EP2393803A1 - Composés d'indol substitués en tant que modulateurs du récepteur 1 de la bradykinine - Google Patents

Composés d'indol substitués en tant que modulateurs du récepteur 1 de la bradykinine

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Publication number
EP2393803A1
EP2393803A1 EP10703016A EP10703016A EP2393803A1 EP 2393803 A1 EP2393803 A1 EP 2393803A1 EP 10703016 A EP10703016 A EP 10703016A EP 10703016 A EP10703016 A EP 10703016A EP 2393803 A1 EP2393803 A1 EP 2393803A1
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Prior art keywords
alkyl
cycloalkyl
phenyl
alkylene
heteroaryl
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EP10703016A
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German (de)
English (en)
Inventor
Stefan Schunk
Melanie Reich
Michael Engels
Tieno Germann
Ruth Jostock
Sabine Hees
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Gruenenthal GmbH
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Gruenenthal GmbH
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Priority to EP10703016A priority Critical patent/EP2393803A1/fr
Publication of EP2393803A1 publication Critical patent/EP2393803A1/fr
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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P25/00—Drugs for disorders of the nervous system
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    • 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]
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    • A61P3/04—Anorexiants; Antiobesity agents
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    • 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
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention relates to substituted indole compounds, processes for their preparation, medicaments containing these compounds and the use of substituted indole compounds 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 pro-inflammatory 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).
  • bradykinin B1 R system can contribute to the chronicity of diseases. This is confirmed by a large number of animal experiments (reviews in Leeb-Lundberg et al., Pharmacol Rev. 2005, 57, 27-77 and Pesquero et al., Biol. Chem. 2006, 387, 119-126). Increased expression of the B1R, eg on enterocytes and macrophages in the affected tissue of patients with inflammatory bowel diseases, has also been shown in humans (Stadnicki et al., Am. J. Physiol. Gastrointest .. Liver Physiol. 2005, 289, G361-366).
  • B1 R antagonists in acute and, in particular, chronic inflammatory diseases. These include diseases of the respiratory tract (bronchial asthma, allergies, COPD / chronic obstructive pulmonary disease, cystic fibrosis, etc.), inflammatory bowel disease (ulcerative colitis, CD / Crohn's disease, etc.), neurological diseases (multiple sclerosis, neurodegeneration, etc.).
  • Inflammation of the skin atopic dermatitis, psoriasis, bacterial infections, etc.
  • mucous membranes 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 an 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, 119-126). 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 (Calixto et al., Br. J. Pharmacol 2004, 1-16), here in particular diabetic neuropathy (Gabra et al., Biol. Chem. 2006, 387, 127-143). Furthermore, they are suitable for the treatment of migraine.
  • D is attached to the indole skeleton in position a or b and is one of the following radicals D1 or D2
  • each of x and y independently of each other, represents 0 or 1; r is 1, 2 or 3;
  • Qi and Q 2 are independently C, CH or N;
  • R 1 and R 2 together with their linking group -Q 1 -Q 2 - form a cycle selected on one or more of its carbon ring members with one or more, for example 2 or 3, radicals independently of one another selected from the group consisting of F, Cl, Br, I, CF 3, Ci -6 alkyl, O-Ci.
  • R 4 is H, Ci- 6 alkyl, C 3rd 8 cycloalkyl, aryl or heteroaryl, or for a a Ci -6 - bound alkylene C. 3 8 -cycloalkyl, aryl or heteroaryl;
  • R 200 stands for 0 to 2 substituents are each independently selected from the group consisting of F, Cl, Br, I 1 CF 3, OCF 3, OH, O-Ci -6 alkyl, Ci -6 - alkyl, Aryl and heteroaryl and / or two adjacent substituents R 200 form a fused aryl or heteroaryl;
  • R 210 stands for 0 to 3 substituents which are each independently selected from the group consisting of F, Cl, Br, I 1 CF 3, OCF 3, OH, Od- ⁇ alkyl, Ci -6 - alkyl, aryl and Hetereoaryl;
  • R 8 is H, Ci-e-alkyl, C 3 . 8 cycloalkyl, aryl or heteroaryl, or for a a Ci -6 - bound alkylene C. 3 8 -cycloalkyl, aryl or heteroaryl; December 22, 2009
  • R 9a and R 9b are each independently H, F, Cl, OH, Ci. 6- alkyl, O-Ci. 6 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl, or a Ci. 6- alkylene-bonded C 3 _ 8 -cycloalkyl, aryl or heteroaryl;
  • 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 14a , R 14b , R 16a and R 16b are each independently H, F, Cl, OH, d. 6- alkyl, O-Ci- 6 -alkyl, C 3 . 8 cycloalkyl, aryl or heteroaryl mean or for a CI_ 6 - are bound alkylene C 3 _ 8 cycloalkyl, aryl or heteroaryl,
  • R 15 and R 17 are each independently H, CI_ 6 alkyl, C 3 _ 8 are cycloalkyl, aryl or heteroaryl, or bound via a Ci-6-alkylene C3-8- cycloalkyl, aryl or heteroaryl;
  • 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;
  • R 126 is H, C- ⁇ - 6 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl, or a bonded via a C 6 alkylene C 3-8 cycloalkyl, aryl or heteroaryl;
  • R 18a is H, Ci- 6 alkyl, C 3rd 8 cycloalkyl, aryl or heteroaryl, or a bonded via a C 6 alkylene C 3-8 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 i is 1 and j is 0, E is CH,
  • R 34 and R 35 are each independently H, d- ⁇ -alkyl, C 3-8 cycloalkyl, aryl or heteroaryl, or a bonded via a C 3 -alkylene aryl, heteroaryl, or C. 3 8 -cycloalkyl; December 22, 2009, or R 34 and R 35 , including E, form a 5- or 6-membered aryl or heteroaryl;
  • h and g are independently 0, 1 or 2;
  • R 38 is H, de-alkyl, C 38 cycloalkyl, aryl or heteroaryl, or a d a. 3 -alkylene-bound aryl, heteroaryl or C 3 - 8 cycloalkyl; December 22, 2009
  • R 18b is H, OH, de-alkyl, C 3-8 cycloalkyl, O-Ci. 6 -alkyl, O- (C 3 8 cycloalkyl.), (D. 6 - alkylene) -0-Ci.6-alkyl, (Ci- 6 alkylene) -O- (C3-.8 cycloalkyl), Aryl, heteroaryl, O-aryl or O-heteroaryl, or an aryl bound via a Ci-6-alkylene group, O-aryl, heteroaryl or O-heteroaryl;
  • R 18b is a group according to the general formula (VI),
  • k 0 or 1
  • R 39 is H, Ci- 6 alkyl, C 3rd 8 -cycloalkyl, aryl or heteroaryl, or a via a Ci. C 3 -C 8 -cycloalkyl, aryl or heteroaryl bonded to 3- alkylene group;
  • R 40 is Ci-6-alkyl, C 3 . 8 cycloalkyl, aryl or heteroaryl, or a bonded via a C alkylene group C. 3 8 -cycloalkyl, aryl or heteroaryl; or
  • I is 0, 1 or 2; and R 41 and R 42 together with the carbon atoms connecting them form a fused aryl or heteroaryl;
  • z is 0 or 1;
  • R 24 is H, Ci- 6 alkyl, C 3-8 cycloalkyl, or a via a C. 3- alkylene-bonded aryl, heteroaryl or C 3 . 8 -cycloalkyl;
  • R 22 represents C. 6 alkyl, C 3 - 8 cycloalkyl, aryl or heteroaryl, or a Ci -6 - means bound alkylene aryl or heteroaryl; or
  • R 22 represents a group according to the general formula (VIII) wherein
  • n 0, 1 or 2;
  • n 0, 1 or 2;
  • w 0 or 1, December 22, 2009
  • M is CH or N
  • R 44a and R 44b are each independently H, F, Cl, Br, I, OH, de-alkyl, OC 1 . 6 alkyl, C3-8 cycloalkyl, aryl or heteroaryl, or a Ci -6 - bound alkylene C 3 - 8 cycloalkyl, aryl or heteroaryl;
  • R 45 is H, Ci- 6 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl, or a d a. 3 -alkylene-bound aryl, heteroaryl or C 3 _ 8 cycloalkyl;
  • radicals C 1 -C 6 -alkyl, C 1-3 -alkylene, C i. 6 alkylene, C 3 - 8 - cycloalkyl, aryl and heteroaryl each may be unsubstituted or substituted by identical or different radicals mono- or polysubstituted, and the radicals defined above d- ⁇ alkyl, Ci 3 alkylene and CI_ 6 alkylene in each case may be branched or unbranched; December 22, 2009 optionally in the form of a single enantiomer or a single diastereomer, the racemate, the enantiomers, the diastereomers, mixtures of enantiomers and / or diastereomers, and in each case in the form of their bases and / or physiologically acceptable salts.
  • halogen is preferably the radicals F, Cl, Br and I 1, in particular the radicals F and Cl.
  • 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 -, 3-, A- or 5-fold, may be substituted with the same or different radicals.
  • the alkyl radicals may be selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, 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, isobutyl and tert-butyl.
  • C 3 _ 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 simply December 22, 2009 or multiple, 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.
  • heteroaryl in the context of the present invention represents a 5-, 6- or 7-membered cyclic aromatic radical which contains at least 1, optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are identical or different may be and the heteroaryl unsubstituted or mono- or polysubstituted, for example, 2-, 3-, 4- or 5-fold, may be substituted with identical or different radicals.
  • the substituents may be attached in any and possible position of the heteroaryl.
  • the heterocycle may also be part of a bicyclic or polycyclic, in particular a mono-, bi- or tricyclic system, which may then be more than 7-membered in total, preferably up to 14-membered.
  • heteroatoms are selected from the group consisting of N, O and S.
  • the heteroaryl radical can be selected from the group consisting of pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, Benzodioxolanyl, benzodioxanyl, benzooxazolyl, benzooxadiazolyl, imidazothiazolyl, dibenzofuranyl, dibenzothienyl, phthaloyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, triazole, tetrazole, isoxazoyl, pyridinyl (pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl,
  • Ci. 3 alkylene group or “d-6 alkylene group” in the sense of the present invention comprises 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, with the same or different radicals and which have a corresponding radical having the general structure link.
  • the 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 - (CHz) 2 -CH 2 -, -CH (CH 3 ) -CH 2 -CH 2 -, -CH 2 -CH (CH 3 ) -CH 2 -, -CH (CHa) -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 ) (CH 2 CH 3 ) -, -CH 2 CH 3 ) -, -C (CH 3 ) (CH 2 CH 3 ) -
  • Cia a C 3 alkylene group, a CI_ 6 alkylene-bound aryl or heteroaryl means for the purposes of the present invention that the Ci -3 - alkylene, Ci. 6 alkylene groups and aryl or heteroaryl have the meanings defined above and the aryl or heteroaryl 3 alkylene or Ci 6 alkylene group is bonded to the parent general structure via a C. Examples include benzyl, phenethyl and phenylpropyl.
  • Ci-e-alkylene bonded C 3 _ 8 cycloalkyl via a C 3 alkylene or Ci-e-alkylene bonded C 3 _ 8 cycloalkyl in the context of the present invention that the Ci -3 - alkylene CI_ 6 alkylene and C. 3 8 -cycloalkyl defined above December 22, 2009
  • alkyl In the context of "alkyl”, “alkylene” and “cycloalkyl”, the term “substituted” in the context of this invention means the substitution of a hydrogen radical by F, Cl, Br, I 1 CF 3 , OCF 3 , CN, NH 2 , NH-d- ⁇ -alkyl, NH-C L6 - alkylene-OH, Ci -6 alkyl, N (Ci- ⁇ -alkyl) 2, N (Ci 6 alkylene-OH.) 2, NO 2, SH, S-Ci- ⁇ alkyl, C 1.
  • 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-Ci. 6 alkyl, NH-Ci 6 alkylene-OH, N (C L6 - alkyl) (Ci. 6 alkylene-OH) 2, N 2, NH-aryl 1, N (aryl 1) 2, N (C -..
  • 6- alkyl-OH, C ( O) Ci. 6 alkyl, NHSO ⁇ de-alkyl, NHCOCi -6 -alkyl, CO 2 H, CH 2 SO 2 -phenyl, CO 2 -C L6 -Al ky I, OCF 3, CF 3, -0-CH 2 -O -, -O-CH 2 -CH 2 -O-, -OC (CH 3 ) 2 - CH 2 -, unsubstituted C 1-6 alkyl, pyrrolidinyl, imidazolyl, benzyloxy, phenoxy, phenyl, naphthyl, pyridinyl, -Ci - 3- alkylene-aryl 1 , benzyl, thienyl, furyl, wherein aryl 1 is phenyl, thiazolyl, thienyl or pyridinyl, on one or different atoms, wherein the abovementioned substituents -
  • aryl and heteroaryl can be made with the same or different substituents.
  • Preferred substituents for aryl and heteroaryl can be selected from the group consisting of -O-C 1-3 -AlkVl 1 unsubstituted C 1-6 alkyl, F, Cl 1 Br, I 1 CN, CF 3 , OCF 3 , OH, SH, -CH 2 -azetidinyl, - CH 2 -pyrrolidinyl, -CH 2 piperidinyl, -CH 2 piperazinyl, -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 -azetidinyl.
  • R 27 means that R 27 can stand for O to 4 substituents R ie 27 may be absent or may 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 may together also be a c 1-3 -alkylene bridge or a fused-on aryl or heteroaryl (also fused-on) may also be substituted for one or more C atoms Aryl or heteroaryl or fused or fused aryl or heteroaryl group), so that R 27 in the general F ormel (III) also has the meanings shown below by way of example, in which R 27 is two substituents on respectively
  • physiologically tolerable salt is preferably understood as meaning salts of the compounds according to the invention with inorganic or organic acids which are physiologically compatible - in particular when used on humans and / or mammals.
  • suitable acids are hydrochloric, hydrobromic, sulfuric, methanesulfonic, formic, acetic, oxalic, succinic, tartaric, mandelic, fumaric, maleic, lactic, citric, glutamic, 1,1-dioxo-1,2-dihydro- 6- benzo [ d] isothiazol-3-one (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, December 22, 2009
  • Hippuric acid phosphoric acid and / or aspartic acid.
  • T, R 200 and R 210 are selected such that the general formula I has one of the general formulas (Ia), (Ib) or (Ic)
  • x is 0, so that the radical D1 assumes the following form DV:
  • D is a radical selected from the group consisting of
  • R 300 stands for 0, 1, 2, 3 or 4 substituents which are independently selected from the group consisting of F, Cl, Br, I, -CF3, -0-CF3, CI_ 4 alkyl and O- Ci. 4- alkyl;
  • R 310 is 0, 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -CF 3 , -O-CF 3 , C 1-4 alkyl and O-Ci - 4- alkyl;
  • R 320 is a substituent selected from the group consisting of H, F, Cl, Br, I, -CF 3 , -O-CF 3 and d. 4- alkyl;
  • R 330 represents a substituent selected from the group consisting of H, Ci- 4 alkyl, aryl, -CH 2 -aryl and heteroaryl;
  • r1 is 1 or 2 and r2 is 1 or 2. December 22, 2009
  • D is a radical selected from the group consisting of
  • R is a substituent selected from the group consisting of F, Cl, Br, I 1 -CF 3 , -O-CF 3 , C 1-4 alkyl and OC 1-4 alkyl;
  • R is a substituent selected from the group consisting of F, Cl, Br, I 1 -CF 3 , -O-CF 3 , C 1-4 alkyl and OC 1-4 alkyl;
  • R is a substituent selected from the group consisting of H, F, Cl, Br, I 1 -CF 3 , -O-CF 3 and C 1-4 -AlkVl and
  • R J is a substituent selected from the group consisting of H, C 1-4 -alkyl, aryl, -CH 2 -aryl and heteroaryl.
  • D is a radical selected from the group consisting of December 22, 2009
  • y is 0, so that the radical D 2 assumes the following form D 2 ':
  • R 3 in the compounds according to the invention is preferably phenyl, naphthyl, chromanyl, indolyl, benzofuranyl, benzothiophenyl (benzothienyl); Benzooxazolyl, benzooxadiazolyl, pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazothiazolyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl (dibenzothienyl) or an over a Ci.
  • Imidazothiazolyl, dibenzofuranyl or for a via a Ci. 3 alkylene group bonded phenyl very particularly preferably represents phenyl, naphthyl, chromanyl, benzothiophenyl (benzothienyl) or bonded via a C 2 alkylene group, or phenyl, where the abovementioned aryl or heteroaryl radicals in each case unsubstituted or mono- or polysubstituted by identical or different, are substituted, wherein the substituents are independently of one another in particular selected from the group consisting of -O-Ci-3-alkyl, C 1-6 alkyl, F, Cl, Br, I, CF 3 , OCF 3 , OH , SH, phenyl, phenoxy, naphthyl, furyl, thienyl and pyridinyl and wherein the abovementioned alkylene groups are each unsubstituted or monosubstitute
  • the radical R 3 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 3 is selected from the group consisting of 4-methoxy-2,3,6-trimethylphenyl, 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-chloronaphthyl, 2-fluoronaphthyl, 2-chloro-4- (trifluoromethoxy) phenyl, 4-chloro-2,5-dimethylphenyl, 2-chloro-6-methylphenyl, 2,3-dichloropheny
  • radical R 3 may be 4-methoxy-2,6-dimethylphenyl, 4-chloro-2,5-dimethylphenyl, 1-naphthyl or 2- (trifluoromethyl) phenyl. December 22, 2009
  • the radical R 4 may be in the compounds of the invention in particular a substituent which is selected from the group consisting of H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert Butyl and cyclopropyl. Particularly preferably, the radical R 4 is H.
  • q is 1 or 2.
  • R 8 is H; de-alkyl, in particular methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl; Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 CF 3 , phenyl, benzyl, phenylethyl, phenylpropyl, or bound via a Ci-3-alkylene cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, each unsubstituted or mono- or polysubstituted by identical or different substituents substituted, stands.
  • R 8 may be H, methyl, ethyl, isopropyl or cyclopropyl.
  • R 9a and R 9b are each independently H; F; Methyl; Ethyl, iso-propyl, CF 3 , methoxy; cyclopropyl; phenyl; Benzyl, phenylethyl, ci- 3 -alkylene-cyclopropyl, C 1-3 -alkylene-cyclobutyl, C 1 -alkylene-cyclopentyl, C i. 3- alkylene-cyclohexyl or Ci. 3- alkylene-CF 3 , in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents, in particular R 9a and R 9b are each H.
  • MIb (purple)
  • R 8 may be H or C 1-6 alkyl, each 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 (Mc) 1 (IHd), (INe) or (IIIf):
  • s and t are each 0.
  • c, d, e and f are each independently 0, 1 or 2;
  • X is CR 14a R 14b , NR 15 or O,
  • Z is CR 18a R 18b or NR 19 ,
  • R 126 is H, C- ⁇ - 4 -alkyl or an optionally via a C 3 alkylene group bonded, unsubstituted or singly or multiply substituted phenyl, pyridyl, imidazolyl, triazolyl, pyrimidyl, thiazolyl or thienyl, wherein the substituents are each independently preferably selected from the group consisting of F, Cl, CF 3, Ci -4 alkyl, OCF 3, OH, and O-Ci. 4- alkyl, December 22, 2009
  • R 15 is H, Ci 4 alkyl, or for an unsubstituted or a Ci. 3- alkylene group, unsubstituted or mono- or polysubstituted phenyl, pyridyl, imidazolyl, triazolyl, pyrimidyl, thiazolyl or thienyl, where the substituents are each preferably selected from the group consisting of F, Cl, CF 3 , Ci. 4- alkyl, OCF 3 , OH and OC 1-4 -alkyl,
  • R 18a is H, d-4 alkyl, C 3rd 6 cycloalkyl, -NH (Ci-C6 alkyl.), -NCC L e-AlkyO ⁇ , unsubstituted or singly or multiply substituted phenyl, pyridyl, imidazolyl, triazolyl, pyrimidyl, thiazolyl or thienyl, or for a - (0) phenyl, pyridyl, imidazolyl, triazolyl, pyrimidyl, thiazolyl or thienyl, each of which is unsubstituted or monosubstituted or polysubstituted, or is attached to the ortho-C 1 -C 6 -alkylene group; wherein the substituents each independently are preferably selected from the group consisting of F, Cl, CF 3 , Ci- 4 alkyl, OCF 3 , OH and O-Ci. 4- alky
  • R 18a represents the radical according to the general formula (IVa)
  • E is N or CH; with the proviso that if i is 1 and j is
  • G is CR 37a R 37b or NR 38 ;
  • R 37a and R 37b are independently H; F or Ci. 4- alkyl, in each case unsubstituted or monosubstituted 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, in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents; and
  • R 45 is H, Ci- ⁇ -alkyl, C 3 . 6 -cycloalkyl or pyridyl.
  • R 18a is H, d-4-alkyl, C 3-6 -cycloalkyl, -NH (C 1 -S -alkyl), -N (C 1-8 -alkyl) 2 , unsubstituted or mono- or polysubstituted phenyl, pyridyl, Imidazolyl, triazolyl, pyrimidyl, thiazolyl or thienyl, or represents an - (COO-rCv ⁇ -alkylene group bonded phenyl, pyridyl, imidazolyl, triazolyl, pyrimidyl, thiazolyl or thienyl, each unsubstituted or mono- or polysubstituted, wherein the substituents in each case 1-4 -alkyl, OCF 3, OH, and O-Ci. are independently preferably selected from the group consisting of F, Cl, CF 3, C 4 alkyl,
  • R 18a represents the radical according to the general formula (IVa)
  • E is N or CH; with the proviso that if i is 1 and j is
  • O is, E is CH;
  • G is CR 37a R 37b or NR 38 ;
  • R 37a and R 37b are independently H; F or C 1-4 -alkyl, in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents, December 22, 2009
  • R 18a stands for the following radical:
  • R 19 for H, Ci. 6- alkyl, C 3 . 8 -cycloalkyl, - (C O) -Ci. 6- alkyl; Ci. 6 alkylene-NH (Ci. 6 alkyl), or phenyl, pyridyl, thienyl, thiazolyl, triazolyl, pyrimidinyl or imidazolyl; in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents; or phenyl bound over a C1.6 alkylene group, pyridyl, thienyl, thiazolyl, pyrimidinyl, triazolyl or imidazolyl; in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents, where the substituents are each independently selected, preferably from the group consisting of F, Cl, CF 3 , C 1-4 -alkyl, OCF
  • 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 C- ⁇ - 6- alkyl, in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents; and
  • R 45 is H, Ci- 6 alkyl, C3-6 cycloalkyl or pyridyl.
  • R 18a is H, Ci-4-alkyl, C 3-6 cycloalkyl, -NH (Ci. 6 alkyl), -N (Ci -6 alkyl) 2, unsubstituted or singly or multiply substituted phenyl, pyridyl, imidazolyl , triazolyl, pyrimidyl, thiazolyl or thienyl, or for a - (O) 0-Ci -i.
  • R -, 18a represents the radical according to the general formula (IVa)
  • E is N or CH; with the proviso that if i is 1 and j is
  • G is CR 37a R 37b or NR 38 ;
  • R 37a and R 37b are independently H; F, or Ci -4 alkyl, each unsubstituted or mono- or polysubstituted by identical or different substituents, December 22, 2009
  • W is O or 1; n is 0 or 1; m is 0 or 1;
  • 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- ⁇ -alkyl, each unsubstituted or mono- or polysubstituted by identical or different substituents; and
  • R 40 is H, Ci- 6 alkyl, C 3 - 6 cycloalkyl or pyridyl.
  • R 8 is H, d-4 alkyl or C 3 - 6 cycloalkyl
  • R 9a and R 9b are each independently H, Ci -4 alkyl or C 3-6 cycloalkyl, preferably both are each H;
  • R 18a is H, d-4-alkyl, Cs-e-cycloalkyl, -NH (C 1-6 alkyl), -N (C L6 -alkyl) 2, unsubstituted or singly or multiply substituted phenyl, pyridyl, imidazolyl, Triazolyl, pyrimidyl, thiazolyl or thienyl, or phenyl bonded via an - (O) O-C 1 -C 6 -alkylene group, pyridyl, imidazolyl, triazolyl, pyrimidyl, thiazolyl or thienyl, each unsubstituted or monosubstituted or polysubstituted; wherein the substituents are each independently from each other preferably selected from the group consisting of F, Cl, CF 3, Ci -4 alkyl, OCF 3, OH, and O-Ci 4 alkyl
  • R 18a represents the radical according to the general formula (IVa)
  • E is N or CH; with the proviso that if i is 1 and j is
  • G is CR 37a R 37b or NR 38 ;
  • R 37a and R 37b are independently H; F or Ci -4 -alkyl, unsubstituted or mono- or poly-substituted 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 de-alkyl, each unsubstituted or mono- or polysubstituted by identical or different substituents;
  • R 45 is H, de-alkyl, C 3 . 6 -cycloalkyl or pyridyl.
  • R 13 is 1 or 2 radicals selected from H and phenyl, unsubstituted or mono- or polysubstituted by identical or different substituents, where the substituents are each independently selected, preferably from the group consisting of F, Cl 1 CF 3 , C 1 -4 alkyl, OCF 3, OH, and O-Ci-4-alkyl;
  • substituents R 13 together form a fused aryl or heteroaryl, in particular a benzo group, each unsubstituted or mono- or polysubstituted by identical or different substituents, wherein the substituents are each independently selected, preferably from the group from F, Cl, CF 3, Ci- 4 alkyl, OCF 3, OH, and O-Ci-4-alkyl;
  • R 16a is H, Ci- 6 alkyl or phenyl or pyridyl, each unsubstituted or mono- or polysubstituted by identical or different substituents, where the substituents are each independently selected preferably from the group consisting of F, Cl, CF 3, Ci- 4 alkyl, OCF 3, OH, and O-Ci-4-alkyl;
  • R18a for H; C 1-6 alkyl; C 3 . 8 cycloalkyl, N (Ci 6 alkyl.) 2; NH (Ci-C6 alkyl.), Azetidinyl; Pyrrolidinyl, piperidinyl, 4- (Ci -6 alkyl) -piperazinyl; Phenyl or pyridyl, each unsubstituted or mono- or polysubstituted by identical or different substituents; or for a - (O) 0 / RCI 6 alkylene group bonded N (C 1 6 alkyl.) 2; NHCd ⁇ -alkyl), azetidinyl; Pyrrolidinyl, piperidinyl, 4- (C 1-6 alkyl) -piperazinyl; Phenyl, imidazolyl, triazolyl, or pyridyl, each unsubstituted or mono- or polysubstituted by
  • 4- alkyl and wherein the substituents of phenyl, imidazolyl, triazolyl, or pyridyl are each independently selected, preferably from the group consisting of F, Cl, CF 3 , C 1-4 alkyl, OCF 3 , OH and OC 1-4 alkyl;
  • R18b for H; OH; Phenyl or pyridyl, in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents, or by phenyl or pyridyl bound via a C 1-6 -alkylene group, in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents; , where the substituents of phenyl and pyridyl are each independently selected preferably from the group consisting of F, Cl, CF 3, d 4 alkyl, OCF 3, OH and OC ⁇ alkyl; December 22, 2009
  • R 19 for H; Ci -6- alkyl; C 3 . 8 -cycloalkyl, phenyl, pyridyl, thienyl, imidazolyl, thiazolyl or triazolyl, in each case unsubstituted or monosubstituted or polysubstituted by identical or different substituents, or by phenyl or pyridyl bonded via a C 1-4 -alkylene group or (C O) group, each unsubstituted or mono- or polysubstituted by identical or different substituents, wherein the substituents of phenyl, pyridyl, thienyl, imidazolyl, thiazolyl, and triazolyl are each independently selected preferably from the group consisting of F, Cl, CF 3 , Ci - 4 alkyl, OCF 3, OH, and O-Ci -4 alkyl;
  • R 120 for H; F; Cl; ; OH; OCH 3, 0-CF3, Ci -6 alkyl; CF 3 , phenyl, unsubstituted or monosubstituted or polysubstituted, wherein the substituents of phenyl are each independently selected, preferably from the group consisting of F, Cl, CF 3 , C 1-4 alkyl, OCF 3 , OH and O-- Ci -4 alkyl;
  • the partial structures SP1, SP2, SP5, SP10, SP23, SP32 and SP26 may preferably be present in the compounds according to the invention.
  • (B) December 22, 2009 is selected from one of the substructures following B.1. to B.57. (B.1.) (B.2.) (B.3.)
  • M 1 , M 2 and M 3 can 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 34 and R 35 are preferably independently of one another methyl or ethyl or, together with the N atom connecting them, are an azetidinyl; Pyrrolidinyl, piperidinyl, 4- (C 1-6 alkyl) -piperazinyl group, each unsubstituted or mono- or polysubstituted with identical or different substituents;
  • R 38 is H, Ci-6-alkyl, C 3 - 6 cycloalkyl or pyridyl;
  • Ci -6 alkyl especially methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or 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, Ci- ⁇ alkyl, C 3 - 6 cycloalkyl or pyridyl;
  • R 190 is 0-4 substituents independently selected from F, Cl, 0-CF 3 , CF 3 or CN.
  • the partial structures B Of the partial structures B, the partial structures B.1., B.3., B.4., B.10., B.1. 1, B.44., B.8., B.17., B. 15., B.54., B.13., B.19., B.20., B.45., B.21., B.49., B.24., B.25., B. 27., B.29., B.47., B.55., B.37., B.36., B.57., B.30., B.32., B.34., B. 48th and B.50. preferably present in the compounds of the invention.
  • M 1 for N and M 2 and M 3 are each CH.
  • R 19 may preferably stand for H.
  • R 19 may preferably be CH 3 and R 190 is preferably F in the 4-position.
  • substructure B.13. may preferably be 0 for 0 or 1 and R 190 for H or F in the 4-position.
  • R 8 may preferably be H, s is 1, t is 1 or 2, M 1 is N and M 2 and M 3 are each CH.
  • R 8 may preferably be CH 3 , S is 1, t is 3, R 34 and R 35 are each CH 3 and R 190 is H.
  • R 8 may be H or CH 3 , s is 1, t is 2 or 3, R 34 and R 35 are each CH 3 and R 190 is H.
  • R 8 may be H, s is 1, t is 0, R 34 and R 35, together with the nitrogen atom linking them, may be azetidinyl and R 190 is H.
  • R 8 may preferably be H, s is 1, t is 3 and R 38 is ethyl.
  • substructure B.47. may preferably be 0 for 0, h and g each for 1 and R 38 for CH 3 .
  • subtree B.37. may preferably M 1 for N, M 2 and M 3 are each CH, r is 2 and R 34 and 35 with the nitrogen atom connecting them to pyrrolidinyl stand.
  • R 190 may preferably be H and R 34 and R 35 may each be CH 3 .
  • substructures B.19. may preferably be 0 for 0 or 1, n and m are each 1 and R 45 is CH 3 .
  • substructure B.49. may preferably be o for 3 and R 34 and R 35 are each CH 3 .
  • substructure B.20. may preferably o for 0, M 1 for N and M 2 and M 3 are each CH.
  • substructure B.24. may preferably be 0 for 1 and R 190 for F in the 4-position.
  • substructure B.25. may preferably be o for 1, M1 for N and M 2 and M 3 are each CH.
  • substituted compounds according to the invention can be selected from the group consisting of
  • 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 (hB1R) and on the B1R receptor of the rat (rB1R).
  • 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% up.
  • Very particular preference is given to compounds which have an inhibition at the human B1R receptor and at the B1R receptor of the rat of at least 70%, in particular of at least 80% and particularly preferably of at least 90% at a concentration of 10 ⁇ M.
  • the agonistic or antagonistic action of substances can be detected on bradykinin receptor 1 (B1R) of the human and rat species with ectopically expressing cell lines (CHO K1 cells) and with the aid of a Ca 2+ -sensitive dye (Fluo-4) in the Fluorescent Imaging Plate Reader (FLIPR).
  • B1R bradykinin receptor 1
  • FLIPR Fluorescent Imaging Plate Reader
  • the indication in% activation is based on the Ca 2+ signal after addition of Lys-Des-Arg 9- bradykiniin (0.5 nM) or Des-Arg 9 -bradykinin (100 nM).
  • Antagonists lead to a suppression of Ca 2+ influx 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. December 22, 2009
  • 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, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, patches / spray patches 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, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, patches / spray patches 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
  • the amounts to be used depend on whether the drug is oral, peroral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, nasal, buccal, rectal or topical, for example on the skin, mucous membranes or in the eyes, to be applied.
  • preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable, for parenteral, topical and inhalative administration solutions, suspensions, easily reconstitutable dry preparations and sprays.
  • Substituted indole compounds according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of agents promoting the main penetration, are suitable percutaneous administration preparations.
  • substituted indole compounds according to the invention can release the substituted indole compounds according to the invention with a delay.
  • the substituted indole compounds according to the invention can also be used in parenteral long-term depot forms such. As implants or implanted pumps are applied. In principle, other active compounds known to the person skilled in the art may be added to the medicaments according to the invention.
  • the amount of drug 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 are administered.
  • a substituted indole compound of the invention present is optionally present as a pure diastereomer and / or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and / or enantiomers. December 22, 2009
  • substituted indole compounds according to the invention can be used in particular 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 indole compound 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 indole compounds of the invention for the manufacture of a medicament for the treatment of inflammatory pain.
  • the invention also provides the use of at least one substituted indole compound 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 indole compound 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 disorders, for example 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 angiogenesis inhibitor. December 22, 2009
  • the invention also provides the use of at least one substituted indole compound according to the invention for the treatment of one of the aforementioned indications.
  • a substituted indole compound used is present as a pure diastereomer and / or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and / or enantiomers.
  • the invention furthermore relates to a method for the treatment, in particular in one of the aforementioned indications, of a non-human mammal or human that requires treatment of the corresponding indication by administering a therapeutically effective dose of a substituted indole compound according to the invention, or of a compound according to the invention drug.
  • Another object of the invention is a method for the treatment of pain, in particular one of the aforementioned forms of pain, of a non-human mammal or human, or the treatment of pain, in particular of acute, visceral, neuropathic or chronic pain or inflammatory pain needed by administration a therapeutically effective dose of a substituted indole compound according to the invention, or of a medicament according to the invention.
  • a further subject of the present invention are processes for the preparation of the substituted indole compounds according to the invention as stated in the description and the examples.
  • step 1 are Sulfonylchlo ⁇ de the general formula (C) wherein R 3 has the abovementioned meaning, in at least one solvent, preferably selected from the group consisting of dichloromethane, acetonitrile, dimethylformamide, diethyl ether, dioxane, tetrahydrofuran, methanol, ethanol and isopropanol with amino acid esters (A), in the presence of at least one inorganic base, preferably selected from the group consisting of potassium carbonate and cesium carbonate, or an organic base, preferably selected from the group consisting of T ⁇ ethylamin, Dnsopropylethylamin and Py ⁇ din and optionally with addition of 4- (D ⁇ methylam ⁇ no) pyr ⁇ d ⁇ n or 1-Hydroxybenzotnazol, reacted at temperatures of preferably -15 ° C to 50 0 C to compounds having the general formula (D)
  • solvent preferably selected from the group consisting of dichlorome
  • step 2 compounds of the general formula (D) in at least one solvent, preferably selected from the group consisting of water, methanol, ethanol, isopropanol, diethyl ether, tetrahydrofuran, toluene, acetonitrile,
  • Dimetylformamide, dioxane and dimethyl sulfoxide with an inorganic base December 22, 2009 preferably selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, Kaliumtertbutanolat, lithium propanethiolate and sodium phenylselenolat, optionally with the addition of HMPA or lithium chloride or with a Lewis acid, preferably selected from the group consisting of trimethylsilyl chloride, boron tribromide and Aluminum trichloride, optionally with the addition of thiols, sodium iodide or lithium chloride, at temperatures of preferably 0 0 C to 100 0 C to give compounds of general formula (E).
  • a Lewis acid preferably selected from the group consisting of trimethylsilyl chloride, boron tribromide and Aluminum trichloride, optionally with the addition of thiols, sodium iodide or lithium chloride, at temperatures of preferably 0 0 C to 100
  • step 3 compounds of general formula (E) in at least one solvent, preferably selected from the group consisting of dichloromethane, acetonitrile, dimethylformamide, diethyl ether, dioxane and tetrahydrofuran with amines (F), with the addition of at least one coupling reagent, preferably selected from A group consisting of carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent), ⁇ / - (3-dimethylaminopropyl) - ⁇ / 'ethylcarbodiimide (EDCI), O- (benzotriazol-1-yl) -N 1 N 1 N ', ⁇ /' - tetramethyluronium tetrafluoroborate (TBTU), ⁇ / . ⁇ / '- dicyclohexylcarbodiimide (DCC) and 1-benzotriazoly
  • the agonistic or antagonistic action of substances can be determined on the bradykinin receptor 1 (B1R) of the human and rat species with the following assay.
  • B1R bradykinin receptor 1
  • Ca 2+ influx through the channel is monitored 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 ).
  • CHO K1 cells Chinese hamster ovary cells
  • hB1R cells human B1R gene
  • rB1R cells B1R gene of the rat
  • hB1R cells Nutrient Mixture Ham's F12, Gibco Invitrogen GmbH, Düsseldorf, Germany or DMEM, Sigma-Aldrich, Taufkirchen, Germany; rB1 R Cells: D-MEM / F12, Gibco Invitrogen GmbH, Düsseldorf, Germany) with 10% by volume FBS (Fetal bovine serum, Gibco Invitrogen GmbH, Düsseldorf, Germany or PAN Biotech GmbH, Aidenbach, Germany).
  • FBS Fetal bovine serum, Gibco Invitrogen GmbH, Düsseldorf, Germany or PAN Biotech GmbH, Aidenbach, Germany.
  • the cells are incubated with 2.13 ⁇ M Fluo-4 (Molecular Probes Europe BV, Leiden Netherlands) in HBSS buffer (Hank 's buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany) with 2.5 mM Probeneid ( Sigma-Aldrich, Taufmün, Germany) and 10 mM HEPES (Sigma-Aldrich, Taufmün, Germany) for 60 min at 37 0 C loaded.
  • HBSS buffer Horco Invitrogen GmbH, Düsseldorf, Germany
  • HBSS buffer which additionally contains 0.1% BSA (bovine serum albumin, Sigma-Aldrich, Taufkirchen, Germany), 5.6 mM glucose and 0.05% gelatin ( Merck KGaA, Darmstadt, Germany). After a further incubation of 20 minutes at room temperature, the plates are used for Ca 2+ measurement in FLIPR. December 22, 2009
  • buffer A 15 mM HEPES 1 80 mM NaCl, 5 mM KCl, 1, 2 mM CaCl 2 , 0.7 mM MgSO 4 , 2 g / L glucose, 2.5 mM Probeneid
  • buffer A 2.5 ⁇ M Fluo-4 and 0.025% Pluronic F127 (Sigma-Aldrich, Taufkirchen, Germany) loaded.
  • Pluronic F127 Sigma-Aldrich, Taufkirchen, Germany
  • 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).
  • Antagonists lead to a suppression of Ca 2+ influx. It will %
  • the compounds have a B1R antagonist activity on the human receptor and / or on the rat receptor. December 22, 2009
  • Step 1 tert-butyl 2- (7-nitro-1H-indol-1-yl) acetate
  • Step 1 tert-butyl 2- (6-nitro-1H-indol-1-yl) acetate
  • Step 2 fer-butyl 2- (6-amino-1H-indol-1-yl) acetate (A-02)
  • Component A-03 Methyl 3- (6-amino-1H-indol-1-yl) propanoate
  • Sulfonic acid chloride C-01 2- (trifluoromethyl) phenyl-1-sulfonyl chloride (CAS No: 776-04-5) is commercially available from e.g. ABCR.
  • Sulfonic acid chloride C-02 4-chloro-2,5-dimethylphenyl-1-sulfonyl chloride (CAS No: 88-49-3) is commercially available at e.g. ABCR.
  • Sulfonic acid chloride C-04 Naphthalene-1-sulfonyl chloride (CAS No: 85-46-1) is commercially available from eg ABCR.
  • Step 1 To a solution of potassium tert-butoxide (1 eq.) In dry benzene (5 mL) was slowly added a solution of 6-nitro-indole (3 mmol) in dry benzene (15 mL) in an ice bath under a nitrogen atmosphere. Then methyl acrylate (2 eq.) was added and the reaction heated to reflux for 16 h. The reaction mixture was diluted after cooling to room temperature with water and acidified with conc. HCl adjusted to pH 4. The reaction mixture was extracted with dichloromethane. The organic phase was washed successively with water and sat. NaCl solution. washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH) and the desired product of the first stage was obtained. Yield: 53%
  • Stage 2 A mixture of the first stage product (0.9 mmol), iron powder (3.3 eq.) And conc. HCl (0.1 ml) was heated to reflux in ethanol (5 ml) for 4 h. After cooling to RT, it was filtered through Celite. The filtrate was concentrated, the concentrated mass was taken up in water and treated with conc. HCl adjusted to pH 4. The mixture was extracted with dichloromethane. The organic phase was washed successively with water and sat. NaCl solution. washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was used directly in the next step. Yield: 90% December 22, 2009
  • Step 3 A mixture of the second stage product (0.45 mmol), 2-bromomethyl-6-chloro-benzoate (1 eq.) And TEA (1.2 eq.) was dissolved in benzene (10 mL) under a nitrogen atmosphere heated to reflux for 16 h. The reaction mixture was concentrated and the concentrated mass was taken up in DCM. The organic phase was washed successively with water and sat. NaCl solution. washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH) to obtain the desired third stage product. Yield: 48.5%
  • Step 4 To a suspension of the third stage product (0.5 mmol) in methanol (40 ml), tetrahydrofuran (40 ml) and water (30 ml) was added LiOH-H 2 O (5 eq.) And the reaction mixture stirred overnight at 25 0 C. Methanol and THF were completely withdrawn. The aqueous phase was acidified with 1 (N) HCl and then filtered. The white solid was stirred in a mixture of 350 ml of acetone and 50 ml of methanol for 1 h. After filtration, the white solid was dried under reduced pressure to give the desired pure product E-15. Yield: 61%
  • Step 1 To a suspension of sodium hydride (1.5 eq.) In DMF (5 mL) was added at 0 ° C the 6-nitroindole (3 mmol) dissolved in DMF (5 mL) and stirred for 30 min. touched. Then tert-butyl-bromoacetate (1.2 equiv.) was added and the mixture was stirred at RT for 15 h. The approach with ges. NH 4 CL solution. quenched and extracted with ethyl acetate. The organic phase was washed successively with water and sat. NaCl solution. washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the desired first-stage product. Yield: 47%
  • Step 2 A mixture of the first stage product (1.44 mmol), iron powder (4 eq.) And ammonium chloride (0.4 eq.) was refluxed in ethanol (10 mL) for 4 h. After cooling to RT, it was filtered through Celite. The filtrate was concentrated and the concentrated mass was taken up in water. It was extracted with dichloromethane. The organic phase was washed successively with water and sat. NaCl solution. washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by recrystallization with ethyl acetate / hexane. Yield: 61%
  • Step 3 A mixture of the second stage product (25 mmol), 2-bromomethyl-6-chloro-benzoate (1.2 equiv.) And TEA (1.2 equiv.) was dissolved in benzene (150 ml) under nitrogen atmosphere heated to reflux for 16 h. The reaction mixture was concentrated and the concentrated mass was taken up in DCM. The organic phase was washed successively with water and sat. NaCl solution. washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH) to obtain the desired third stage product. Yield: 42%
  • Step 4 To a suspension of the third stage product (15 mmol) in methanol (25 ml), tetrahydrofuran (25 ml) and water (50 ml) was LiOH. H 2 O (5 eq.) was added and the reaction mixture stirred at 25 0 C overnight. Methanol and THF were completely withdrawn. The aqueous phase was acidified with 1 (N) HCl and then filtered. The white solid was dried under reduced pressure to give the desired product E-16. Yield: 98% December 22, 2009
  • Step 1 To a solution of 7-nitroindole (6 mmol) in acetonitrile (10 ml) was slowly added the DBU at 0 ° C. The solution was stirred at RT for 20 h. Then the reaction mixture was concentrated and the crude mass diluted with ethyl acetate. The ethyl acetate phase was washed with sat. NH 4 CL solution, water and sat. NaCl solution. washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the desired first-stage product. Yield: 35%
  • Step 2 To a solution of the first stage product (1.2 mmol) in methanol (10 ml) was added Pd / C 10% under nitrogen atmosphere and the mixture was hydrogenated for 16 h under a pressure of 2 bar. The reaction was filtered and the filtrate was concentrated. The product of the second step was obtained, which was used directly in the next step without further purification. Yield: 63.5% December 22, 2009
  • Step 3 A mixture of the second stage product (0.45 mmol), 2-bromomethyl-6-chloro-benzoate (1 eq.) And TEA (1.2 eq.) was dissolved in benzene (10 mL) under nitrogen atmosphere heated to reflux for 16 h. The reaction mixture was concentrated and the concentrated mass was taken up in DCM. The organic phase was washed successively with water and sat. NaCl solution. washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH) to obtain the desired third stage product. Yield: 40%
  • Step 4 To a suspension of the third stage product (0.5 mmol) in methanol (40 ml), tetrahydrofuran (40 ml) and water (30 ml) was LiOH. H 2 O (5 eq.) was added and the reaction mixture stirred at 25 0 C overnight. Methanol and THF were completely withdrawn. The aqueous phase was acidified with 1 (N) HCl and then filtered. The white solid was stirred in a mixture of 350 ml of acetone and 50 ml of methanol for 1 h. After filtration, the white solid was dried under reduced pressure to give the desired pure product E-17. Yield: 55%
  • Step 1 To a suspension of sodium hydride (1.5 eq.) In DMF (5 mL) at 0 ° C was added the 6-nitroindole (30 mmol) dissolved in DMF (100 mL) and stirred for 30 min. touched. Subsequently, tert-butyl-bromoacetate (1.2 equiv.) was added and the mixture was stirred at RT for 15 h. The approach with ges. NH 4 CL-L-Sg. quenched and extracted with ethyl acetate. The organic phase was washed successively with water and sat. NaCl solution. washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the desired first-stage product. Yield: 82%
  • Step 2 To a solution of the first step product (1.44 mmol) in methanol (10 mL) was added Pd / C 10% under nitrogen atmosphere and the mixture was hydrogenated for 16 h under a pressure of 2 bar. The reaction was filtered and the filtrate was concentrated. The product of the second step was obtained, which was used directly in the next step without further purification. Yield: 89%
  • Step 3 A mixture of the second stage product (25 mmol), 2-bromomethyl-6-chloro-benzoate (1.2 equiv.) And TEA (1.2 equiv.) was dissolved in benzene (150 ml) under nitrogen atmosphere heated to reflux for 16 h. The reaction mixture was concentrated and the concentrated mass was taken up in DCM. The organic phase was washed successively with water and sat. NaCl solution. washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH) to obtain the desired third stage product. Yield: 48.5%
  • Step 4 To a suspension of the third stage product (15 mmol) in methanol (25 ml), tetrahydrofuran (25 ml) and water (50 ml) was LiOH. H 2 O (5 eq.) was added and the reaction mixture stirred at 25 0 C overnight. Methanol and THF were completely withdrawn. The aqueous phase was acidified with 1 (N) HCl and then filtered. The white solid was stirred in a mixture of 350 ml of acetone and 50 ml of methanol for 1 h. After filtration, the white solid was dried under reduced pressure to give the desired pure product E-18. Yield: 80% December 22, 2009
  • Step-1 (E) -methyl 2- (2-chloro-6-nitrophenyl) -3-hydroxybut-2-enoate
  • Methyl 4-chloro-2-methyl-1H-indole-3-carboxylate (13.45 mmol, 1.0 equiv.) was dissolved in DMF (7 ml) and added at 0 ° C to a suspension of NaH (26.90 mmol, 2.0 equiv. ) in DMF (13 ml). Then, it was stirred for 30 minutes. Methyl iodide (20.17 mmol, 1.5 equiv) was added dropwise at 0 ° C and stirred at 25 ° C for 2 h. The reaction mixture was diluted with NH 4 Cl solution (20 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic phases were washed with water and sat. NaCl solution (50 ml each), dried over Na 2 SO 4 and concentrated to dryness under reduced pressure. Yield: 72%
  • Step-4 Methyl 2- (bromo-methyl) -4-chloro-1-methyl-1H-indole-3-carboxylate
  • Step 5 Methyl 2 - ((1- (2-tert-butoxy-2-oxoethyl) -1H-indol-6-ylamino) methyl) -4-chloro-1-methyl-1H-indole-3 carboxylate
  • Step -6 tert -Butyl 2- (6- (8-chloro-4-methyl-1-oxopyrrolo [3,4-b] indole-2 (1H, 3H, 4H) -yl) -1H-indole 1-yl) acetate
  • Step-7 2- (6- (8-Chloro-4-methyl-1-oxopyrrolo [3,4-b] indole-2 (1H, 3H, 4H) -yl) -1H-indol-1-yl) Acetic acid tert-butyl 2- (6- (8-chloro-4-methyl-1-oxopyrrolo [3,4-b] indole-2 (1H, 3H, 4H) -yl) -1H-indole-1 yl) acetate (1.6 mmol, 1 equiv.) was dissolved in DCM (40 ml), treated with TFA (16 ml) and stirred at 25 0 C for 2 h. The solvent was reduced under reduced pressure, the residue was added 2x dichloromethane and again concentrated to dryness. The residue was used without further purification in the next step. December 22, 2009 Intermediate A:
  • Step-1 tert-butyl 2- (6-nitro-1H-indol-1-yl) acetate
  • Step-2 tert-butyl 2- (6-amino-1H-indol-1-yl) acetate
  • Step-3 Ethyl 2- (6- (7-methyl-1-oxoisoindolin-2-yl) -1H-indol-1-yl) acetate
  • Step 4 2- (6- (7-Methyl-1-oxoisoindolin-2-yl) -1H-indol-1-yl) acetic acid
  • Step-1 Ethyl 2- (6-nitro-1H-indol-1-yl) acetate
  • Step 2 Ethyl 2- (6-amino-1H-indol-1-yl) acetate
  • Step-1 tert-butyl 2-formyl-5-methyl-1H-pyrrole-1-carboxylate
  • Step-2 tert -Butyl 2 - ((1- (2-tert-butoxy-2-oxoethyl) -1H-indol-6-ylamino) methyl) -5-methyl-1H-pyrrole-1-carboxylate
  • Step-3 2- (6- (5-Methyl-3-oxo-1H-pyrrolo [1,2-c] imidazol-2 (3H) -yl) -1H-indol-1-yl) acetic acid
  • the aqueous phase was adjusted to acidic pH with acetic acid and extracted with ethyl acetate (2 x 50 ml). The combined organic phases were dried over Na 2 SO 4 and concentrated under reduced pressure. From the residue, the product was crystallized with hexane. Yield: 81% December 22, 2009
  • Step-3 tert-butyl 2- (6- (3-chloro-1H-indole-2-carboxamido) -1H-indol-1-yl) acetate
  • Step-4 tert -Butyl 2- (6- (10-chloro-1-oxo-3,4-dihydropyrazino [1,2-a] indol-2 (1H) -yl) -1H-indol-1-yl tert-Butyl 2- (6- (3-chloro-1H-indole-2-carboxamido) -1H-indol-1-yl) acetate (1.41 mmol, 1.0 equiv.) and TBAB (1.41 mmol, 1.0 Equiv.) Were dissolved in 1 N NaOH (12 mL), 1,2-dibromoethane (14.18 mmol, 10.0 equiv.) was added and the mixture was stirred at 25 ° C for 12 h.
  • Step -5 2- (6- (10-Chloro-1 -oxo-3,4-dihydropyrazino [1,2-a] indole-2 (1H) -yl) -1H-indol-1-yl) tert-Butyl 2- (6- (10-chloro-1-oxo-3,4-dihydropyrazino [1,2-a] indole-2 (1H) -yl) -1H-indol-1-yl) acetate (2.22 mmol, 1.0 equiv.) was dissolved in DCM (15 ml), TFA (3 ml) added and the mixture stirred at 25 ° C for 2 h.
  • Methyl 3-chloro-1 H-pyrrole-2-carboxylate (. 18.86 mmol, 1.0 equiv) was dissolved in MeOH-H 2 O: dissolved at 0 0 C was added LiOH (2 1, 120 ml). H 2 O (75.4 mmol, 4 equiv.) was added and the mixture stirred at 25 ° C for 16 h. The methanol was concentrated under reduced pressure, the aqueous residue diluted with water (60 ml) and extracted with ethyl acetate (2 x 50 ml). The aqueous phase was adjusted to pH 3-4 with 1 M HCl and the resulting solid was filtered off. Yield: 90%
  • Step-4 tert-butyl 2- (5- (3-chloro-1H-pyrrole-2-carboxamido) -1H-indol-1-yl) acetate
  • Step-5 tert -Butyl 2- (5- (8-chloro-1-oxo-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -1H-indol-1-yl )acetate
  • 1,2-Dibromoethane (22.7 mmol, 10.0 equiv.) was added to a solution of tert -butyl 2- (5- (8-chloro-1-oxo-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -1H-indol-1-yl) acetate (2.27 mmol, 1.0 equiv.) And tetrabutylammonium bromide (2.27 mmol, 1.0 equiv.) In 1 N NaOH (14 ml) and the mixture was stirred for 12 h stirred at 25 ° C.
  • Step-6 2- (5- (8-Chloro-1-oxo-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) -1H-indol-1-yl) acetic acid
  • Amin F-01 Dimethyl- (3-piperazin-1-yl-propyl) -amine [877-96-3] commercially available at e.g. Acros.
  • Amine F-02 1- (1-methylpiperidin-4-yl) piperazine [12345-34-56] commercially available at e.g. Aldrich.
  • Amin F-03 3- (4-ethyl-piperazin-1-yl) -propyl-amine [4524-96-3] commercially available at e.g. Fluorochem.
  • Amin F-05 4- (2-pyrrolidin-1-yl-ethyl) -piperidine [14759-08-1] commercially available at e.g. ABCR.
  • Step 2 1-Benzyl- ⁇ /, ⁇ / -dimethyl-4-phenylpiperidin-4-amine
  • reaction solution was cooled to 0 ° C., treated with saturated NH 4 Cl solution, extracted with ethyl acetate (3 ⁇ 300 ml) and the combined organic phases were dried with Na 2 SO 4 .
  • the solvent was removed under reduced pressure and purified by column chromatography (silica gel, 1% MeOH / CHCl 3 ). 30 g (35%) of product were obtained in the form of a yellow solid.
  • Step 3 Benzyloxycarbonyl-4- (dimethylamino) -4-phenylpiperidine
  • Step 4 tert-Butyloxycarbonyl-4- (dimethylamino) -4-phenyl-piperidine
  • Amin F-08 ri- (2-amino-ethl-1) -4-thiophene-2-vl-piperidin-4-yl-dimethy-amine trihydrochloride
  • Step 1 terf-butyloxycarbonyl-4-cyano-4- (dimethylamino) piperidine
  • Step 2 Complete butyloxycarbonyl-4- (dimethylamino) -4- (thiophen-2-yl) piperidine
  • the Grignard reagent just prepared was added dropwise to a solution of 20 g (1 equiv) of tert-butyloxycarbonyl-4-cyano-4- (dimethylamino) piperidine dissolved in 200 ml of THF and stirred overnight at room temperature. The course of the reaction was monitored by thin layer chromatography (50% EtOAc / hexane). After complete conversion, the reaction solution was cooled to 0 0 C, treated with saturated NH 4 Cl solution, extracted with ethyl acetate (3x100 ml) and the combined organic phases dried with Na 2 SO 4 . The solvent was removed under reduced pressure and purified by column chromatography (Alox Neutral, 30% EtOAc / hexane). 6.1 g (25%) of product was obtained as a white solid.
  • Step 3 ⁇ /, ⁇ / -dimethyl-4- (thiophen-2-yl) piperidin-4-amine
  • Step 5 1- (2-Aminoethyl) - ⁇ /, ⁇ / -dimethyl-4- (thiophen-2-yl) piperidine-4-amine tris hydrochloride
  • Amin F-09 Dimethyl- [1- (3-methylamino-propyl) -4-thiophen-2-yl-piperidin-4-yl] -amine
  • reaction mixture was filtered through Celite and the filtrate concentrated under reduced pressure. The residue was admixed with 300 ml of water and extracted with 2 ⁇ 250 ml of ethyl acetate. The combined organic phases were dried over Na 2 SO 4 . After removing the December 22, 2009
  • Step 2 tert-butyl-3- (tert-butyldimethylsilyloxy) propyl carbamate
  • reaction mixture was filtered through Celite, the filtrate was treated with 200 ml of water and extracted with dichloromethane. The combined organic phases were dried over Na 2 SO 4 . After removal of the solvent under reduced pressure, 32 g (84%) of product was obtained in the form of an oil.
  • Step 3 tert -Butyl 3- (terf-butyldimethylsilyloxy) propyl (methyl) carbamate
  • Step 5 tert-butyl methyl (3-oxopropyl) carbamate
  • Step 6 ⁇ /, ⁇ / -dimethyl-4- (thiophen-2-yl) piperidin-4-amine to hydrochloride
  • Step 7 tert -Butyl 3- (4- (dimethylamino) -4- (thiophen-2-yl) piperidin-1-yl) propyl (methyl) carbamate
  • Step 8 ⁇ /, ⁇ / -dimethyl-1 - (3- (methylamino) propyl) -4- (thiophen-2-yl) piperidine-4-amine tris hydrochloride
  • Step 1 tert-butyloxycarbonyl-4-cyano-4- (dimethylamino) piperidine
  • Step 2 tert-Butyloxycarbonyl-4- (dimethylamino) -4- (thiophen-2-yl) piperidine
  • the Grignard reagent just prepared was added dropwise to a solution of 20 g (1 equiv) of tert-butyloxycarbonyl-4-cyano-4- (dimethylamino) piperidine dissolved in 200 ml of THF and stirred overnight at room temperature. After complete conversion, the reaction solution was cooled to 0 0 C, treated with saturated NH 4 Cl solution, extracted with ethyl acetate (3x100 ml) and the combined organic phases dried with Na 2 SO 4 . The solvent was removed under reduced pressure and purified by column chromatography (Alox Neutral, 30% EtOAc / hexane). 6.1 g (25%) of product was obtained as a white solid.
  • Amin F-11 Dimethvl-ri- (3-methvlamino-propyl) -4-phenyl-piperidin-4-vn-amine trihydrochloride
  • Step 1 tert-Butyl 3- (4- (dimethylamino) -4-phenyl-piperidin-1-yl) -propyl (methyl) carbamate
  • Step 2 ⁇ /, ⁇ / -dimethyl-1- (3- (methylamino) propyl) -4-phenylpiperidin-4-amine hydrochloride
  • Amine F-12 [4- (Azetidin-1-yl) -4-phenylcyclohexyl] amine hydrochloride
  • Step 1 4- (Azetidin-1-yl) -4-phenylcyclohexanone oxime
  • Amine F-13 2- (1-pyridin-4-yl-piperidin-4-yl) -ethyl-amine dihydrochloride
  • Amine F-14 3-pyridin-4-yl-3,9-diazaspiro [5.5] undecane dihydrochloride
  • Boc cleavage can also be performed in the presence of TFA in DCM.
  • Amine F-15 (1-pyridin-4-yl-piperidin-4-yl) -methyl-amine dihydrochloride
  • Amine F-16 1- (4-fluorophenyl) piperazine [16141-90-5] commercially available at e.g. Aldrich.
  • Amine F-17 2-piperazin-1-yl-pyrimidine [20980-22-7] commercially available at e.g. Aldrich.
  • Amine F-18 1-pyridin-4-yl-piperazine [1008-91-9] commercially available at e.g. ABCR.
  • Amin F-20 4-pyridin-2-yl-piperidin-4-ol [50461-56-8] available commercially from e.g. Tyger Scientific.
  • Amine F-21 1-methyl-4-piperidin-4-ylpiperazine [436099-90-0] available commercially from e.g. ABCR.
  • Amine F-22 1 - [(1-methylpiperidin-4-yl) methyl] piperazine [735262-46-1] commercially available at e.g. Otava.
  • Amine F-23 3- (4-fluorophenyl) -3,8-diazaspiro [4.5] decan-4-one hydrochloride (MDL No .: MFCD05861564) available commercially from e.g. ASW MedChem.
  • Amine F-25 1- (4-fluorophenyl) -3-methyl-3,8-diazaspiro [4.5] decan-4-one hydrochloride (MDL No: MFCD08460813) available commercially from e.g. ASW MedChem.
  • Amin F-26 3-r (4-fluorophenyl) methyl-3.8-diazaspiror4.51decan-4-one hydrochloride (MDL No: MFCD08461093) available commercially from e.g. ASW MedChem.
  • Amin F-27 3-Benzyl-3,8-diazaspiro [4.5] decan-4-one hydrochloride (MDL No: MFCD02179153) available commercially from e.g. ASW MedChem.
  • Amin F-28_i 3-Benzyl-3,7-diazaspiro [4.4] nonane (MDL No: MFCD04115133) available commercially from e.g. Tyger.
  • Amine F-31 was prepared from tert-butyl 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate by reaction with the corresponding aldehyde and subsequent deprotection analogous to amine F-31.
  • Amine F-32 (1-pyridin-4-yl-piperidin-4-yl) -amine dihydrochloride (MDL No: MFCD06797043) available commercially from e.g. ABCR.
  • Amin F-33 4-phenyl-2,4,8-triazaspiro [4.5] decan-1-one (MDL No: MFCD00005977) available commercially from e.g. ABCR.
  • Amine F-34 N - [[4- (4-Methyl-piperazin-1-yl) -piperidin-4-yl] -methyl] -pyridine-4-carboxylic acid amide dihydrochloride
  • Step 1 To a methanolic solution (20 ml) of N-benzyl piperidone (52.9 mmol) was added water (1, 2 ml), N-methylpiperazine (1 equiv.) Acetic acid (1 equiv.) And KCN (1, 1 eq.). The reaction mixture was stirred for 1 h at 25 0 C, it precipitated a solid. The reaction was then added with 35% ammonium hydroxide (300 ml) and ice (100 g). The solid was filtered off, washed several times with water and then dried. Yield: 45%
  • Step 2 To a cold (O 0 C) suspension of LiAlH (3 eq.) In THF (2 mL / mmol) under argon atmosphere was added dropwise a solution of conc. H 2 SO 4 (1.5 eq) in THF (1 mL / mmol) was added (very exothermic). The suspension was for 90 min. stirred at 25 0 C and then cooled to 0 ° C. To this cold reaction mixture the cyano component (1 eq.) was added dropwise in THF (2 ml / mmol) and after complete addition for 12 h at 5O 0 C heated (TLC control). The approach was careful with a ges. Quenched sodium sulfate solution and filtered through Celite. The residue was washed with ethyl acetate, the organic December 22, 2009
  • Step 3 To a solution of the amine from the second stage (74.5 mmol) in dichloromethane (5 ml / mmol) at 0 0 C. TEA (5 eq.) And Trifuoressigklare anhydride added (2 eq.). The reaction mixture was stirred for 2 h at 25 ° C (TLC control). It was diluted with dichloromethane, washed successively with water and sat. NaCl solution. washed and dried over sodium sulfate. Concentration under reduced pressure gave the crude product, which was purified by column chromatography (10% methanol in dichloromethane).
  • Step 4 A solution of the third stage benzylated product (19 g) in methanol (285 ml) was degassed under argon. To this was added Pd (OH) 2 10% (9.5 g) and AcOH (7.6 ml) and the mixture hydrogenated for 16 h at normal pressure (TLC and LCMS control). It was filtered through Celite, the residue washed with methanol and the combined organic phases evaporated to dryness under reduced pressure. The resulting crude product was used directly in the next step without further purification. Yield: 14.8 g (quantitative)
  • Step 5 To a solution of the fourth step amine (14.8 g, 48 mmol) in dichloromethane (240 mL) at 0 ° C was added DIPEA (1.5 eq.) And boc anhydride (1.2 eq. ). The reaction mixture was stirred for 3 h at RT. It was diluted with dichloromethane, washed successively with water and sat. NaCl solution. washed and dried over sodium sulfate. Concentration under reduced pressure gave the crude product, which was purified by column chromatography (10% methanol in dichloromethane). Yield: 12.5 g (63%)
  • Step 6 To a solution of the Boc-protected product of the fifth step in methanol (80 ml) was added 0 N NaOH (120 ml) at 0 ° C and the reaction mixture stirred for 2 h at 25 ° C (TLC control). It was diluted with ethyl acetate, the aqueous phase extracted several times with ethyl acetate and the combined org. Phases with sat. NaCl solution. washed. After drying over sodium sulfate, the organic phase was concentrated under reduced pressure and December 22, 2009, the crude product obtained without further purification used directly in the next stage. Yield: 7.7 g (83%)
  • Step 7 To a cold (0 0 C) solution of the amino component of the sixth stage (. 1 eq) in dichloromethane was added triethylamine (2.5 eq.) And isonicotinoyl chloride hydrochloride (1 eq.) Was added. The reaction mixture was stirred for 2 h at 25 ° C (TLC control). It was quenched with crushed ice, diluted with dichloromethane and the org. Phase in turn with water and sat. NaCl solution. washed. After drying over sodium sulfate, the organic phase was concentrated under reduced pressure and the resulting crude product was purified by column chromatography (alumina neutral, methanol in dichloromethane 1: 9). Yield: 70%
  • Step 8 To a solution of the Boc-protected product of the seventh step in dioxane (2 mL / mmol) was added HCl in dioxane (2M, 6 mL / mmol) at 0 ° C and the reaction mixture stirred at 25 ° C for 3 h (TLC). The precipitated solid was filtered off, washed with ether under inert gas (very hygroscopic!) And then dried in vacuo. Yield: 80%
  • Amine F-35 1- (pyridin-2-ylmethyl) - [1,4] diazepan [247118-06-5] commercially available at e.g. ChemCollect.
  • Amin F-36 4-pyrrolidine-3-vinyl-propridine [150281-47-3] available commercially from e.g. Interchim.
  • Amin F-37 piperazin-1-yl-pyridin-3-yl-methanone [39640-08-9] commercially available at e.g. Fluorochem.
  • Amine F-38 8- (pyridin-4-yl) -2,8-diazaspiro [4.5] decane dihydrochloride
  • step (i) tert-butyl 2,8-diazaspiro [4.5] decane-2-carboxylate was reacted with 4-chloropyridinium chloride (yield: 22%).
  • step (ii) the Boc protecting group was cleaved off.
  • the residue taken up in ethanol, cooled and treated with acetone.
  • the resulting suspension was stirred for 30 minutes in an ice bath, the precipitate was suctioned off, washed with acetone and dried under vacuum (yield: 92%). December 22, 2009
  • Amine F-39 3- (pyridin-4-yl) -1-oxa-2,8-diazaspiro [4.5] dec-2-ene bis (2,2,2-trifluoroacetate)
  • methyltriphenylphosphonium bromide 53.82 g, 150 mmol was slurried in diethyl ether (300 ml) and cooled to 0 ° C.
  • Potassium tert-butoxide (15.78 g, 140 mmol) was added portionwise, the suspension stirred for 30 min.
  • Boc-4-piperidone (20 g, 100 mmol) dissolved in diethyl ether (200 mL) was slowly added dropwise, then warmed to room temperature and stirred for 15 h.
  • Amine F -40 6- (piperidine-1-ylmethyl) -2- (pyrrolidin-3-yl) -1, 2,3,4-tetrahydroisoquinoline trihydrochloride
  • step (i) tert-butyl 2,7-diazaspiro [4.4] nonane-2-carboxylate was reacted with 4-chloropyridinium chloride (yield: 50%).
  • step (ii) the Boc protecting group was cleaved off.
  • the residue was taken up in ethanol, cooled and acetone was added.
  • the resulting suspension was stirred for 30 minutes in an ice bath, the precipitate was suctioned off, washed with acetone and dried under vacuum. (Yield: 73%).
  • Amine F-42 9- (azetidin-1-yl) -3-azaspiro [5.5] undecane dihydrochloride
  • step ( iv) amine-F43) (1 g, 3.74 mmol) and azetidine (0.25 mL, 3.74 mmol) were initially charged in 1, 2-dichloroethane (15 mL) and washed with sodium triacetoxyborohydride (1, 1 g, 5 , 23 mmol). The reaction mixture was stirred for 3 d in a room-temperature mixture and then treated with saturated sodium bicarbonate solution.
  • Amine F-43 9- (pyridin-4-yloxy) -3-azaspiro [5.5] undecane dihydrochloride
  • 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).
  • Amine F-44 9- (3,3-difluoroazetidin-1-yl) -3-azaspiro [5.5] undecane dihydrochloride
  • Amin F-45 dimethyl [4- (2-methylaminoethyl) -1-phenylcyclohexyl] amine dihydrochloride (F-45)
  • step 2 To a solution of the alcohol obtained in step 1 (1 eq.) In DCM (5 ml / mmol) was added methane sulfonyl chloride (1.1 eq.) At 0 0 C under a nitrogen atmosphere. After complete addition, the reaction mixture was stirred for 2 h at 25 ° C, diluted with dichloromethane, the organic phase successively with water and sat. December 22, 2009
  • stage 5 The amine (1 eq.) Obtained in stage 5 was admixed at 0 ° C. with aqueous hydrochloric acid solution (6N, 2 ml / mmol). The resulting reaction mixture was stirred for 20 h at RT. Subsequently, the aqueous phase was washed with ethyl acetate and then adjusted to pH 14 with 6 N aqueous sodium hydroxide solution. The aqueous phase was extracted with dichloromethane and the combined org. Phase in turn with water and sat. Sodium chloride solution washed. The united org. Phases were dried over sodium sulfate, the solvent concentrated under reduced pressure, and the resulting crude product used in the next step without further purification. Yield: 80% (crude product)
  • step 7 To a solution of the Boc-amine (84.3 mmol) in methanol (45 ml) obtained in step 7 was added at 0 ° C 40% aqueous dimethylamine solution (71 ml) and acetic acid (26.5 ml) and KCN (1.5 eq.). given. The resulting reaction mixture was stirred for 16 h at RT. Then 35% ammonium hydroxide solution (300 ml) and ice (300 g) were added, the aqueous phase was extracted with ethyl acetate and the combined org. Phases successively with water, sat. Sodium chloride solution and washed with aqueous iron sulfate solution. After drying over sodium sulfate, the org.
  • N (H) (R 2 XR 2 ' ) is N (H) (R 8 ) - [CR 9a R 9b ] r A (R 10 ) (R 11 ).
  • the amine F (optionally in the form of the corresponding hydrochloride (xHCl)) (1.5 equiv.), Dissolved in a mixture of dichloromethane / N, N-dimethylformamide (3: 2) and triethylamine (2-3 equiv.), added dropwise and the reaction mixture stirred for 1 to 3 days at room temperature (TLC control). The mixture was added with a little water and concentrated in vacuo. The residue was then taken up in dichloromethane and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The aqueous phase was extracted with dichloromethane (2 ⁇ ) and the combined organic phases were washed again with saturated sodium chloride solution. It was then dried over sodium sulfate or magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel).
  • Example Compound G-24 4-Methoxy-2,6-dimethyl-N - [[1- [2-oxo-2- (9-pyridin-4-yl-3,9-diazaspiro [5.5] undecan-3-yl ) -ethyl] -1H-indol-7-yl] -methyl] -benzenesulfonic acid amide
  • Step I Ethyl 2- (7-cyano-1H-indol-1-yl) acetate
  • Step II 2- (7-cyano-1H-indol-1-yl) acetic acid
  • Step III 2- (7- (Aminomethyl) -1H-indol-1-yl) acetic acid
  • Step IV 2- (7 - ((tert-butoxycarbonylamino) methyl) -1H-indol-1-yl) acetic acid
  • Step-V tert -Butyl (1- (2-oxo-2- (9- (pyridin-4-yl) -3,9-diazaspiro [5.5] undecan-3-yl) ethyl) -1H-indole-7 yl) methyl carbamate
  • Step VIII 2- (7- (Aminomethyl) -1H-indol-1-yl) -1- (9- (pyridin-4-yl) -3,9-diazaspiro [5.5] undecan-3-yl) ethanone
  • Step VII 4-Methoxy-2,6-dimethyl-N - ((1- (2-oxo-2- (9- (pyridin-4-yl) -3,9-diazaspiro [5.5] undecane-3 yl) ethyl) -1H-indol-7-yl) methyl) benzenesulfonamide
  • the acid moieties E were synthesized in parallel with the amines F to form the amides G_CC.
  • the correlation of product to reagent, building block and method can be found in the synthesis matrix.
  • MassLynx Single Quadrupole MS Detector Atlantis dC18 column 30 x 2 1 mm, 3 ⁇ m, column temperature 40 ° C, eluent A Purified water + 0 1% formic acid, eluent B Acetonite (gradient grade) + 0 1% formic acid, gradient 0% B to 100% B in 2 3 min, 100% B for 0 4 min, 100% B to 0% B in 0 01 min, 0% B for 0 8 min, Flow 1 0 ml / mm, Ionization ES +, 25V, make up to 100 ⁇ L / min 70% methanol + 0 2% formic acid, UV 200-400 nm 22 December 2009
  • the present as a hydrochloride amines are used with Hunigs base in 0.5 M excess (with respect Hydrochlond) and with 500 ul N, N-D ⁇ methylformam ⁇ d veange, then filled with dichloromethane to 2 ml total volume and thus dissolved or suspended as the free Base present amines are dissolved or suspended in dichloromethane and / or N, N-D ⁇ methylformam ⁇ d

Abstract

La présente invention concerne des composés d'indol substitués de formule générale (I), un procédé permettant leur préparation, des produits pharmaceutiques contenant ces composés et l'utilisation de composés d'indol substitués pour la préparation de produits pharmaceutiques.
EP10703016A 2009-02-04 2010-02-02 Composés d'indol substitués en tant que modulateurs du récepteur 1 de la bradykinine Withdrawn EP2393803A1 (fr)

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EP10703016A EP2393803A1 (fr) 2009-02-04 2010-02-02 Composés d'indol substitués en tant que modulateurs du récepteur 1 de la bradykinine
PCT/EP2010/000630 WO2010089084A1 (fr) 2009-02-04 2010-02-02 Composés d'indol substitués en tant que modulateurs du récepteur 1 de la bradykinine

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ES2598653T3 (es) 2012-03-16 2017-01-30 Vitae Pharmaceuticals, Inc. Moduladores del receptor X del hígado
CN104945416B (zh) * 2014-03-24 2017-11-17 中国科学院上海药物研究所 一类螺异噁唑啉衍生物、其制备方法及医药用途
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GB0017256D0 (en) 2000-07-13 2000-08-30 Merck Sharp & Dohme Therapeutic agents
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US20060128765A1 (en) * 2004-12-10 2006-06-15 Wood Michael R 2-(Bicyclo)alkylamino-derivatives as mediators of chronic pain and inflammation
WO2007101007A2 (fr) 2006-02-23 2007-09-07 Neurogen Corporation Heterocycles sulfonyl aryliques
WO2007140383A2 (fr) 2006-05-30 2007-12-06 Neurogen Corporation Sulfonamides spirocycliques et composés apparentés
WO2008033739A2 (fr) * 2006-09-12 2008-03-20 Neurogen Corporation Dérivés de benzimidazolecarboxamide
SI2066659T1 (sl) 2006-09-29 2013-10-30 Grunenthal Gmbh Substituirani sulfonamidni derivati
WO2008046573A1 (fr) 2006-10-16 2008-04-24 Grünenthal GmbH Dérivés de sulfonamide substitués en tant que modulateurs du récepteur de bradykinine-1

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AR074967A1 (es) 2011-02-23
AU2010211251A1 (en) 2011-09-29
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CA2751402A1 (fr) 2010-08-12
BRPI1011522A2 (pt) 2016-03-29

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