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EP2350003A1 - Disulfonamides substitués en tant que modulateurs de bri - Google Patents

Disulfonamides substitués en tant que modulateurs de bri

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Publication number
EP2350003A1
EP2350003A1 EP09747796A EP09747796A EP2350003A1 EP 2350003 A1 EP2350003 A1 EP 2350003A1 EP 09747796 A EP09747796 A EP 09747796A EP 09747796 A EP09747796 A EP 09747796A EP 2350003 A1 EP2350003 A1 EP 2350003A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
aryl
heteroaryl
cycloalkyl
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09747796A
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German (de)
English (en)
Inventor
Melanie Reich
Stefan Schunk
Ruth Jostock
Sabine Hees
Tieno Germann
Michael Franz-Martin Engels
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
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Filing date
Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Priority to EP09747796A priority Critical patent/EP2350003A1/fr
Publication of EP2350003A1 publication Critical patent/EP2350003A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • A61P25/06—Antimigraine 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • the present invention relates to substituted disulfonamides, processes for their preparation, medicaments containing these compounds and the use of substituted disulfonamides for the preparation of medicaments.
  • the bradykinin 1 receptor (B1 R) is not or only weakly expressed in most tissues.
  • the expression of the B1 R is inducible on different cells. For example, in the course of inflammatory reactions, a rapid and pronounced induction of the B1 R on neuronal cells but also on various peripheral cells such as fibroblasts, endothelial cells, granulocytes, macrophages and lymphocytes. Thus, in the course of inflammatory reactions, there is a switch from a B2R to a B1R dominance on the cells involved.
  • cytokines interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF ⁇ ) are of considerable importance in this downregulation (Passos et al., J. Immunol., 2004, 172, 1839-1847).
  • B1 R-expressing cells can subsequently self-secrete proinflammatory cytokines such as IL-6 and IL-8 (Hayashi et al., Eur. Respir. J. 2000, 16, 452-458). This leads to the immigration of further inflammatory cells, for example neutrophilic granulocytes (Pesquero et al., PNAS 2000, 97, 8140-8145).
  • the bradykinin B1 R system can contribute to the chronicity of diseases.
  • diseases of the respiratory tract include asthma, allergies, COPD / chronic obstructive pulmonary disease, cystic fibrosis, etc.
  • inflammatory bowel disease include inflammatory colitis, CD / Crohn's disease, etc.
  • neurological diseases multiple sclerosis, neurodegeneration, etc.
  • inflammation of the skin atopic dermatitis, psoriasis, bacterial infections, etc.
  • mucous membranes M Behcet, pelvitis, prostatitis, etc.
  • rheumatic diseases rheumatoid arthritis, osteoarthritis, etc.
  • septic shock and reperfusion syndrome after heart attack, stroke
  • bradykinin (receptor) system is also involved in the regulation of angiogenesis (potential as angiogenesis inhibitor in cancer as well as macular degeneration in the eye) and B1 R knockout mice are protected from the induction of obesity by a high fat diet (Pesquero et al, Biol Chem 2006, 387, 1 19-126) B1 R antagonists are therefore also suitable for the treatment of obesity
  • B1 R antagonists are particularly suitable for the treatment of pain, in particular inflammatory pain and neuropathic pain (Cahxto et al, Br J Pharmacol 2004 1-16), here in particular of diabetic neuropathy (Gabra et al, Biol Chem 2006, 387, 127-143 Furthermore, they are suitable for the treatment of migraine
  • Patent applications WO 2008/040492 and WO 2008/046573 describe compounds which show antagonistic activity in in vitro assays both on the human B1 receptor and on the B1 receptor of the rat.
  • An object of the invention are therefore substituted disulfonamides of general formula I.
  • R 2 and R 3 are as described under ( ⁇ ) or ( ⁇ ) are defined
  • R 2 is H, C 1 6 alkyl, C 3 8 cycloalkyl, aryl or heteroaryl, or R 2 is a via a C 1 ⁇ -alkylene group, C 2 6 alkenylene group or C 2 -6-Alk ⁇ nylenement C 3 -C 8 -cycloalkyl, aryl or heteroaryl,
  • R 3 is H, F 1 Cl, Br, I 1 is -CF 3, -OCF 3, OH, 0-C 1 6 alkyl, C 1 6 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl or R 3, a via a C 6 alkylene group, C 2 6 - alkenylene or C 2 6 -Alk ⁇ nylenfest bound is C 3 8 cycloalkyl, aryl or heteroaryl,
  • R 2 and R 3 together with the group connecting them -N- (CR 4a R 4b ) a -CH- form a heterocycle which is independently selected from one or more of its carbon ring members having one or more radicals
  • R 8 is H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl, or a via a C 1 - 6 - bound alkylene C 3-8 cycloalkyl, aryl or heteroaryl;
  • R 9a and R 9b are each independently H 1 F, Cl, OH, C 1-6 alkyl, OC 1-6 alkyl, C 3 - 8 cycloalkyl, aryl or heteroaryl, or a C 1-6 - alkylene group bonded C 3 _ 8 cycloalkyl, aryl or heteroaryl group;
  • A is N or CH
  • radicals R 10 and R 11 including A, represent a spirocyclic or cyclic group according to one of the general formulas (II) or (III),
  • c, d, e, f, u and v are each independently 0, 1 or 2
  • X is CR 14a R 14b , NR 15 or O,
  • Y is CR 16a R 16b , NR 17 or O
  • R 15 and R 17 are each independently H, C 1-6 alkyl, C3 8 cycloalkyl, aryl or heteroaryl, or bonded via a C 1-6 alkylene C 3-8 - cycloalkyl, aryl or heteroaryl mean,
  • Z in the general formula (II) is CR 18a R 18b , NR 19 or O,
  • R 124 and R 125 together with the carbon atoms connecting them form a fused aryl or heteroaryl, or
  • R 126 is H, Ci 6 alkyl C 3 8 cycloalkyl, aryl or heteroaryl, or a bonded via a C 6 alkylene group means C 3 8 cycloalkyl, aryl or heteroaryl,
  • R 18a is H, C 1-6 -alkyl, Aryl or heteroaryl, or one over one bound Ca- ⁇ -cycloalkyl, aryl or heteroaryl,
  • R 18a represents a group according to the general formula (IV),
  • i and j are each independently 0 or 1
  • E is N or CH, with the proviso that when ⁇ is 1 and j is 0, E is CH
  • R 34 and R 35 are each independently H, C 1- 6 alkyl, C 3 8 cycloalkyl, aryl or heteroaryl, or a Ci. 3- alkylene group bonded aryl, heteroaryl or C 3 8 cycloalkyl,
  • R 34 and R 35 including E, form a 5- or 6-membered aryl or heteroaryl,
  • R 38 is H, C 1-6 alkyl, C 3 _ 8 cycloalkyl, aryl or heteroaryl, or a bonded via a C 1- 3 -alkylene aryl, heteroaryl or C 3-8 cycloalkyl;
  • R 18b is H, OH, C 1-6 alkyl, C 3 _ 8 cycloalkyl, OC ⁇ -alkyl, O- (C 3-8 -cycloalkyl), (C 1-6 - alkylene) -OC 1-6 alkyl, (C1-6 alkylene) -O- (C 3-8 cycloalkyl), aryl, heteroaryl, O-aryl or O-heteroaryl, or bonded via a C 1- 6 alkylene-aryl, O -Aryl, heteroaryl or O-heteroaryl;
  • R 18b is a group according to the general formula (VI),
  • R is H, C 1-6 alkyl, Cs-s-cycloalkyl, aryl or heteroaryl, or a C 3-8 cycloalkyl bound via a C 1-3 alkylene group, aryl or heteroaryl;
  • R is C 1-5 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl, or C 3-8 cycloalkyl bound via a C 1-6 alkylene group, aryl or heteroaryl;
  • R 24 is H, C 1-6 alkyl, C 3-8 cycloalkyl, or a bonded via a C 1-3 alkylene aryl, heteroaryl or C 3-8 cycloalkyl;
  • R 22 is C 1-6 alkyl, aryl or heteroaryl, or one over one bonded aryl or heteroaryl; or
  • R 22 represents a group according to the general formula (VIII),
  • n 0, 1 or 2;
  • n 0, 1 or 2;
  • w 0 or 1
  • M is CH or N
  • R 44a and R 44b are each independently H, F, Cl, Br, I, OH, C 1 6 alkyl, 0-C 1- 6 alkyl, C 3 8 cycloalkyl, aryl or heteroaryl, or via C 3 -C 8 -cycloalkyl, aryl or heteroaryl bonded to a C 1 ⁇ -alkylene group,
  • R 45 is H, C 1-6 alkyl, C3- ⁇ cycloalkyl, aryl or heteroaryl, or a bonded via a C 1- 3 -alkylene aryl, heteroaryl or C 3 8 cycloalkyl,
  • radicals C 1 6-alkyl, C 1 3 -alkylene, C ⁇ -alkylene, C 2 6 - alkenylene, C 2-6 -alkylene, C 3 ⁇ -cycloalkyl, C 3 8 -cycloalkyl, aryl and heteroaryl each unsubstituted or may be monosubstituted or polysubstituted by identical or different radicals
  • the above-mentioned radicals C 1 6 alkyl, C 1 3 alkylene, C 1-6 - alkylene, C 2 - 6 alkenylene and C 2 6 -Alk ⁇ nylen each branched or unbranched
  • Ci 6 alkyl includes acyclic saturated hydrocarbon residues with 1, 2, 3, 4, 5 or 6 carbon atoms, the branched or straight chain (unbranched) and unsubstituted or mono- or polysubstituted, for example 2
  • the alkyl radicals may be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl and hexyl
  • Particularly preferred alkyl radicals can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec Butyl, iso-butyl and tert-butyl
  • C 3 8 -cycloalkyl means cyclic saturated hydrocarbons having 3, 4, 5, 6, 7 or 8 carbon atoms which are unsubstituted or mono- or polysubstituted on one or more ring members, for example 2, 3, 4 may be substituted or 5, identical or different radicals
  • C3- 8 cycloalkyl may be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl
  • aryl in the context of this invention means aromatic hydrocarbons, in particular phenyls and naphthyls.
  • the aryl radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems.
  • Each aryl radical can be unsubstituted or mono- or polysubstituted, for example 2- , 3-, 4- or 5-fold, substituted, wherein the aryl substituents may be the same or different and in any and possible position of the aryl.
  • aryl may be selected from the group consisting of phenyl, 1-naphthyl and 2 -Naphthyl, which may each be unsubstituted or mono- or polysubstituted, for example, with 2, 3, 4 or 5 radicals substituted
  • heteroaryl in the context of the present invention is a 5-, 6- or 7-gl ⁇ ed ⁇ gen cyclic aromatic radical containing at least 1, optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are the same or different and the heteroaryl can be unsubstituted or monosubstituted or polysubstituted, for example 2-, 3-, 4- or 5-fold, with identical or different radicals.
  • the substituents can be bonded in any desired and possible position of the heteroaryl.
  • the heterocycle can also Part of a b ⁇ or polycyclic, in particular a mono-, bi- or tricyclic system, which may be more than 7-gl ⁇ edr ⁇ g total, preferably up to 14-gl ⁇ edr ⁇ g Preferred heteroatoms are selected from the group consisting of N, O and S.
  • the heteroaryl group may be selected from the group consisting of pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazoly l, benzothiazolyl, benzotiazolyl, benzodioxolanyl, benzodioxanyl, benzooxazolyl, benzooxadiazolyl, imidazothiazolyl, dibenzofuranyl, dibenzothienyl, phthaloyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, tnazole, tetrazole, isoxazoyl, pyridinyl (pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl , Indazolyl, purin
  • Ci 6 alkylene group for the purposes of the present invention acyclic saturated hydrocarbon residues with 1, 2 or 3, or with 1, 2, 3, 4, 5 or 6 C atoms which may be branched - or straight-chain (unbranched) and unsubstituted or mono- or polysubstituted, for example 2-, 3-, 4- or 5-fold, may be substituted by the same or different radicals and which link a corresponding radical with the parent general structure
  • Alkylene groups may be selected from the group consisting of -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 2) 2 -CH 2, -CH (CH 3) -CH 2
  • C 2 -alkenylene group for the purposes of the present invention acychsche, single or multiple, for example, 2-, 3- or 4-fold, unsaturated hydrocarbon radicals having 2, 3, 4, 5 or 6 carbon atoms, the branched - or straight-chain (unbranched) and unsubstituted or mono- or polysubstituted, for example, 2-, 3-, 4- or 5-fold, may be substituted by the same or different radicals and linking a corresponding radical with the parent general structure
  • C 2 6 -Alk ⁇ nylenoli in the context of the invention acychsche, single or multiple, for example, 2-, 3- or 4-fold, unsaturated hydrocarbon radicals having 2 3, 4, 5 or 6 carbon atoms, the branched or straight-chain (unbranched) and unsubstituted or mono- or polysubstituted, for example 2-, 3-, 4- or 5-fold, with identical or different radicals
  • the alkynylene groups have at least one C ⁇ C triple bond.
  • the alkynylene groups may be selected from the group consisting of 2 2 2 , 2 2 2
  • a C 1-3 alkylene group, a Ci-6 alkylene, C 2, ⁇ - alkenylene group or C 2 _ 6 -Alk ⁇ nylenement aryl or heteroaryl bonded in the context of the present invention is that the C 1-3 - Alkylene groups, C 1-6 -alkylene groups, C 2-6 -alkenylene groups, C 2-6 -alkylene groups and also aryl or heteroaryl have the meanings defined above and the aryl or heteroaryl have a C 1-3 -alkylene group, Alkenylene group or C 2-6 - Alkmylene group is bound to the parent general structure is exemplified by benzyl, phenethyl and phenylpropyl
  • C 1- 3-alkylene group, C 1- 6 alkylene group, C 2-6 - alkenylene or C 2 6 -Alk ⁇ nylendung bonded C 3-8 cycloalkyl and heterocycloalkyl in the context of the present invention that the C 1-3 alkylene group, Ci.
  • C 2- 6 alkylene group, C 2- 6 alkenylene group, C 2- 6-Alk ⁇ nylenement, C 3-S - cycloalkyl, and heterocycloalkyl are as defined above and C 3 8 - cycloalkyl, and heterocycloalkyl via a C 1-3 alkylene group, C 1 -6- Alkylenadmi, C 2-6 -alkenylene or C 2-6 -Alk ⁇ nylenocc is bound to the general structure above
  • substituents for example.
  • here is the substitution of one or more hydrogen radicals by F, Cl, NH 2 , OH, phenyl, 0-CF 3 or especially methoxy be understood
  • aryl and “heteroaryl” is meant in the context of this invention by “substituted” the one or more, for example, 2-, 3-, 4- or 5-fold, substitution of one or more hydrogen atoms of the corresponding ring system by F , Cl, Br, I, CN, NH 2 , NH-C 1-6 -alkyl, NH-C 1-6 -alkylene-OH, N (C 1-6 -alkyl) 2 , N (C 1-6 - alkylene-OH) 2, NH-aryl 1, N (aryl 1) 2, N (C 1-6 alkyl) aryl 1, pyrrolinyl, piperazinyl, morpholinyl, azetidinyl, piperidinyl, thiazolinyl, azepanyl, diazepanyl, (C 1- 3- alkylene) -Azet ⁇ d ⁇ nyl, (C 1-3 alkylene) -Pyrrol ⁇ nyl
  • aryl and heteroaryl may be made with the same or different substituents.
  • Preferred substituents for aryl and heteroaryl may be selected from the group consisting of -O-C 1-3 -alkyl, unsubstituted C 1-6 -alkyl, F, Cl, Br, I , CN, CF 3 , OCF 3 , OH, SH, -CH 2 -Azet ⁇ dinyl, - CH 2 pyrrolidinyl, -CH 2 -P ⁇ per ⁇ dinyl, -CH 2 -P ⁇ perazinyl, -CH 2 -Morpholinyl, phenyl, naphthyl, thiazolyl, thienyl and pyridinyl, in particular from the group consisting of F, Cl, CN, CF 3 , CH 3 , OCH 3 , OCF 3 , and -CH 2 -Azet ⁇ dinyl.
  • Substitution pattern also the symbol " ⁇ " used, which group is not bound to a particular atom within the chemical structural formula, in contrast to the representation of a bond to a particular atom (R a is here exemplified by a substituent R with a by the variable "a "numbering shown).
  • R 27 can stand for 0 to 4 substituents, so R 27 may be absent or 1, 2 , 3 or 4 of the C-bonded hydrogen atoms within the partial structure represented by the general formula (III) may be replaced by a substituent provided for in the definition of the radical R 27 , wherein the respective substituents may be selected independently of one another, and thus also have different meanings
  • R 27 in each case two of the substituents R 27 can also be substituted by one or more C atoms or a fused aryl or heteroaryl (also called fused aryl or heteroaryl or fused / fused aryl or heteroaryl group), so that R 27 in the general formula (III) also has the meanings shown below by way of example, in which R 27 is two substituents in each case different C atoms and in the second example the variable u stands for 1:
  • physiologically compatible salt preferably means salts of the compounds according to the invention with inorganic or organic acids which are physiologically-in particular when used on humans and / or mammals.
  • suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid , Methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid, 1, 1-D ⁇ oxo-1, 2-d ⁇ hydro1 ⁇ 6 -benzo [d] ⁇ soth ⁇ azol-3-one (saccharic acid) , Monomethylsebacinsaure, 5-oxo-prol ⁇ n, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-Am ⁇ nobenzoesaure, 2,4,6-Tr ⁇ methyl-benzoic acid, ⁇ -L ⁇
  • R 1 in the compounds according to the invention preferably represents phenyl, naphthyl, chromanyl, indolyl, benzofuranyl, benzothiophenyl (benzothienyl), benzooxazolyl, benzooxadiazolyl, pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazothiazolyl, carbazolyl, dibenzofuranyl, Dibenzothiophenyl (dibenzothienyl), quinolinyl, isoquinolinyl, or a phenyl or naphthyl bonded through a do-alkylene group, more preferably phenyl, naphthyl, chromanyl, benzothiophenyl (benzothienyl), quinolinyl, isoquinolinyl, thienyl, or a
  • the radical R 1 may in particular be phenyl or naphthyl, where the phenyl or naphthyl is unsubstituted or mono- or polysubstituted, for example 2-, 3-, 4- or 5-fold, with identical or different radicals selected from methyl, methoxy, CF 3 , OCF 3 , F and Cl is substituted.
  • the radical R 1 is selected from the group consisting of 4-methoxy-2,3,6-trimethylphenyi, 4-methoxy-2,6-dimethylphenyl, 4-methoxy-2,3,5- trimethylphenyl, 2,4,6-trimethylphenyl, 2-chloro-6-methylphenyl, 2,4,6-trichlorophenyl, 1,3-dichloro-5-trifluoromethylphenyl, 2-chloro-6- (trifluoromethyl) phenyl, 2.6 Dichloro-4-methoxyphenyl, 2,6-dichloro-4-trifluoromethyl, 2-methylnaphthyl, 2-chloro-naphthyl, 2-fluoronaphthyl, 2-chloro-4- (trifluoromethoxy) -phenyl, 4-chloro-2,5-dimethylphenyl, 2-chloro-6-methylphenyl, 2,3-dichlor
  • the radical R 1 is selected from the group consisting of 4-methoxy-2,3,6-trimethylphenyl, 4-methoxy-2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 2, 6-dichloro-4- (trifluoromethyl) phenyl, 2-chloro-6-methylphenyl, 2,4,6-trichlorophenyl, 2,4,5-trichlorophenyl, 4-fluoro-2,6-dimethylphenyl, 2,6-dichloro 4-methoxyphenyl, 2,6-dichlorophenyl, 2,6-dichloro-3-methylphenyl, 6-methoxy-2-naphthyl, 2-methyl-1-naphthyl, 2-chloro-1-naphthyl, 2-fluoro-1 -naphthyl, 2-chloro-4- (trifluoromethoxy) phenyl, 4-chloro-2,
  • radical R 1 may be 4-methoxy-2,6-dimethylphenyl or 2-chloro-6-methylphenyl.
  • R 200 is 0-4 substituents which are independently selected from the group consisting of F, Cl, -CF 3 and -O-CF 3 , in particular F or CF 3 , or two of the radicals R 200 together form a fused aryl or heteroaryl, in particular a benzo group.
  • R 200 can thus also stand for two aryls fused to the heterocycle, in particular benzo groups.
  • R 200 is 0 substituent, so it is absent.
  • substructure Ac I can stand for one of the groups listed below:
  • R 200 is 0-4 substituents which are independently selected from the group consisting of F, Cl 1 -CF 3 and -O-CF 3 , in particular F or CF 3 , and / or two adjacent radicals R 200 form together a fused aryl or heteroaryl, in particular a benzo group,
  • R 210 is 0-4 substituents independently of one another selected from the group consisting of -O-C 1-3 -alkyl, C 1-6 -alkyl, F, Cl, Br, I, CF 3 , OCF 3 , OH, SH, phenyl, naphthyl, furyl, thienyl and pyridinyl, in particular from the group consisting of methyl, methoxy, CF 3 , OCF 3 , F, Cl and Br,
  • R 51 is C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl or a C 1 3 - bound alkylene is C 3 8 cycloalkyl, aryl or heteroaryl
  • R 200 and / or R 210 are 0 substituents, ie they are each absent
  • R 2 is H, C 1-6 alkyl, C 3- 6 cycloalkyl, aryl, heteroaryl, or a bonded via a C 3 -alkylene C 3 6 cycloalkyl, aryl or heteroaryl, each unsubstituted or monosubstituted or polysubstituted with the same or
  • R 2 may be H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl or cyclopropyl, in each case unsubstituted or monosubstituted or polysubstituted by identical or various radicals selected from the group consisting of F, Cl, OH, OCH 3 and OCF 3 or R 2 is phenyl or pyndyl which is unsubstituted or mono- or polysubstituted with identical or various radicals selected from the group consisting of F, Cl,
  • R 3 is H, F, Cl, -CF 3, -OH, -O-C 1 6 alkyl, C 1-6 alkyl, aryl, or a C 1-3 -
  • R 3 may be H, F, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, or alkenyl, or unsubstituted or mono- or polysubstituted by identical or different radicals , Methoxy or ethoxy, in each case unsubstituted or monosubstituted or polysubstituted by identical or different radicals selected from the group consisting of F, Cl, OH, OCH 3 and OCF 3 or the R 3 is phenyl or benzyl, where the aromatic is in each case unsubstituted or mono- or polysubstituted with identical or different radicals selected from C
  • R 4a , R 4b , R 5a , R 5b , R 6a and / or R 6b are H, F, Cl, -CF 3 , OH, OCF 3 , or O. -C 1 6 -alkyl, preferably for H or F, in particular H
  • R 8 is preferably H; C 1-5 alkyl; in particular methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl; Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 CF 3 , phenyl, benzyl, phenylethyl, phenylpropyl, or bound via a C 1-3 alkylene cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, each unsubstituted or mono- or polysubstituted by identical or different Substituents
  • R 9a and R 9b are each independently H; F; Methyl; Ethyl, iso-propyl, CF 3 , methoxy; cyclopropyl; phenyl; Benzyl, phenylethyl or an over a Ci. 3- alkylene-bonded cycloalkyl or -CF 3 , in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents.
  • R 9a and R 9b are H.
  • R 8 is H or Ci 6 alkyl, in each case unsubstituted or mono- or polysubstituted by identical or different radicals, and R 9a and R 9b are each H
  • preferred embodiments of the compounds according to the invention are those compounds in which the substructures according to the formulas (IIIa) and (IIIb) shown above assume one of the following substructures (Illc), (IIId) or (Never)
  • s and t are each 0
  • preferred embodiments of the compounds according to the invention are those in which the substructures according to the formulas (IIIa) and (IIIb) shown above assume one of the substructures (Illc) or (IMe) likewise shown above, s for 1 and t for 1, 2 or 3 are
  • the compounds of this invention R 8 represents H, C 1 6 alkyl or C 3 6 cycloalkyl, each unsubstituted or mono- or polysubstituted
  • the partial structure according to formula (IIb) shown above has the following partial structure (Hc):
  • the substructures shown above according to the formulas (IHc) or (MId) assume one of the following substructures (HIf) or (MIg),
  • R 27 is H and / or two of the substituents R 27 form a fused aryl or heteroaryl, in particular a benzo group
  • preferred embodiments of the compounds according to the invention are those compounds in which the partial structures IMc or (MId) shown above represent one of the following radicals A to H. -R "
  • radicals A to H comprises all possible stereoisomers of these radicals.
  • R 9a and R 9b are each H.
  • u and v are each independently 0 or 1.
  • u and v are both 1.
  • Further preferred embodiments of the compounds according to the invention are those compounds in which in the substructures according to the formulas (HIf) or (MIg) shown above:
  • R18a for H; C 1-6 alkyl; Cs- ⁇ -cycloalkyl, -NH (CL 6 Al kVl), -N (C 1-6 alkyl) 2 , phenyl, pyridyl, thienyl, pyrimidyl, thiazolyl, imidazolyl or triazolyl, each unsubstituted or mono- or polysubstituted; phenyl, pyridyl, thienyl, pyrimidyl, thiazolyl, imidazolyl or triazolyl bonded via an - (0) oiC- ⁇ - 6- alkylene group, in each case unsubstituted or monosubstituted or polysubstituted; or
  • R 18a is a radical according to the general formula VIIa
  • E is N or CH; with the proviso that if i is 1 and j is
  • E is CH; G is CR 37a R 37b or NR 38 ;
  • R 37a and R 37b are independently H, F or C 1-6 alkyl
  • R 19 for H; C 1-6 alkyl; C 3-8 cycloalkyl, or C 1-5 alkyl joined via (C O) O -I ; Phenyl, pyridyl, thienyl, thiazolyl, triazolyl, pyrimidinyl or imidazolyl; in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents; a C 1- 6 alkylene group bonded phenyl, pyridyl, thienyl, thiazolyl, pyrimidinyl, triazolyl or imidazolyl; each unsubstituted or mono- or polysubstituted by identical or different substituents;
  • M is CH or N, with the proviso that when w is 0,
  • M is CH; L is CR 44a R 44b or NR 45 ,
  • R 44a and R 44b are independently H, F or Ci_6-alkyl, each unsubstituted or mono- or polysubstituted by identical or different substituents;
  • R 45 for H C ⁇ -alkyl, C 3 - ⁇ -alkyl or pyridyl, each unsubstituted or mono- or polysubstituted by identical or different substituents.
  • Further preferred embodiments of the compounds according to the invention are those compounds in which in the Tei structures shown above according to the formulas (Never) or (HId) one of the following groups A to H represent-
  • R18a for H; C 1-6 alkyl; N (C 1-6 alkyl) 2 ; NH (C 1-6 alkyl); azetidinyl; Pyrrolidinyl, piperidinyl, 4- (C 1-6 alkyl) -piperazinyl; Phenyl or pyridyl, each unsubstituted or mono- or polysubstituted by identical or different substituents; a - (O) 0- rC 1-6 alkylene bonded N (C 1- 6 alkyl) 2; NH (C 1-6 alkyl); azetidinyl; Pyrrolidinyl, piperidinyl, 4- (C 1-6 alkyl) piperazinyl, phenyl, imidazolyl, triazole or pyridyl, each unsubstituted or monosubstituted or polysubstituted by identical or different substituents;
  • R18b for H; OH; C 1-6 alkyl; Phenyl or pyridyl, each unsubstituted or mono- or polysubstituted by identical or different substituents; phenyl or pyridyl bonded via a C 1-6 -alkylene group, in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents;
  • Further preferred embodiments of the compounds according to the invention are those compounds in which in the substructures shown above according to the formulas (IMh) or (Uli):
  • R18a for H; C 1 -6 alkyl; C M -cycloalkyl, N (C 1-6 -alkyl) 2 ; NH (C 1-6 alkyl), azetidinyl; Pyrrolidinyl, piperidinyl, 4- (C 1-e alkyl) piperazinyl; Phenyl or pyridyl, each unsubstituted or mono- or polysubstituted by identical or different substituents; a - (0) o / iC 1-6 alkylene bonded N (C 1- 6 alkyl) 2; NH (Ci-C6 alkyl.), Azetidinyl; Pyrrolidinyl, piperidinyl, 4- (C 1-6 alkyl) piperazinyl; Phenyl, imidazolyl, triazolyl, or pyridyl, each unsubstituted or mono- or polysubstituted by identical or different substituents;
  • R18b for H; OH; Phenyl or pyridyl, each unsubstituted or mono- or polysubstituted by identical or different substituents; phenyl or pyridyl bonded via a C 1-6 -alkylene group, in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents;
  • substituents R 13 together form a fused aryl or heteroaryl, in particular a benzo group, in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents,
  • R 15 is H 1 C 1-6 -AlkVl, C 3-8 -CyClOaIkYl, phenyl, Py ⁇ dyl, each unsubstituted or mono- or polysubstituted by identical or different substituents, via a C 1 ⁇ -alkylene group bound phenyl or Py ⁇ dyl, respectively unsubstituted or monosubstituted or polysubstituted by identical or different substituents,
  • R 16a represents H, C 1-6 -alkyl, phenyl or pyridyl, in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents
  • R 18a is H, C 1- ⁇ alkyl, C 3 8 -cycloalkyl N (C 1-6 -alkyl) 2, NH (C 1-6 alkyl), Azetidmyl, pyrrolidinyl, Pipe ⁇ dinyl, 4- (Ci 6Alkyl) -P ⁇ peraz ⁇ nyl, phenyl or pyndyl, each unsubstituted or mono- or polysubstituted by identical or different substituents, via a - (O) 0 / rCi 6 alkylene-bound N (C 1 6 alkyl) 2 , NH (C 1-6 - alkyl), Azetidmyl, pyrrolidinyl, Piperidmyl, 4- (
  • R 18b each unsubstituted H, OH, Ci 6 alkyl, phenyl or Py ⁇ dyl, each unsubstituted or mono- or polysubstituted by identical or different substituents, bonded via a C 1-6 alkylene or phenyl Pyndyl or mono- or polysubstituted by same or different substituents, stands,
  • R 120 is H, F, Cl, OH, OCH 3, O-CF 3, Ci 6 alkyl, CF 3, phenyl, unsubstituted or substituted one or more times, is,
  • R 126 is H, C 1-6 alkyl, C 3 6 cycloalkyl, phenyl or Pyndyl, via a C 3 - C 3 alkylene group bound 6 cycloalkyl, phenyl or Pyndyl, each unsubstituted or mono- or polysubstituted by identical or different substituents
  • (B) is selected from one of the following substructures B.1. to B.47.
  • M 1 , M 2 and M 3 may each independently be N or CH, where one of M 1 , M 2 and M 3 is N and the other two are CH;
  • R 8 for H; C 1-6 alkyl, especially methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert -butyl; C 3-6 cycloalkyl, in particular cyclopropyl, in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents;
  • R 19 is selected from H; C 1 ⁇ alkyl, especially methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl; C 1-6 cycloalkyl, in particular cyclopropyl; in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents;
  • R 34 and R 35 are preferably independently of one another methyl or ethyl or together with the N atom connecting them form an azetidinyl, pyrrolidinyl, piperidinyl, 4- (C 1-6 alkyl) piperazinyl group, in each case unsubstituted or simple or polysubstituted with identical or different substituents;
  • R 38 is H, C 1- ⁇ alkyl, C 3-6 cycloalkyl, or pyridyl;
  • R 39 is selected from H; C 1-6 alkyl, especially methyl, ethyl, n-propyl, iso -propyl, n-butyl, sec-butyl, iso-butyl and tert -butyl; C 3 - 6 cycloalkyl, in particular cyclopropyl, in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents; and R 45 is H, C 1-6 -alkyl, C 36 -cycloalkyl or pyridyl,
  • R 190 represents 0-4 substituents which are independently selected from F, Cl, 0-CF 3 , CF 3 or CN
  • Te ⁇ structures B 1 to B 46, R 8 , R 9a , R 9b , R 19 and R 39 are each, independently of one another, H or methyl
  • o is preferably 0 or 1 in the partial structures B27 and B 28 is preferably 1 or 2
  • R 190 when attached to a phenyl group, is preferably a substituent selected from the group consisting of F, CF 3 and CN, and preferably in the 3- or 4-position on the phenyl ring is bound
  • a is 0, 1 or 2
  • a1 is O, 1 or 2
  • a 1 is CH 2 , O or NR 50
  • a 2 is CH 2 , O or NR 50 b is 1, 2, 3 or 4
  • these are compounds according to the above general formulas C1 to C13, in which - if present in the respective general formula,
  • a is 0, 1 or 2
  • a1 is 0, 1 or 2
  • a 1 is CH 2
  • O or NR 50 is A 2 is CH 2
  • O or NR 50 is b is 1, 2, 3 or 4
  • c, d, e and f each independently, represent 0 or 1 s stands for 1,
  • t 1, 2 or 3
  • u and v independently of one another, stand for 0 or 1,
  • R 1 is phenyl or naphthyl, where the phenyl or naphthyl is unsubstituted or mono- or polysubstituted, for example 2-, 3-, 4- or 5-fold, with identical or different radicals selected from methyl, methoxy, CF 3 , OCF 3 , F, Cl and Br is substituted,
  • R 8 is H, methyl, ethyl, n -propyl, iso -propyl, n -butyl, iso -butyl, sec -butyl, tert -butyl, cyclopropyl, cyclobutyl, phenyl, benzyl, phenylethyl, phenylpropyl, or for more than one bonded cyclopropyl, in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents,
  • R 12 is absent or is 1, 2, 3 or 4 radicals selected from F and methyl
  • R 13 and R 27 are each independently absent or are 1, 2, 3 or 4 radicals selected from F and methyl or are a fused, unsubstituted or mono- or polysubstituted by identical or different substituents benzo group,
  • R 18a is H, C 1 6 alkyl, C3-8 cycloalkyl, N (C 1-6 alkyl) 2, NH (d. 6 alkyl), azetidinyl, pyrrolidinyl, piperidinyl, 4- (Ci 6 alkyl ) -P ⁇ peraz ⁇ nyl, phenyl or Py ⁇ dyl, each unsubstituted or monosubstituted or polysubstituted, via a - (O) 0 /i-Ci.6- alkylene bound N (C 1-6 alkyl) 2 , NH (Ci 6-alkyl) , azetidinyl, pyrrolidinyl, piperidinyl, 4- (Ci. 6 alkyl) -P ⁇ peraz ⁇ nyl, phenyl, imidazolyl, triazolyl, or Pyndyl, each unsubstituted or substituted one or more times, is,
  • R 200 is 0-4 substituents independently selected from F, Cl, -CF 3 and -O-CF 3 , in particular F or CF 3 , and / or two adjacent R 200 together form a fused aryl or heteroaryl, in particular a benzo moiety
  • a is 0, A 1 is CH 2 , a 1 is 0 and A 2 is CH 2 , a is 0, A 1 is CH 2 , a 1 is 1 and A 2 is CH 2 , a is 1, A 1 is CH 2 , a1 is 0 and A 2 is CH 2 , a is 1, A 1 is CH 2 , a1 is 0 and A 2 is CH 2 , a is 1, A 1 is CH 2 , a1 is 0 and A 2 is O, a is 0, A 1 is CH 2 , a1 is 2 and A 2 for CH 2 , a is 1, A 1 is CH 2 , a 1 is 1 and A 2 is CH 2 or a is 2, A 1 is CH 2 , a1 is 0 and A 2 is CH 2
  • the substituted compounds according to the invention can be selected from the group consisting of 72 (S) -4- (1- (3- (1- (2,6-Dicyclo-4- (trifluoromethyl) phenylsulfonyl) pyrrolidinyl-2-yl) -propylsulfonyl) -p ⁇ pe ⁇ d ⁇ n-4-yloxy) pyridine
  • the compounds according to the invention preferably have an antagonistic effect on the human B1R receptor or the B1R receptor of the rat.
  • the compounds according to the invention have an antagonistic effect both on the human B1R receptor ( hB1 R) as well as at the B1 R receptor of the rat (rB1 R).
  • the compounds according to the invention have an inhibition of at least 15%, 25%, 50% in the FLIPR assay at a concentration of 10 ⁇ M at the human B1R receptor and / or at the B1R receptor of the rat. 70%, 80% or 90%. Very particular preference is given to compounds which inhibit the human B1R receptor and the B1R receptor of the rat by at least 70%, in particular by at least 80% and particularly preferably by at least 90% have a concentration of 10 ⁇ M
  • the indication in% activation is based on the Ca 2+ signal after addition of Lys-Des-Arg 9 -bradykinin (0.5 nM), or des-Arg 9 -bradykinin (100 nM).
  • Antagonists lead to a suppression of the Ca 2+ -injection after the addition of the agonist. Indicated are% inhibition compared to the maximum achievable inhibition.
  • the substances according to the invention preferably act, for example, on the B1R relevant in connection with various diseases, so that they are suitable as pharmaceutical active ingredient in medicaments
  • Another object of the invention are therefore medicaments containing at least one compound of the invention, and optionally suitable additives and / or auxiliaries and / or optionally other active ingredients.
  • the medicaments according to the invention optionally contain suitable additives and / or adjuvants, such as carrier materials, fillers, solvents, diluents, dyes and / or binders and can be used as liquid dosage forms in the form of injection solutions, drops or juices Semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, patches / aerosols or aerosols
  • suitable additives and / or adjuvants such as carrier materials, fillers, solvents, diluents, dyes and / or binders and can be used as liquid dosage forms in the form of injection solutions, drops or juices
  • Semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, patches / aerosols or aerosols The choice of excipients etc and the quantities
  • the amount of active substance to be administered to the patient varies depending on the weight of the patient, the mode of administration, the indication and the severity of the disease. Usually, 0.00005 to 50 mg / kg, in particular 0.01 to 5 mg / kg, of at least one compound according to the invention applied
  • a substituted substituted disulfonamide according to the invention is present as a pure diastereomer and / or enantiomer, as a racemate or as an equimolar or equimolar mixture of the diastereomers and / or enantiomers B1 R is particularly involved in pain.
  • the disulfonamides according to the invention can be used for the preparation of a medicament for the treatment of pain, in particular of acute, visceral, neuropathic or chronic pain or inflammatory pain
  • Another object of the invention is therefore the use of at least one substituted disulfonamide according to the invention for the manufacture of a medicament for the treatment of pain, in particular of acute, visceral, neuropathic or chronic pain.
  • a specific embodiment of the present invention is the use of at least one of the substituted disulfonamides according to the invention for the preparation a medicine for the treatment of inflammatory pain
  • the invention also provides the use of at least one substituted disulfonamide according to the invention for the treatment of pain, in particular of acute, visceral, neuropathic or chronic pain or inflammatory pain
  • Another object of the invention is the use of at least one substituted disulfonamide according to the invention for the manufacture of a medicament for the treatment of diabetes, respiratory diseases, for example bronchial asthma, allergies, COPD / chronic obstructive pulmonary disease or cystic fibrosis, inflammatory bowel disease, for example ulcerative colitis or CD / Crohn's disease, neurological diseases such as multiple sclerosis or neurodegeneration, inflammation of the skin, for example, atopic dermatitis, psoriasis or bacterial infections, rheumatic diseases, for example, rheumatoid arthritis or osteoarthritis, septic shock, reperfusion syndrome, for example, after heart attack or stroke, obesity , and as an angiognesis inhibitor, the invention also provides the use of at least one substituted disulfonamide according to the invention for the treatment of one of the aforementioned indications In one of the above uses, it may be preferred if a substituted disulfonamide used is present as a pure diaste
  • Another object of the invention is a method for the treatment, in particular in one of the aforementioned indications, a non-human mammal or human who or a treatment in particular pain, in particular acute, visceral, neuropathic or chronic pain or inflammatory pain needed by administering a therapeutically effective dose of an appropriately substituted disulfonamide, or of a medicament according to the invention
  • a further subject of the invention are processes for the preparation of the substituted disulfonamides according to the invention as stated in the description and the examples
  • a further subject of the present invention is a process for the preparation of the substituted disulfonamides according to the invention as stated in the description and the examples
  • AIBN N, N-azobiphenylsilane
  • DBU 1, 8-diazacyclo (5 4 0) undec-7-ene
  • DEAD diethyl azodicarboxylate
  • DIAD dnsopropyl azodicarboxylate
  • DIBAL-H dnsobutylaluminum hydride
  • DIPEA N, NN, N-diisopropylethylamine
  • LAH lithium aluminum hydride
  • LHMDS lithium hexamethyldisilazide
  • NMP N-methylpyrrolidone
  • Oxone ® 2KHSO 5 KHSO 4 K 2 SO 4
  • the protective group (PG) is a suitable nitrogen protecting group, preferably tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn) or p-methoxybenzyl (PMB)
  • Protecting groups can be introduced and cleaved by customary literature methods known to those skilled in the art, as for example in Philip J Kocienski, Protectmg Groups, 3rd Edition, Georg Thieme Verlag, 2005 (ISBN 3-13-135603-0) or Peter GM Wuts, Theodora W Greene, Greene's Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience, 2007 (ISBN-13 978-0-471-69754-1)
  • the separation of diastereomers and / or enantiomers can also be carried out by customary methods known to those skilled in the art, for example by Umk ⁇ stallisation, chromatography or in particular HPLC chromatography or crystallization with an optionally chiral acid or base and separation of the salts or chiral HPLC chromatography (Fogassy et al, Optical resolution methods, Org Biomol Chem 2006, 4, 3011-3030)
  • amino alcohols used, compounds of the general formulas (A) and (F), are commercially available or known from the literature.
  • Non-commercially available amino alcohols of the general formulas (A) and (F) can be prepared analogously to syntheses known from the literature, for example from the corresponding carboxylic acid esters or carboxylic acids using metal hydrides, for example lithium aluminum hydride, diisobutylaluminum hydride, diborane or borane complexes, as reducing agents.
  • metal hydrides for example lithium aluminum hydride, diisobutylaluminum hydride, diborane or borane complexes, as reducing agents.
  • the employed amine building blocks (RRNH) are commercially available, known from the literature or can be prepared by methods known to the person skilled in the art.
  • the reaction of compounds of the general formula (A) to give compounds of the general formula (B) can be carried out sequentially in two stages, the alcohol (A) being initially dissolved in a suitable solvent, such as, for example, dichloromethane, tetrahydrofuran, Acetone, N, N-dimethylformamide or pyridine, if appropriate also in the presence of a suitable base, for example 4- (dimethylamino) pyridine, pyridine, N 1 NN 1 N-diisopropylethylamine (DIPEA) or triethylamine, if appropriate additionally in the presence of a tetraalkylammonium Salt, for example, tetra-n-butylammonium bromide, with a suitable reagent or reagent mixture, for example carbon tetrabromide / triphenylphosphine, methanesulfonyl chloride or p-toluenesulfonyl chloride
  • a suitable solvent preferably selected from the group consisting of acetone, methyl ethyl ketone or N, N-dimethylformamide in the presence of a suitable iodine-containing salt, for example sodium iodide or potassium iodide, optionally in addition in the presence of a tetraalkylammonium salt, for example tetra-n- Butylammonium iodide, at a temperature of preferably -20 0 C to 200 0 C, optionally in a microwave, converted into compounds of general formula (B).
  • a suitable iodine-containing salt for example sodium iodide or potassium iodide
  • a tetraalkylammonium salt for example tetra-n- Butylammonium iodide
  • compounds of general formula (B) in an intermolecular radical addition with pentafluorophenyl-vinylsulfonate in the presence of a chain carrier preferably selected from the group consisting of tri-n-butyltin hydride, tristrimethylsilylsilane or N-ethylpiperidinium hypophosphite (EPHP), and in Presence of a suitable free-radical initiator, for example triethylborane (plus air) or AIBN (plus heat), optionally additionally in the presence of a suitable reducing agent, for example sodium borohydride, in at least one suitable solvent, preferably selected from the group consisting of dichloromethane, toluene or 1,4 -Dioxane, preferably at temperatures between 0 0 C and reflux temperature, converted into compounds of general formula (C).
  • a chain carrier preferably selected from the group consisting of tri-n-butyltin hydride, tristrimethylsilylsilane or
  • the compounds of general formula (C) thus obtained are reacted with amines (RRNH) in a suitable solvent, preferably selected from the group consisting of N, N-dimethylformamide, tetrahydrofuran, toluene, dichloromethane, NMP, methanol, water or mixtures thereof, in the presence at least a suitable base, for example DBU, triethylamine, sodium hydride, LHMDS, if appropriate additionally in the presence of an ammonium salt, for example Tetraalkylammoniumhalogenide, in particular tetra-n-butylammonium chloride, preferably at temperatures from 0 0 C to 200 0 C, optionally in a microwave, to give compounds of general formula (D) implemented.
  • a suitable solvent preferably selected from the group consisting of N, N-dimethylformamide, tetrahydrofuran, toluene, dichloromethane, NMP, methanol, water or mixtures thereof
  • BOC protecting groups may be in at least one solvent, preferably selected from the group consisting of acetonitrile, diethyl ether, tetrahydrofuran, methanol, ethanol, dichloromethane, 1,4-dioxane, ethyl acetate and dimethylformamide with an acid preferably selected from the group consisting of trifluoroacetic acid, hydrochloric acid, methanesulfonic acid and sulfuric acid at temperatures of preferably 0 ° C. to the reflux temperature.
  • Cbz protecting groups can be removed under acidic conditions, for example by reaction with a HBr / glacial acetic acid mixture, a mixture of trifluoroacetic acid in 1, 4-dioxane / water or HCl in methanol or ethanol.
  • reagents such as trimethylsilyl iodide in solvents such as dichloromethane, chloroform or acetonitrile, BF 3 - etherate with addition of ethanethiol or Me 2 S in solvents such as dichloromethane, a mixture of aluminum chloride / anisole in a mixture of dichloromethane and nitromethane or Triethylsilane / PdCb in methanol with the addition of triethylamine.
  • Another method is the hydrogenolytic cleavage of the protective group under elevated pressure or without pressure with the aid of catalysts such as Pd on carbon, Pd (OH) 2 , PdCl 2 , Raney nickel or PtO 2 in solvents such as methanol, ethanol, 2-propanol , Tetrahydrofuran, acetic acid, ethyl acetate or chloroform if necessary with the addition of HCl, formic acid or trifluoroacetic acid.
  • catalysts such as Pd on carbon, Pd (OH) 2 , PdCl 2 , Raney nickel or PtO 2
  • solvents such as methanol, ethanol, 2-propanol , Tetrahydrofuran, acetic acid, ethyl acetate or chloroform if necessary with the addition of HCl, formic acid or trifluoroacetic acid.
  • an organic or inorganic base preferably selected from the group consisting from potassium carbonate, sodium carbonate, Sodium bicarbonate, N
  • b1 is 0, 1 or 2 and the group NRR is - (NR 8 ) s - (CR 9a R 9b ) t -AR 10 R 11 .
  • Compounds of general formula (G) are then in the presence of a suitable base, for example imidazole, pyridine or 4- (dimethylamino) -pyridine, optionally in the presence of Tnphenylphoshin (or corresponding polymer-bound or fluorinated variants) in an iodination with iodine, sodium iodide or Potassium iodide in at least one suitable solvent, for example diethyl ether, acetonitrile, toluene, benzene or pyridine, reacted at a temperature of preferably -20 0 C to reflux temperature to compounds of general formula (H).
  • a suitable base for example imidazole, pyridine or 4- (dimethylamino) -pyridine
  • Tnphenylphoshin or corresponding polymer-bound or fluorinated variants
  • reaction of compounds of the general formula (G) to give compounds of the general formula (H) can be carried out sequentially in two stages, the alcohol (G) being initially dissolved in a suitable solvent such as, for example, dichloromethane, tetrahydrofuran, acetone, N, N- Dymethylformamide or pyridine, if appropriate also in the presence of a suitable base, for example 4- (D ⁇ methylam ⁇ no) pyridine, pyridine, N 1 NN 1 N-diisopropylethylamine (DIPEA) or triethylamine, optionally additionally in the presence of a tetraalkylammonium salt, for example tetra-n- Butylammon ⁇ umbromid, with a suitable reagent or reagent mixture, for example, carbon tetrabromide / T ⁇ phenylphosphin, methanesulfonyl chloride or p-toluenesulfonyl chloride at
  • a suitable solvent preferably selected from the group consisting of acetone, methyl ethyl ketone or N, N-dimethylformamide in the presence of a suitable iodine-containing salt, beispielswesie sodium iodide or potassium iodide, optionally in addition in the presence of a tetraalkylammonium salt, for example tetra-n- Butylammoniumiod ⁇ d, at a temperature of preferably -20 0 C to 200 0 C, optionally in a microwave, in compounds of general formula (H) überbowt
  • compounds of general formula (H) in an intermolecular radical addition with pentafluorophenyl-vinyl sulfonate in the presence of a chain carrier preferably selected from the group consisting of tri-n-butylzinnhyd ⁇ d, Trist ⁇ methylsilylsilan or N-Ethylp ⁇ pe ⁇ d ⁇ n
  • the compounds of general formula (J) thus obtained are reacted with amines (RRNH) in a suitable solvent, preferably selected from the group consisting of N, N-D ⁇ methylformam ⁇ d, tetrahydrofuran, toluene, dichloromethane, NMP, methanol, water or mixtures thereof presence of at least one suitable base, for example DBU, Tnethylamin, sodium hydride, LHMDS, optionally additionally in the presence of an ammonium salt such as tetraalkylammonium halides, especially tetra-n-butylammon ⁇ umchlor ⁇ d, preferably at temperatures of 0 0 C to 200 0 C, optionally in a microwave, reacted to give the compounds of the general formula (I) according to the invention
  • a suitable solvent preferably selected from the group consisting of N, N-D ⁇ methylformam ⁇ d, tetrahydrofuran, toluene, dichloromethane, NMP, methanol
  • NRR is the Grouping - (NR 8 ) s - (CR 9a R 9b ) r AR 10 R 11 and X is halogen (preferably bromine, iodine) or OSO 2 R (where R is phenyl, ToIyI, trifluoromethyl or methyl, preferably methyl) ,
  • compounds of the general formula (G) may optionally be converted into compounds of the general formula (Q)
  • compounds of the general formula (G) are known by methods known Oxailationsmethoden, such as The Jones, Corey-Kim, Sarett or Swern oxidation, implemented Typical reaction conditions for the Jones oxidation are Cr 2 C> 3 in H 2 SO 4 in solvents such as diethyl ether, typical conditions for the Corey-Kim oxidation are N-Chlorsucc ⁇ n ⁇ m ⁇ d and dimethyl sulfide in, for example, toluene, while in the Sarett Oxidation Collms reagent (CrO 3 * 2 Py ⁇ din) is used
  • the Swern oxidation is carried out in the presence of a mixture of Oxalylchlo ⁇ d and DMSO in the presence of a base such as methylamine or Py ⁇ din also find use TEMPO / p-
  • the compounds of general formula (Q) thus obtained are in a Wittig-Horner reaction in the presence of ethyl 2- (d ⁇ methoxyphosphoryl) acetate and bases such as NaH, K 2 CO 3 , sodium ethoxide, potassium tert-butylate, lithium dnsopropylamid or n -Butyll ⁇ th ⁇ um in solvents such as water, THF, diethyl ether, hexane, benzene, toluene, 1, 2-D ⁇ methoxyethan, DMF or DMSO, optionally in the presence of MgBr 2 , T ⁇ ethylamin or HMPT, in compounds of general formula (R) überbowt
  • bases such as NaH, K 2 CO 3 , sodium ethoxide, potassium tert-butylate, lithium dnsopropylamid or n -Butyll ⁇ th ⁇ um in solvents such as water, THF, diethyl ether, hex
  • the aldehyde thus obtained can subsequently be obtained by reduction methods known to the person skilled in the art be converted into the corresponding alcohol of the
  • compounds of the general formula (G) if appropriate in the presence of a suitable base, for example imidazole, Py ⁇ din, N, NN, N-D ⁇ sopropylethylam ⁇ n (DIPEA), T ⁇ ethylamin or 4- (D ⁇ methylam ⁇ no) -pyr ⁇ d ⁇ n, if appropriate also in the presence of T ⁇ phenylphoshin ( or corresponding polymer-bound or fluorinated variants) and / or in the presence of a tetraalkylammonium salt, for example tetra-n-butylammon ⁇ umbrom ⁇ d, in a halogenation with iodine, Nat ⁇ umiodid, potassium iodide, carbon tetrabromocarbon / triphenylphosphine, PCI 3 , PBr 3 or alternative halogenating reagents known in the art in at least a suitable solvent, for example dichloromethane, tetrahydrofuran
  • a suitable solvent or solvent mixtures preferably selected from the group consisting of N, N-dimethylformamide, dichloromethane, tetrahydrofuran, methanol or water in the presence of chlorine gas, or a suitable acid, for example formic acid, acetic acid or trifluoroacetic acid, optionally in combination with a suitable oxidizing agent, for example hydrogen peroxide or Oxone ® , optionally additionally in the presence of potassium acetate, preferably at temperatures from -20 0 C to 150 0 C, to compounds of general formula (M).
  • a suitable solvent or solvent mixtures preferably selected from the group consisting of N, N-dimethylformamide, dichloromethane, tetrahydrofuran, methanol or water in the presence of chlorine gas, or a suitable acid, for example formic acid, acetic acid or trifluoroacetic acid, optionally in combination with a suitable oxidizing agent, for example hydrogen peroxide or Oxone ® , optionally additionally in the presence
  • Compounds of the general formula (M) are in at least one suitable solvent, preferably selected from the group consisting of N, N-dimethylformamide, dichloromethane, tetrahydrofuran, toluene or benzene in the presence of a Chlon mecanicsreagenzes, preferably selected from the group consisting of oxalyl chloride, phosphorus oxychloride, Phorsphorpentachlorid or thionyl chloride, preferably at temperatures of preferably -20 0 C to 150 ° C, converted to sulfonyl chlorides of the general formula (N).
  • suitable solvent preferably selected from the group consisting of N, N-dimethylformamide, dichloromethane, tetrahydrofuran, toluene or benzene in the presence of a Chlon mecaniczes, preferably selected from the group consisting of oxalyl chloride, phosphorus oxychloride, Phorsphorpent
  • sulfonyl chlorides of general formula (N) can be obtained in 2 stages via compounds of general formula (O) from compounds of general formula (K).
  • compounds of general formula (K) are in a suitable solvent or solvent mixture, preferably selected from the group consisting of water, methanol, ethanol, iso-propanol or tert-butanol in the presence of Na 2 SOa, preferably at temperatures of -20 0 C to 200 0 C, to give compounds of general formula (O), which are then in at least one suitable solvent, preferably selected from the group consisting of N, N-D ⁇ methylformam ⁇ d, dichloromethane, tetrahydrofuran, toluene or benzene in the presence of a chlorinating reagent, preferably selected from the group consisting of oxalyl chloride, Phosphoroxychlo ⁇ d, Phorsphorpentachlond or Thionylchlo ⁇ d, preferably at temperatures of preferably
  • compounds of the general formula (II) are reacted in a sulphonylation with amines (RRNH), if appropriate in the presence of an organic or inorganic base, preferably selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, N, N-diisopropylethylamine (DIPEA), triethylamine, Pyridine, 4- (D ⁇ methylam ⁇ no) -py ⁇ d ⁇ n, diethylamine or DBU, preferably in an organic solvent, such as acetone, acetonitrile, dichloromethane or tetrahydrofuran and mixtures thereof, at a temperature of 0 0 C to reflux temperature to the compounds of general formula (I ) implemented
  • an organic or inorganic base preferably selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, N, N-diisopropylethylamine (DIPEA), triethylamine, Pyridine, 4-
  • the agonistic or antagonistic action of substances can be determined on the bradykinin receptor 1 (B1 R) of the species human and rat with the following assay.
  • B1 R bradykinin receptor 1
  • CHO K1 cells Chinese hamster ovary cells
  • hB1 R cells human B1 R gene
  • rB1 R cells B1 R gene of the rat
  • the cells are incubated with 2.13 ⁇ M Fluo-4 (Molecular Probes Europe BV, Leiden Netherlands) in HBSS buffer (Hank's buffered cream solution, Gibc Invitrogen GmbH, Düsseldorf, Germany) with 2.5 mM Probenecid (Sigma Ald ⁇ ch, Taufmün Germany) and 10 mM HEPES (Sigma Ald ⁇ ch, Taufmün, Germany) for 60 min at 37 0 C loaded then the plates with 2 x Washed HBSS buffer and treated with HBSS buffer containing in addition 0.1% BSA (bovine serum albumin, Sigma-Ald ⁇ ch, Taufmaschinen Germany), 5.6 mM glucose and 0.05% gelatin (Merck KGaA, Darmstadt, Germany) for a further 20 minutes incubation at room temperature, the plates are used for Ca 2+ measurement in the FLIPR Alternatively, washed with buffer A (15 mM HEPES, 80 mM NaCl, 5 mM KCl, 1, 2 mM CaCl
  • the FLIPR protocol consists of 2 substance additions. First, be
  • Test substances (10 ⁇ M) were pipetted onto the cells and the Ca 2+ influx with the
  • Bradykinin (10 ⁇ M).
  • Arg 9 - bradykinin (rB1 R) was administered in the concentration of ECso and also the
  • Antagonists lead to a suppression of Ca 2+ influx. It will %
  • the compounds have a B1 R antagonistic effect on the human receptor and / or on the rat receptor.
  • the invention will be explained by way of examples, without limiting the general idea of the invention.
  • the chemicals and solvents used were purchased commercially from the traditional suppliers (Acros, Aldrich, Fluka, Lancaster, Maybridge, TCI, Fluorochem, Tyger, ABCR, Fulcrum, Frontier Scientific, Milestone, etc.).
  • the reactions were z.T. under inert gas (nitrogen).
  • the yields of the compounds produced are not optimized.
  • the mixing ratios of solvents are always stated in the ratio volume / volume.
  • HPLC Waters Alliance 2795 with Waters 2998 PDA; MS: Micromass Quattro Micro TM API; Column: Waters Atlantis T3 ®, 3 .mu.m, 100 A, 2.1 x 30 mm; Column temperature: 40 ° C., eluent A: purified water + 0.1% formic acid; Eluent B: acetonitrile (gradient grade) + 0.1% formic acid; Gradient: 0% B to 100% B in 8.8 minutes, 100% B for 0.4 minutes, 100% B to 0% B in 0.01 minutes, 0% B for 0.8 minutes; Flow: 1, 0 ml / min; Ionization: ES +, 25V; Batch: 100 ⁇ l / min 70% methanol + 0.2% formic acid; UV: 200-400 nm. Preparation of the non-commercially acquired starting materials used:
  • this reaction can also be carried out with 4-fluoropyridine (or the corresponding hydrochloride).
  • the target compound can alternatively via Hartwig-Buchwald coupling with 4-bromopyridine in the presence of a suitable palladium catalyst such as tris (dibenzylideneacetone) dipalladium / (S) - (-) - 2,2'-bis (diphenylphosphino) -1, 1 ' -Binapthyl be prepared in toluene and in the presence of a suitable base, for example sodium tert-butylate, at 90 0 C.
  • a suitable palladium catalyst such as tris (dibenzylideneacetone) dipalladium / (S) - (-) - 2,2'-bis (diphenylphosphino) -1, 1 ' -Binapthyl be prepared in toluene and in the presence of a suitable base, for example sodium tert-butylate, at 90
  • the deprotection can be carried out at temparatures between 0 0 C and room temperature with an excess of trifluoroacetic acid in dichloromethane]
  • Boc-Nortropinone (2.5 g, 11.107 mmol) was dissolved in methanol (20 mL) and cooled with an ice bath. Under inert gas slowly sodium borohydride (1, 26 g, After stirring at room temperature for 4 h, hydrolysis was carried out with saturated sodium hydrogencarbonate solution (30 ml), methanol was removed under vacuum and the aqueous phase was extracted with ethyl acetate (3 ⁇ 50 ml).
  • Step (iii): Benzyl 4-formylpiperidine-1-carboxylate A solution of 1-benzyl 4-methyl-piperidine-1,4-dicarboxylate (10 g) in toluene (100 ml) under nitrogen was cooled to -78 ° C. Then DIBAL-H (60.9 ml) was added dropwise at -78 ° C and the mixture for 1 h at this temperature stirred (TLC control). Due to incomplete reaction, another 0.2 eq of DIBAL-H was added and stirred for a further 30 min (TLC check: some starting material and the corresponding alcohol were to be recognized). To the reaction mixture was added slowly at -78 ° C methanol (40 ml), followed by sat.
  • Boc anhydride (9.4 ml) and potassium carbonate (7.56 g) were added to benzyl 9-oxo-3-azaspiro [5.5] undec-7-ene-3-carboxylate (8.2 g) in EtOH / water ( 9: 1) (200 ml).
  • Pd / C (1 g) was added and hydrogenolyzed for 4 h at 80 psi (TLC control).
  • the mixture was filtered through celite and rinsed with ethanol and ethyl acetate. The filtrate was dried (Na 2 SO 4 ) and concentrated under vacuum.
  • tert -Butyl 9-oxo-3-azaspiro [5.5] undecane-3-carboxylate (1, 5 g) was dissolved in THF (7.5 ml) and cooled to -5 ° C. Then NaBH 4 (0.212 g) was added and the mixture was stirred for 1 h at room temperature (TLC control). After completion of the reaction, acetic acid was added to the mixture and then the methanol was distilled off. The residue was taken up in water (50 ml) and extracted with ethyl acetate (2 x 50 ml).
  • Step-1 tert -Butyl 9-hydroxy-9- (pyridi ⁇ -3-yl) -3-azaspiro [5.5] undecane-3-carboxylate
  • 3-Bromopyrrolidine (22.47 mmol, 2 eq) was dissolved in diethyl ether (10 ml) and dissolved at -78 ° C. in a solution of n-BuLi (24.7 mmol, 2.2 eq) in diethyl ether (70 ml). The resulting mixture was stirred 30 mm tert-butyl 9-oxo-3-azaspiro [5 5] undecane-3-carboxylate (see above for synthesis) (11, 23 mmol, 1 eq) was dissolved in diethyl ether (10 ml), slowly added and the reaction mixture then stirred for 1 h at -78 ° C.
  • Step-2 tert -Butyl 9- (pyridin-3-yl) -9- (2- (pyrrolidin-1-yl) ethoxy) -3-azaspiro [5.5] undecane-3-carboxylate
  • Triethylborane solution (1, 6 ml, 1 mol / l) was added, then compressed air was passed through for 5 seconds. After stirring for 5 minutes, the triethylborane solution-compressed air addition was repeated with the same amount. The cooling bath was removed, stirred for 10 minutes, then the reaction mixture was washed with water (20 ml) and saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane / diethyl ether (2: 1). Yield: 2.81 g (36%)
  • Example compounds listed in the table below were prepared from the corresponding starting materials in close accordance with the procedure described for Example 32.
  • the reaction temperatures and quantitative equivalents used of the reagents may differ for analogous reactions.
  • the respective course of the reaction was monitored by thin-layer chromatography [stage (.mu.) Bis (v )] and, based on this, the reaction times are adapted accordingly.
  • the educts used are commercially available or were prepared as described To stage (iv):
  • the reaction mixture was dried under vacuum.
  • Solvent was dichloromethane). (iii) In some examples, following in the presence of HCl in
  • Step (iii), AAV-1 The corresponding amine dihydrochloride (-0.5 mmol) was dissolved in dichloromethane (3.0 mL) and pyridine (6.0 mL) with the desired sulfonyl chloride ( ⁇ 0.9 mmol). and stirred at room temperature for 15 h. The reaction mixture was diluted with ethyl acetate (50 mL), saturated four times Sodium hydrogencarbonate solution (30 ml) and saturated Natriumchlo ⁇ dlosung (20 ml), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (silica gel, ethyl acetate / hexane gradient 80 20 to 90 10)
  • Step (iii), AAV-2 The corresponding amine dihydrochloride ( ⁇ 0 25 mmol, 1 eq) was dissolved in a mixture of dichloromethane (2.6 ml) and triethylamine (4 eq) with the desired sulfonyl chloride (2 eq). and stirred for 15 h at room temperature. The reaction mixture was washed with sat
  • Nat ⁇ umhyd ⁇ d (0.346 g, 8.679 mmol, 60%), washed with hexane and dried with inert gas, was under protective gas in N, N-D ⁇ methylformam ⁇ d (10 ml) presented, (1- (4-methoxy-2,6-dimethylphenylsulfonyl) p ⁇ pe ⁇ d ⁇ n Methanol (1.36g, 4.34mmol) was added, then stirred at room temperature for 30min.
  • Triethylborane solution (0.03 ml, 1 mol / l) was added to the reaction mixture, then compressed air was passed through for 10 sec. After stirring for 5 minutes, the triethylborane solution-compressed air addition was repeated with the same amount. After thin-layer chromatography, the triethylborane solution for compressed air was repeated with the same amount again.
  • the reaction mixture was washed with chilled water (10 ml) and cooled, saturated sodium bicarbonate sols (10 ml), dried over sodium sulfate and concentrated in vacuo.
  • the crude product was purified by column chromatography (silica gel) with hexane / diethyl ether / dichloromethane (6: 1: 1). Yield: 50 mg (13%)
  • Methanesulfonic acid chloride (0.23 ml, 3 mmol) was added, stirred for 10 min in an ice bath, then saturated sodium bicarbonate solution (10 ml) was added, and ethyl acetate (10 ml) phase separation, the aqueous phase was extracted with ethyl acetate (2 x 20 ml), the combined organic phases were washed with saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. Yield 0.54 g (77%)
  • Oxalylchloride (3.3 mmol, 2 eq) was dissolved in dichloromethane and at -78 ° C under argon DMSO (4 eq) was added and the reaction was then stirred at this temperature for 15 min (1- (2-chloro-6-methylphenylsulfonyl ) P ⁇ per ⁇ d ⁇ n-2-yl) methanol (1, 65 mmol) was dissolved in dichloromethane (15 ml) and at -78X to the Reaction solution was added dropwise. The resulting mixture was stirred for 1 h. Thereafter, triethylamine (8.25 mmol, 5 eq) was added, the reaction mixture was warmed to room temperature and stirred for 1 h.
  • Step-9 3- (3- (1- (4-Methoxy-2,6-dimethylphenylsulfonyl) piperidin-2-yl) propylsulfonyl) -9- (pyridin-3-yl) -9- (2- (pyrrolidine) 1-yl) ethoxy) -3-azaspiro [5.5] undecane

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Abstract

La présente invention concerne des disulfonamides substitués de formule (I), leurs procédés de fabrication, des médicaments contenant ces composés et l’utilisation de disulfonamides substitués pour la fabrication de médicaments.
EP09747796A 2008-11-06 2009-11-04 Disulfonamides substitués en tant que modulateurs de bri Withdrawn EP2350003A1 (fr)

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MA41898A (fr) 2015-04-10 2018-02-13 Hoffmann La Roche Dérivés de quinazolinone bicyclique
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CA2742741A1 (fr) 2010-05-14
WO2010051977A1 (fr) 2010-05-14
US8119805B2 (en) 2012-02-21
TW201020247A (en) 2010-06-01

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