Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• 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.
• 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.
• 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).
• migraine US2002 / 0128277
• cognitive disorders Gribkoff, Expert Opin Ther Targets 2003; 7 (6): 737-748
• epilepsy Wickenden et al., Expert Opin Ther Pat 2004; 14 (4): 457-469
• urinary incontinence Strictly et al., J Urol 2004; 172: 2054-2058.
• 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.
• R 6 is d- 6 alkyl, branched or unbranched, unsubstituted or mono- or polysubstituted; Aryl or heteroaryl, unsubstituted or singly or multiply - A -
• R 4a, R 5a and R 6a are independently H or Ci -6 alkyl
• 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 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 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 13 Ci 6 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted;
• 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- ⁇ -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
• Ci 3 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.
• 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.
• C 3 _s-cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
• 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.
• 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.
• aryl is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, which may each be unsubstituted or mono- or polysubstituted.
• 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
• 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.
• 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.
• 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 dihydro1 ⁇ 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 , ⁇ -lipoic acid
• 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 8 Ci- 6 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; Aryl, heteroaryl, heterocyclyl or C 3 - ⁇ -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 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 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 13 C- ⁇ - 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,
• 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- ⁇ -alkyl OH, Ci.
• 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- ⁇ -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 CH 2 CH 2 CH 2
• 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,
• 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 CH 2
• 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
• 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.
• 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.
• 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.
• 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.
• 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.
• an organic acid for example acetic acid, 6 - 48 h at room temperature stirred or b
• an alcohol for example ethanol or methanol
• an organic acid for example acetic acid or citric acid at a temperature
• 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.
• organic solvent for example, DCM, chloroform, ethyl acetate or diethyl ether.
• 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.
• 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.
• 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.
• 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.
• solvents such as DCM, chloroform, 1, 2-
• a base for example sodium methoxide, N-methylmorpholine, diisopropylamine, triethylamine or diisopropylethylamine
• 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 Dicarbonklarealkylesterchlorid or bromide or by reaction with the corresponding carboxylic acid anhydride.
• the reaction of the Monoalkyldicarbonklareesters with the corresponding amine is carried out using bases and optionally coupling reagents in solvents such as methanol, DMF or DCM reacted.
• 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 Dicarbon Tarrealkylesterchloride 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
• solvents such as DCM, benzene, toluene, THF, DMF, acetonitrile, pyridine, dioxane, water or 1-methyl-pyrrolidin-2-one or mixtures of these solvents
• 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.
• solvents such as DCM, chloroform, 1, 2-dichloroethane, acetone, acetonitrile, dioxane, THF, DMF,
• 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.
• 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.
• an organic base for example triethylamine, diisopropylethylamine, diisopropylamine or pyridine
• 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.
• a reaction medium preferably selected from the group consisting of ethanol, n-butanol, toluene or chloroform
• a basic salt preferably Na 2 CO 3 or K 2 CO 3
• an alkali metal halide preferably potassium iodide or sodium i
• 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.
• a base for example diisopropylamine, triethylamine or diisopropylethylamine
• a coupling reagent for example EDCI or CDI
• 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.
• a base for example triethylamine, diisopropylethylamine or diisopropylamine
• organic solvent for example DCE or DCM
• 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.
• 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.
• 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.
• 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.
• an organic solvent for example DCE, DCM, chloroform, benzene, toluene, ethanol, acetone, diethyl ether, petroleum ether, dioxane or THF
• 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.
• solvents such as dioxane, water, acetone, diethyl ether or acetonitrile, or mixtures of these solvents
• a base such as triethylamine, NaOH, KOH or K 2 CO 3 obtained.
• DCM or THF carried out at 0-100 0 C, preferably 20 0 C to 69 ° C.
• 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.
• organic solvent for example acetonitrile, benzene, toluene, ethanol, DMF, THF or dioxane
• a base for example potassium carbonate, NaOH, KOH, sodium amide, sodium ethoxide, potassium tert.
• 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.
• 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.
• a base for example diisopropylamine, thethylamine or diisopropylethylamine
• a coupling reagent for example EDCI or CDI
• 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
• 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.
• 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.
• 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
• 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.
• a sugar substitute e.g. Saccharin, cyclamate or acesulfame
• 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.
• substituted tetrahydropyrrolopyrazine compounds according to the invention 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.
• 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.
• 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.
• 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.
• physiologically acceptable excipients 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.
• 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.
• radicals R 4a , R 5a and R 6a are each H.
• 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.
• 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.
• 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.
• 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
• 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.
• a solution of the corresponding malonic acid or succinic acid derivative (250 ⁇ 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.
• 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.
• 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 TM cell counter (Model TCC, Shurfe System) to subsequently transfer 20,000 cells / well / 100 ⁇ l of the described nutrient medium to the 96 well Corning TM CellBIND TM (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 TM BuIk format part R8123 for FLIPR, Molecular Devices TM) 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.
• Extracellular Buffer ES buffer, 120 mM NaCl, 1mM KCl, 10mM HEPES, 2mM CaCl 2 , 2mM MgCl 2 , 10mM glucose, pH 7.4
• the fluorescence measurements are performed with a BMG Labtech FLUOstar TM or BMG Labtech POLARstar TM 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 ⁇ l 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.
• 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 with - are compared by control cells. - is determined by IF) ⁇ VF) ⁇ 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 target connection is an increase of - to observe.
• 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).
• Example 2 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.
• mice 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.
• Example 2 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.
• PS diimide a polymer bound carbodiimide having the following structure Loading: 0.9-1.4 mmol / g particle size: 75-150 ⁇ m

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