EP2606033A1 - Substituierte cyclische carboxamid- und harnstoff-derivate als liganden des vanilloid-rezeptors - Google Patents

Substituierte cyclische carboxamid- und harnstoff-derivate als liganden des vanilloid-rezeptors

Info

Publication number
EP2606033A1
EP2606033A1 EP11755260.4A EP11755260A EP2606033A1 EP 2606033 A1 EP2606033 A1 EP 2606033A1 EP 11755260 A EP11755260 A EP 11755260A EP 2606033 A1 EP2606033 A1 EP 2606033A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
methyl
unsubstituted
chlorophenyl
polysubstituted
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Withdrawn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
EP11755260.4A
Other languages
German (de)
English (en)
French (fr)
Inventor
Robert Frank
Gregor Bahrenberg
Thomas Christoph
Klaus Schiene
Jean De Vry
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Priority to EP11755260.4A priority Critical patent/EP2606033A1/de
Publication of EP2606033A1 publication Critical patent/EP2606033A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to substituted cyclic carboxamide and urea derivatives, 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 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
  • a suitable starting point for the treatment of pain in particular pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain, more preferably of
  • neuropathic pain represents the vanilloid receptor subtype 1 (VR1 / TRPV1), which is often referred to as the capsaicin receptor.
  • This receptor is u.a. by vanilloids such as e.g. Capsaicin, heat and protons stimulates and plays a central role in the onset of pain.
  • vanilloids such as e.g. Capsaicin
  • heat and protons stimulates and plays a central role in the onset of pain.
  • it is important for a variety of other physiological and pathophysiological processes and is a suitable target for the therapy of a variety of other diseases such as migraine,
  • Anxiety epilepsy, cough, diarrhea, pruritus, inflammation, disorders of the cardiovascular system, disorders of ingestion, drug dependence, drug abuse, and especially urinary incontinence.
  • CONFIRMATION COPY thus, it may be advantageous to improve the metabolic stability, the solubility in aqueous media or the permeability of the compounds. These factors may be beneficial to oral bioavailability or may affect PK / PD
  • An object of the invention was therefore to provide new compounds which have advantages over the compounds of the prior art.
  • the compounds should prove particularly useful as pharmacological agents in
  • Medicaments are suitable, preferably in medicaments for the treatment and / or prophylaxis of disorders or diseases which are at least partially mediated by vanilloid receptors 1 (VR1 / TRPV1 receptors).
  • VR1 / TRPV1 receptors vanilloid receptors 1
  • Vanilloid receptor subtype 1 (VR1 / TRPV1 receptor) and are therefore particularly suitable for the prophylaxis and / or treatment of disorders or diseases that are at least partially mediated by vanilloid receptors 1 (VR1 / TRPV1).
  • substituted compounds represented by the following general formula (I) have anti-inflammatory activity.
  • X is CR 3 or N, where R 3 is H; or C -10 -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; stands;
  • A is N, C or CH
  • T is N, C or CR 7b ,
  • At least one unsaturated bond with the proviso that when A is N, A is not part of an unsaturated bond, and provided that when T is N, T is not part of an unsaturated bond,
  • P is 1, 2 or 3; preferably is 1; n is 0, 1, 2, 3 or 4, preferably 10; particularly preferably C 1-10 -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted; C3-i 0 -cycloalkyl or heterocyclyl, in each case saturated or unsaturated, unsubstituted or monosubstituted or polysubstituted; Aryl or heteroaryl, in each case unsubstituted or monosubstituted or polysubstituted; Ci-8-alkyl bridged C ⁇ o-cycloalkyl or heterocyclyl, in each case saturated or unsaturated, unsubstituted or monosubstituted or polysubstituted, wherein the Each alkyl chain can be branched or unbranched, saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; or
  • R 1 for H; C 0 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted; C 3 .i 0 -cycloalkyl 1 or heterocyclyl 1 , in each case saturated or unsaturated, unsubstituted or monosubstituted or polysubstituted; Aryl or heteroaryl, in each case unsubstituted or monosubstituted or polysubstituted; 3- i be about Ci-e-alkyl bridged C 0 -cycloalkyl 1 or heterocyclyl 1, in each case saturated or unsaturated, unsubstituted or mono- or polysubstituted, where in each case the alkyl chain branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted can; or aryl or heteroaryl bridged by C 1-8 -alkyl, in each case unsub
  • R 2 for H; R °; N0 2 ; CN; OH; SH; F; Cl; Br; I; CF 3 ; CF 2 H; CFH 2 ; CF 2 Cl; CFCI 2 ; CH 2 CF 3 ;
  • R 4 for H; F; Cl; Br; I; OH; C 1-10 -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted; stands;
  • R 5 , R 6 and R 8 are each independently H; F; Cl; Br; I; OH; OR °; or R ° mean;
  • alkyl or "C 1-10 -alkyl”, “C 1-8 -alkyl”, “C 1-4 -alkyl”, “C 1-4 -alkyl” for the purposes of this invention include acyclic saturated or unsaturated aliphatic
  • Hydrocarbon radicals that is Ci -10 aliphatic radicals, C 1-8 aliphatic radicals, C 1-6 - aliphatic radicals and C 1-4 aliphatic radicals which in each case branched or unbranched and unsubstituted or may be mono- or polysubstituted, having 1 to 10 or 1 to 8 or 1 to 6 or 1 to 4 carbon atoms, ie C 1-10 -Alkanyle, C 2-10 alkenyls, and C 2 i 0 - alkynyls or Ci-e-alkanyls , C2-8 alkenyls and C2-8 alkynyls or C -6 -Alkanyle, C2-6 alkenyls and C2-6 alkynyls or Ci-4-alkanyls, C2-4 alkenyls and C 2 ⁇ alkynyls.
  • Alkenyls have at least one CC double bond and alkynyls at least one CC triple bond.
  • cycloalkyl or "C 3-10 cycloalkyl” and “cycloalkyl 1" and “Q M o-cycloalkyl 1" mean for the purposes of this invention cyclic aliphatic (cycloaliphatic)
  • 10- cycloaliphatic radicals wherein the hydrocarbons may be saturated or unsaturated (but not aromatic), unsubstituted or mono- or polysubstituted.
  • the bonding of the cycloalkyl to the respective general structure above can take place via any and possible ring member of the cycloalkyl radical.
  • the cycloalkyl radicals can also be reacted with further saturated, (partially) unsaturated, (hetero) cyclic,
  • aromatic or heteroaromatic ring systems ie be condensed with cycloalkyl, heterocyclyl, aryl or heteroaryl, which in turn may be unsubstituted or mono- or polysubstituted.
  • the cycloalkyl radicals can furthermore be mono- or polysubstituted be bridged as in the case of adamantyl, bicyclo [2.2.1] heptyl or bicyclo [2.2.2] octyl.
  • cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl,
  • heterocyclyl or “heterocycloalkyl” and “heterocyclyl 1"
  • Heterocycles are thus heterocycloaliphatic radicals.
  • the bonding of the heterocyclyl to the general structure above can take place via any and possible ring member of the heterocyclyl radical.
  • the heterocyclyl radicals can also be reacted with further saturated, (partially) unsaturated (hetero) cyclic or aromatic or heteroaromatic ring systems, i. be fused with cycloalkyl, heterocyclyl, aryl or heteroaryl, which in turn may be unsubstituted or mono- or polysubstituted.
  • heterocyclyl radicals from the group comprising azetidinyl, aziridinyl, azepanyl, azocanyl, diazepanyl, dithiolanyl, dihydroquinolinyl, dihydropyrrolyl, dioxanyl, dioxolanyl, dioxepanyl, dihydroindenyl, dihydropyridinyl, dihydrofuranyl, dihydroisoquinolinyl, dihydroindolinyl, dihydroisoindolyl, imidazolidinyl, isoxazolidinyl, morpholinyl, oxiranyl, Oxetanyl, pyrrolidinyl, piperazinyl, 4-ethylpiperazinyl, piperidinyl, pyrazolidinyl, pyranyl, tetrahydropyrrolyl, tetrahydropyranyl, te
  • aryl in the context of this invention means aromatic hydrocarbons having up to 14 ring members, including phenyls and naphthyls.
  • 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.
  • the attachment of the aryl to the overall general structure can be via any and possible ring member of the aryl radical done.
  • the aryl radicals can also be reacted with further saturated, (partially) unsaturated, (hetero) cyclic, aromatic or
  • heteroaromatic ring systems i. with cycloalkyl, heterocyclyl, aryl or heteroaryl, which in turn may be unsubstituted or monosubstituted or polysubstituted.
  • fused aryl radicals are benzodioxolanyl and benzodioxanyl.
  • Aryl is preferably selected from the group comprising phenyl, 1-naphthyl and 2-naphthyl, which may each be unsubstituted or monosubstituted or polysubstituted.
  • a particularly preferred aryl is phenyl, unsubstituted or mono- or polysubstituted
  • heteroaryl represents a 5- or 6-membered cyclic aromatic radical containing at least 1, optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are each independently selected from the group S, N and O and the heteroaryl radical may be unsubstituted or mono- or polysubstituted; in the case of heteroaryl substitution, the substituents may be the same or different and may be in any and possible position of the heteroaryl.
  • heteroaryl may also be part of a bi- or polycyclic system having up to 14 ring members, which ring system may be formed with further saturated, (partially) unsaturated, (hetero) cyclic or aromatic or heteroaromatic rings, i. with cycloalkyl, heterocyclyl, aryl or heteroaryl, which in turn may be unsubstituted or monosubstituted or polysubstituted.
  • the heteroaryl radical is selected from the group consisting of benzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl,
  • aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclyl 1 or cycloalkyl 1 bridged via C 1-4 -alkyl or C 1-8 -alkyl in the meaning of the invention mean that C 1-4 -alkyl or C 1-8 -alkyl and Aryl or heteroaryl or heterocyclyl or cycloalkyl or heterocyclyl 1 or cycloalkyl 1 have the meanings defined above and the aryl or heteroaryl or heterocyclyl or cycloalkyl or heterocyclyl 1 or cycloalkyl 1 radical over a C 1-4 Alkyl or a C 1-8 alkyl group is bonded to the respective parent general structure.
  • the alkyl chain of the alkyl group can be branched in all cases or
  • alkyl chain of the alkyl group may further be saturated or unsaturated, in all cases, that is, an alkylene group, ie, a C -4 alkylene group or a C 1-8 alkylene group, a
  • Alkenylene group ie, a C 2- 4-alkenylene or C 2- 8-alkenylene group or an alkynylene group, ie, a C 2- 4-alkynylene group or a C 2 be _8-alkynylene group.
  • C 1-4 -alkyl is selected from the group comprising -CH 2 -, -CH 2 -CH 2 -, -CH (CH 3 ) -, -CH 2 -CH 2 -CH 2 -, -CH (CH 3 ) -CH 2 -, -CH (CH 2 CH 3 ) -, -CH 2 - (CH 2 ) 2 -CH 2 -, -CH (CH 3 ) - CH 2 -CH 2 -, -CH 2 -CH (CH 3 ) -CH 2 -, -CH (CH 3 ) -CH (CH 3 ) -, -CH (CH 2 CH 3 ) -CH 2 -, -C (CH 3 ) 2 -CH 2 -, -CH (CH 2 CH 2 CH 3 ) -, -C (CH 3 ) 2 -CH 2 -, -CH (CH 2 CH 2 CH 3 ) -, -C (CH 3 ) 2 -CH
  • a substituent may optionally in turn be monosubstituted or polysubstituted.
  • aryl and heteroaryl substituents are F; Cl; Br; I; N0 2 ; CF 3 ; CN;
  • the 3rd generation substituents may not be substituted again, i. then there are no 4th generation substituents.
  • the substituents of the second generation can not be substituted again, ie there are already no substituents of the 3rd generation.
  • the functional groups for R 1 to R 8 may each be optionally substituted, the respective ones
  • the compounds of the invention are defined by substituents which represent or carry an aryl or heteroaryl radical, each unsubstituted or monosubstituted or polysubstituted or which together with the carbon or heteroatom (s) connecting them as ring member or as Ring members form a ring, for example an aryl or heteroaryl, in each case unsubstituted or monosubstituted or polysubstituted. Both these aryl or heteroaryl radicals and the thus formed
  • aromatic ring systems may optionally be condensed with C ⁇ o-cycloalkyl or heterocyclyl, in each case saturated or unsaturated, or aryl or heteroaryl that is a C 3- 10 cycloalkyl such as cyclopentyl or a heterocyclyl such as morpholinyl, or an aryl such as phenyl or a heteroaryl such as pyridyl, wherein the thus condensed C 3- i 0 -cycloalkyl or HeterocyclyI radicals, aryl or heteroaryl radicals in turn each be unsubstituted or mono- or polysubstituted.
  • compounds of the invention are defined by substituents, a C 3- i represent 0 cycloalkyl or heterocyclyl radical, or wear, respectively
  • Both these Cs o -cycloalkyl or HeterocyclyI radicals and the aliphatic ring systems formed may optionally be fused with aryl or heteroaryl or with Cs-io-cycloalkyl or heterocyclyl, i. with an aryl such as phenyl or a heteroaryl such as pyridyl or a C ⁇ o-cycloalkyl such as
  • Cyclohexyl or a heterocyclyl such as morpholinyl wherein the thus condensed aryl or Heteroaryl radicals, or C 3 i 0 cycloalkyl or heterocyclyl radicals may in turn be substituted in each case unsubstituted or mono- or polysubstituted.
  • (R ° or H)" within a radical means that R ° and H can occur within this radical in any possible combination.
  • the radical “N (R ° or H) 2 " may stand for “NH 2 ", “NHR °” and M N (R 0 ) 2 "When R ° is as in the case of" N (R °) 2 "occurs multiple times within a residue, then R ° can each have the same or different meanings: in the present example of" N (R °) 2 ", R ° can for example be twice for aryl, whereby the functional group" N (aryl) 2 "or R ° may be once aryl and once C 1-10 alkyl to give the functional group” N (aryl) (C 1-10 alkyl) ".
  • 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,
  • citric acid and hydrochloric acid Particularly preferred are citric acid and hydrochloric acid.
  • Physiologically acceptable salts with cations or bases are salts of the respective compound - as an anion with at least one, preferably inorganic, cation, which are physiologically compatible - especially when used in humans and / or mammals.
  • unbranched C lJ ⁇ alkyl radical in particular (mono-) or (di) sodium, (mono-) or (di) potassium, magnesium or calcium salts.
  • Another object of the present invention are compounds of general formula (I) wherein
  • X is CR 3 or N, where R 3 is H; or C 1-0 -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted; stands;
  • A is N, C or CH
  • T is N, C or CR 7b ,
  • the non-aromatic ring ta may optionally have at least one unsaturated bond, with the proviso that when A is N, A is not part of an unsaturated bond, and provided that when T is is N, T is not part of an unsaturated bond, p is 1, 2 or 3; n is 1, 2, 3 or 4;
  • R ° is C 1-10 -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted; C 3 i 0 cycloalkyl or heterocyclyl, in each case saturated or unsaturated, unsubstituted or monosubstituted or polysubstituted; Aryl or heteroaryl, in each case unsubstituted or monosubstituted or polysubstituted; bridged via C 1-8 alkyl C ⁇ 10 cycloalkyl or heterocyclyl, in each case saturated or unsaturated, unsubstituted or mono- or polysubstituted, wherein the alkyl chain in each case branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; or via C 1-8 -alkyl-bridged aryl or heteroaryl, in each case unsubstituted or monosubstit
  • R 1 for H; C 0 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted; C 3 i 0 1 cycloalkyl or heterocyclyl 1, in each case saturated or unsaturated, unsubstituted or mono- or polysubstituted; Aryl or heteroaryl, in each case unsubstituted or monosubstituted or polysubstituted; via C 1-8 alkyl bridged C3-i0 cycloalkyl or heterocyclyl 1 1, substituted saturated or unsaturated, unsubstituted or mono- or polysubstituted, wherein the alkyl chain in each case branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted can; or via C 1-8 -alkyl-bridged aryl or heteroaryl, in each case unsubstituted or monosubstituted
  • R 4 is H
  • R 5 , R 6 and R 8 are each independently H; F; Cl; Br; I; OH; OR °; or R ° mean;
  • n is 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 1 or 2, most preferably 1.
  • Ring ta may optionally have at least one, preferably exactly one, unsaturated bond, provided that when A is N, A is not part of the unsaturated bond, and further provided that when T is N, T is not part of the unsaturated bond.
  • the radical R 1 is 1 H. In a further preferred embodiment of the compounds of the general formula (I) according to the invention, the radical is
  • R 11a and R 1b are each independently H; F; Cl; Br; I; N0 2 ; CF 3 ; CN; OH; OCF 3 ; NH 2 ; C 1-4 alkyl, O-C 1-4 alkyl, NH-C 1-4 alkyl, N (C 1-4 alkyl) 2 , wherein each C alkyl is saturated or unsaturated, branched or unbranched, unsubstituted or may be monosubstituted or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, O-C 1-8 alkyl, OH and OCF 3 ; stand; with the proviso that when R 11a and R 11b are attached to the same carbon atom, only one of the substituents R 11a and R 11b is OH, OCF 3 , NH 2 , OC ⁇ alkyl,
  • NH-C 1-4 -alkyl or N (C 1-4 -alkyl) 2 may stand; m is 0, 1, 2, 3 or 4;
  • Z is C 1-4 -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted with one or more
  • Each independently of one another represents H; F; Cl; Br; I; N0 2 ; CF 3 ; CN; OH; OCF 3 ; NH 2 ; C 1-4 alkyl, O-C 1-4 alkyl, NH-C 1-4 alkyl, N (C 1-4 alkyl) 2 , wherein C 1-4 alkyl is in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted may be substituted by one or more substituents each independently selected from the group consisting of F, Cl, Br, I, 0-C 4 alkyl, OH and OCF 3 ; stand.
  • the rest is
  • R 1 a and R 11b are each independently H; F; Cl; Br; I; N0 2 ; CF 3 ; CN; Methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec-butyl; tert-butyl; CH 2 CF 3 ; OH; O-methyl; O-ethyl; O- (CH 2 ) 2 -O-CH 3 ; 0- (CH 2 ) 2 -OH; OCF 3 ; NH 2 ; NH-methyl; N (methyl) 2 ; NH-ethyl; N (ethyl) 2 ; or N (methyl) (ethyl); stand; with the proviso that when R 11a and R 11b are attached to the same carbon atom, only one of the substituents R 11a and R 11b is OH; OCF 3 ; O-methyl; O-ethyl; 0- (CH 2 ) 2 -O-CH 3
  • Phenyl where benzyl and phenyl may each be unsubstituted or monosubstituted or polysubstituted with one or more substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, OH, OC ⁇ -alkyl, OCF 3 ,
  • Each independently of one another represents H; F; Cl; Br; I; N0 2 ; CF 3 ; CN; Methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec-butyl; tert-butyl; CH 2 CF 3 ; OH; O-methyl; O-ethyl; O- (CH 2 ) 2 -O-CH 3 ; 0- (CH 2 ) 2 -OH; OCF 3 ; NH 2 ; NH-methyl; N (methyl) 2 ; NH-ethyl; N (ethyl) 2 ; or N (methyl) (ethyl); stand.
  • R 11a and R 11b are each independently H; F; Cl; Br; I; Methyl; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; tert-butyl; OH; O-methyl; O-ethyl; stand; with the proviso that when R 11a and R 11b are attached to the same carbon atom, only one of the substituents R 11a and R 11b is OH; O-methyl; O-ethyl; can stand; m is 0, 1 or 2;
  • Z is C 1-4 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, OH, Od-4 Alkyl, OCF 3 , and CF 3 ; C 1-6 cycloalkyl 1 , saturated or unsaturated, unsubstituted or mono- or polysubstituted with one or more substituents each
  • radicals R 11a and R 11b can , taking into account the above proviso, be based both on the same carbon atom and on different ones
  • Each independently of one another represents H; F; Cl; Br; I; Methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec-butyl; tert-butyl; OH; O-methyl; O-ethyl; stand.
  • Z is Ci-4-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, OH, 0-Ci_4- alkyl; C 1-6 cycloalkyl, saturated or unsaturated, morpholinyl, piperidinyl, 4-methylpiperazinyl, piperazinyl, each unsubstituted or mono- or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, OH , 0-C 1-4 -alkyl and C 1-4 -alkyl; Phenyl or pyridyl, each unsubstituted or monosubstituted or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, CN, OH, 0-C 1-4 alky
  • the radicals R 11a and R 11b may each independently be H for the same carbon atom or for different carbon atoms; Methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec-butyl; tert-butyl; stand.
  • R 11a and R 11b are each independently H; Methyl; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; tert-butyl; stand; m is 0, 1 or 2; Z is C 1-4 -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, OH, 0-C -4- alkyl; C 1-6 cycloalkyl 1 , saturated or unsaturated, morpholinyl, piperidinyl, 4-methylpiperazinyl, piperazinyl, each unsubstituted or monosubstituted or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, OH, O-C 1-4 -alkyl and C
  • radicals R 11a and R 11b may each independently of one another represent H for the same carbon atom and for different carbon atoms; Methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec-butyl; tert-butyl; stand.
  • R 2 for H; F; Cl; Br; I; CN; N0 2 ; CF 3 ; CF 2 H; CFH 2 ; CF 2 Cl; CFCI 2 ; OH; OCF 3 ; OCF 2 H;
  • the rest is
  • R 2 for H; F; Cl; Br; I; CN; CF 3 ; CF 2 H; CFH 2 ; CF 2 Cl; CFCI 2 ; OH; OCF 3 ; OCF 2 H; OCFH 2 ;
  • NH (C 1-4 alkyl), N (C 1-4 alkyl) 2 , SH, SC 1-8 alkyl, SCF 3 , benzyl, phenyl, pyridyl and thienyl, where benzyl, phenyl, pyridyl, thienyl, may each be unsubstituted or monosubstituted or polysubstituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, CN, OH, 0-C 1-8 -alkyl, OCF 3 , C 1-4 Alkyl, C ( O) -OH, CF 3 , NH 2 , NH (C 1-4 -alkyl),
  • Nid ⁇ -Alkyljz, SH, SC 1-4 alkyl, SCF 3 and S ( 0) 2 OH, where the alkyl chain in each case branched or unbranched, saturated or unsaturated, may be unsubstituted.
  • R 2 for H; F; Cl; Br; I; CN; C 1-0 -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I and OH; C 1-6 -cycloalkyl, saturated or unsaturated, unsub- stituiert; or C 1- alkyl bridged C ⁇ o-cycloalkyl, saturated or unsaturated, unsubstituted, wherein the alkyl chain is branched or unbranched, saturated or unsaturated, may be unsubstituted; or phenyl, pyridyl, thienyl, each unsubstituted or mono- or polysubstituted with one or more
  • Substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, F, Cl, Br, I, CF 3 , OCF 3 , OH, SH and SCF 3 ; or phenyl, pyridyl or thienyl bridged by C 1-4 -alkyl, in each case unsubstituted or monosubstituted or polysubstituted, with one or more substituents independently
  • C 1-4 -alkyl selected from the group consisting of C 1-4 -alkyl, C 1 -C 4 -alkyl, F, Cl, Br, I, CF 3 , OCF 3 , OH, SH and SCF 3 , where the alkyl chain is branched or unbranched, saturated or unsaturated, may be unsubstituted.
  • R 2 is selected from the group consisting of H; F; Cl; Br; I; CN; cyclopropyl;
  • Ci.io-alkyl saturated or unsaturated, branched or unbranched, unsubstituted, or mono- or polysubstituted with one or more
  • Substituents independently selected from the group consisting of F, Cl, Br; Phenyl, unsubstituted or mono- or polysubstituted independently of one another selected from the group consisting of C 1-4 alkyl, 0-C 1-4 alkyl, F, Cl, Br, I, CF 3 and OCF 3 with one or more substituents ,
  • R 2 for H; F; Cl; Br; I; CF 3 ; CN; Methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec-butyl; tert-butyl; cyclopropyl; cyclobutyl; Phenyl, unsubstituted or mono- or polysubstituted independently of one another selected from the group consisting of one or more substituents selected from C 1-4 alkyl, O-Ci-4-alkyl, F, Cl, Br, I, CF 3 and OCF 3;
  • the radical R 2 is 1 H.
  • R 2 is tert-butyl or CF 3 .
  • X is CR 3 or N, preferably CR 3 , where R 3 is H; C 1-0 -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted, monosubstituted or polysubstituted by one or more
  • X is CR 3 or N, preferably CR, where R 3 is H; Ci.io-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted; or for CF 3 .
  • X is CR 3 or N, preferably CR 3 , where R 3 is H; Methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec-butyl; tert-butyl; or CF 3 is.
  • X is CR 3 or N, preferably CR 3 , where R 3 is H.
  • p is 1 or 2, preferably 1.
  • the radical is R 4 for H; Ci. 10 -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted with one or more
  • the rest is
  • R 4 for H or Ci.io-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted; even more preferred for H.
  • R 4 for H; Methyl; ethyl; n-propyl; or iso-propyl; especially for H.
  • the radical R 4 is H.
  • R 5 , R 6 and R 8 are each independently H; OH; C 1-10 -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted with one or more substituents each independently selected from the group consisting of O-Ci-4-alkyl, F, Cl, Br, I and OH.
  • R 5 , R 6 and R 8 are each independently H; d-10-alkyl, saturated or
  • radicals are particularly preferred.
  • R 5 , R 6 and R 8 are each independently H.
  • the radical is
  • R 13a and R 13b are each independently H; F; Cl; Br; I; N0 2 ; CF 3 ; CN; OH;
  • OCF 3 NH 2 ; C 1-4 alkyl, OC 1-4 alkyl, NH-C 1-4 alkyl, N (C 1-4 alkyl) 2l each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted with one or more Each independently selected from the group consisting of F, Cl, Br, I, O-C 1-4 alkyl, OH and OCF 3 ; stand; with the proviso that if R 13a and R 13b at the same
  • radicals R 13a and R 13b can , taking into account the above proviso, be used both on the same carbon atom and on different ones
  • Each independently of one another represents H; F; Cl; Br; I; N0 2 ; CF 3 ; CN; OH; OCF 3 ; NH 2 ; C 1-4 alkyl, O-C 1-4 alkyl, NH-C 1-4 alkyl, N (C alkyl) 2 , wherein each of C 1-4 alkyl is saturated or unsaturated, branched or unbranched, unsubstituted or may be mono- or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, 0-C -4 alkyl, OH, and OCF 3; stand.
  • radical R 7a stands for the partial structure (T2), wherein
  • R 13a and R 3b are each independently H; F; Cl; Br; I; N0 2 ; CF 3 ; CN;
  • Carbon atom are bonded, only one of the substituents R 11a and R 1b for OH; OCF 3 ; O-methyl; O-ethyl; 0- (CH 2 ) 2 -O-CH 3 ; 0- (CH 2 ) 2 -OH; NH 2 ; NH-methyl; N (methyl) 2 ; NH-ethyl; N (ethyl) 2 ; or N (methyl) (ethyl) may stand; s is 0, 1, 2, 3 or 4; preferably represents 0, 1 or 2;
  • Phenyl, pyridyl and thienyl each unsubstituted or monosubstituted or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, O-C 1-4 -alkyl, OCF 3, C ⁇ alkyl, mono- or disubstituted with OH substituted C 1-4 alkyl, CF 3, NH 2, NH (Ci-4-alkyl), N (C 1-4 alkyl) 2, SH, SC ⁇ -alkyl, SCF 3 , benzyl, phenyl, pyridyl and thienyl, where benzyl, phenyl, pyridyl, thienyl can each be unsubstituted or monosubstituted or polysubstituted with one or more substituents independently of one another selected from the group consisting of F, Cl, Br, I, NO 2
  • radicals R 13a and R 3b may be selected taking into account
  • the radical R 7a stands for the partial structure (T2), in which
  • R 13a and R 13b are each independently H; F; Cl; Br; I; Methyl; ethyl; n-
  • R 11a and R 11b are OH; O-methyl; O-ethyl; can stand; s is 0, 1, 2, 3 or 4; preferably represents 0, 1 or 2; U is d-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, OH, O-Ci-4 Alkyl, OCF 3 , and CF 3 ; C 1-6 cycloalkyl, saturated or unsaturated, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, 4-methylpiperazinyl,
  • Piperazinyl each unsubstituted or monosubstituted or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, O-C 1-4 -alkyl, OCF 3 , Ci-4-alkyl, CF 3l NH 2 , NHiC ⁇ -alkyl), N (C 1-4 -alkyl) 2 , SH, SC 1-4 -alkyl, SCF 3 ; Phenyl, pyridyl or thienyl, each unsubstituted or mono- or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, N0 2 , CN, OH, 0-C 1-4 alkyl , OCF 3 , C 1-4 -alkyl, mono- or di-OH-substituted C 1-4 -alkyl, CF 3 ,
  • radicals R 13a and R 13b may take into account the
  • R 13a and R 13b are each independently H; Methyl; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; tert-butyl; stand; s is 0, 1, 2, 3 or 4; preferably represents 0, 1 or 2; U is Ci-4-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, OH, 0-C - 4- alkyl, OCF 3 , and CF 3 ; C3-io-Cycloalkyl, saturated or unsaturated, morpholinyl, piperidinyl, pyrrolidinyl, 4-methylpiperazinyl, piperazinyl, each unsubstituted or mono- or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl,
  • radicals R 3a and R 13b may take into account the
  • ethyl n-propyl; iso-propyl; n-butyl; sec-butyl; tert-butyl; stand.
  • R 7a stands for the partial structure (T2)
  • radicals R 13a and R 13b may take into account the
  • ethyl n-propyl; iso-propyl; n-butyl; sec-butyl; tert-butyl.
  • the rest is
  • R 7b for H; F; Cl; Br; or OH.
  • the radical R 7b is H; or OH.
  • the radical R 7b is H.
  • the compounds of the general formula (I) according to the invention have the general formula (Ie)
  • X is CR 3 or N, preferably CR 3 ; wherein R 3 is H; or d.io-alkyl, saturated or unsaturated, branched or unbranched, is unsubstituted;
  • A is N, C or CH
  • T is N, C or CR 7b , where R 7b is H; F; Cl; Br; I; or OH is;
  • the symbol '-' means that the non-aromatic ring ta may optionally have at least one, preferably exactly one, unsaturated bond, with the proviso that when A is N, A is not part of an unsaturated bond, and with the proviso that when T is N, T is not part of an unsaturated bond for which the partial structure is (T1-1)
  • R 1 a and R 11b are each independently H; Methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec-butyl; tert-butyl; stand; m is 0, 1 or 2;
  • Z is C 1-4 -alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, OH, and 0- C 1-4 alkyl; C 3-10 - cycloalkyl 1 , saturated or unsaturated, morpholinyl, piperidinyl, 4-methylpiperazinyl, piperazinyl, each unsubstituted or mono- or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I , OH, O-C 1-4 -alkyl and C 1-4 -alkyl; Phenyl or pyridyl, each unsubstituted or monosubstituted or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, CN,
  • R 7a for the partial structure (T2) stands for ⁇ (V) r- (CR 13a R 13b ) s - U (T2)
  • R 13a and R 13b are each independently H; Methyl; ethyl; n-propyl;
  • U is d-4-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br, I, OH, OC ⁇ alkyl , OCF 3 , and CF 3 ; C 3 i 0 cycloalkyl, saturated or unsaturated, morpholinyl, piperidinyl, pyrrolidinyl, 4-methylpiperazinyl, piperazinyl, each unsubstituted or mono- or polysubstituted with one or more substituents each independently selected from the group consisting of F, Cl, Br , I, CN, OH, O-C 1-4 alkyl, OCF 3 , C 1-4 alkyl, CF 3 ; Phenyl, pyridyl or thienyl, each unsubstituted or monosubstituted or polysubstituted with
  • compounds of the general formula (I) according to the invention which are preferred in the FLIPR assay with CHO K1 cells transfected with the human VR1 gene in a concentration of less than 2000 nM, preferably less than 1000 nM, particularly preferably less than 300 nM, most preferably less than 100 nM, even more preferably less than 75 nM, more preferably less than 50 nM, most preferably less than 10 nM, effect a 50 percent displacement of capsaicin present at a concentration of 100 nM.
  • the Ca 2+ influx is determined using a Ca 2+ -sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden Netherlands) in the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, USA). quantified as below described.
  • a further subject of the present invention is a process for the preparation of compounds of the general formula (I) given above, according to which at least one compound of the general formula (II)
  • Reaction medium if appropriate in the presence of at least one suitable coupling reagent, if appropriate in the presence of at least one base, with a compound of the general formula (III) or (IV),
  • (III) (IV) in the shark is a halogen, preferably Cl or Br, and R 5 , R 6 , R 7a , R 8 , p and T have one of the above meanings and A is CH or C, in one
  • Reaction medium in the presence of phenyl chloroformate, if appropriate in the presence of at least one base and / or a coupling reagent, is reacted, and this is optionally purified and / or isolated, and a compound of general formula (V) with a compound of general formula ( VI)
  • n of R 5 , R 6 , R 7a , R 8 , p and T have one of the above meanings and A is N, in a reaction medium, optionally in the presence of at least one suitable Coupling reagent, optionally in the presence of at least one base to give a compound of general formula (I) is reacted,
  • reaction of compounds of the abovementioned general formulas (II) or (VI) with carboxylic acids of the abovementioned general formula (III) to give compounds of the abovementioned general formula (I) is preferably carried out in a reaction medium selected from the group consisting of diethyl ether,
  • DCC Dicyclohexylcarbodiimide
  • EDCI diisoproylcarbodiimide
  • CDI 1,1'-carbonyldiimidazole
  • HATU N- [(dimethylamino) -1H-1,2,3 triazolo [4,5-b] pyridino-1-ylmethylene] -N-methylmethanaminium hexafluorophosphate N-oxide
  • HATU 0- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate
  • HBTU 0- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate
  • TBTU N-hydroxybenzotriazole
  • HOBt 1-hydroxy-7-
  • Diisopropylethylamine preferably at temperatures from -70 ° C to 100 ° C.
  • intermediates and end products can each be purified and / or isolated by customary methods known to the person skilled in the art. Suitable purification methods are, for example, extraction methods and chromatographic methods, such as column chromatography or preparative chromatography. All of the above-described process steps and in each case also the purification and / or isolation of intermediate or end products can be carried out partially or completely under an inert gas atmosphere, preferably under a nitrogen atmosphere.
  • substituted compounds of the abovementioned general formula (I) according to the invention and corresponding stereoisomers can be isolated both in the form of their free bases, their free acids and in the form of corresponding salts, in particular physiologically compatible salts.
  • the free bases of the respective substituted compounds according to the invention of the abovementioned general formula (I) and corresponding stereoisomers can be synthesized, for example, by reaction with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid.
  • an inorganic or organic acid preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid.
  • Glutamic acid, saccharic acid, monomethyl sebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -lipoic acid, acetylglycine, hippuric acid, Phosphoric acid and / or aspartic acid are converted into the corresponding salts, preferably physiologically acceptable salts.
  • the free bases of the respective substituted compounds of the above general formula (I) and corresponding stereoisomers can also be converted with the free acid or a salt of a sugar substitute, such as saccharin, cyclamate or acesulfame, into the corresponding physiologically acceptable salts.
  • the free acids of the substituted compounds of the abovementioned general formula (I) and corresponding stereoisomers can be converted into the corresponding physiologically tolerable salts by reaction with a suitable base.
  • substituted compounds according to the invention of the abovementioned general formula (I) and corresponding stereoisomers may, if appropriate, as well as the corresponding acids, the corresponding bases or salts of these compounds, according to customary methods known to the person skilled in the art, also in the form of their solvates, preferably in the form of their Hydrate, to be obtained.
  • substituted compounds of the abovementioned general formula (I) according to the invention are obtained 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 prepared by customary methods known to the person skilled in the art separated and possibly 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. In particular, single enantiomers, e.g. by HPLC on a chiral stationary phase or by means of
  • substituted compounds according to the invention of the abovementioned general formula (I) and corresponding stereoisomers and in each case the corresponding acids, bases, salts and solvates are toxicologically harmless and are therefore suitable as pharmaceutical active ingredients in medicaments.
  • a further subject of the present invention is therefore a medicament containing at least one compound according to the invention of the abovementioned general formula (I), in each case optionally in the form of one of its pure stereoisomers, in particular Enantiomers or diastereomers, their racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and / or diastereomers, in any mixing ratio, or each in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and optionally one or more
  • medicaments according to the invention are particularly suitable for vanilloid receptor 1 (VR1 / TRPV1) regulation, preferably for vanilloid receptor 1 (VR1 / TRPV1) inhibition and / or for vanilloid receptor 1 (VR1 / TRPV1) stimulation, ie they have an agonistic or antagonistic effect.
  • the medicaments according to the invention are likewise preferably suitable for the prophylaxis and / or treatment of disorders or diseases which are at least partially mediated by vanilloid receptors 1.
  • the pharmaceutical composition of the invention is suitable for administration to adults and children, including infants and babies.
  • the medicament according to the invention may be in the form of 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 , and be administered as such.
  • the medicament of the invention usually contains other physiologically acceptable pharmaceutical excipients, for example
  • support materials can be selected from the group consisting of support materials, 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
  • 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 compounds according to the invention which are used according to the invention in a depot in dissolved form or in a plaster, optionally with the addition of skin penetration promoting agents, are suitable percutaneous administration preparations. Orally or percutaneously applicable preparation forms can release the particular substituted compound according to the invention also delayed.
  • the preparation of the pharmaceutical compositions according to the invention is carried out by means of conventional means, devices, methods and processes known from the prior art, as described, for example, in "Remington's Pharmaceutical Sciences", published by AR Gennaro, 17th edition, Mack Publishing Company, Easton, Pa , 1985, in particular in part 8, chapters 76 to 93.
  • the corresponding description is hereby incorporated by reference and is part of the disclosure
  • the amount of the respective substituted compounds according to the invention of the above-indicated general formula I to be administered to the patient may vary and depends, for example, on the weight or age of the patient as well as the mode of administration, the indication and the severity of the disease. Usually 0.001 to 100 mg / kg, preferably 0.05 to 75 mg / kg, more preferably 0.05 to 50 mg / kg, body weight the patient of at least one such verbin invention applied.
  • the medicament according to the invention is preferably suitable for the treatment and / or
  • hyperalgesia allodynia; causalgia; Migraine; Depressions; Neuropathy;
  • Nerve injuries preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficits, particularly preferred memory disorders; Epilepsy; Respiratory diseases,
  • Inflammation of the intestine, eyes, bladder, skin or nasal mucosa diarrhea; pruritus; Osteoporosis; Arthritis; osteoarthritis; rheumatic diseases;
  • Food ingestion preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; Drug addiction;
  • cardiovascular system for vigilance increase; for the treatment of wounds and / or burns; for the treatment of severed nerves; for libido increase; for the modulation of the movement activity; to anxiolysis; for local anesthesia and / or for
  • Inhibition of unwanted side effects preferably selected from the group consisting of hyperthermia, hypertension and bronchoconstriction, triggered by the administration of vanilloid receptor 1 (VR1 / TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, Olvanil , Arvanil, Nuvanil and Capsavanil.
  • VR1 / TRPV1 receptor vanilloid receptor 1
  • the medicament according to the invention is particularly preferably suitable for the treatment and / or prophylaxis 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 and visceral pain; Joint pain; Migraine; Depressions; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Morbus
  • preferably cognitive deficiencies particularly preferred memory disorders
  • Inflammation preferably inflammation of the intestine, eyes, bladder, skin or nasal mucosa
  • urinary incontinence preferably an overactive bladder (overactive bladder, OAB);
  • Drug addiction preferably Drug abuse; Withdrawal symptoms in drug dependence;
  • Development of tolerance to drugs preferably development of tolerance to natural or synthetic opioids;
  • Drug addiction Drug addiction; Drug abuse; Withdrawal symptoms in drug addiction; Alcohol dependency; Alcohol abuse and withdrawal symptoms at
  • the pharmaceutical composition according to the invention is suitable for the treatment and / or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain, and / or urinary incontinence.
  • Another object of the present invention is the use of at least one compound of the invention and optionally one or more pharmaceutically
  • Particularly preferred is the use of at least one compound of the invention and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment and / or prophylaxis of one or more
  • pain selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic
  • Particularly preferred is the use of at least one compound of the invention and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment and / or prophylaxis of one or more
  • Parkinson's disease preferably Alzheimer's disease
  • Huntington's disease cognitive dysfunctions, preferably cognitive deficits, particularly preferred memory disorders
  • Epilepsy Respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pneumonia; To cough; urinary incontinence; an overactive bladder (overactive bladder, OAB); Diseases and / or injuries of the gastrointestinal tract tract; Duodenal ulcers; Stomach ulcers; Irritable bowel syndrome; Stroke; Eye irritation; Skin irritation; neurotic skin diseases; allergic
  • Inflammation of the intestine, eyes, bladder, skin or nasal mucosa diarrhea; pruritus; Osteoporosis; Arthritis; osteoarthritis; rheumatic diseases;
  • Food ingestion preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; Drug addiction;
  • cardiovascular system for vigilance increase; for the treatment of wounds and / or burns; for the treatment of severed nerves; for libido increase; for the modulation of the movement activity; to anxiolysis; for local anesthesia and / or for
  • Inhibition of undesirable side effects preferably selected from the group consisting of hyperthermia, hypertension and bronchoconstriction, triggered by the administration of vanilloid receptor 1 (VR1 TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, Olvanil, Arvanil, SDZ-249665, SDZ-249482, Nuvanil and Capsavanil.
  • VR1 TRPV1 receptor vanilloid receptor 1
  • At least one substituted compound according to the invention and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment and / or prophylaxis 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 and visceral pain;
  • Drug addiction Development of tolerance to drugs, preferably development of tolerance to natural or synthetic opioids;
  • Drug addiction Drug addiction; Drug abuse; Withdrawal symptoms in drug addiction; Alcohol dependency; Alcohol abuse and withdrawal symptoms at
  • At least one substituted compound of the invention and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment and / or prophylaxis of pain, preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain , and / or urinary incontinence.
  • Another object of the present invention is at least one substituted compound according to the invention and optionally one or more pharmaceutically acceptable excipients for use in the vanilloid receptor 1- (VR1 / TRPV1) regulation, preferably the vanilloid receptor 1 (VR1 / TRPV1) Inhibition and / or to the vanilloid receptor
  • At least one compound of the invention and optionally one or more pharmaceutically acceptable excipients for use in the treatment and / or prophylaxis 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 and visceral pain and joint pain.
  • At least one compound of the invention and optionally one or more pharmaceutically acceptable excipients for use in the treatment and / or prophylaxis of one or more diseases selected from the group consisting of hyperalgesia; allodynia; causalgia; Migraine; Depressions; Neuropathy; Nerve injuries; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficits, particularly preferred memory disorders; Epilepsy; Respiratory diseases,
  • Inflammation of the intestine, eyes, bladder, skin or nasal mucosa diarrhea; pruritus; Osteoporosis; Arthritis; osteoarthritis; rheumatic diseases;
  • Food ingestion preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; Drug addiction;
  • cardiovascular system for vigilance increase; for the treatment of wounds and / or burns; for the treatment of severed nerves; for libido increase; for the modulation of the movement activity; to anxiolysis; for local anesthesia and / or for
  • Inhibition of unwanted side effects preferably selected from the group consisting of hyperthermia, hypertension and bronchoconstriction, triggered by the administration of vanilloid receptor 1 (VR1 / TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, Olvanil , Arvanil, SDZ-249665, SDZ-249482, Nuvanil and Capsavanil.
  • VR1 / TRPV1 receptor vanilloid receptor 1
  • At least one compound according to the invention and optionally one or more pharmaceutically acceptable excipients for use in the treatment and / or prophylaxis 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 and visceral pain; Joint pain; Migraine; Depressions; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Morbus
  • preferably cognitive deficiencies particularly preferred memory disorders
  • Inflammation preferably inflammation of the intestine, eyes, bladder, skin or nasal mucosa
  • urinary incontinence preferably an overactive bladder (overactive bladder, OAB);
  • Drug addiction preferably inflammation of the intestine, eyes, bladder, skin or nasal mucosa
  • overactive bladder overactive bladder, OAB
  • Drug addiction preferably inflammation of the intestine, eyes, bladder, skin or nasal mucosa
  • OAB overactive bladder
  • Drug addiction Drug abuse
  • Withdrawal symptoms in drug dependence Development of tolerance to drugs, preferably development of tolerance to natural or synthetic opioids
  • Drug addiction Drug abuse
  • Withdrawal symptoms in drug addiction preferably Alcohol dependency
  • At least one compound of the invention and optionally one or more pharmaceutically acceptable excipients for use in the treatment and / or prophylaxis of pain, preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain, and / or urinary incontinence.
  • Another object of the present invention is a use of at least one substituted compound of the invention and optionally one or more
  • At least one substituted compound of the invention is administered to a human or mammal in a therapeutically effective amount.
  • At least one compound of the invention and optionally one or more pharmaceutically acceptable excipients for the treatment and / or prophylaxis 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 and visceral pain and joint pain, preferably by administering to a human or mammal at least one substituted compound of the invention in a therapeutically effective amount.
  • At least one compound of the invention and optionally one or more pharmaceutically acceptable excipients for treatment and / or prophylaxis of one or more diseases selected from the group consisting of hyperalgesia; allodynia; causalgia; Migraine; Depressions; Neuropathy; Nerve injuries; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficits, particularly preferred memory disorders; Epilepsy; Respiratory diseases,
  • bronchitis preferably selected from the group consisting of asthma, bronchitis and
  • Inflammation of the intestine, eyes, bladder, skin or nasal mucosa diarrhea; pruritus; Osteoporosis; Arthritis; osteoarthritis; rheumatic diseases;
  • Food ingestion preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; Drug addiction;
  • cardiovascular system for vigilance increase; for the treatment of wounds and / or burns; for the treatment of severed nerves; for libido increase; for the modulation of the movement activity; to anxiolysis; for local anesthesia and / or for
  • Inhibition of unwanted side effects preferably selected from the group consisting of hyperthermia, hypertension and bronchoconstriction, triggered by the administration of vanilloid receptor 1 (VR1 / TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, Olvanil , Arvanil, SDZ-249665, SDZ-249482, Nuvanil and capsavanil, preferably in that at least one substituted or substituted human or mammal according to the invention
  • VR1 / TRPV1 receptor vanilloid receptor 1
  • Compound is administered in a therapeutically effective amount.
  • At least one compound of the invention and optionally one or more pharmaceutically acceptable excipients for the treatment and / or prophylaxis 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 and visceral pain; Joint pain; Migraine; Depressions; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficits, particularly preferred memory disorders; Inflammation, preferably inflammation of the intestine, eyes, bladder, skin or nasal mucosa; urinary incontinence; an overactive bladder (overactive bladder, OAB); Drug addiction; Drug abuse; Withdrawal symptoms in drug dependence; Development of tolerance to drugs, preferably development of tolerance to natural or synthetic opioids;
  • Drug addiction Drug addiction; Drug abuse; Withdrawal symptoms in drug addiction; Alcohol dependency; Alcohol abuse and withdrawal symptoms at
  • Alcohol dependence preferably by administering to a human or mammal at least one substituted compound of the invention in a therapeutically effective amount.
  • a compound and optionally one or more pharmaceutically acceptable excipients for the treatment and / or prophylaxis of pain preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain, and / or urinary incontinence, preferably in that one
  • At least one substituted compound of the invention is administered to a human or mammal in a therapeutically effective amount.
  • the agonistic or antagonistic action of the substances to be tested on the vanilloid receptor 1 (VR1 / TRPV1) of the rat species can be determined by the following assay. According to this assay, Ca 2+ influx through the receptor channel is induced by Ca 2+ -sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden
  • FCS fetal calf serum, Gibco Invitrogen GmbH, Düsseldorf, Germany
  • AA solution antioxidants / antimycotics solution, PAA, Pasching, Austria
  • 25 ng / ml medium NGF 2.5S, Gibco Invitrogen GmbH, Düsseldorf, Germany
  • Cell culture plate Poly-D-lysine-coated black 96-well plates with clear bottom (96 well black / clear plate, BD Biosciences, Heidelberg, Germany) are additionally coated with laminin (Gibco Invitrogen GmbH, Düsseldorf, Germany) laminin to a concentration of 100 pg / ml with PBS (Ca-Mg-free PBS, Gibco Invitrogen GmbH,
  • Decapitated rats are removed from the spinal column and placed directly in cold, ie in an ice bath, HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany) with 1% by volume (volume percent) of an AA solution (antibiotics / antimycotics solution, PAA, Pasching, Austria).
  • HBSS buffer Horco Invitrogen GmbH, Düsseldorf, Germany
  • AA solution antibiotics / antimycotics solution, PAA, Pasching, Austria
  • the spinal column is severed longitudinally and taken together with fascia the vertebral canal. Subsequently, the dorsal root ganglia (DRGs) are removed and again stored in cold HBSS buffer mixed with 1% by volume of an AA solution.
  • DDGs dorsal root ganglia
  • the DRGs are each transferred into 500 .mu.l of cold collagenase type 2 (PAA, Pasching, Austria) and incubated at 37.degree. C. for 35 minutes. After addition of 2.5% by volume of trypsin (PAA, Pasching, Austria) is incubated for a further 10 minutes at 37 ° C. After the complete incubation, the enzyme solution is carefully pipetted off and the remaining DRGs are each mixed with 500 ⁇ l of complete medium. The DRGs are each repeatedly suspended, drawn through a syringe through cannulas No. 1, No. 12 and No. 16 and transferred to 50 mL Falcon tubes and this with
  • the number of cells in the suspension is adjusted to 3 ⁇ 10 5 per mL and in each case 150 ⁇ l of this suspension are added to a well of the cell culture plates coated as described above. In the incubator, the plates are allowed to stand at 37 ° C, 5% by volume C0 2 and 95% relative humidity for two to three days.
  • the cells are incubated with 2 pM Fluo-4 and 0.01% by volume Pluronic F127 (Molecular Probes Europe BV, Leiden Netherlands) in HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany) for 30 min at 37 ° C, washed 3 times with HBSS buffer and used after a further incubation of 15 minutes at RT for Ca 2+ measurement in FLIPR assay.
  • the Ca 2+ -dependent fluorescence is before and after the addition of
  • the FLIPR protocol consists of 2 substance additions. First the compounds to be tested (10 ⁇ ) are pipetted onto the cells and the Ca 2+ influx is compared with the control (capsaicin 10 pM). This gives the indication in% activation based on the Ca 2+ signal after addition of 10 pM capsaicin (CP). After 5 minutes of incubation, 100 nM capsaicin are administered and also the influx of Ca 2+ is determined. Desensitising agonists and antagonists lead to a suppression of the Ca 2+ influx. % Inhibition is calculated in comparison with the maximum achievable inhibition with 10 ⁇ capsaicin.
  • the agonistic or antagonistic effect of the substances to be examined on vanilloid receptor (VR1) can also be determined by the following assay.
  • Ca 2+ influx through the channel is monitored using a Ca 2+ -sensitive dye (Fluo-4 type, Molecular Probes, Europe BV, Leiden, The Netherlands) in the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale , USA).
  • FLIPR Fluorescent Imaging Plate Reader
  • CHO K1 cells Chinese hamster ovary cells (CHO K1 cells, European Collection of Cell Cultures (ECACC) Great Britain) are stably transfected with the VR1 gene. For functional studies, these cells are plated on poly-D-lysine coated black 96-well clear bottom plates (BD Biosciences, Heidelberg, Germany) at a density of 25,000 cells / well. Overnight, the cells are incubated at 37 ° C and 5% C0 2 in a culture medium (Nutrient Mixture 's F12, 10% by volume FCS (Fetal calf serum), 18 pg / ml L-proline).
  • a culture medium Nutrient Mixture 's F12, 10% by volume FCS (Fetal calf serum), 18 pg / ml L-proline.
  • the FLIPR protocol consists of 2 substance additions. First, the substances to be tested (10 ⁇ ) are pipetted onto the cells and the Ca 2+ influx with the control
  • Capsaicin 10 ⁇ (Capsaicin 10 ⁇ ) (% activation based on the Ca 2+ signal after addition of 10 ⁇ capsaicin). After 5 minutes of incubation, 100 nM capsaicin are administered and also the influx of Ca 2+ is determined.
  • the first (early) phase (0 to 15 minutes after formalin injection) and the second (late) phase (15 to 60 minutes after formalin injection).
  • the early phase represents a model of acute pain as a direct response to formalin injection, while the late phase is considered a model of persistent (chronic) pain (T J. Coderre et al., Pain 1993, 52, 259-285).
  • the corresponding literature descriptions are hereby incorporated by reference and are considered part of the disclosure.
  • the compounds according to the invention are investigated in the second phase of the formalin test in order to obtain statements about substance effects on chronic / inflammatory pain.
  • the application time of the compounds according to the invention before the formalin injection is selected.
  • the intravenous administration of 10 mg / kg body weight of the test substances takes place 5 minutes before the formalin injection. This is done by a single subcutaneous Formalin injection (20 ⁇ _, 1% aqueous solution) in the dorsal side of the right hindpaw, so that in nociceptive animals a nociceptive reaction is induced, resulting in significant licking and biting of the paw manifests.
  • Pain behavior is quantified by summing the seconds in which the animals show licking and biting of the affected paw during the study period.
  • Substance effect in the formalin test determined as a change from the corresponding control in percent.
  • equivalents Means molar equivalents, "RT” room temperature, "M” and “N” are concentrations in mol / l, “aq.” Aqueous, “total.” saturated, “sol.” solution, “conc.” concentrated.
  • the stationary phase used for column chromathography was silica gel 60 (0.04-0.063 mm) from E. Merck, Darmstadt.
  • step j01 an acid halide J-O in which Hal is preferably Cl or Br may be esterified to compound JI using methanol by methods well known to those skilled in the art.
  • the methyl pivalate J1 can be prepared by methods known to the person skilled in the art, for example using an alkylnitrile R 3 CH 2 -CN, if appropriate in the presence of a base
  • the compound J-IV can be substituted by methods known in the art in N-position, for example.
  • a halide R 1 -Hal optionally in the presence of a base and / or a coupling reagent, wherein Hai preferably Cl, Br or I is or by use of a boronic acid B (OH) 2 R 1 or a corresponding one
  • the substitution can be carried out by methods known to the person skilled in the art, for example with the aid of peroxy reagents and subsequent conversion into ether.
  • the substitution for example by sulfonylation with sulfonyl chlorides, take place.
  • the preparation can be effected, for example, by reaction with disulphides or else with sulfenyl chlorides or sulfenamides, or else by conversion into the mercaptan by means of methods known to the person skilled in the art and subsequent conversion into the thioether.
  • a second synthesis route is suitable, in which in step k01 first an ester K-0 is reduced to the aldehyde Kl by methods known to the person skilled in the art, for example by using suitable hydrogenating reagents such as metal hydrides.
  • step k02 the aldehyde K-l can then be reacted with a hydrazine K-V, which can be obtained starting from the primary amine K-IV by methods known to those skilled in step k05, with elimination of water by means known to those skilled methods for hydrazine K-II.
  • the hydrazine K-II can be halogenated by means known to those skilled in the art to obtain the double bond, preferably chlorinated, such as, for example
  • step k04 the hydrazone halide K-III may be known to one skilled in the art
  • the compound J-V can be hydrogenated by methods known to the person skilled in the art, for example by using a suitable catalyst such as palladium / activated carbon or by using suitable hydrogenating reagents and thus the compound (II) can be obtained.
  • the compound (II) can be converted into the compound (V) by methods known to the person skilled in the art, for example using phenyl chloroformate, if appropriate in the presence of a coupling reagent and / or a base.
  • phenyl chloroformate if appropriate in the presence of a coupling reagent and / or a base.
  • This can, for example, by reaction with an acid halide, preferably a chloride of the formula (IV) by means of methods familiar to those skilled in the art, if appropriate in the presence of a base or by reaction with an acid of the formula (III), if appropriate in the presence of a suitable
  • Coupling reagents such as HATU or CDI, optionally with the addition of a base can be achieved.
  • a carboxylic acid alkyl ester L-O preferably a methyl or ethyl ester
  • hydrazine hydrate can be reacted with hydrazine hydrate by methods familiar to one skilled in the art for the hydrazide L-1.
  • step I02 the amino-substituted nitrile L-2 or its salts can be reacted with Boc anhydride by methods known to the person skilled in the art for the urethane L-3.
  • L-1 and L-3 may be in the presence of a base, preferably a
  • Alkali alcoholate particularly preferably sodium
  • step I05 the ester group in L-4 may be preferred in the presence of an acid
  • Trifluoroacetic acid or hydrochloric acid are cleaved by methods known to those skilled in the art and so the amine (II) can be obtained.
  • step vi the compound (VI) can be converted into the compound (via) using methods known to the person skilled in the art, for example using phenyl chloroformate, if appropriate in the presence of a coupling reagent and / or a base.
  • references may be made from common databases such as the Elsevier, Amsterdam, NL, or the SciFinder® database of the American Chemical Society, Washington, US, of the Reaxys® database.
  • Step j01 within 30 minutes, to a solution of MeOH (120 mL) at 0 ° C was added dropwise pivaloyl chloride (J-O) (1 eq, 60 g) and stirred at room temperature for 1 h. After addition of water (120 mL), the separated organic phase was washed with water (120 mL), dried over sodium sulfate and co-distilled with dichloromethane (150 mL). The liquid product J-1 could be obtained in 98.6% purity (57 g).
  • J-O dropwise pivaloyl chloride
  • Step j02 NaH (50% in paraffin oil) (1.2 eq, 4.6 g) was dissolved in 1,4-dioxane (120 mL) and stirred for a few minutes. Acetonitrile (1.2 eq., 4.2 g) was added dropwise within 15 min and stirred for a further 30 min. The methyl pivalate (J-I) (1 eq, 10 g) was added dropwise over 15 min and the reaction mixture was refluxed for 3 h. After completion of the reaction, the reaction mixture was poured into ice-water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12 x 250 mL). The combined organic phases were dried over sodium sulfate, distilled and, after recrystallization from hexane (100 ml), 5 g of the product (J-II) (51% yield) were obtained as a brown solid.
  • Step j03 At room temperature, 4,4-dimethyl-3-oxopentanenitrile (J-II) (1 eq, 5 g) was taken up in EtOH (100 mL), hydrazine hydrate (2 eq., 4.42 g) added and 3 h refluxed. The residue obtained after distilling off the EtOH was taken up in water (100 ml) and extracted with EA (300 ml). The combined organic phases were over
  • Step j04 3-tert-butyl-1H-pyrazol-5-amine (J-III) (1 eq, 40 g) was dissolved in dilute HCl (120 mL HCl in 120 mL water) and at 0-5 ° C was added dropwise with NaNO 2 (1.03 eq., 25 g in 100 mL) over a period of 30 min. After stirring for 30 minutes, the reaction mixture was neutralized with Na 2 CO 3 . A diazonium salt obtained by reacting KCN (2.4 eq, 48 g), water (120 mL) and CuCN (1.12 eq, 31 g) was added dropwise to the reaction mixture over 30 min and stirred at 75 ° C for a further 30 min.
  • Step j05 (Method 1):
  • Step j06
  • step j05 may also be performed as follows (method 2): step j05 (method 2):
  • the residue obtained is purified by column chromatography (Si0 2 , various mixture of EE and cyclohexane as eluent) to obtain the product JV.
  • Step k01
  • Step k05
  • Step k02
  • Step k03
  • Step k04
  • Step j06 (Method 3):
  • the compound J-VI can be monosubstituted in the N-position by methods known to those skilled in the art, for example by using a halide R 7a -Hal, if appropriate in the presence of a base and / or a coupling reagent, wherein Hai preferably Cl, Br or I is.
  • Step j11 To a mixture of AICI 3 (1.2 eq, 416 g) and fluorobenzene (1 eq, 250 g) was added dropwise at 4 ° C over a period of 1 h acetic anhydride (1.2 eq, 320 g) and 2 h stirred. The reaction mixture was added to a solution of ice-water (2.5 kg) and HCl (250 ml), the organic phase separated and distilled at 150 ° C / 10 mm. 1- (4-fluorophenyl) ethanone was obtained in 30% yield (108 g) as a pale yellow liquid.
  • Step j12 1- (4-Fluorophenyl) ethanone (1 eq, 25 g) was dissolved in MeOH (200 mL) and added portionwise over 45 min at 4 ° C to NaBH 4 (1 eq, 6.5 g) and 30 stirred for a few minutes. After addition of water (100 mL), the reaction mixture was extracted with EA (3 ⁇ 100 mL). The combined organic phases were dried over sodium sulfate. After removal of the solvent in vacuo, the liquid product 1- (4-fluorophenyl) ethanol (25 g, 99% yield) could be obtained.
  • Step j13 1- (4-fluorophenyl) ethanol (1 eq, 25 g) was taken up in dichloromethane (150 mL) and PBr3 (0.7 eq, 12 mL) was added dropwise at 4 ° C over a period of 20 min. The reaction mixture was stirred at room temperature for 4 h, then added to ice-water (200 g) and extracted with dichloromethane (3 x 100 mL). The combined organic phases were dried over sodium sulfate, concentrated in vacuo and the liquid product 1- (1-bromoethyl) -4-fluorobenzene (30 g, 83% yield).
  • Step j14 To a solution of tert -butyl-piperazine-1-carboxylate (1 eq, 15 g) in DMF (15 mL) at room temperature was added 1- (1-bromoethyl) -4-fluorobenzene (1.2 eq. 18 g) and K 2 C0 3 (2 eq., 22 g) and stirred for 2 h. After adding cold water (20 mL), it was extracted with hexane (10 x 60 mL). The combined organic phases were over
  • Step j15 tert -Butyl 4- (1- (4-fluorophenyl) ethyl) piperazine-1-carboxylate (16.2 mmol, 5 g) was dissolved in MeOH (100 mL), isopropanolic HCl (106 mL) added dropwise at 4 ° C and stirred for 12 h at room temperature. After removal of the solvent in vacuo, the residue was taken up in diethyl ether (100 mL).
  • Step j07 To a solution of (3-tert-butyl-1- (3-chlorophenyl) -1H-pyrazol-5-yl) methanamine (5 g, 18 mmol, 1 equiv.) In DMF (25 mL) became potassium carbonate (9.16 g, 66 mmol, 3.5 equiv.) And the resulting reaction mixture cooled to 0 ° C. Phenyl chloroformate (3.28 g (2.65 mL), 20 mmol, 1.1 eq.) was dissolved in
  • Step j07 At room temperature, a solution of (1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methanamine (2.5 g, 9.1 mmol, 1 eq.) In dichloromethane (50 mL with phenyl chloroformate (1.28 mL, 10.2 mmol, 1.12 eq.) and triethylamine (1.5 mL, 10.9 mmol, 1.2 eq.). After stirring at room temperature for 12 h, the reaction mixture was extracted with Na 2 CO 3 solution (1 ⁇ 25 mL) and dichloromethane (2 ⁇ 25 mL). The combined organic phases were dried over agnesiumsulfat and in
  • Step a To a solution of diisopropylamine (57 mL, 404 mmol, 2.3 eq.) In THF (400 mL) at -20 ° C over a period of 2 h n-buli (1.6 molar, 258.3 mL, 380 mmol, 2.2 Aq.) was added dropwise and stirred at 0 ° C for 45 min. After the reaction mixture had cooled to -75 ° C., ethyl 2,2,2-trifluoroacetate (25 g, 170 mmol) in THF (200 mL) was added dropwise over 2 h and added at -75 ° C. for 1 h and for an additional hour Room temperature stirred.
  • n-buli 1.6 molar, 258.3 mL, 380 mmol, 2.2 Aq.
  • Step b 4,4,4-Trifluoro-2-methyl-3-oxobutanenitrile (10 g, 66 mmol, 1 eq.) was taken up in ethanolic HCl solution (300 mL) and 3-chlorophenylhydrazine (9.43 g, 66 mmol , 1 Aq.) Added. After stirring for 2 h under reflux, the solvent was in
  • Step c Copper bromide (11.33 g, 51.1 mmol, 1.2 eq.) Was taken up in acetonitrile (176 mL) and heated to 150 ° C. After addition of n-butylnitrite (6.59 g (7.47 mL), 63 mmol, 1.5 eq.) Was added dropwise over a period of 30 min obtained in step b 1- (3-chlorophenyl) -4-methyl-3- (trifluoromethyl ) -1 H-pyrazole-5-amine (11.75 g, 42 mmol) in acetonitrile (176 mL) was added and this mixture stirred at 150 ° C for 15 min. The
  • Step d The product from step c (13 g, 38 mmol, 1 eq.) was taken up in NMP (130 mL) and copper cyanide (6.8 g, 76 mmol, 2 eq.) And sodium iodide (100 mg, catalytic) were added and Stirred at 180 ° C for 8 h.
  • the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (5 x 100 mL). The combined organic phases were washed with cold water (5 ⁇ 50 ml), dried over sodium sulfate and concentrated in vacuo. After column chromatographic purification (Si0 2 , EtOAc / n-hexane 2/98, v / v), the product was obtained as a yellow solid (8 g).
  • Step e 1- (3-Chlorophenyl) -4-methyl-3- (trifluoromethyl) -1H-pyrazole-5-carbonitrile (5 g, 17 mmol) was dissolved in dry THF (30 mL). At 5 ° C, borane-THF in THF (70 mL) was added dropwise over 30 min. The reaction mixture slowly rose Heated to 50 ° C and stirred for 12 h. After complete conversion, the reaction mixture was acidified at 5 ° C with concentrated HCl and stirred for 2 h at room temperature. The reaction mixture was then adjusted to pH ⁇ 12 with 10% NaOH and the product extracted with EtOAc (5 x 50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The resulting solid was washed with 10% diethyl ether / n-hexane mixture and dried. The product was obtained as a white solid (3 g, 59% yield).
  • Step a To a freshly prepared sodium ethoxide solution (prepared by dissolving sodium (1 g, 8.2 mmol, 1.2 eq.) In EtOH (30 mL)) was added diethyl oxalate (0.92 mL, 6.85 mmol, 1 eq) at rt and then cyclopropyl methyl ketone dropwise (0.74 mL, 7.5 mmol, 1.1 eq.) At 0 ° C. The reaction mixture was warmed slowly to RT and stirred for a further 3 h. Ice-cold water (10 mL) was added and the EtOH was distilled off under reduced pressure.
  • Step b To the product obtained from step a (200 mg, 0.543 mmol, 1 eq.) In EtOH (8 mL) was added methoxylamine hydrochloride (30% solution in water, 0.4 mL, 0.651 mmol, 1.2 eq) at room temperature and the Reaction mixture stirred for 1 h at RT. EtOH was evaporated under reduced pressure and the remaining aqueous phase was extracted with EA (15 mL). The organic phase was washed with water (10 mL), saturated
  • Step c A mixture of the product obtained from step b (1.1 g, 5.164 mmol, 1 Aq) and 3-chlorophenyl hydrazine hydrochloride (1.84 g, 10.27 mmol, 2 Aq) was added to a mixture of acetic acid (20 mL), 2-methoxyethanol (10 mL) and the resulting mixture heated to 105 ° C for 3 h. The solvents were distilled off and the remaining mixture extracted with EA (60 mL). The organic phase was washed with water (10 mL), saturated sodium chloride solution (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. After SC (Si0 2 , EA / petroleum ether, 4/96, v / v), a pale brown semi-solid was obtained as the desired product (1.15 g, 77% yield).
  • Step d To a solution of the product obtained from step c (2.5 g, 8.62 mmol, 1 Aq) in THF-MeOH-water (15 mL - 9 mL - 3 mL) was LiOH (1.08 g, 25.71 mmol, 3 Aq). at 0 ° C and the mixture stirred for 2 h at RT. The solvents were distilled off and the residue acidified to pH ⁇ 3 with 2N hydrochloric acid (1.2 mL).). The acidic solution was then extracted with EA 2 ⁇ 60 mL). The combined organic phases were washed with water (10 mL), saturated sodium chloride solution (10 mL), dried over Na 2 SO, and concentrated under reduced pressure. A white solid was obtained (1.4 g, 62% yield).
  • Steps To a solution of the product obtained from step d (1.4 g, 5.34 mmol, 1 Aq) in 1, 4-dioxane (30 mL) were pyridine (0.25 mL, 3.2 mmol, 0.6 Aq) and di-tert-butyl dicarbonate (1.4 mL , 6.37 mmol, 1.2 Aq) were added at 0 ° C and the resulting mixture stirred for 30 minutes at 0 ° C. Ammonium bicarbonate (0.84 g, 10.63 mmol, 2 equiv.) was added at 0 ° C and the mixture was stirred at RT overnight, then diluted with water (10 mL).
  • Step f To a solution of the product obtained from step e (2 g, 7.66 mmol, 1 Aq) in THF (25 mL) was added BH 3 .DMS (1.44 mL, 15.32 mmol, 2 equiv.) At 0 ° C and the mixture was then allowed to stand for Heated at 70 ° C for 3 h. Then the reaction mixture was cooled to 0 ° C and MeOH (15 mL) added and then refluxed for 1 h. It was then cooled to RT and the solvents distilled off under reduced pressure.
  • Step a To a solution of 2-chloropyridine (20 g, 170 mmol) in EtOH (100 mL) was added hydrazine hydrate (132 mL) and the reaction mixture was refluxed for 15 h. The course of the reaction was monitored by thin-layer chromatography (40% EA in n-hexane, Rf-0.1). After completion of the reaction, the ethanolic hydrazine hydrochloride was distilled off completely at 100 ° C and the residue taken up in DCM (500 mL) and washed with saturated Na 2 C0 3 solution (100 mL). The organic phase was dried over Na 2 SO 4 and concentrated under reduced pressure.
  • Step b To a solution of the product obtained from step a (1 1 g) in EtOH (1 10 mL) was added 4,4-dimethyl-3-oxopentanenitrile (1 1.3 g, 90 mmol, 0.9 Aq) in portions
  • Step c To a solution of the product obtained from step b (4 g, 10 mmol) in
  • Acetonitrile 80 mL was added copper chloride (12.3 g, 90 mmol, 5 Aq) and then a solution of tert-butyl nitrite (2.8 (3.3 mL), 23 mmol, 1.5 Aq) in acetonitrile (40 mL (total 120 mL )) was added dropwise over the course of 10 minutes and then the mixture was stirred at RT for 5 h.
  • Acetonitrile was distilled off, the residue was taken up in water (100 ml) and the mixture was then extracted with EA (2 ⁇ 200 ml). The combined organic phases were dried over Na 2 SO 4 and concentrated under reduced pressure. After SC (Si0 2 , EA / n-hexane 4:96, v / v), a light yellowish oil was obtained as the desired product (2.1 g, 48% yield).
  • Step d To a stirred solution of the product obtained from step c (2.1 g, 8 mmol) in NMP (21 mL) was added copper cyanide (1.56 g, 17 mmol, 2 Aq) portionwise, followed by a catalytically active amount of Nal. The mixture was then heated to 180 ° C and stirred for 4 h at this temperature. It was diluted with EA, filtered through Celite and the filtrate was washed with cold water (50 mL). The organic phase was dried over Na 2 SO 4 and concentrated under reduced pressure. After SC (Si0 2 , EA / n-hexane 8:92, v / v) a white solid was obtained (800 mg, 40% yield).
  • Step e To a solution of the product obtained from step d (1.5 g, 6 mmol) in MeOH (20 mL) was added Raney Nickel in a catalytically active amount and then hydrogenated with hydrogen (1 h at 60 psi). The course of the reaction was monitored by thin-layer chromatography (EA / n-hexane 15:85, Rf ⁇ 0.1). After completion of the reaction, it was filtered through Celite and washed with MeOH. The filtrate was concentrated and the residue purified by SC (Si0 2 , EA / n-hexane 6/94, v / v). The product was obtained as a cream colored oil (1 .4 g, 97% yield). 5.4 Preparation of (1- (4-methoxybenzyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methanamine (for the synthesis of Example 11)
  • Step a 4-Dimethylaminopyridine (4.25 g, 34 mmol, 0.01 Aq) was added to DCM (3000 mL) and cooled to 10 ° C. Trifluoroacetic anhydride (765g (510mL), 3200mmol, 1.05 Aq) was added followed by the dropwise addition of ethyl vinyl ether (250g, 3040mmol) over 45 minutes at -10 ° C. The mixture was then stirred at 0 ° C. for 8 h and then stirred at RT overnight. It was quenched with saturated NaHCO 3 solution (600 mL) and the organic phase separated. The aqueous phase was extracted with DCM (2 ⁇ 500 mL). The combined organic phases were washed with water (2 x 1000 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give the crude product as a brown oil (450 g).
  • Step b Hydrazine dihydrochloride (225 g, 2140 mmol, 1.6 Aq) was taken up in EtOH (1400 mL) and the mixture was stirred. TEA (135.4 g (185.4 mL), 1340 mmol, 1 Aq) was then added dropwise over 45 minutes at RT. Then, Step a product (225 g, crude product) was added dropwise at RT and the mixture was refluxed overnight. EtOH was distilled off and the residue is taken into ice water (500 mL) and the mixture then extracted with EA (2 ⁇ 400 mL). The combined extracts were washed with ice water (300 mL), dried over Na 2 S0 4 and concentrated under reduced pressure to give the crude product as a white solid (195 g).
  • Step c NaH (33.08 g (19.85, 60%), 1.5 Aq) was added to a small amount of n-hexane and the mixture was stirred for 10 minutes. n-Hexane was decanted, dry DMF (500 mL) added dropwise under N 2 atmosphere and the mixture stirred. A solution of the product obtained in step b (75 g, 550 mmol) in DMF (125 mL) was added dropwise under N 2 atmosphere. Then a solution of 4-methoxybenzoyl chloride (86.3 g, 550 mmol, 1 Aq) in DMF (125 mL) was added dropwise
  • Step d Diisopropylamine (28.4 (39.4 mL), 1.2 Aq) was taken up in THF (500 mL), stirred and cooled to 0 ° C. n-Buu (234.4 mL, 1.5 Aq) was added dropwise at 0 ° C and the mixture was then cooled to -78 ° C. A solution of the product obtained in step c (62 g, 240 mmol) in THF (200 mL) was added dropwise over 30 minutes and the mixture was stirred at -78 ° C for 30 minutes. Then, dry CO 2 gas was passed through the mixture for 1.5 hours.
  • the course of the reaction was monitored by thin-layer chromatography (10% EA in n-hexane 15:85, Rf ⁇ 0.1). After completion of the reaction, the mixture was poured into ice-water (300 ml) and the aqueous phase was made alkaline and extracted with EA (2 ⁇ 200 ml). Then, the aqueous phase was acidified with a 20% HCl solution and extracted with EA (2 x 200 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated under reduced pressure. The desired product was obtained as a white solid (42 g, 58% yield).
  • Step e To a stirred solution of the product obtained from step d (50 g, 160 mol) in DCM (750 mL) was added DMF in a catalytically active amount and the mixture was cooled to 0 ° C. Thionyl chloride (99.3 g (61 mL), 830 mmol, 5 Aq) was added dropwise over 30 minutes at 0 ° C. The mixture was then slowly heated and heated at reflux for 2 hours. After completion of the reaction, the DCM was distilled off. The crude product was taken up in DCM (500 mL) and the resulting solution was added dropwise to an aqueous ammonia solution at 0 ° C (600-700 mL) at 0 ° C.
  • Step f Lithium aluminum hydride (4.7 g, 120 mmol, 1 equiv.) was added to a small amount of n-hexane and then the solution was stirred for 10 min. n-Hexane was decanted and THF (250 mL) was added to the lithium aluminum hydride. A solution of the product obtained in step e (37 g, 120 mmol) in THF (125 mL) was added dropwise at 0 ° C and then the mixture was refluxed for 5 h. Then lithium aluminum hydride (2.3 g) was added again and the mixture was refluxed again for 4 h.
  • Step g To a solution of the product obtained in step f (80 g, 280 mmol) in DCM (600 mL) at 0 ° C was added TEA (22.7 g (30.2 mL), 0.026 mol, 0.8 eq) dropwise over the duration for 10 minutes, then di-tert-butyl dicarbonate (61.2 g, 62.5 mL, 280 mmol, 1 Aq) added dropwise in DCM (200 mL) over 20-30 minutes at 0 ° C The mixture was stirred for half an hour at 0 ° C.
  • Step h The step-g product (5 g, 12 mmol) was taken up in DCM (30 mL) and cooled to 0 ° C. HCl gas was passed through the mixture for 45 minutes at 0 ° C. Then the DCM was distilled off and the residue was taken up in ice-water (200 ml) and the product was extracted with 20% ethyl acetate (EA) in n-hexane (2 ⁇ 100 ml). The aqueous phase was basified to pH ⁇ 10 with a 2N NaOH solution and then extracted with EA 5 * 100 mL).
  • EA ethyl acetate
  • Step a Tetrahydropyran-4-one (7.5 g, 75 mmol, 1 equiv.) In MeOH (75 mL) was cooled to 0 ° C. NaBH 4 (1425 g, 37.5 mmol, 0.5 Aq) was added portionwise at 0 ° C. The mixture was warmed to RT and stirred at RT for 1 h. MeOH was distilled off and the mixture was diluted with ice water, neutralized with acetic acid and extracted with EA (3 x 30 mL). The organic phase was concentrated under reduced pressure to give the product as a colorless oil (4.3 g, 56% yield).
  • Step b To step-a product (4.3 g, 43 mmol, 1 equiv.) In DCM (43 mL) was added TEA (13 g, 129 mmol, 3 equiv.) And it was cooled to 0 ° C. Mesyl chloride (4.47 g, 43 mmol, 1 equiv.) was added and stirred at 0 ° C for 1 h. It was then washed with ice-water (1 ⁇ 50 ml) and the phases were separated. The organic phase was dried over Na 2 SO 4 and concentrated under reduced pressure to give 7 g (90% yield) of the product as a yellow solid,
  • Step c To a stirred solution of tert-butyl (1- (4-methoxybenzyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methylcarbamate (20 g, 52 mmol) in toluene (300 mL), Cooled to 0 ° C, AICI 3 was added (17.34 g, 129 mmol, 2.5 Aq) in portions over 30 minutes. The reaction mixture was heated to 50-60 ° C and stirred at this temperature for 2 h. Then, dilute HCl, and ice-water (300 mL) were added and it was extracted with EA (2 100 mL).
  • the aqueous phase was basified with a NaOH solution and then extracted with EA, dried over Na 2 SO 4 and concentrated under reduced pressure to yield brown-colored crude product (4.6 g).
  • the crude product was used directly in the next step without further purification.
  • Step d Step-c product (0.7 g, 42 mmol, 1 Aq) was taken up in DCM (70 mL) and then TEA (5.86 mL, 72 mmol, 1Aq) was added at RT and stirred for 10 minutes and then brought to 0 cooled to - 5 ° C.
  • Step e NaH (0.54 g, 22 mmol, 2 equiv.) In DMF (10 mL) was cooled to 0 ° C. Step-d product (3 g, 1.3 mmol, 1 equiv) was added at 0 ° C and solution 1 kept at 0 ° C. Step-b product (3.46 g, 19 mmol, 1.7 eq.) was added and the mixture was warmed to RT then slowly heated to 90 ° C and stirred for 12 h at 90 ° C. Then the mixture was poured into ice-water (20 mL) and extracted with EA (3 x 15 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated under reduced pressure. After SC (Si0 2 , EA / n-hexane 5:95, v / v) a white solid was obtained (600 mg, 15% yield).
  • Step f Step-e product (390 mg, 1.1 mmol, 1 Aq) was taken up in MeOH (3 mL) and HCl in isopropyl alcohol (279 ⁇ , 1.7 mmol, 1.5 Aq) was added and the
  • Step a In dichloromethane (30 mL) was placed aminoacetonitrile hydrochloride (5 g, 54 mmol). To this was added a solution of di-tert-butyl dicarbonate (11.9 g, 54.6 mmol, 1.01 eq.) And TEA (24.6 g, 33.7 mL, 243 mmol, 4.5 eq.) In dichloromethane (25 mL). After completion of the dosing, the mixture was heated to reflux for 16 h. After cooling, the reaction mixture was filtered, the filtrate was washed with water (50 mL), dried over magnesium sulfate and dried under reduced pressure
  • Step b N-Boc-aminoacetonitrile (5.75 g, 36.8 mmol) was initially charged in methanol (90 mL). Sodium methoxide (383 mg, 7.36 mmol, 0.2 equiv.) was added portionwise to the solution. The mixture was stirred at room temperature for 2.5 h, pivaloylhydrazide (4.28 g, 36.8 mmol, 1 eq.) was added and the mixture was heated at reflux for 18 h.
  • Step c In a microwave glass, copper iodide (28 mg, 0.16 mmol, 0.05 eq.), Potassium carbonate (906 mg, 6.57 mmol, 2.1 eq.) And tert-butyl (3-tert-butyl-1 H-1, 2 , 4-triazol-5-yl) methylcarbamate (752 mg, 3.13 mmol). It was evacuated three times and purged with nitrogen.
  • Step a In ethanol (1.4 mL), ethyl trifluoroacetate (1.03 g, 0.865 mL, 7.25 mmol) and hydrazine monohydrate (80% w / w, 0.498 g, 0.475 mL, 7.97 mmol, 1.1 eq.) Were dissolved and heated to reflux for 3 h , The solvent was removed under reduced pressure, the residue was taken up in EtOAc (10 mL) and extracted with water (10 mL). The aqueous phase was extracted with EtOAc (4 ⁇ 10 mL), the combined organic phases were washed with water (5 mL), dried over magnesium sulfate and freed from the solvent under reduced pressure. The residue became
  • Step b Aminoacetonitrile hydrochloride (5.00 g, 54.0 mmol) was placed in 30 mL dichloromethane. To this was added a solution of di-tert-butyl dicarbonate (11.9 g, 54.6 mmol, 1.01 eq.) And TEA (24.6 g, 33.7 mL, 243 mmol, 4.5 eq.) In dichloromethane (25 mL). After completion of the dosing, the mixture was heated to reflux for 16 h. After cooling, the reaction mixture was filtered, the filtrate was washed with water (50 mL), dried over magnesium sulfate and dried under reduced pressure
  • N-Boc-aminoacetonitrile (.58 g, 66% yield) as a brownish oil, which were used without further purification.
  • Step c N-Boc-aminoacetonitrile (3.81 g, 24.4 mmol) was initially charged in methanol (75 mL). Sodium methoxide (254 mg, 4.88 mmol, 0.2 equiv.) was added portionwise to the solution. The mixture was stirred at room temperature for 2.5 h,
  • Trifluoroacetic acid hydrazide (3.12 g, 24.4 mmol, 1 eq.) Dissolved in MeOH (10 mL) was added and the mixture was heated at reflux for 18 h. The solvent was removed under reduced pressure, the residue was taken up in dichloromethane (200 mL), washed with saturated sodium chloride solution (120 mL), the aqueous phase was extracted with dichloromethane (2 ⁇ 50 mL), and the combined organic phases were transferred Dried magnesium sulfate and freed from the solvent under reduced pressure. The residue was purified by column chromatography (SiO 2 , methyl tert-butyl ether / dichloromethane 1/2, v / v). Tert -Butyl (3- (trifluoromethyl) -1H-1,2,4-triazol-5-yl) methylcarbamate (3.84 g, 59% yield) was obtained as a colorless solid.
  • Step d To a suspension of sodium hydride (60% w / w in mineral oil, 18 mg, 0.47 mmol, 1.25 eq.) In dimethylformamide (1.2 mL) at 0 ° C was tert-butyl (3- (trifluoromethyl) -1 H-1, 2,4-triazol-5-yl) methylcarbamate (101 mg, 0.379 mmol). The mixture was stirred at 0 ° C for 45 min, warmed to room temperature, and n-hexyl iodide (301 mg, 1.42 mmol, 3.75 eq.) Was added.
  • Carboxylic acids of general formula (III) or carboxylic acid derivatives of general formula (IV) to compounds of general formula (I) with A CH or C (amides) according to Scheme 1a (step j09).
  • Chlorinating agent preferably treated with thionyl chloride and refluxing the resulting mixture and the acid (III) is converted into the corresponding acid chloride (IV).
  • the amine of general formula (II) (1.1 equivalents) is dissolved in dichloromethane (1 mmol acid in 6 mL) and treated at 0 ° C with triethylamine (3 equivalents). The Reaction mixture is stirred for 20 h at room temperature and the crude product purified by column chromatography (Si0 2, n-hexane / EE in various mixing ratios such as 2: 1) to obtain (I).
  • Phenyl ester (IVa) (1 equivalent) and the amine (II) (1.1 equivalents) are dissolved in THF (10 mmol of the reaction mixture in 120 ml) and for 16 h at room temperature after addition of DBU (1.5 Equivalents). After distilling off the solvent under reduced pressure, the crude product is purified by column chromatography (Si0 2 , n-hexane / EA in different mixing ratios such as 2: 1) to obtain (I).
  • Step j07 / v1 The amine of the general formula (II) or (VI) (1 equivalent) is in
  • Step j08 / v2 The obtained carbamic acid phenyl ester (V) or (Via) (1 equivalent) and the corresponding amine (VI) or (II) (1.1 equivalents) are dissolved in THF (10 mmol of the
  • the compounds of the formula (I) indicated above have an excellent affinity for the VR1 / TRPV1 receptor (Table 1).
  • the value after the "@" sign indicates the concentration at which the inhibition (in percent) was determined.
EP11755260.4A 2010-08-20 2011-08-19 Substituierte cyclische carboxamid- und harnstoff-derivate als liganden des vanilloid-rezeptors Withdrawn EP2606033A1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP11755260.4A EP2606033A1 (de) 2010-08-20 2011-08-19 Substituierte cyclische carboxamid- und harnstoff-derivate als liganden des vanilloid-rezeptors

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP10008723 2010-08-20
EP11755260.4A EP2606033A1 (de) 2010-08-20 2011-08-19 Substituierte cyclische carboxamid- und harnstoff-derivate als liganden des vanilloid-rezeptors
PCT/EP2011/004183 WO2012022487A1 (de) 2010-08-20 2011-08-19 Substituierte cyclische carboxamid- und harnstoff-derivate als liganden des vanilloid-rezeptors

Publications (1)

Publication Number Publication Date
EP2606033A1 true EP2606033A1 (de) 2013-06-26

Family

ID=42985573

Family Applications (1)

Application Number Title Priority Date Filing Date
EP11755260.4A Withdrawn EP2606033A1 (de) 2010-08-20 2011-08-19 Substituierte cyclische carboxamid- und harnstoff-derivate als liganden des vanilloid-rezeptors

Country Status (10)

Country Link
US (1) US20120046301A1 (ja)
EP (1) EP2606033A1 (ja)
JP (1) JP2013534229A (ja)
AR (1) AR082498A1 (ja)
AU (1) AU2011291034A1 (ja)
BR (1) BR112013003815A2 (ja)
CA (1) CA2806634A1 (ja)
MX (1) MX2013002011A (ja)
TW (1) TW201211029A (ja)
WO (1) WO2012022487A1 (ja)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN2014MN02127A (ja) 2012-05-02 2015-09-11 Lupin Ltd
EP2984074A1 (en) 2012-12-14 2016-02-17 Basf Se Malononitrile compounds for controlling animal pests
SG11201607267SA (en) 2014-03-07 2016-09-29 Biocryst Pharm Inc Human plasma kallikrein inhibitors
US10857121B2 (en) 2014-04-17 2020-12-08 Merial Inc. Use of malononitrile compounds for protecting animals from parasites
WO2016198691A1 (en) * 2015-06-11 2016-12-15 Basilea Pharmaceutica Ag Efflux-pump inhibitors and therapeutic uses thereof
AU2017275657B2 (en) 2016-06-02 2021-08-19 Novartis Ag Potassium channel modulators
US9975886B1 (en) 2017-01-23 2018-05-22 Cadent Therapeutics, Inc. Potassium channel modulators
CN109232422B (zh) * 2018-09-17 2020-07-07 烟台万润药业有限公司 一种塞来昔布的制备方法
US11459340B2 (en) 2018-09-18 2022-10-04 Nikang Therapeutics, Inc. Tri-substituted heteroaryl derivatives as Src homology-2 phosphatase inhibitors
CN112480004B (zh) * 2020-11-04 2022-08-12 华南理工大学 一种5-三氟甲基取代吡唑衍生物及其合成方法与应用

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6387900B1 (en) * 1999-08-12 2002-05-14 Pharmacia & Upjohn S.P.A. 3(5)-ureido-pyrazole derivatives process for their preparation and their use as antitumor agents
US6723730B2 (en) * 2000-07-20 2004-04-20 Neurogen Corporation Capsaicin receptor ligands
US20050209297A1 (en) * 2000-08-31 2005-09-22 Pfizer Inc Pyrazole derivatives
CN101935315A (zh) * 2003-07-24 2011-01-05 欧洲凯尔蒂克公司 用于治疗或预防疼痛的杂芳基-四氢哌啶基化合物
US7453002B2 (en) * 2004-06-15 2008-11-18 Bristol-Myers Squibb Company Five-membered heterocycles useful as serine protease inhibitors
TW200633990A (en) * 2004-11-18 2006-10-01 Takeda Pharmaceuticals Co Amide compound
US20060116368A1 (en) * 2004-11-29 2006-06-01 Calvo Raul R 4-Piperidinecarboxamide modulators of vanilloid VR1 receptor
JP5197014B2 (ja) * 2004-12-10 2013-05-15 イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・エルレ・エルレ ヒストンデアセチラーゼ（ｈｄａｃ）阻害剤としての複素環誘導体
WO2008010061A2 (en) * 2006-07-17 2008-01-24 Glenmark Pharmaceuticals S.A. 3-azabicyclo [3.1.0] hexane vanilloid receptor ligands, pharmaceutical compositions containing them, and processes for their preparation
JP4785881B2 (ja) * 2007-02-27 2011-10-05 大塚製薬株式会社 医薬
MX2009012765A (es) * 2007-05-25 2009-12-16 Janssen Pharmaceutica Nv Moduladores de urea con heteroarilo sustituido de acido graso amida hidrolasa.
WO2009026701A1 (en) * 2007-08-29 2009-03-05 Methylgene Inc. Sirtuin inhibitors
EP2215080A1 (en) * 2007-10-25 2010-08-11 Boehringer Ingelheim International GmbH Diazepane compounds which modulate the cb2 receptor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2012022487A1 *

Also Published As

Publication number Publication date
US20120046301A1 (en) 2012-02-23
BR112013003815A2 (pt) 2019-09-24
TW201211029A (en) 2012-03-16
MX2013002011A (es) 2013-03-25
AU2011291034A1 (en) 2013-03-14
AR082498A1 (es) 2012-12-12
WO2012022487A1 (de) 2012-02-23
JP2013534229A (ja) 2013-09-02
CA2806634A1 (en) 2012-02-23

Similar Documents

Publication Publication Date Title
WO2012022487A1 (de) Substituierte cyclische carboxamid- und harnstoff-derivate als liganden des vanilloid-rezeptors
EP1888541B1 (de) Benzo (d) isoxazol-3-yl-amin- verbindungen und deren verwendung als vanilloid-rezeptor liganden
CA2759951C (en) Substituted phenylureas and phenylamides as vanilloid receptor ligands
DE69830403T2 (de) Inhibitoren des faktors xa mit einer neutralen gruppe mit p1-spezifität
EP1742925B1 (de) SUBSTITUIERTE 5, 6, 7, 8-TETRAHYDRO-PYRIDO[4, 3-d]PYRIMIDIN-2-YL- UND 5, 6, 7, 8-TETRAHYDRO-CHINAZOLIN-2-YL-VERBINDUNGEN
US20120115903A1 (en) Substituted Heteroaromatic Carboxamide and Urea Compounds as Vanilloid Receptor Ligands
DE69837675T2 (de) Pyrazolderivate
EP1891004B1 (de) Pentafluorsulfanyl-substituierte verbindung und deren verwendung zur herstellung von arzneimitteln
EP2146959B1 (de) Vanilloid-rezeptor liganden und ihre verwendung zur herstellung von arzneimitteln
EP1812405A1 (de) Neue bradykinin-b1-antagonisten, verfahren zu deren herstellung sowie deren verwendung als arzneimittel
MX2011011800A (es) Derivados de carboxamida y urea aromaticas sustituidas como ligandos del receptor de vanilloides.
EP2292625A1 (de) Substituierte Spiro-Verbindungen und deren Verwendung zur Herstellung von Arzneimitteln gegen Schmerz
EP1890695B1 (de) Verwendung von 2,5-disubstituierten thiazol-4-on-derivaten in arzneimitteln
DE102005044814A1 (de) Substituierte Sprio-Verbindungen und deren Verwendung zur Herstellung von Arzneimitteln
KR20140091041A (ko) 바닐로이드 수용체 리간드로서의 so2-함유 그룹으로 치환된 페닐 모이어티를 갖는 치환된 피라졸릴계 카복사미드 및 우레아 유도체들
US20120115893A1 (en) Substituted Bicyclic Carboxamide and Urea Compounds as Vanilloid Receptor Ligands
EP2332529A1 (de) Substituierte aromatische Diamine als Liganden der vesikulären Glutamat-Transporter 1 und 2 (vGLUT1 und vGLUT2)
KR20140093260A (ko) 바닐로이드 수용체 리간드로서의 ｎ－사이클릭 그룹으로 치환된 페닐 모이어티를 갖는 치환된 피라졸릴계 카복스아미드 및 우레아 유도체들
DE102005050408A1 (de) Neue Vanilloidrezeptor-Liganden und ihre Verwendung zur Herstellung von Arzneimitteln

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20130320

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20140325

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20141007