6 alkyl NH- OH, Ci _-6 alkyl, N (Ci _-6 alkyl) _2, N (C _1-6 alkyl-OH) _2, NO _2, SH, _{S-Ci-6-alkyl,} S- benzyl, O- Ci _-6 alkyl, OH, _{O-Ci-6-alkyl-OH,} = O, O-benzyl, C (= O) C _1-6 alkyl, CO ₂ H, CO ₂ -ci- ₆ alkyl, Phenyl or benzyl and "aryl substituted" and "heteroaryl substituted" for the one or more, for example two, three or four times, substitution of one or more hydrogen atoms of the ring system by F, Cl ₁ Br, I, CN, NH ₂ , NH-Ci _-6 alkyl, NH- d _-6 alkyl-OH, N (C _{1- 6} alkyl) _2, N _{(Ci-6-alkyl-OH) 2,} NO _2, SH, S-Ci _-6 alkyl, OH, _{O-Ci-6-alkyl, O-Ci-6-alkyl-OH,} C (= O) aryl; C (= O) Ci _-6 alkyl, C (= O) NHCi _-6 alkyl; C (= O) -N-morpholine; C (= O) - piperidine; (C = O) -pyrrolidine; (C = O) piperazine; NHSO ₂ Ci _-6 alkyl, NHCOCi _-6 alkyl, CO ₂ H, CH ₂ SO ₂ -phenyl, CO ₂ -C _1-6 -alkyl, OCF ₃ , CF ₃ , * I, ^x ', Ci. _6- alkyl, pyrolidinyl, piperidinyl, morpholinyl, benzyloxy, phenoxy, phenyl, pyridyl, alkylaryl, thienyl or furyl; in the form of the Razemats; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers, or a single enantiomer or diastereomer; the bases and / or salts of physiologically acceptable acids. 4. Substituted tetrahydropyrrolopyrazines according to any one of claims 1, 2 or 3, wherein R ¹ , R ² and R ^{3 are} independently hydrogen or Ci- ₆ alkyl, branched or unbranched, in particular for H. 5. Substituted tetrahydropyrrolopyrazines according to any one of claims 1, 2 or 3, wherein R ⁴ and R ^{5 are} independently H or Ci-e-alkyl, in particular H, are. 6. Substituted tetrahydropyrrolopyrazines according to any one of claims 1, 2 or 3, wherein R ^{6 is} phenyl, thienyl, furyl, pyridyl or benzyl, unsubstituted or simple or doubly substituted with OCH ₃ , F, Cl, CH ₃ , isopropyl or ; Methyl or tert-butyl. 7. Substituted tetrahydropyrrolopyrazines according to any one of claims 1 or 3, wherein R ^{7 is} CH ₂ CH ₂ C (= O) R ⁸ , CH ₂ CH ₂ CH ₂ C (= O) R ⁸ or CH ₂ CH ₂ CH ₂ CH ₂ CC = O) R ⁸ , in particular CH ₂ CH ₂ CH ₂ C (= O) R ⁸ . 8. Substituted tetrahydropyrrolopyrazines according to any one of claims 1 or 3, wherein R ^{7 is} C (= O) CH ₂ CH ₂ (C = O) R ⁸ . 9. Substituted tetrahydropyrrolopyrazines according to any one of claims 1, 3, 7 or 8, wherein R ^{8 is} NR ⁹ R ¹⁰ , R ^{9 is} H and R ^{10 is} optionally aryl, heteroaryl bonded via a C _1-3 -alkyl chain, Heterocyclyl or C ₃ - ₈ cycloalkyl may be, in each case unsubstituted or mono- or polysubstituted, wherein the alkyl chain in each case saturated or unsaturated, branched or unbranched; Ci _-6- alkyl, saturated, unsubstituted, branched or unbranched, means or the radicals R ⁹ and R ¹⁰ together represent CH ₂ CH ₂ OCH ₂ CH ₂ , CH ₂ CH ₂ NR ¹⁴ CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ CH ₂ or CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ where R ^{14 is} H; Benzyl or phenyl, each unsubstituted or monosubstituted or polysubstituted; C (= O) R ¹³ means. 10. Substituted tetrahydropyrrolopyrazines according to claim 9, wherein R ^{8 is} NR ⁹ R ¹⁰ , R ^{9 is} H and R ^{10 is} phenyl, benzyl, phenethyl, methylthienyl, methylfuryl, methylpyridyl, ethylthienyl, ethylfuryl or ethylpyridyl, in each case monosubstituted or polysubstituted; Piperidyl, pyrrolidinyl, methylpiperidyl, methylpyrrolidinyl, ethylpiperidyl or ethylpyrrolidinyl, each singly or multiply substituted; Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Propyl, butyl or pentyl, or the radicals R ⁹ and R ¹⁰ together represent CH ₂ CH ₂ OCH ₂ CH ₂ , CH ₂ CH ₂ NR ¹⁴ CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ CH ₂ or CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ where R ^{14 is} H; Benzyl or phenyl, each unsubstituted or monosubstituted or polysubstituted; C (= O) CH ₃ means. 11. Substituted tetrahydropyrrolopyrazine derivatives according to any one of claims 1 or 3, wherein R ^{7 is} (C = O) CH ₂ NR ¹¹ R ¹² , (C = O) CH ₂ CH ₂ NR ¹¹ R ¹² or (C = O) CH ₂ CH ₂ CH ₂ NR ¹¹ R ¹² , and R ^{11 is} C ( = O) R ²⁰ , and R ¹² H; Ci _-6 -alkyl, branched or unbranched; C _3-8 - Cycloalkyl, especially H; Methyl, ethyl, propyl, butyl or cyclopropyl, wherein R ^{20 is} NR ²¹ R ²² ; Phenyl, furyl, benzyl, phenethyl, phenethenyl, propylphenyl or Cyclopropyl, in each case unsubstituted or monosubstituted or polysubstituted; Methyl, ethyl, propyl or butyl, in particular for NR ²¹ R ²² ; Phenyl, benzyl, phenethyl or propylphenyl, each unsubstituted or mono- or polysubstituted by CF 3, or CH ₃ ; Cyclopropyl, unsubstituted or substituted with phenyl; or furyl, where R ²¹ and R ²² preferably each independently represent H or C-ι- ₆ -alkyl, preferably H, CH _3, tert-butyl or isopropyl. 12. Tetrahydropyrrolopyrazine derivatives according to claim 1 from the group 1 4- [1- (4-Chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -4-oxo-N- (3-trifluoromethylbenzyl ) butyramide 2 4-Oxo-4- (1-phenyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -N- (3-trifluoromethylbenzyl) -butyramide 3 N-sec-Butyl-2- [1- (2-methoxyphenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -acetamide 4 N-Cyclopropyl-3- [1- (3-fluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -3-oxo-propionamide 5 4-Oxo-4- (1-m-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -N- (3-trifluoromethyl-benzyl) -butyramide 6 3- {2- [1- (2-chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -2-oxo-ethyl} -1, 1-dimethylurea 7 4- [1- (4-fluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N-isobutyl-4-oxo-butyramide 8 2- [1- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N acetamide (3-trifluoromethyl-benzyl) - 9 2- [1- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] - np-tolyl-acetamide 10 3-tert-Butyl-1- {2- [1- (2,4-difluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -2 - oxo-ethyl} -1-isopropylurea 11 2- [1- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] - N-isopropyl-acetamide 12 3-tert-butyl-1-isopropyl-1 - [2-oxo-2- (1-m-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) ethyl] urea 13 N-Cyclopropyl-N- [2- (1-furan-3-yl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl) -2-oxoethyl] - 4-methyl-benzamide Cyclopropanecarboxylic acid {2- [1- (3,4-dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2a-pyrazino-2-yl] -2-oxo-ethyl} -isopropyl -amide 1-Cyclopropyl-1- {2- [1- (2,4-difluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -2- oxo-ethyl} -3-isopropyl-urea 1- (4-acetylpiperazin-1-yl) -2- [1- (2,4-difluoro-phenyl) -3,4-dihydro-1H-pyrrolo [ 1,2-a] pyrazin-2-yl] -ethanone Furan-2-carboxylic acid-cyclopropyl {2- [1- (3,4-dichlorophenyl) -3,4-dihydro-1H-pyrrolo [1 , 2-a] pyrazin-2-yl] -2-oxo-ethyl} -amide N-tert-butyl-N- [2-oxo-2- (1-p-tolyl-3,4-dihydro-1H -pyrrolo [1,2-a] pyrazine-2-yl) -ethyl] -isobutyramide N-cyclopropyl-N-ti-S-dichloro-phenyl-S-dihydro-1H-pyrrololi-aJpyrazine yl] -2-oxo-ethyl} -isobutyramide 2- (1- (3-methoxyphenyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (3 (trifluoromethyl) benzyl) acetamide 1-Ethyl-3,3-dimethyl-1- [2-oxo-2- (1-phenyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2 - yl) -ethyl] -urea Quinoline-8-sulfonic acid {2- [1- (2,4-difluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2 yl] -2-ox o-ethyl} -ethyl-amide N-cyclopropyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide Cyclopropanecarboxylic acid tert-butyl [2-oxo-2 - (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl) -ethyl] -amide furan-2-carboxylic acid tert-butyl {2- [ 1 - (3,4-dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazino-2-yl] -2-oxo-ethyl} -amide 2- [1 - ( 2-chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazino-2-yl] -1-piperidine-1-yl-ethanone 2-phenylcyclopropanecarboxylic acid ethyl [2 -oxo-2- (1-phenyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -ethyl] -amide N- (4-fluoro-phenyl) -4- [1- (3-methoxyphenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -4-oxo-butyramide N-ethyl-N- [2-oxo -2- (1-phenyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -ethyl] -butyramide N- (1,2-dimethyl-propyl) -2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide N-sec-butyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazino-2-yl) -acetamide N- {2- [1- (3 , 4-dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -2-oxo-ethyl} - N-ethyl-isobutyramide 4- [1- (3-Methoxy-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazino-2-yl] -4-oxo-N-pyridin-4-ylmethyl-butyramide Furan-2-carboxylic acid isopropyl {2- [1- (4-isopropylphenyl) -3,4-dihydro-1 H -pyrrolo [1,2-a] pyrazin-2-yl] -2-oxo ethyl} -amide 1- [1- (3-methoxyphenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -3-morpholin-4-yl-propane 1,3-dione 2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -N- (3-trifluoromethyl-benzyl) -acetamide N-pyridin-3-ylmethyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl) -acetamide 2- [1 - (2, 4-difluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N-furan-2-ylmethyl-acetamide N-Benzyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide N- (3,4-dimethyl-phenyl) -3 - [1- (3-methoxy-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -3-oxo-propionamide 4- [1 - (3-chloro -phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N-isopropyl-4-oxobutyramide N- (1-benzyl-piperidin-4-yl) -2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide 2- [1- (4-chloro-phenyl) -3, 4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -1- [4- (2-chlorophenyl) -piperazin-1-yl] -ethanone N- (1-benzyl- piperidin-4-yl) -2- [1- (4-chlorophenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -acetamide 1 - (4- Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2- [1- (4-chlorophenyl) -3,4-dihydro- 1 H-pyrrolo [1,2-a] pyrazine-2-yl] -ethanone N-phenethyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide 2- [1- (3,4-dichloro-2-yl) -acetamide phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N- (2-pyridin-2-yl-ethyl) -acetamide 1- (4-benzo [1 , 3] dioxol-5-ylmethylpiperazin-1-yl) -2- (1-p-tolyl-3,4-dihydro-1 H -pyrrolo [1,2-a] pyrazine-2-yl) -ethanone 2- [1- (3,4-dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazino-2-yl] -N-pyridin-3-ylmethyl-acetamide 1 (4-Benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -2- [1- (2-chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1, 2] a] pyrazin-2-yl] -ethanone 1- (4-benzylpiperazin-1-yl) -2- [1- (4-chlorophenyl) -3,4-dihydro-1H-pyrrolo [1, 2- a] pyrazine-2-yl] -ethanone 2- [1- (4-Chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl] -N-phenethyl-acetamide 2- [1- (2- Chlorophenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N-phenethyl-acetamide 2- [1- (3,4-dichloro-phenyl) -3, 4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N- (4-fluoro-benzyl) -acetamide 1- (4-benzyl-piperazin-1-yl) -2- [ 1- (2-chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2a-pyrazino-2-yl] -ethanone N -Cyclohexyl-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide 1- (4-benzylpiperazin-1-y !) - 2- (1 -p-toly! -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) ethanone 2- [1- (4-chloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N- (1,2-dimethyl-propyl) -acetamide N- (2-piperidin-1-yl-ethyl ) -2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide N- (4-fluoro-phenyl) -2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazino-2-yl) -acetamide furan-2-carboxylic acid ethyl [2-oxo-2- (1-p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazin-2-yl) -ethyl] -amide 2- [1- ( 4-fluoro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N-isopropyl-acetamide 2- [1- (3,4-dichloro-phenyl) -3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl] -N-isobutyl-acetamide 2- [1- (4-chloro-phenyl) -3,4-dihydro-1H -pyrrolo [1,2-a] pyrazino-2-yl] -N- (2-pyrrolidin-1-yl-ethyl) -acetamide N-Benzo [1,3] dioxol-5-ylmethyl-2- (1 -) p-tolyl-3,4-dihydro-1H-pyrrolo [1,2-a] pyrazine-2-yl) -acetamide 2- (1- (4-chlorophenyl) -3,4-dihydropyrrolo [1, 2] a] pyrazine-2 (1H) -yl) -N- (4-fluorobenzyl) acetamide 2- (1- (4-Chloro-phenyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H ) -yl) -N- (3- (trifluoromethyl) benzyl) acetamide 2- (1- (4-Chlorophenyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) - 1 - (4- (4-methoxyphenyl) piperazin-1-yl) ethanone N- (2,4-dichlorophenethyl) -2- (1- (3,4-dichlorophenyl) -3,4-dihydropyrrolo [1, 2] a] pyrazine-2 (1H) -yl) acetamide 1- (4- (3- Chlorophenyl) piperazin-1-yl) -4- (1-m-tolyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -butane-1,4-dione 76 4-Oxo-4- (1 - (thiophen-2-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (3- (trifluoromethyl) benzyl ) butanamide 77 4-Oxo-4- (1- (pyridin-2-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (3- (trifluoromethyl) benzyl ) butanamide 78 4- (1-tert-Butyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -4-oxo-N- (3- (trifluoromethyl) benzyl) butanamide 79 4-Oxo-4- (1- (pyridin-4-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (3- (trifluoromethyl) benzyl) butanamide 80 4- (1-Benzyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -4-oxo-N- (1- (3- (trifluoromethyl) phenyl) -ethyl) butanamide 81 4-Oxo-4- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (1- (3- (trifluoromethyl) phenyl) ethyl) butanamide 82 4-Oxo-4- (1- (thiophene-2-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (1- (3-) trifluoromethyl) phenyl) ethyl) butanamide 83 4-Oxo-4- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (thiophen-2-ylmethyl) butanamide 84 4-Oxo-4- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (1- (3- (pyridin-3-yl) phenyl) ethyl) butanamide 85 N- (4-fluorobenzyl) -4- (1-methyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -4-oxobutanamide 86 4- (1-Methyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -4-oxo-N- (3- (trifluoromethyl) benzyl) butanamide 87 N- (2-Oxo-2- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1 H) -yl) ethyl) -3- (3- (trifluoromethyl) phenyl) propanamide 88 N- (2-Oxo-2- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) ethyl) -4-phenylbutanamide 89 3-Oxo-3- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (3- (trifluoromethyl) benzyl) propanamide 90 3-Oxo-3- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (3- (trifluoromethyl) phenyl) propanamide 91 2- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -N- (3- (trifluoromethyl) benzyl) acetamide 92 (E) -3- (2-fluorophenyl) -N- (2-oxo-2- (1-phenyl-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) ethyl ) acrylamide 13. A pharmaceutical composition comprising at least one substituted tetrahydropyrrolopyrazine derivative according to claim 1, optionally in the form of the racemate; the enantiomers, Diastereomers, mixtures of the enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and / or salts of physiologically acceptable acids, and optionally containing suitable additives and / or adjuvants and / or optionally other active ingredients. Use of substituted tetrahydropyrrolopyrazine compounds according to claim 1 for the manufacture of a medicament for the treatment of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain. 15. Use of compounds according to claim 1 for the manufacture of a medicament for the treatment of epilepsy, migraine, anxiety and urinary incontinence. 16. A process for the preparation of tetrahydropyrrolopyrazine derivatives of general formula Ia according to claim 1, wherein R ^{7 is} C (= O) (CH 2) _n (C = O) R ⁸ , _11--66 -AikyI a) the corresponding tetrahydropyrrolopyrazine with addition of an organic base, for example triethylamine, diisopropylethylamine, diisopropylamine or pyhdine, in an organic solvent, for example DCE or DCM, with an acid of the general formula HOOC (CH ₂ ) _n (C =O) OCi ₆ -alkyl, wherein Ci- ₆ alkyl preferably ethyl, methyl or tert-butyl, at a temperature of 30 - 100 ⁰ C, preferably 30-83 ⁰ C optionally using bases, for example, sodium, TEA, DIEA or N-methylmorpholine, and optionally coupling reagents, for example EDCI, HOBt, DCC, CDI, HBTU, DMAP or pentafluorophenyldiphenylphosphinate, in solvents, for example Methanol, DMF or DCM, it is implemented within one hour to three days, b) the protecting group Ci _-6 alkyl with the aid of an acid, for example HCl, trifluoroacetic acid or p-toluenesulfonic acid, optionally in a suitable organic solvent, for example acetonitrile, diethyl ether . THF, DCM or toluene, or aqueous inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate in an organic solvent, for example methanol, ethanol, dioxane, DCM, THF, diethyl ether or in these solvents as mixtures, at a temperature of -10-120 ⁰ C is cleaved or deprotected tetrahydropyrrolopyrazine acid with omission of steps a and b by reaction of the corresponding anhydride in solvents such as DCM, chloroform, 1, 2-dichloroethane, acetone, acetonitrile, Dioxane, THF, DMF, diethyl ether, benzene, toluene, ethyl acetate, water, methanol, ethanol, propanol or i-propanol by addition of bases, for example triethylamine, diethylamine, diisopropylethylamine, pyridine, NaH, optionally with the addition of 18-crown-6 , NaOH, KOH, sodium acetate, potassium acetate or potassium carbonate or by addition of acids, for example sulfuric acid, optionally using coupling reagents such as DMAP, DCC or DIC, c) the tetrahydropyrrolopyrazine with the addition of a base, for example sodium methoxide, N-methylmorpholine, Diisopropylamine, triethylamine or diisopropylethylamine, and a coupling reagent, for example EDCI or CDI, DCC, HBTU, DMAP or Pentafluorophenyldiphenylphosphinat and optionally Hydroxybenzotriazolhydrat with the corresponding amine NHR ⁹ R ¹⁰ in an organic solvent, for example DMF, DCM or THF, at 0-100 ⁰ C, preferably 20 ⁰ C to 69 ° C is reacted. 17. Preparation of tetrahydropyrrolopyrazines according to claim 1, wherein R ^{7 is} (C = O) (CH ₂ ) _m NR ¹¹ R ¹² wherein the tetrahydropyrrolopyrazine is reacted with addition of an organic base, for example triethylamine, diisopropylethylamine, diisopropylamine or pyridine, with chloroacetic acid chloride at a temperature of 40-100 ⁰ C, preferably 40-83 ⁰ C, and the resulting product with a primary or secondary amine in a reaction medium, preferably ethanol, n-butanol, toluene or chloroform, if appropriate with the addition of a basic salt, preferably Na ₂ CO ₃ or K ₂ CO ₃ , optionally with the addition of an alkali metal halide, preferably potassium iodide or sodium iodide, if appropriate with the addition of a Base, preferably triethylamine, diisopropylethylamine and 4-dimethylamino-pyridine, particularly preferably triethylamine, at temperatures of 0-160 ⁰ C, preferably 20-12O ⁰ C is reacted. 18. Preparation of tetrahydropyrrolopyrazines according to claim 1, wherein R ^{7 is} C (= O) CH ₂ NR ¹¹ C (= O) R ²⁰ Alkyl. _,O wherein a glycine-alkyl ester with the corresponding acid of the general formula R ²⁰ (CO) OH using bases, for example sodium methoxide, TEA, DIEA or N-methylmorpholine, and optionally coupling reagents, for example EDCI, HOBt, DCC, CDI, HBTU, DMAP or pentafluorophenyldiphenylphosphinate, in solvents, for example methanol, DMF or DCM, within one hour to three days or the glycine-alkyl ester with the corresponding acid chloride or bromide of the general formula R ²⁰ (CO) Cl or R ²⁰ (CO) Br in a suitable solvent, for example. DCM, benzene, toluene, THF, DMF, acetonitrile, pyridine, dioxane, water or 1-methyl-pyrrolidin-2-one or mixtures of these solvents, using bases, for example pyridine, DIEA, TEA, N-methylmorpholine or sodium bicarbonate, optionally reacted with addition of a coupling reagent, for example DCC, the alkyl esters prepared by one of the abovementioned methods with the aid of an acid, for example HCl, trifluoroacetic acid or p-toluenesulfonic acid, if appropriate in a suitable organic solvent, for example acetonitrile, diethyl ether, THF, DCM or toluene, or with aqueous inorganic bases such as lithium hydroxide, potassium hydroxide, Sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate in an organic solvent, For example, methanol, ethanol, dioxane, DCM, THF, diethyl ether or cleaved in this solvent as mixtures at a temperature of -10-120 ° C. and the resulting glycine derivative to the corresponding tetrahydropyrrolopyrazine using bases, for example sodium methoxide, TEA, DIEA or N-methylmorpholine, and optionally coupling reagents, for example EDCI, HOBt, DCC, CDI, HBTU, DMAP or pentafluorophenyldiphenylphosphinate, in solvents, for example methanol, DMF or DCM, within a reaction time of one hour and three days.