EP2144913A2 - Composés tétrahydropyrrolopyrazine substitués comme inhibiteurs du recaptage de la monoamine et leur utilisation en tant que medicaments - Google Patents

Composés tétrahydropyrrolopyrazine substitués comme inhibiteurs du recaptage de la monoamine et leur utilisation en tant que medicaments

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Publication number
EP2144913A2
EP2144913A2 EP07819026A EP07819026A EP2144913A2 EP 2144913 A2 EP2144913 A2 EP 2144913A2 EP 07819026 A EP07819026 A EP 07819026A EP 07819026 A EP07819026 A EP 07819026A EP 2144913 A2 EP2144913 A2 EP 2144913A2
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EP
European Patent Office
Prior art keywords
alkyl
pyrazine
methanone
dihydropyrrolo
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07819026A
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German (de)
English (en)
Inventor
Beatrix Merla
Thomas Christoph
Stefan OBERBÖRSCH
Klaus Schiene
Gregor Bahrenberg
Robert Frank
Sven KÜHNERT
Wolfgang Schröder
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Gruenenthal GmbH
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Gruenenthal GmbH
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Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Publication of EP2144913A2 publication Critical patent/EP2144913A2/fr
Withdrawn legal-status Critical Current

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    • 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.
  • Pain therapies The urgent need for a patient - oriented and goal - oriented treatment of chronic and non - chronic pain, including the successful and satisfactory treatment of pain
  • TCAs tricyclic antidepressants
  • SSRIs selective serotonin reuptake inhibitors
  • SNRIs mixed serotonin and norepinephrine reuptake inhibitors
  • monoamine oxidase inhibitors and Modulators of various serotonin and
  • Noradrenaline receptor subtype broadly recognized (Berman et al., Biol Psychiatry, 2002 Mar 15; 51 (6): 469-73).
  • antidepressants are important adjuvants in pain management, especially in chronic pain.
  • a self-contained analgesic effect is also induced by monoamine reuptake inhibitors by activating the descending inhibition of spinal nociceptive signals.
  • good results in the treatment of urinary incontinence by the use of monoamine reuptake inhibitors are described (Sorbera et al., Drugs of the future, 2000, VoI 25, pages 907-916).
  • Monoamine reuptake inhibitors are also used to treat anxiety, fibromyalgia, eating disorders, Bulimia, hyperactivity disorder (ADHD), drug addiction, addiction and withdrawal, trichotillomania, skin conditions such as postherpetic neuralgia and pruritus, memory disorders, cognitive disorders, and Alzheimer's disease.
  • ADHD hyperactivity disorder
  • drug addiction addiction and withdrawal
  • trichotillomania skin conditions such as postherpetic neuralgia and pruritus, memory disorders, cognitive disorders, and Alzheimer's disease.
  • the object underlying the invention is the provision of new potent Monoaminwiederinghemmem with therapeutically relevant components of action in depression, anxiety and pain.
  • the effects should be based, at least in part, on a reuptake inhibition of serotonin (5-HT), norepinephrine (NA), or a combination of these mechanisms.
  • substituted tetrahydropyrrolopyrazine compounds of the general formula I given below are suitable for the treatment of pain and also have a good inhibition of noradrenaline and / or serotonin reuptake and are therefore suitable for the treatment of disorders or diseases which are at least be partially mediated via noradrenaline and / or serotonin reuptake.
  • An object of the present invention are therefore substituted tetrahydropyrrolopyrazine compounds of general formula I,
  • 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 1 I, CN, NH 2, NH-d -6 alkyl, NH-Ci-6-alkyl-OH, N (C 1-6 alkyl) 2, N (C 1.
  • R 6 is C- ⁇ - 6 alkyl, branched or unbranched, unsubstituted or mono- or polysubstituted; Aryl or heteroaryl, unsubstituted or singly or multiply substituted in; 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 13 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 C-5-alkyl chain aryl, heteroaryl, heterocyclyl or C 3-8 cycloalkyl, respectively unsubstituted or singly or multiply substituted, wherein the alkyl chain can be branched or unbranched, saturated or unsaturated group;
  • R 6 is CH 3
  • R 6 is phenyl and R 7 is C (O) R 13
  • R 13 is not 3-trifluoromethylphenyl, 3,4-dimethoxyphenyl, furanyl, 4-nitrophenyl or 4-methylphenyl.
  • phenyl In the context of "phenyl”, “phenyloxy”, “benzyl”, “benzyloxy”, “alkylaryl”, the term includes the unsubstituted structure as well as those represented by F, Cl, OCH 3 , OCF 3 , SCF 3 and CF 3 and CH 3 substituted structure.
  • d- C3 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 d- 3- Alkanyle, C 2-3 alkenyls and C 2-3 alkenyls or Ci - 5 -Alkanyle, C2-s-alkenyls and C2-5 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 one.
  • cycloalkyl or "C 3 _3 -cycloalkyl” means for the purposes of this
  • 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, including phenyls and naphthyls.
  • the aryl radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems.
  • Each aryl radical can be unsubstituted or monosubstituted or polysubstituted, the aryl substituents being the same or different and being in any desired and possible position of the aryl can.
  • 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
  • C- ⁇ - 3 alkyl bound aryl, heteroaryl, heterocyclyl or cycloalkyl and "on C- ⁇ - 5 alkyl bound aryl, heteroaryl, heterocyclyl or cycloalkyl” mean for the purposes of the present invention that C- ⁇ - 3 alkyl and aryl or 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 is bonded to the compound of general structure I.
  • 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. Particularly advantageous for the purposes of this invention is phenyl, benzyl and phenethyl.
  • alkyl 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 -CN 1 NH 2, NH-Ci -6 alkyl, NH-Ci-6-alkyl-OH, Ci -6 - alkyl, N (C 1 6 alkyl.) 2, N (C 1-6 alkyl-OH) 2) NO 2, SH, S- Ci -6 alkyl, S-benzyl, OC 1-6 alkyl, OH, O-Ci.
  • 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 1 1 NH 2, NH-de-alkyl, NH-C 1-6 alkyl-OH, N (Ci 6 alkyl.) 2, N (Ci -6 - alkyl-OH) 2l NO2, .
  • 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 compatible acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, ants.
  • citric 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-dihydro-1, 6- benzo [cf] isothiazol-3-one (saccharic acid) , Monomethylsebacin Textre, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, ⁇ -lipoic acid, acetylglycine, hippuric acid, phosphoric acid and / or aspartic acid , Particularly preferred are citric acid and hydrochloric acid.
  • R 6 is C 1-6 -alkyl, branched or unbranched, unsubstituted or monosubstituted 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 C 1-6 alkyl;
  • R 13 is Ci-e-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 linked via a Ci -5 alkyl aryl, heteroaryl or C3-8 cycloalkyl, each unsubstituted or mono- or polysubstituted, wherein the alkyl chain can be branched or unbranched, saturated or unsaturated group;
  • R 6 is CH 3
  • R 6 is phenyl and R 7 is C (O) R 13 , R 13 is not 3-trifluoromethylphenyl
  • 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, CN, NH 2 , NH-C 1-6 alkyl, NH- Ci -6 alkyl-OH, N (C 1- 6 alkyl) 2, N (Ci.
  • 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,.
  • Phenethyl unsubstituted or substituted once or several times;
  • radicals R 4a , R 5a and R 6a are hydrogen.
  • R 13 is Cv ⁇ -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted; Phenyl or naphthyl, each unsubstituted or monosubstituted or polysubstituted; Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each unsubstituted or monosubstituted or polysubstituted; Furanyl, thienyl or pyridyl, each unsubstituted or monosubstituted or polysubstituted; each unsubstituted or substituted, or a C- ⁇ - 5 alkyl chain linked phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furany
  • R 13 Ci 6 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted with OCH 3 or OH; Phenyl or naphthyl,
  • 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 wherein the radicals R 1 - R 7 have the meaning given above, and optionally one or more
  • medicaments according to the invention are suitable for influencing the serotonin and / or norepinephrine reuptake. This also applies to compounds whose structure is already known but whose suitability as a pharmaceutical is unknown.
  • the invention therefore also relates to medicaments comprising at least one compound of the general formula I
  • 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- ⁇ -alkyl, NH-Ci-6-alkyl-OH, N (Ci.
  • 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 a d -3 alkyl chain linked aryl or heteroaryl, unsubstituted or mono- or polysubstituted group;
  • R 4a, R 5a and R 6a independently represent H or C 6 alkyl
  • R 13 is C 1-6 -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted;
  • phenyl In the context of "phenyl”, “phenyloxy”, “benzyl”, “benzyloxy”, “alkylaryl”, the term includes the unsubstituted structure as well as those represented by F 1 Cl, OCH 3 , OCF 3 , SCF 3 and CF 3 and CH 3 substituted structure.
  • the medicaments according to the invention are suitable for the treatment of disorders or diseases which are mediated at least in part by the serotonin or noradrenaline reuptake.
  • the medicaments according to the invention are preferably suitable for the treatment of pain, depression, anxiety, fibromyalgia, eating disorders, bulimia, attention deficit hyperactivity disorder (ADHD), drug addiction, addiction and withdrawal, trichotillomania, skin diseases such as postherpetic
  • Neuralgia and pruritus, memory disorders, cognitive disorders and Alzheimer's disease preferably pain, especially chronic and / or neuropathic pain, depression and anxiety.
  • Another object of the present invention is 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 disorders or diseases that mediates at least partially by the serotonin or norepinephrine reuptake become.
  • ADHD Attention Deficit Hyperactivity Disorder
  • Drug addiction Drug addiction, addiction and withdrawal, Trichotillomania
  • Skin disorders such as Postherpetic Neuralgia and Pruritus, Memory Disorders, Cognitive Disorders, and Alzheimer's Disease.
  • 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, in particular chronic and / or neuropathic pain, depression and anxiety.
  • a further subject of the present invention is a process for the preparation of the substituted tetrahydropyrrolopyrazine compounds according to the invention, which are used in the reactions described above coming chemicals and reaction components are commercially available or can be prepared in each case by customary methods known in the art.
  • a solution of the optionally substituted 2- (1H-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 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 20 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 and refluxed on a water.
  • an organic acid for example acetic acid, 6 - 48 h at room temperature or b
  • an alcohol for example ethanol or methanol
  • an organic acid for example acetic acid or citric acid at a temperature of 0-100
  • 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.
  • aqueous basic solution for example sodium carbonate solution, sodium bicarbonate solution, potassium carbonate solution, sodium hydroxide solution or potassium hydroxide solution.
  • an acid with the addition of a base for example diisopropylamine, triethylamine or diisopropylethylamine, and 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, at 0-100 0 C, preferably 20 0 C to 69 ° C are reacted.
  • a base for example diisopropylamine, triethylamine or diisopropylethy
  • a tetrahydropyrrolopyrazine may be reacted with an acid chloride at a temperature of 0-100 ° C, preferably 20 ° C to 80 ° C with addition of a base, for example triethylamine, diisopropylethylamine or diisopropylamine, in an organic solvent, for example DCE or DCM.
  • a base for example triethylamine, diisopropylethylamine or diisopropylamine
  • an inorganic base for example sodium carbonate, sodium bicarbonate, potassium carbonate,
  • Sodium hydroxide or potassium hydroxide are made basic. Subsequently, the organic phase can be separated, washed with water and concentrated.
  • suitable scavanger resins may be used, or acidified after addition of a suitable solvent such as DCM, chloroform, ethyl acetate or diethyl ether.
  • 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.
  • substituted tetrahydropyrrolopyrazine compounds according to the invention can be used both in the form of their free bases, their free acids and in each case in Form of appropriate salts, in particular physiologically acceptable salts isolated.
  • 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 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 hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, carbonic, formic, acetic, oxalic, maleic, malic and succinic acids , Tartaric acid, mandelic acid, fumaric acid, lactic acid,
  • 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.
  • Tetrahydropyrrolopyrazin- compounds according to the invention after their preparation in the form of a mixture of their stereoisomers, preferably in the form of their racemates or other mixtures of their various Enantiomeric and / or diastereomers are obtained, these can be separated by conventional methods known in the art and optionally isolated. 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.
  • 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 solution was prepared by first adding 3 mol eq. TEA were dissolved in DCE and then 1 mol eq. of the 1-aryl-tetrahydropyrrolo-pyrazine was added. Subsequently, the solution thus prepared was homogenized in an ultrasonic bath and diluted to the extent that the concentration of 1-aryl-tetrahydropyrrolopyrazins 0.1 - 0, 25 mol / l was.
  • 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.
  • Example 72 eluent: ethyl acetate / cyclohexane, 1: 2
  • Example 74 eluent: ethyl acetate / cyclohexane, 1: 5

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  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
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Abstract

L'invention concerne des composés tétrahydropyrrolopyrazine substitués, des procédés permettant de les produire, des médicaments contenant lesdits composés et l'utilisation de ces composés pour produire des médicaments.
EP07819026A 2006-10-17 2007-10-16 Composés tétrahydropyrrolopyrazine substitués comme inhibiteurs du recaptage de la monoamine et leur utilisation en tant que medicaments Withdrawn EP2144913A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006049452A DE102006049452A1 (de) 2006-10-17 2006-10-17 Substituierte Tetrahydropyrolopiperazin-Verbindungen und deren Verwendung in Arzneimitteln
PCT/EP2007/008956 WO2008046581A2 (fr) 2006-10-17 2007-10-16 Composés tétrahydropyrrolopyrazine substitués et leur utilisation dans des médicaments

Publications (1)

Publication Number Publication Date
EP2144913A2 true EP2144913A2 (fr) 2010-01-20

Family

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Application Number Title Priority Date Filing Date
EP07819026A Withdrawn EP2144913A2 (fr) 2006-10-17 2007-10-16 Composés tétrahydropyrrolopyrazine substitués comme inhibiteurs du recaptage de la monoamine et leur utilisation en tant que medicaments
EP07819027A Withdrawn EP2112993A1 (fr) 2006-10-17 2007-10-16 Composés tétrahydropyrrolopyrazine substitués, à affinité avec le canal kcnq2/3+, et leur utilisation dans des médicaments

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EP07819027A Withdrawn EP2112993A1 (fr) 2006-10-17 2007-10-16 Composés tétrahydropyrrolopyrazine substitués, à affinité avec le canal kcnq2/3+, et leur utilisation dans des médicaments

Country Status (17)

Country Link
US (3) US7625900B2 (fr)
EP (2) EP2144913A2 (fr)
JP (1) JP5256203B2 (fr)
KR (1) KR20090084873A (fr)
CN (1) CN101547925A (fr)
AU (1) AU2007312557B2 (fr)
BR (1) BRPI0715298A2 (fr)
CA (1) CA2666647A1 (fr)
CO (1) CO6160331A2 (fr)
DE (1) DE102006049452A1 (fr)
EC (1) ECSP099320A (fr)
IL (1) IL198073A (fr)
MX (1) MX2009004108A (fr)
NO (1) NO20091509L (fr)
NZ (1) NZ576021A (fr)
RU (1) RU2469037C2 (fr)
WO (2) WO2008046582A1 (fr)

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BRPI0919898A2 (pt) * 2008-10-24 2016-02-16 Gruenenthal Gmbh 4,5,6,7-tetra-hidrotienopiridinas substituídas como moduladores de kcnq2/3
US8367700B2 (en) 2008-12-17 2013-02-05 Gruenenthal Gmbh Substituted 4-(1.2,3,4-tetrahydroisoquinolin-2-yl)-4-oxobutyric acid amide as KCNQ2/3 modulators
JP2012518603A (ja) * 2009-02-23 2012-08-16 メルク カナダ インコーポレイテッド ステアロイル−コエンザイムａデルタ−９デサチュラーゼの阻害剤としての複素環誘導体
TWI504395B (zh) 2009-03-10 2015-10-21 Substituted 3-amino-2-mercaptoquinoline as a KCNQ2 / 3 modifier
TW201038565A (en) 2009-03-12 2010-11-01 Gruenenthal Gmbh Substituted 2-mercapto-3-aminopyridines as KCNQ2/3 modulators
TWI461197B (zh) 2009-03-12 2014-11-21 2-mercaptoquinoline-3-carboxamide as a KCNQ2 / 3 modifier
US8470852B2 (en) 2010-08-27 2013-06-25 Gruenenthal Gmbh Substituted 2-amino-quinoline-3-carboxamides as KCNQ2/3 modulators
AU2011295407B2 (en) 2010-08-27 2016-01-21 Grunenthal Gmbh Substituted quinoline-3-carboxamides as KCNQ2/3 modulators
AR082731A1 (es) 2010-08-27 2012-12-26 Gruenenthal Gmbh 2-oxo- y 2-tioxo-dihidroquinolin-3-carboxamidas sustituidas como moduladoras de kcnq2/3
WO2012025236A1 (fr) 2010-08-27 2012-03-01 Grünenthal GmbH 2-oxyquinoléine-3-carboxamides substitués comme modulateurs de kcnq2/3
US8618129B2 (en) 2010-09-01 2013-12-31 Gruenenthal Gmbh Substituted 1-oxo-dihydroisoquinoline-3-carboxamides as KCNQ2/3 modulators
US9168259B2 (en) 2010-10-20 2015-10-27 Grünenthal GmbH Substituted 6-amino-nicotinamides as KCNQ2/3 modulators
NZ628871A (en) 2010-10-20 2015-07-31 Gruenenthal Chemie Substituted 6-amino-nicotinamides as kcnq2/3 modulators
BR112013011188B1 (pt) 2010-11-05 2022-01-04 Senomyx, Inc Método não-médico para modular canal potencial de receptor transiente de melastina 8 (trpm8), método não-médico para modular a sensação de resfriamento de uma composição, método não-médico para induzir uma sensação de resfriamento em um humano ou animal e composto
CN102229610B (zh) * 2011-04-22 2014-10-29 中山大学 一种光学纯手性1,2,3,4-四氢吡咯并[1,2-a]吡嗪化合物的合成方法
EP2844645A1 (fr) 2012-04-18 2015-03-11 Grünenthal GmbH 4-aminobenzamides substitués utilisés comme modulateurs de kcnq2/3
MX2014012494A (es) 2012-04-18 2015-01-15 Grünenthal GmbH 6-amino-nicotinamidas sustituidas que portan un grupo que contiene oh como moduladores de kcnq2/3.
EP2925759A1 (fr) 2012-11-28 2015-10-07 Grünenthal GmbH Hétéroquinoline-3-carboxamides utilisés en tant que modulateurs kcnq2/3
US9248122B2 (en) 2012-11-28 2016-02-02 Grünenthal GmbH Heteroquinoline-3-carboxamides as KCNQ2/3 modulators
BR112015012418A2 (pt) 2012-11-28 2017-07-11 Gruenenthal Gmbh carboxamidas específicas como moduladores de kcnq2/3
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Also Published As

Publication number Publication date
RU2009118491A (ru) 2010-11-27
US20090258880A1 (en) 2009-10-15
US7879858B2 (en) 2011-02-01
AU2007312557A8 (en) 2009-06-25
US20080167315A1 (en) 2008-07-10
RU2469037C2 (ru) 2012-12-10
US8017772B2 (en) 2011-09-13
WO2008046582A1 (fr) 2008-04-24
JP5256203B2 (ja) 2013-08-07
IL198073A (en) 2013-03-24
DE102006049452A1 (de) 2008-05-08
WO2008046581A3 (fr) 2008-06-12
NO20091509L (no) 2009-05-28
JP2010506869A (ja) 2010-03-04
BRPI0715298A2 (pt) 2014-10-29
AU2007312557A1 (en) 2008-04-24
KR20090084873A (ko) 2009-08-05
US7625900B2 (en) 2009-12-01
WO2008046581A2 (fr) 2008-04-24
CN101547925A (zh) 2009-09-30
MX2009004108A (es) 2009-04-28
US20100004252A1 (en) 2010-01-07
ECSP099320A (es) 2009-06-30
CA2666647A1 (fr) 2008-04-24
AU2007312557B2 (en) 2013-06-13
EP2112993A1 (fr) 2009-11-04
IL198073A0 (en) 2009-12-24
NZ576021A (en) 2011-03-31
CO6160331A2 (es) 2010-05-20

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