US20080153843A1 - Substituted sulfonamide compounds - Google Patents

Substituted sulfonamide compounds Download PDF

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US20080153843A1
US20080153843A1 US11/905,381 US90538107A US2008153843A1 US 20080153843 A1 US20080153843 A1 US 20080153843A1 US 90538107 A US90538107 A US 90538107A US 2008153843 A1 US2008153843 A1 US 2008153843A1
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Prior art keywords
methoxy
piperidin
ethanone
dimethylphenylsulfonyl
piperazin
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Inventor
Stefan Oberboersch
Melanie REICH
Stefan SCHUNK
Sabine HEES
Ruth Jostock
Michael Franz-Martin ENGELS
Achim Kless
Thomas Christoph
Klaus Schiene
Tieno Germann
Edward Bijsterveld
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Gruenenthal GmbH
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Gruenenthal GmbH
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Priority to US11/905,381 priority Critical patent/US20080153843A1/en
Publication of US20080153843A1 publication Critical patent/US20080153843A1/en
Assigned to GRUENENTHAL GMBH reassignment GRUENENTHAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHRISTOPH, THOMAS, BIJSTERVELD, EDWARD, KLESS, ACHIM, SCHIENE, KLAUS, ENGELS, MICHAEL FRANZ-MARTIN, GERMANN, TIENO, HEES, SABINE, JOSTOCK, RUTH, OBERBOERSCH, STEFAN, REICH, MELANIE, SCHUNK, STEFAN
Priority to US12/862,271 priority patent/US20100324009A1/en
Priority to US12/862,297 priority patent/US8435978B2/en
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    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • 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
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    • 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
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    • A—HUMAN NECESSITIES
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    • 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
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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
    • 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
    • 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
    • C07D403/14—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 three or more hetero rings
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    • 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to substituted sulfonamide derivatives, to a process for their preparation, to medicaments containing these compounds, and to the use of substituted sulfonamide derivatives in the preparation of pharmaceutical compositions and in treatment and/or inhibition of pain and/or various disease states.
  • the bradykinin 1 receptor (B1R) is not expressed or is expressed only weakly in most tissues.
  • B1R the expression of B1R in various cells is inducible. For example, following inflammation reactions there is a rapid and pronounced induction of B1R in neuronal cells but also in various peripheral cells such as fibroblasts, endothelial cells, granulocytes, macrophages and lymphocytes. Accordingly, following inflammation reactions there is a switch from B2R to B1R dominance in the cells that are involved.
  • cytokines interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF ⁇ ) play a substantial part in this B1R up-regulation (Passos et al., J. Immunol. 2004, 172, 1839-1847).
  • B1R-expressing cells are then themselves able to secrete inflammation-promoting cytokines such as IL-6 and IL-8 (Hayashi et al., Eur. Respir. J. 2000, 16, 452-458). This results in the immigration of further inflammatory cells, for example neutrophilic granulocytes (Pesquero et al., PNAS 2000, 97, 8140-8145).
  • bradykinin B1R system can contribute to the chronification of diseases. This is proved by a large number of animal experiments (overviews in Leeb-Lundberg et al., Pharmacol. Rev. 2005, 57, 27-77 and Pesquero et al., Biol. Chem. 2006, 387, 119-126). In humans too, enhanced expression of B1R is found, for example in enterocytes and macrophages in the affected tissue of patients with inflammatory intestinal diseases (Stadnicki et al., Am. J. Physiol. Gastrointest. Liver Physiol.
  • B1R antagonists in acute and, in particular, chronic inflammatory diseases. These include respiratory diseases (Asthma bronchiale, allergies, COPD/chronic-obstructive pulmonary disease, cystic fibrosis, etc.), inflammatory intestinal diseases (ulcerative colitis, CD/Crohn's disease, etc.), neurological diseases (multiple sclerosis, neurodegeneration, etc.), inflammations of the skin (atopic dermatitis, psoriasis, bacterial infections, etc.) and mucosa (Behcet's disease, pelvitis, prostatitis, etc.), rheumatic diseases (rheumatoid arthritis, osteoarthritis, etc.), septic shock and reperfusion syndrome (following heart attack, stroke).
  • respiratory diseases Asthma bronchiale, allergies, COPD/chronic-obstructive pulmonary disease, cystic fibrosis, etc.
  • inflammatory intestinal diseases ulcerative colitis, CD/Crohn's disease, etc
  • bradykinin (receptor) system is also involved in regulating angiogenesis (potential as an angiogenesis inhibitor in cancer and macular degeneration of the eye), and B1R knockout mice are protected against the induction of excess weight as a result of a particularly high-fat diet (Pesquero et al., Biol. Chem. 2006, 387, 119-126). B1R antagonists are therefore suitable also for the treatment of obesity.
  • B1R antagonists are suitable in particular for the treatment of pain, in particular inflammatory pain and neuropathic pain (Calixto et al., Br. J. Pharmacol. 2004, 1-16), in particular diabetic neuropathy (Gabra et al., Biol. Chem. 2006, 387, 127-143). They are also suitable for the treatment of migraine.
  • a particular object of the invention is to provide compounds which a suitable for use in the treatment or inhibition of disorders or diseases which are at least in part related to the B1R-receptor.
  • Another object of the invention is to provide methods of treating or inhibiting disorders or disease states which are at least in part mediated by the B1R-receptor.
  • C 1-3 -alkyl C 1-6 -alkyl
  • C 1-10 -alkyl denote acyclic saturated or unsaturated hydrocarbon radicals which can be branched- or straight-chained as well as unsubstituted or mono- or poly-substituted, having from 1 to 3 carbon atoms or from 1 to 6 carbon atoms or from 1 to 10 carbon atoms, respectively, that is to say C 1-3 -alkanyls, C 2-3 -alkenyls and C 2-3 -alkynyls or C 1-6 -alkanyls, C 2-6 -alkenyls and C 2-6 -alkynyls or C 1-10 -alkanyls, C 2-10 -alkenyls and C 2-10 -alkynyls.
  • Alkenyls have at least one C—C double bond and alkynyls have at least one C—C triple bond.
  • Alkyl is advantageously selected from the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptanyl, octanyl, nonanyl, decyl, ethylenyl(vinyl), ethynyl, propenyl (—CH 2 CH ⁇ CH 2 , —CH ⁇ CH—CH 3 , —C( ⁇ CH 2 )—CH 3 ), propynyl (—CH—C ⁇ CH, —C ⁇ C—CH 3 ), butenyl, butynyl, pentenyl, pentynyl, hexenyl
  • cycloalkyl or “C 3-8 -cycloalkyl” denotes cyclic hydrocarbons having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein the hydrocarbons can be saturated or unsaturated (but not aromatic), unsubstituted or monosubstituted on one or more ring members.
  • C 3-4 -Cycloalkyl is advantageously selected from the group comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • heterocyclyl denotes mono- or poly-cyclic organic radicals in which at least one ring contains one hetero atom or 2, 3, 4 or 5 identical or different hetero atoms selected from the group consisting of N, O and S.
  • Each heterocyclyl radical can be unsubstituted or monosubstituted on one or more ring members.
  • Saturated and unsaturated heterocyclyl are understood as being in particular monocyclic 5- or 6-membered compounds having at least one hetero atom from the group N, O and S, wherein a further 5- or 6-membered, saturated, unsaturated or aromatic ring, which can likewise contain at least one hetero atom from the group N, O and S, can be fused to those compounds.
  • a saturated or unsaturated heterocyclyl radical is preferably selected from the group comprising pyrrolidinyl, piperidinyl, piperazinyl, pyrazolinyl, morpholinyl, tetrahydropyranyl, dioxanyl, dioxolanyl, indolinyl, isoindolinyl, or
  • heterocyclyl radical can take place via any desired position of the heterocyclyl radical.
  • aryl denotes aromatic hydrocarbons, including phenyls and naphthyls.
  • the aryl radicals can also be fused to further saturated, (partially) unsaturated or aromatic ring systems.
  • Each aryl radical can be unsubstituted or mono- or poly-substituted, wherein the aryl substituents can be identical or different and can be located at any desired and possible position of the aryl.
  • Aryl is advantageously selected from the group comprising phenyl, 1-naphthyl and 2-naphthyl, each of which can be unsubstituted or mono- or poly-substituted.
  • heteroaryl is synonymous with “aromatic heterocyclyl” and denotes a 5-, 6- or 7-membered cyclic aromatic radical containing at least one, optionally also 2, 3, 4 or 5, hetero atom(s), the hetero atoms being identical or different and the heterocycle being unsubstituted or mono- or poly-substituted; in the case of substitution on the heterocycle, the substituents can be identical or different and can be located at any desired and possible position of the heteroaryl.
  • the heterocycle can also be part of a bi- or poly-cyclic system, which can then be more than 7-membered in total, preferably up to 14-membered.
  • Preferred hetero atoms are nitrogen, oxygen and sulfur.
  • heteroaryl radical is selected from the group comprising pyrrolyl, indolyl, furyl(furanyl), benzofuranyl, thienyl(thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl, phthalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenazinyl, phenothiazinyl and oxadiazolyl, it
  • aryl or heteroaryl bonded via C 1-3 -alkyl means, for the purposes of the present invention, that C 1-3 -alkyl and aryl or heteroaryl have the meanings defined above and the aryl or heteroaryl radical is bonded to the compound of the general structure I via a C 1-3 -alkyl group. Phenyl, benzyl and phenethyl are particularly advantageous within the scope of this invention.
  • aralkyl denotes an alkyl group substituted by an aryl group.
  • the aralkyl group is preferably selected from the group consisting of benzyl, phenylethyl and phenylpropyl.
  • alkyl and “cycloalkyl”
  • substituted within the scope of this invention is understood as meaning the substitution of a hydrogen radical by F, Cl, Br, I, —CN, NH 2 , NH—C 1-6 -alkyl, NH—C 1-6 -alkyl-OH, C 1-6 -alkyl, N(C 1-6 -alkyl) 2 , N(C 1-6 -alkyl-OH) 2 , NO 2 , SH, S—C 1-6 -alkyl, S-benzyl, O—C 1-6 -alkyl, OH, O—C 1-6 -alkyl-OH, ⁇ O, O-benzyl, C( ⁇ O)C 1-6 -alkyl, CO 2 H, CO 2 —C 1-6 -alkyl or benzyl, polysubstituted radicals being understood as being those radicals that are polysubstituted, for example di- or tri-substit
  • the term “substituted” is understood as meaning the substitution of a hydrogen radical on one or more ring members by F, Cl, Br, I, —CN, NH 2 , NH—C 1-6 -alkyl, NH—C 1-6 -alkyl-OH, C 1-6 -alkyl, N(C 1-6 -alkyl) 2 , N(C 1-6 -alkyl-OH) 2 , pyrrolinyl, piperazinyl, morpholinyl, NO 2 , SH, S—C 1-6 -alkyl, S-benzyl, O—C 1-6 -alkyl, OH, O—C 1-6 -alkyl-OH, ⁇ O, O-benzyl, C( ⁇ O)C 1-6 -alkyl, CO 2 H, CO 2 —C 1-6 alkyl or benzyl.
  • the hydrogen bonded to a N hetero atom can be substituted in
  • aryl and “heteroaryl” or “aromatic heterocyclyl” “mono- or poly-substituted” within the scope of this invention means the substitution of one or more hydrogen atoms of the ring system one or more times, for example two, three or four times, by F, Cl, Br, I, CN, NH 2 , NH—C 1-6 -alkyl, NH—C 1-6 -alkyl-OH, N(C 1-6 -alkyl) 2 , N(C 1-6 -alkyl-OH) 2 , NHaryl, N(aryl) 2 , N(C 1-6 -alkyl)aryl, pyrrolinyl, piperazinyl, morpholinyl, NO 2 , SH, S—C 1-6 -alkyl, OH, O—C 1-6 -alkyl, O—C 1-6 -alkyl-OH, C( ⁇ O)C 1-6 -alkyl, NHSO 2 C
  • a salt formed with a physiologically acceptable acid is understood as meaning salts of the active ingredient in question with inorganic or organic acids that are physiologically acceptable—in particular when used in humans and/or mammals.
  • the hydrochloride is particularly preferred.
  • physiologically acceptable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro1 ⁇ 6 -benzo[d]isothiazol-3-one (saccharinic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, ⁇ -liponic acid, acetylglycine, hippuric acid, phosphoric acid and/or aspartic acid.
  • Citric acid and hydrochloric acid are particularly preferred.
  • a basic radical is understood as being a group that is able to react while taking up protons. In particular, it is understood as being a group that contains at least one protonisable nitrogen.
  • a basic radical can in particular represent an optionally fused heterocycle containing at least one nitrogen atom as hetero atom, wherein the heterocycle can optionally be monosubstituted on one or more ring members by C 1-6 -alkyl, O—C 1-6 -alkyl, heterocyclyl, OH, F, Cl, Br, I, —CN, NH 2 , NH(C 1-6 -alkyl), N(C 1-6 -alkyl) 2 , —NH(aryl), —N(C 1-3 -alkyl)(aryl), wherein the aryl radicals bonded to these amino groups can be mono- or poly-substituted by F, Cl, Br, CF 3 , CN, OH or OMe.
  • heterocycles referred to as basic radicals are piperidine, pyrrolidine, azepane, azetidine, azocane, pyrazine, pyridine, imidazole, imidazolidine, 1,2,4-triazole, diazepane, pyrimidine, imidazoline, piperazine, morpholine, quinazoline or quinoxaline.
  • N(C 1-6 -alkyl) 2 NHC 1-6 -alkyl, a N(C 1-6 -alkyl) 2 -substituted aryl radical, in particular phenyl or naphthyl, an aryl or heteroaryl radical, in particular phenyl, naphthyl or pyridinyl, substituted by a 5- to 7-membered heterocyclyl containing at least one N hetero atom, in particular pyrrolidinyl, piperidinyl, 4-methylpiperidinyl or morpholinyl.
  • the bridging chain contains a terminal O or N atom, then that atom can be bonded to the basic radical or to the structure to be bonded to the basic radical.
  • the bridging —(CH 2 ) p — groups or the C 1-3 -alkyl chain can optionally be substituted by ⁇ O, F, Cl, Br, I, —CN, phenyl or pyridinyl.
  • Further examples of basic radicals within the scope of the present invention are C 1-6 -alkylN(C 1-6 -alkyl) 2 or C 1-6 -alkylNH(C 1-6 -alkyl). If the basic radical is fused to the heterocycle formed from R 5 and R 6 , it can represent a 6-membered, saturated, unsaturated or aromatic heterocycle containing at least one N hetero atom, preferably pyridine or thiazole.
  • a basic radical is also understood as being in particular a pyridyl, pyrrolyl, imidazolyl, pyrimidinyl or pyrazinyl radical, each of which can be linked via a C 1-3 -alkyl chain.
  • Further examples of basic radicals are groups having the structure shown below:
  • k 0, 1 or 2
  • L represents H or C 1-6 -alkyl
  • K represents C 1-6 -alkyl
  • M represents C 1-6 -alkyl or N(CH 3 ) 2 .
  • J represents 2-, 3- or 4-pyridyl, phenyl, piperidyl or C 1-6 -alkyl.
  • a non-basic radical is understood as being a group that does not possess basic properties. In particular, it is understood as being a group that does not carry a protonatable nitrogen.
  • Examples of such non-basic radicals are —CN, C 1-6 -alkyl, optionally substituted by methoxy or C 1-3 -alkoxy; or aryl, heteroaryl, 3- to 7-membered heterocycles containing at least one oxygen or sulfur atom, in particular tetrahydropyran or thiophene, each unsubstituted or mono- or poly-substituted.
  • the substituents of the non-basic groups aryl, heteroaryl, 3- to 7-membered heterocycle and C 3-4 -cycloalkyl are preferably selected from F, Cl, Br, I, CN, NO 2 , aralkyl, SH, S—C 1-6 -alkyl, OH, O—C 1-6 -alkyl, O—C 1-6 -alkyl-OH, C( ⁇ O)C 1-6 -alkyl, CO 2 H, CH 2 SO 2 -phenyl, CO 2 —C 1-6 alkyl, OCF 3 , CF 3 ,
  • radicals from the group aryl, heteroaryl, C 3-4 -cycloalkyl each unsubstituted or substituted as described above, which can be linked to the structure of the general formula I via a C 1-3 -alkyl chain, wherein the alkyl chain can be substituted by ⁇ O.
  • C 4-4 -heterocyclyl in connection with R 6 represents a saturated or unsaturated, 4- to 8-membered cyclic radical which can contain 1, 2, 3, 4 or 5 identical or different hetero atoms in the ring system, wherein the hetero atoms are preferably selected from the group N, O and S and wherein both the bond of the heterocyclyl radical to the general basic structure of formula I and the optional substitution with the basic or non-basic groups can be present at any desired ring member.
  • the C 4-4 -heterocyclyl radical is preferably selected from the group consisting of piperidinyl, 2,6-dimethylpiperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl and tetrahydrofuranyl.
  • a basic heteroaryl radical in connection with R 6 represents a 5- to 10-membered, fused or non-fused hetero-atom-containing radical which contains at least one nitrogen atom as hetero atom and wherein both the bond of the heteroaryl radical to the general basic structure of formula I, or the bond of the heteroaryl radical to the bridging C 1-4 -alkyl group, and the optional substitution can be present at any desired ring member of the heteroaryl radical.
  • the basic heteroaryl is preferably pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, benzoimidazolyl and quinolinyl, quinoxalinyl, quinazolinyl.
  • a 5- to 10-membered, aromatic or unsaturated ring fused to an aryl group and optionally containing one or more hetero atoms represents, in connection with R 6 , a ring selected from the group:
  • R 7 represents H or C 1-6 -alkyl.
  • a 5- to 10-membered, saturated or unsaturated ring fused to a C 3-4 -cycloalkyl ring and optionally containing one or more hetero atoms represents, in connection with R 6 , a ring selected from the group: phenyl, pyridinyl, cyclopentane, cyclohexane and cycloheptane.
  • an aromatic, unsaturated or saturated 4- to 10-membered ring fused to the 4- to 8-membered ring formed by R 5 and R 6 represents a ring selected from the group consisting of C 4-10 -cycloalkane, C 4-10 -cycloalkene and C 6-10 -aromatic compounds and 6-membered heteroaromatic compounds.
  • R 1 represents phenyl or benzothiophenyl, especially phenyl, unsubstituted or mono- or poly-substituted by C 1-3 -alkoxy, C 1-6 -alkyl, Cl, F, I, CF 3 , OCF 3 , OH, SH, aryl or heteroaryl, each unsubstituted or mono- or poly-substituted.
  • R 1 in the substituted sulfonamide derivatives according to the invention represents phenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, furanyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazothiazolyl, carbazolyl, dibenzofuranyl and dibenzothiophenyl, preferably phenyl, naphthyl, benzothiophenyl, benzoxadiazolyl, thiophenyl, pyridinyl, imidazothiazolyl and dibenzofuranyl, particularly preferably phenyl, naphthyl and benzothiophenyl, wherein all those radicals can be unsubstituted or mono- or poly-substituted
  • R 1 represents phenyl or naphthyl, especially phenyl, optionally mono- or poly-substituted by methyl, methoxy, CF 3 , Cl, Br and/or F.
  • R 1 represents phenyl substituted in the 4-position by aryl or heteroaryl and in the 2-, 3-, 5- and/or 6-position position by methyl, methoxy, Cl or F, preferably in the 2- and 6-position by methyl.
  • R 1 represents 2,6-dimethyl-4-methoxyphenyl, 2,6-dichloro-4-trifluoromethylphenyl, 2,6-dimethyl-4-bromophenyl, 2,6-dichloro-4-bromophenyl, 2,4,6-trichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl.
  • R 2a-c , R 3 and R 4 represent H or, with an adjacent radical R 2a-c , R 3 or R 4 , form an aromatic ring, preferably a benzene group, which is optionally mono- or poly-substituted, preferably by methyl, methoxy, CF 3 , Cl, Br and/or F.
  • R 2a-c , R 3 and R 4 represent H.
  • n in the group (CR 2a-c ) n represents 1 or 2, preferably 2.
  • m in the general formula I is 1.
  • the group NR 5 R 6 in the general formula I forms a cyclic group according to formula a1, a2, a3 or a4
  • B represents a basic radical, preferably selected from the group consisting of —NR 8 R 9 , wherein R 8 and R 9 , independently of one another, can represent H or C 1-6 -alkyl, and a radical having the general formula aa1
  • R 10 represents a 4- to 10-membered, aromatic, unsaturated or saturated, mono- or poly-cyclic heterocyclyl group which can contain 1, 2, 3 or 4 N hetero atoms and optionally O and/or S as further hetero atoms, wherein the heterocyclyl group is unsubstituted or monosubstituted on one or more ring members.
  • R 10 can further represent an aryl group substituted by at least one group —NR 11 R 12 or a 5- or 6-membered, monocyclic N-containing aromatic, saturated or unsaturated heterocycle containing 1 or 2 N hetero atoms, wherein R 11 and R 12 , independently of one another, represent H or C 1-6 -alkyl, and the aryl group can optionally carry further substituents.
  • R 10 can further represent a group of the general formula aa2:
  • R 13 can be H or C 1-3 -alkyl
  • R 14 for each chain member d independently, can be H or an optionally substituted aryl or N-heteroaryl group, preferably phenyl, naphthyl or pyridinyl, wherein R 14 can be H only once within the alkyl chain defined by d
  • R 15 is a 5- to 7-membered, saturated or unsaturated heterocyclyl group which is optionally mono-substituted on one or more ring members, contains 1 or 2 N hetero atoms and can contain O or S as further hetero atoms, preferably morpholinyl, piperidinyl or 4-methylpiperazinyl.
  • the cyclic group formed by the group NR 5 R 6 is selected from the group consisting of
  • the basic radical B is selected from the group comprising: —N(C 1-6 -alkyl), preferably —N(CH 3 ) 2 ; a radical having the general formula (aa1), wherein R 10 is selected from the group comprising:
  • radicals can be unsubstituted or monosubstituted on one or more ring members, preferably by C 1-6 -alkyl, especially methyl or ethyl, F, Cl or Br; or R 10 represents
  • the cyclic group formed by the group NR 5 R 6 is
  • the group NR 5 R 6 in the general formula I is a cyclic group according to one of the general formulae b1 and b2:
  • k 1 or 2, preferably 2,
  • l 1, 2 or 3, preferably 2,
  • Z can be NR 17 or O, and R 17 is H or C 1-6 -alkyl, and
  • R 16 represents H or a group of the general formula bb1:
  • R 18 is selected from the group consisting of unsubstituted or mono- or poly-substituted aryl or heteroaryl, wherein the heteroaryl contains at least one N hetero atom, preferably 1, 2 or 3 N hetero atoms, and can contain O and S as further hetero atoms; saturated or unsaturated 5- to 7-membered heterocyclyl, wherein the heterocyclyl contains at least one hetero atom selected from the group N, O and S, preferably 1 or 2 N hetero atoms, and can optionally be monosubstituted or monosubstituted on a plurality of ring members; C 1-6 -alkyl, optionally mono- or poly-substituted; C
  • the cyclic group formed by the group NR 5 R 6 is selected from the group consisting of:
  • R 18 is preferably selected from the group consisting of:
  • those groups can be unsubstituted or mono- or poly-substituted, preferably by C 1-3 -alkyl, especially methyl and/or ethyl; C 1-3 -alkoxy, especially methoxy; F, Cl, Br, I; —CN; CF 3 ; N(C 1-3 -alkyl) 2 , NH(C 1-3 -alkyl), N(C 1-3 -alkyl)(aryl), especially N(C 1-3 -alkyl)(phenyl or phenethyl), wherein phenyl or phenethyl can be mono- or poly-substituted; benzyl or
  • substituents can likewise be mono- or poly-substituted, preferably by F, Cl, Br, —CN, —CF 3 , C 1-3 -alkyl; pyrrolidinyl, piperidinyl, 4-methylpiperidinyl or morpholinyl.
  • R 18 can further represent a heterocyclyl selected from the group consisting of:
  • heterocyclyl groups can be monosubstituted on one or more ring members.
  • R 18 can represent cyclopentyl, cyclohexyl, optionally monosubstituted on one or more ring members, or C 1-3 -alkyl, optionally mono- or poly-substituted.
  • the cyclic group formed by the group NR 5 R 6 is
  • phenyl group can be substituted, preferably monosubstituted by F, Cl or Br, especially F, preferably in the 4-position.
  • R 5 is selected from the group consisting of H and C 1-6 -alkyl, optionally mono- or poly-substituted
  • R 6 is selected from groups of the general formulae c1 and c2 shown below:
  • R 21 is an unsubstituted or substituted aryl group, preferably phenyl or naphthyl, both substituted or unsubstituted, R 22 and R 23 , independently of one another, represent —H or C 1-6 -alkyl, or the group —NR 22 R 23 together represents a 5-, 6- or 7-membered, saturated or unsaturated heterocycle which contains at least one N hetero atom and can optionally be monosubstituted or monosubstituted on a plurality of ring members;
  • R 5 in the group NR 5 R 6 from the general formula I is selected from the group consisting of H and methyl, ethyl, propyl and isopropyl, optionally mono- or poly-substituted.
  • R 5 is a group according to the general formula c1 shown above, wherein:
  • N-heterocycles can be unsubstituted or monosubstituted on one or more ring members, or R 6 represents a group of the general formula c2 shown above, wherein Y represents phenyl, naphthyl, benzooxadiazole, cyclopentyl, cyclohexyl or cycloheptyl, all optionally monosubstituted on one or more ring members, and Z is selected from the group consisting of:
  • R 30 , R 31 and R 40 can represent H, methyl, ethyl, propyl or isopropyl, optionally mono- or poly-substituted, or Z is selected from the group consisting of:
  • R 32 , R 33 and R 34 are selected from H, methyl, ethyl, propyl and isopropyl, optionally mono- or poly-substituted, and the N-heterocycles can optionally be monosubstituted on one or more ring members; or Z is a group NR 24 R 25 wherein R 24 and R 25 , independently of one another, represent methyl, ethyl, propyl or isopropyl, or Z represents a group —C( ⁇ O)—(CH 2 ) d —NR 26 R 27 wherein d is 1 or 2 and NR 26 R 27 together forms a heterocycle selected from
  • R 35 and R 36 can represent methyl, ethyl, propyl or isopropyl, optionally mono- or poly-substituted.
  • R 5 is selected from the group consisting of H, methyl, ethyl, propyl and isopropyl, preferably methyl
  • R 5 in the group NR 5 R 6 from the general formula I is selected from the group consisting of H, C 1-6 -alkyl, optionally mono- or poly-substituted, C 3-8 -cycloalkyl, optionally monosubstituted on one or more ring members.
  • R 6 is selected from groups of the general formula d1
  • R 5 is selected from the group consisting of H and methyl, ethyl, propyl and isopropyl, optionally mono- or poly-substituted
  • R 6 represents a group according to formula d1 shown above wherein J is selected from the group:
  • K is selected from the group consisting of H, phenyl, naphthyl, pyridinyl, all optionally mono- or poly-substituted.
  • R 5 is selected from the group consisting of H, C 1-6 -alkyl, aryl and aralkyl
  • R 41 , R 42 and R 43 are selected from H, methyl, ethyl, propyl and isopropyl, optionally mono- or poly-substituted, and the N-heteroaryls can optionally be mono- or poly-substituted.
  • k 0, 1 or 2
  • L represents H or C 1-6 -alkyl
  • K represents C 1-6 -alkyl
  • M represents C 1-6 -alkyl or N(CH 3 ) 2 ,
  • J represents 2-, 3- or 4-pyridyl, phenyl, piperidyl or C 1-6 -alkyl.
  • k 0, 1 or 2
  • L represents H or C 1-6 -alkyl
  • K represents C 1-6 -alkyl
  • M represents C 1-6 -alkyl or N(CH 3 ) 2 ,
  • J represents 2-, 3- or 4-pyridyl, phenyl, piperidyl or C 1-6 -alkyl
  • R 5 represents H and R 6 represents aryl or C 3-8 -cycloalkyl; or an aryl radical linked via a C 1-3 -alkyl chain, wherein the aryl or C 3-8 -cycloalkyl ring is substituted by at least one basic radical from the group
  • k 0, 1 or 2
  • L represents H or C 1-6 -alkyl
  • K represents C 1-6 -alkyl
  • M represents C 1-6 -alkyl or N(CH 3 ) 2 ,
  • J represents 2-, 3- or 4-pyridyl, phenyl, piperidyl or C 1-6 -alkyl.
  • substituted sulfonamide derivatives of the general formula I wherein R 5 represents H or CH 3 and R 6 represents benzyl or phenethyl substituted by pyrrolidine, piperazine, morpholine or piperidine, wherein these radicals are themselves unsubstituted or monosubstituted by methyl or ethyl and are optionally linked via a C 1-3 -alkyl chain, wherein the benzyl or phenethyl radical is optionally substituted by a further basic radical,
  • R 6 represents
  • R 5 represents H or C 1-5 -alkyl and R 6 represents C 4-8 -heterocyclyl, wherein the heterocyclyl radical is linked to the structure of the general formula I via a carbon atom; or R 6 represents a C 4-8 -heterocyclyl radical linked via a C 1-3 -alkyl chain, wherein the heterocyclyl ring is substituted by a basic radical from the group
  • k 0, 1 or 2
  • L represents H or C 1-6 -alkyl
  • K represents C 1-6 -alkyl
  • M represents C 1-6 -alkyl or N(CH 3 ) 2 .
  • J represents 2-, 3- or 4-pyridyl, phenyl, piperidyl or C 1-6 -alkyl
  • R 5 represents H, methyl or ethyl and R 6 represents piperidine, pyrrolidine, azepane; piperidine, pyrrolidine, azepane, diazepane or piperazine linked via a C 1-3 -alkyl chain; each substituted by phenyl, pyrrolidine, piperazine, morpholine or piperidine linked via a C 1-3 -alkyl chain and unsubstituted or monosubstituted by methyl or ethyl.
  • substituted sulfonamide compounds selected from the group consisting of
  • the compounds according to the invention exhibit an antagonistic action on the human B1R receptor or the B1R receptor of the rat.
  • the substances according to the invention exhibit an antagonistic action both on the human B1R receptor and on the B1R receptor of the rat.
  • the agonistic or antagonistic action of substances can be quantified on the bradykinin receptor 1 (B1R) of the species human and rat with ectopically expressing cell lines (CHO K1 cells) and with the aid of a Ca 2+ -sensitive dye (Fluo-4) using a 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 -bradykinin (0.5 nM) or Des-Arg 9 -bradykinin (100 nM).
  • Antagonists result in a suppression of the Ca 2+ influx following administration of the agonist.
  • the % inhibition in comparison with the maximum achievable inhibition is indicated.
  • the substances according to the invention are active, for example, on B1R, which is relevant in connection with various diseases, so that they are suitable as a pharmaceutical active ingredient in a medicament.
  • the invention therefore further provides pharmaceutical compositions or medicaments comprising at least one substituted sulfonamide derivative according to the invention as well as, optionally, suitable additives and/or auxiliary substances and/or, optionally, further active ingredients.
  • the pharmaceutical compositions according to the invention optionally comprise suitable additives and/or auxiliary substances, that is to say carriers, fillers, solvents, diluents, colorings and/or binders, and can be administered as liquid pharmaceutical dosage forms in the form of injection solutions, drops or juices, as semi-solid pharmaceutical dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters/spray-on plasters or aerosols.
  • suitable additives and/or auxiliary substances that is to say carriers, fillers, solvents, diluents, colorings and/or binders, and can be administered as liquid pharmaceutical dosage forms in the form of injection solutions, drops or juices, as semi-solid pharmaceutical dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters/spray-on plasters or aerosols.
  • suitable additives and/or auxiliary substances that is to say carriers, fillers, solvents, diluents, colorings and/or binders
  • Preparations suitable for oral administration are in the form of tablets, dragées, capsules, granules, drops, juices and syrups, and those suitable for parenteral and topical administration and administration by inhalation are solutions, suspensions, readily reconstitutable dry preparations and sprays.
  • Substituted sulfonamide derivatives according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of agents promoting penetration through the skin, are suitable percutaneous forms of administration.
  • Forms of preparation for oral or percutaneous administration can release the substituted sulfonamide derivatives according to the invention in a delayed manner.
  • the substituted sulfonamide derivatives according to the invention can also be administered in parenteral long-term depot forms, such as, for example, implants or implanted pumps.
  • parenteral long-term depot forms such as, for example, implants or implanted pumps.
  • other further active ingredients known to the person skilled in the art can be added to the medicaments according to the invention.
  • the amount of active ingredient to be administered to the patient varies depending on the weight of the patient, the manner of administration, the indication and the severity of the disease. Usually, from 0.00005 to 50 mg/kg, preferably from 0.01 to 5 mg/kg, of at least one substituted sulfonamide derivative according to the invention are administered.
  • a substituted sulfonamide derivative according to the invention that is present is in the form of a pure diastereoisomer and/or enantiomer, in the form of a racemate or in the form of a non-equimolar or equimolar mixture of the diastereoisomers and/or enantiomers.
  • substituted sulfonamide derivatives according to the invention can be used in the treatment of pain, in particular of acute, visceral, neuropathic or chronic pain.
  • the invention accordingly relates further to the use of a substituted sulfonamide derivative according to the invention in the treatment of pain, in particular of acute, visceral, neuropathic or chronic pain.
  • the invention relates further to the use of a substituted sulfonamide derivative according to the invention in the treatment of diabetes, respiratory diseases, inflammatory intestinal diseases, neurological diseases, inflammations of the skin, rheumatic diseases, septic shock, reperfusion syndrome and obesity, and as an angiogenesis inhibitor.
  • a substituted sulfonamide derivative that is used to be in the form of a pure diastereoisomer and/or enantiomer, in the form of a racemate or in the form of a non-equimolar or equimolar mixture of the diastereoisomers and/or enantiomers.
  • the invention further provides a method of treating, in particular in one of the above-mentioned indications, a non-human mammal or a human requiring treatment for pain, in particular for chronic pain, by administering a therapeutically effective dose of a substituted sulfonamide derivative according to the invention or of a medicament according to the invention.
  • the invention further provides a process for the preparation of the substituted sulfonamide derivatives according to the invention as set out in the following description, examples and claims.
  • the compounds according to the invention can be obtained according to the following synthesis scheme.
  • the racemic (R and S configuration) or enantiomerically pure (R or S configuration) amino acids/acid esters A are converted into an amino alcohol B by means of a reduction, using metal hydrides as reducing agents, such as, for example, LiAlH 4 , BH 3 ⁇ DMS, BH 3 ⁇ THF or NaBH 4 , in an organic solvent, such as THF or diethyl ether, in a temperature range of from ⁇ 20° C. to +100° C., preferably at from 0° C. to +70° C.
  • metal hydrides as, for example, LiAlH 4 , BH 3 ⁇ DMS, BH 3 ⁇ THF or NaBH 4
  • organic solvent such as THF or diethyl ether
  • the amino alcohols B are converted into the sulfonylated amino alcohols G in a sulfonylation using sulfonyl chlorides, bromides or pentafluorophenolates R 1 SO 2 X (X ⁇ Br, Cl or OPFP) in the presence of an organic or inorganic base, for example potassium carbonate, sodium hydrogen carbonate, diisopropylethylamine, triethylamine, pyridine, diethylamine or dimethylaminopyridine, or in the presence of tetra-n-butylammonium chloride and in an organic solvent, for example acetonitrile, dichloromethane or N,N-dimethylformamide, in a temperature range of from 0° C.
  • an organic or inorganic base for example potassium carbonate, sodium hydrogen carbonate, diisopropylethylamine, triethylamine, pyridine, diethylamine or dimethylaminopyridine, or in the presence
  • the racemic (R and S configuration) or enantiomerically pure (R or S configuration) amino acids C are esterified to the amino esters D using water-removing reagents, for example inorganic acids such as H 2 SO 4 or phosphorus oxides, or organic reagents, such as thionyl chloride, in organic solvents, such as THF, diethyl ether, methanol, ethanol or dichloromethane, in a temperature range of from 0° C.
  • water-removing reagents for example inorganic acids such as H 2 SO 4 or phosphorus oxides, or organic reagents, such as thionyl chloride, in organic solvents, such as THF, diethyl ether, methanol, ethanol or dichloromethane, in a temperature range of from 0° C.
  • sulfonylated amino esters E in an ester cleavage using organic acids, such as trifluoroacetic acid, or aqueous inorganic acids, such as hydrochloric acid, or using aqueous inorganic bases, such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, in organic solvents, such as methanol, dioxane, dichloromethane, THF, diethyl ether or those solvents in the form of mixtures, in a temperature range of from ⁇ 20° C. to +25° C., preferably at room temperature, yield the sulfonylated amino acids F.
  • organic acids such as trifluoroacetic acid
  • aqueous inorganic acids such as hydrochloric acid
  • aqueous inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate
  • organic solvents such as m
  • the sulfonylated amino alcohols G are then converted into the products of the general structure H in an alkylation reaction with halogenated ester derivatives using tetrabutyl-ammonium chloride or bromide or tetrabutylammonium hydrogen sulfate in a phase-transfer reaction using an organic solvent, such as toluene, benzene or xylene, and inorganic base, such as potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, or in the presence of an organic or inorganic base
  • conventional inorganic bases are metal alcoholates, such as sodium methanolate, sodium ethanolate, potassium tert-butoxide, lithium or sodium bases, such as lithium diisopropylamide, butyllithium, tert-butyllithium, sodium methoxide, or metal hydrides, such as potassium hydride, lithium hydride, sodium hydride; conventional organic bases are diisopropyleth
  • the carboxylic acids I are converted into the end products of the general formula J in an amide formation using primary or secondary amines, in the presence of water-removing agents, such as sodium or magnesium sulfate, phosphorus oxide or reagents such as, for example, CDI, DCC, TBTU, EDCI or benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), also in the presence of HOAt or HOBt and of an organic base, for example DIPEA, pyridine or 4-methylmorpholine, in an organic solvent, such as THF, dichloromethane, diethyl ether, dioxane, DMF or acetonitrile, 0° C. to +40° C., preferably at room temperature.
  • water-removing agents such as sodium or magnesium sulfate, phosphorus oxide or reagents such as, for example, CDI, DCC, TBTU, EDCI or benzo
  • the synthesis preferably begins at the stage of the starting materials Ga.
  • the amines or the corresponding hydrochlorides of the general formula J b can be converted into compounds of the general formula J c using aldehydes or ketones in a reductive amination, optionally in the presence of an organic base, such as triethylamine or diisopropylethylamine, and in the presence of a suitable reducing agent, for example sodium triacetoxyborohydride, sodium cyanoborohydride or sodium diacetoxyborohydride, or those or similar reducing agents in the form of polymer-bonded variants, optionally in the presence of acetic acid, in an organic solvent, for example tetrahydrofuran, dichloromethane, 1,2-dichloroethane or those solvents in the form of mixtures, in a temperature range of from ⁇ 0° C. to +25° C.
  • an organic base such as triethylamine or diisopropylethylamine
  • a suitable reducing agent for example sodium triacetoxyborohydride, sodium
  • ketones of the general formula J d can be prepared, as described in method 1 and 2, from commercially available amino alcohols which are used as structural units B and are finally reacted, in the last step, in an amide formation, with piperidin-4-one.
  • the ketones of the general formula J d can be converted into compounds of the general formula J e using amines in a reductive amination, optionally in the presence of an organic base, such as triethylamine or diisopropylethylamine, and in the presence of a suitable reducing agent, for example sodium triacetoxyborohydride, sodium cyanoborohydride or sodium diacetoxy-borohydride, or those or similar reducing agents in the form of polymer-bonded variants, optionally in the presence of acetic acid, in an organic solvent, for example tetrahydrofuran, dichloromethane, 1,2-dichloroethane or those solvents in the form of mixtures, in a temperature range of from ⁇ 0° C. to
  • the commercially available, protected amino alcohols of the general formula J f can be converted into the products of the general structure J g in an alkylation reaction with halogenated ester derivatives using tetrabutylammonium chloride or bromide or tetra-butylammonium hydrogen sulfate in a phase-transfer reaction using an organic solvent, such as toluene, benzene or xylene, and an inorganic base, such as potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, or in the presence of an organic or inorganic base
  • conventional inorganic bases are metal alcoholates, such as sodium methanolate, sodium ethanolate, potassium tert-butoxide, lithium or sodium bases, such as lithium diisopropylamide, butyllithium, tert-butyllithium, sodium methoxide, or metal hydrides, such as potassium hydride, lithium hydride, sodium hydride; conventional organic bases are di
  • the carboxylic acids J h can be converted into the products of the general formula J l , in an amide formation using primary or secondary amines, in the presence of water-removing agents, such as sodium or magnesium sulfate, phosphorus oxide or reagents such as, for example, CDI, DCC, TBTU, EDCI or benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), also in the presence of HOAt or HOBt and an organic base, for example DIPEA, pyridine or 4-methylmorpholine, in an organic solvent, such as THF, dichloromethane, diethyl ether, dioxane, DMF or acetonitrile, at from 0° C.
  • water-removing agents such as sodium or magnesium sulfate, phosphorus oxide or reagents
  • phosphorus oxide or reagents such as, for example, CDI, DCC, TBTU,
  • the compounds J l can be deprotected in the presence of an inorganic or organic acid, such as HCl, trifluoroacetic acid or formic acid, in an organic solvent, such as THF, dichloro-methane, diethyl ether, dioxane, MeOH or chloroform, at from 0° C. to +40° C., preferably at from +25 to +40° C., to form the products of the general formula J j .
  • an inorganic or organic acid such as HCl, trifluoroacetic acid or formic acid
  • organic solvent such as THF, dichloro-methane, diethyl ether, dioxane, MeOH or chloroform
  • the amines J j are converted into the sulfonamides J k in a sulfonylation using sulfonyl chlorides, bromides or pentafluorophenolates R 1 SO 2 X (X ⁇ Br, Cl or OPFP) in the presence of an organic or inorganic base, for example potassium carbonate, sodium hydrogen carbonate, diisopropylethylamine, triethylamine, pyridine, diethylamine, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) and/or dimethylaminopyridine, or in the presence of tetra-n-butylammonium chloride and in an organic solvent, for example acetonitrile, dichloromethane, THF or N,N-dimethylformamide, in a temperature range of from 0° C. to 120° C., preferably at from +25° C. to +70° C.
  • the separation of diastereoisomers and/or enantiomers is carried out according to methods known to the person skilled in the art, for example by recrystallization, chromatography or, in particular, HPLC chromatography or crystallization using an optionally chiral acid or base and with separation of the salts, or chiral HPLC chromatography (Fogassy et al., Optical resolution methods, Org. Biomol. Chem. 2006, 4, 3011-3030).
  • ether means diethyl ether
  • EE means ethyl acetate
  • DCM dichloromethane
  • DMF means dimethylformamide
  • DME dimethoxyethane
  • DMSO means dimethyl sulfoxide
  • THF tetrahydrofuran
  • TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate
  • CDI 1,1′-carbonyldiimidazole
  • EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • DIPEA N,N-diisopropylamine
  • HOBt 1-hydroxybenzotriazole
  • n-Bu 4 NCl (10 mmol) was added to a solution of the product from step 2 (31 mmol) in toluene (200 ml); the mixture was cooled to 0° C., and first aqueous 35% NaOH (200 ml) and then bromoacetic acid tert-butyl ester (46 mmol) were added dropwise. The reaction mixture was stirred for 3 h and then washed with water until neutral and dried over Na 2 SO 4 , and the organic solvent was removed in vacuo. The crude product was used in the next step without being purified further or was purified by column chromatography. 4.
  • step 3 The product from step 3 (30 mmol) was dissolved in CH 2 Cl 2 (200 ml); TFA (30 ml) was added, and stirring was carried out for 2 h at RT. The solvent was largely removed in vacuo, and the crude product was purified by recrystallization or chromatography.
  • the solution was diluted with a small amount of CH 2 Cl 2 and washed, in succession, with 0.5 M KHSO 4 , saturated aqueous NaHCO 3 solution and saturated aqueous NaCl solution.
  • the organic phase was separated off and dried over Na 2 SO 4 , the solvent was removed in vacuo, and the crude product was purified by means of column chromatography. 3.
  • 4 M NaOH (153 ml, 610 mmol, 4.5 equivalents) was added, with stirring, to a solution of the product from step 2 (136 mmol) in a methanol/dioxane/4 M NaOH mixture in a ratio of 15/4/1 (1020 ml, 203 mmol NaOH, 1.5 equivalents), and stirring was carried out overnight at RT.
  • n-Bu 4 NCl (10 mmol, 2.9 g) was added to a solution of the product from step 4 (31 mmol) in toluene (175 ml), and the mixture was cooled to 0° C.; aqueous 35% NaOH (200 ml) was added first, and then bromoacetic acid tert-butyl ester (48 mmol, 7 ml) was added dropwise.
  • the reaction mixture was stirred for 3 hours and then washed with water until neutral and dried over Na 2 SO 4 , and the organic solvent was removed in vacuo.
  • the crude product was used in the next step without being purified further. 6.
  • the product from step 5 (30 mmol) was dissolved in a mixture of MeOH/dioxane/4 M NaOH in a ratio of 15/4/1 (236 ml, 47 mmol NaOH); further NaOH (4 M, 35 ml, 141 mmol) was added, and stirring was carried out overnight at RT.
  • the solvent was reduced in vacuo, and the residue was diluted with ethyl acetate and washed with 0.5 M KHSO 4 .
  • n-Bu 4 NCl (10 mmol) was added to a solution of the product from step 1 (31 mmol) in toluene (200 ml); the mixture was cooled to 0° C., and first aqueous 35% NaOH (200 ml) and then bromoacetic acid tert-butyl ester (46 mmol) were added dropwise. The reaction mixture was stirred for 3 h and then washed with water until neutral and dried over Na 2 SO 4 , and the organic solvent was removed in vacuo. The crude product was used in the next step without being purified further or was purified by column chromatography.
  • n-Bu 4 NCl (8.8 mmol) was added to a solution of bromoacetic acid tert-butyl ester (40 mmol) in toluene (100 ml).
  • the reaction mixture was cooled to 0° C., and 35% NaOH (150 ml) and then, dropwise, the alcohol (27 mmol) dissolved in toluene (50 ml) were added.
  • the organic phase was separated off and extracted with water (4 ⁇ 150 ml) and with saturated NaCl solution (150 ml).
  • the organic phase was separated off and dried over Na 2 SO 4 ; filtration was carried out, and then the solvent was removed in vacuo.
  • the crude product was purified by column chromatography. 5.
  • the tert-butyl ester (16 mmol) was stirred overnight at RT in 4 M HCl in dioxane (70 ml, 27 mmol). After removal of the solvent, the crude product was purified by column chromatography.
  • n-Bu 4 NCl (9 mmol) was added to a solution of bromoacetic acid tert-butyl ester (42 mmol) in toluene (100 ml).
  • the reaction mixture was cooled to 0° C., and 35% NaOH (150 ml) and then, dropwise, the alcohol (28 mmol) dissolved in toluene (50 ml) were added.
  • the organic phase was separated off and extracted with water (4 ⁇ 150 ml) and with saturated NaCl solution (150 ml).
  • the organic phase was separated off and dried over Na 2 SO 4 ; filtration was carried out, and then the solvent was removed in vacuo.
  • the crude product was purified by column chromatography. 5.
  • the tert-butyl ester (16 mmol) was stirred overnight at RT in 4 M HCl in dioxane (70 ml, 27 mmol). After removal of the solvent, the crude product was purified by column chromatography
  • step 1 A solution of step 1 (1 mmol) dissolved in THF (5 ml) was added dropwise, under a nitrogen atmosphere, to a stirred suspension of LAH (4 mmol) in THF (5 ml).
  • the reaction mixture was stirred at 25° C.; after 16 to 20 h, it was cooled with ice, and aqueous saturated Na 2 SO 4 solution was added dropwise.
  • ethyl acetate 3 ⁇ 10 ml
  • the solvent was largely removed and HCl gas was introduced at 0-5° C.
  • the precipitate was filtered off and washed with ether.
  • the amine hydrochlorides were obtained in the form of products which were used without being worked up further.
  • step 1 A solution of step 1 (1 mmol) dissolved in THF (5 ml) was added dropwise, under a nitrogen atmosphere, to a stirred suspension of LAH (4 mmol) in THF (5 ml).
  • the reaction mixture was heated under reflux for 6 h and cooled with ice, and aqueous saturated Na 2 SO 4 solution was added dropwise. After filtration, the residue was washed with a solvent mixture (ethyl acetate and 10% methanol, 3 ⁇ 10 ml). After removal of the solvent, the amines were obtained, which were used without being worked up further.
  • step 1 (1 mmol) dissolved in THF (5 ml) was added dropwise, under a nitrogen atmosphere, to a stirred suspension of LAH (4 mmol) in THF (5 ml). The reaction mixture was heated under reflux for 6 h and cooled with ice, and aqueous saturated Na 2 SO 4 solution was added dropwise. After filtration, the residue was washed with a solvent mixture (ethyl acetate and 10% methanol, 3 ⁇ 10 ml). The solvent was largely removed in vacuo and the amine was obtained in the form of the hydrochloride by introduction of HCl gas.
  • a reaction mixture of 4-morpholinebenzoic acid (0.5 g) and methanolic HCl solution (6 ml, 4%) was heated under reflux for 6 h, with stirring. After removal of the solvent in vacuo, water (10 ml) was added to the residue and the mixture was neutralized with aqueous saturated NaHCO 3 solution. The solution was extracted with ethyl acetate (3 ⁇ 20 ml). The organic phase was separated off and dried over Na 2 SO 4 . After filtration and removal of the solvent, the product was obtained, which was used in the next step without being worked up further. 2.
  • a reaction mixture of product step 1 (4 g), NH 3 (25 ml) and methanol (20 ml) was heated for 4 d at 120° C.
  • Methanesulfonyl chloride (11 mmol) was added dropwise at 0° C., under nitrogen, to a solution of the alcohol (10 mmol) in CH 2 Cl 2 (50 ml). The reaction mixture was stirred for a further 2 h and then diluted with CH 2 Cl 2 . After extraction with aqueous saturated NaCl solution, drying over Na 2 SO 4 was carried out. After filtration and removal of the solvent, the crude product was obtained in a yield of 80%. 5. A 2 M solution of methylamine in CH 2 Cl 2 (10 ml) was added to a solution of the Ms-protected alcohol (5 mmol) in THF (5 ml), and the reaction solution was heated for 16 h at 100° C.
  • the aqueous phase was removed and discarded. 3 ml of H 2 O and 0.5 ml of CH 2 Cl 2 were added to the organic phase; vortexing was carried out, followed by intensive mixing for 15 min. After centrifugation, the aqueous phase was separated off and discarded. The organic phase was extracted in an analogous manner for a second time with 3 ml of saturated NaCl solution. The organic phase was then removed, introduced into a test glass and dried over a MgSO 4 cartridge. After removal of the solvent by distillation, the crude products were analysed by means of LC-MS and purified by HPLC.
  • N,N′-Carbonyldiimidazole (114 mg, 0.706 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (250 mg, 0.673 mmol) in dichloromethane (15 ml), and the mixture was stirred for 1 h at room temperature.
  • a solution of 1-(1-methylpiperidin-4-yl)piperazine (123 mg, 0.673 mmol) in dichloromethane (5 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature.
  • the reaction mixture was then extracted with water (20 ml) and saturated sodium chloride solution (20 ml), and the organic phase was dried over magnesium sulfate and concentrated in vacuo.
  • the crude product was purified by flash chromatography using dichloromethane/methanol (97:3 ⁇ 90:10).
  • N,N′-Carbonyldiimidazole (272 mg, 1.696 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (600 mg, 1.615 mmol) in dichloromethane (15 ml), and the mixture was stirred for 1 h at room temperature.
  • a solution of 1-(1-methylpiperidin-4-yl)piperazine (293 mg, 1.615 mmol) in dichloromethane (5 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature.
  • N,N′-Carbonyldiimidazole (68 mg, 0.424 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (150 mg, 0.404 mmol) in dichloromethane (4 ml), and the mixture was stirred for 1 h at room temperature.
  • a solution of 3-(piperazin-1-ylmethyl)benzonitrile (81 mg, 0.404 mmol) in dichloromethane (1 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature.
  • N,N′Carbonyldiimidazole (71 mg, 0.441 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetic acid (150 mg, 0.420 mmol) in dichloromethane (7 ml), and the mixture was stirred for 1 h at room temperature.
  • a solution of 3-(piperazin-1-ylmethyl)benzonitrile (84 mg, 0.420 mmol) in dichloromethane (3 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature.
  • N,N′-Carbonyldiimidazole (68 mg, 0.424 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (150 mg, 0.404 mmol) in dichloromethane (4 ml), and the mixture was stirred for 1 h at room temperature.
  • a solution of 4-(2-(pyrrolidin-1-yl)ethyl)piperidine (73 mg, 0.404 mmol) in dichloromethane (1 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature.
  • N,N′-Carbonyldiimidazole (71 mg, 0.441 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetic acid (150 mg, 0.420 mmol) in dichloromethane (7 ml), and the mixture was stirred for 1 h at room temperature.
  • a solution of 4-(2-(pyrrolidin-1-yl)ethyl)piperidine (76 mg, 0.420 mmol) in dichloromethane (3 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature.
  • N,N′-Carbonyldiimidazole (68 mg, 0.424 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (150 mg, 0.404 mmol) in dichloromethane (4 ml), and the mixture was stirred for 1 h at room temperature.
  • a solution of 1,2,3,4-tetrahydro-2,6-naphthyridine 54 mg, 0.404 mmol) in dichloromethane (1 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature.
  • the example compounds listed in the following table were prepared from acid structural unit S27 by reaction with the corresponding amines (R 5 R 6 NH) closely following the processes described for Examples 8 and 92-96.
  • the amines used are commercially available, can be prepared by methods known to the person skilled in the art, or were synthesized according to described processes. Instead of the solvent dichloromethane, the solvent N,N-dimethylformamide was used in the synthesis of the following example compounds: Example 113, 143 and 146.
  • ⁇ HCl a corresponding amount of triethylamine was added to the reaction (eq.
  • Example 99 the formation of the hydrochloride was carried out analogously to the process described for Example 97.
  • Examples 106 and 112 were converted into the corresponding hydrochlorides ( ⁇ HCl) by the following general process: The free bases were in each case dissolved in a small amount of methyl ethyl ketone, and 2 M hydrogen chloride solution in diethyl ether (4-5 eq.) was added. Where appropriate, the mixture was cooled to 0° C. and/or diethyl ether was added before the hydrochloride ( ⁇ HCl) was filtered out.
  • the aqueous phase was extracted with diethyl ether (2 ⁇ 30 ml) and the organic phase was in turn washed with saturated sodium chloride solution (20 ml).
  • the organic phase was dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product was purified by column chromatography (silica gel) using ethyl acetate/hexane/methanol/ammonia solution (25% aq.) (100:10:10:1).
  • the amine was prepared analogously to 2-(piperidin-4-yl)-1,2,3,4-tetrahydro-2,6-naphthyridine trihydrochloride from octahydro-1H-pyrido[1,2-a]pyrazine and tert-butyl 4-oxopiperidine-1-carboxylate (steps iv and v).
  • the combined organic phases were extracted with 1 M hydrochloric acid (20 ml) and water (20 ml).
  • the aqueous phases were combined, adjusted to pH 12 with 1 M sodium hydroxide solution and then extracted with dichloromethane (4 ⁇ 20 ml).
  • the organic phase was then washed with saturated sodium chloride solution (20 ml), dried (Na 2 SO 4 ) and concentrated in vacuo.
  • the crude product was then purified by column chromatography (silica gel) using ethyl acetate/hexane (10:1).
  • the amine was prepared analogously to 3-(piperidin-4-yloxy)pyridine hydrochloride from tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate and 3-pyrrolidinol.
  • 7-Chloro-4-(pyrrolidin-1-yl)quinazoline (A) was prepared from 2-amino-4-chlorobenzoic acid analogously to the following procedure, known from the literature, for the preparation of aminoquinazolines: H. Hayashi et al., Bioorg. Med. Chem., 2003, 11, 383. [Review zur Synthese von Chinazolinen: P. J. Guiry et al., Tetrahedron, 2005, 61, 10153.]
  • reaction mixture was then heated for 15 h at 100° C.
  • the reaction mixture was cooled to room temperature, and water (25 ml) and ethyl acetate (25 ml) were added.
  • the aqueous phase was extracted with ethyl acetate (2 ⁇ 25 ml), and the combined organic phases were washed with saturated sodium chloride solution (20 ml).
  • the organic phase was then dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product was purified by column chromatography (silica gel) using ethyl acetate/dichloromethane/ammonia solution (25% aq.) (50:10:0.5) and ethyl acetate/dichloro-methane/methyl tert-butyl ether/ammonia solution (25% aq.) (50:10:10:0.7).
  • Example Compound 137 was prepared from acid structural unit S32 in a yield of 79% by reaction with 1-(1-methylpiperidin-4-yl)piperazine closely following the process described for Examples 8 and 92-96. MS, m/z 535.2 (MH + )
  • Example compound 164 was prepared from the corresponding acid structural unit in a yield of 80% by reaction with 1-(1-methylpiperidin-4-yl)piperazine closely following the process described for Examples 8 and 92-96.
  • the acid structural unit was prepared analogously to the process described under Method 1 for the preparation of acid structural units for parallel synthesis.
  • Example Compound 178 was prepared from the corresponding acid structural unit in a yield of 29% by reaction with 1-(1-methylpiperidin-4-yl)piperazine closely following the process described for Examples 8 and 92-96.
  • the acid structural unit was prepared analogously to the process described under Method 1 for the preparation of acid structural units for parallel synthesis.
  • the hydrochloride precipitation of the free base relating to Example 178 was carried out from a methyl ethyl ketone/diethyl ether solution of the base with addition of 2 M hydrogen chloride solution in diethyl ether.
  • the reaction mixture was heated to room temperature and stirred for 1 h at that temperature.
  • the phases were separated and the aqueous phase was extracted with diethyl ether (2 ⁇ 25 ml).
  • the combined organic phases were washed with saturated sodium chloride solution (20 ml), dried (Na 2 SO 4 ) and concentrated in vacuo.
  • the crude product was purified by column chromatography (silica gel) using hexane/diethyl ether (3:1).
  • Example compounds listed in the following table were prepared from 1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-(piperidin-2-ylmethoxy)ethanone trihydrochloride by reaction with the corresponding sulfonyl chlorides (R 1 SO 2 Cl) closely following the process described for Example 108 (step (v)).
  • the progress of the reaction was monitored by thin-layer chromatography; the reaction time was in most cases from 15 h to 3 d.
  • the amounts of the reagents used varied as follows: sulfonyl chloride (from 0.9 to 1.5 eq.), triethylamine (3.5-4.5 eq.).
  • the reactions were in some cases carried out in tetrahydrofuran as an alternative to dichloromethane.
  • the sulfonyl chlorides used are commercially available, can be prepared by methods known to the person skilled in the art, or were synthesized according to described processes.
  • the bases were converted into the corresponding dihydrochlorides (2 ⁇ HCl) according to the following general process:
  • the free bases were in each case dissolved in a small amount of dichloromethane or methyl ethyl ketone, and 2 M hydrogen chloride solution in diethyl ether (4-5 eq.) was added. In some cases, the mixture was cooled to 0° C. and/or diethyl ether was added thereto, before the dihydrochloride was filtered out.
  • Example 102 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(piperazin-1-yl)ethanone hydrochloride (Example 102) by reaction with the corresponding ketones (R a R b C ⁇ O) closely following the process described for Example 104 (step (ii)).
  • the reactions were monitored by thin-layer chromatography and had reaction times of from 1 to 15 h.
  • the ketones used are commercially available.
  • Example 102 The example compound shown in the following table was prepared from 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(piperazin-1-yl)ethanone hydrochloride (Example 102) by reaction with the corresponding aldehyde (R a R b C ⁇ O) closely following the process described for Example 117 (step (ii)).
  • the aldehyde used is commercially available.
  • the example compounds listed in the following table were prepared from 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(piperazin-1-yl)ethanone by reaction with the corresponding aldehydes (R a HC ⁇ O) closely following the process described for Example 197 (step (ii)).
  • the aldehydes used are commercially available, can be prepared by methods known to the person skilled in the art, or were synthesized according to described processes.
  • Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.42 g, 3.230 mmol) was then added to the mixture, and stirring was carried out for 3 d at room temperature. The mixture was then concentrated in vacuo, and the residue was taken up in ethyl acetate (30 ml) and saturated sodium hydrogen carbonate solution (20 ml); the aqueous phase was extracted with ethyl acetate (4 ⁇ 10 ml). The combined organic phases were washed with saturated sodium hydrogen carbonate solution (20 ml) and saturated sodium chloride solution (20 ml), dried (MgSO 4 ), and concentrated in vacuo.
  • Example 116 The example compounds listed in the following table were prepared from 1-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetyl)piperidin-4-one (Example 116) by reaction with the corresponding amines (R c R d NH) closely following the process described for Example 130 (step (ii)).
  • the reactions were monitored by thin-layer chromatography and had reaction times of about 15 h. In some cases, additional sodium triacetoxyborohydride was added subsequently. If the amine was not present in the form of the hydrochloride ( ⁇ HCl), no triethylamine was added.
  • the amines used are commercially available, can be prepared by methods known to the person skilled in the art, or were synthesized by described processes.
  • the reaction mixture was stirred for 21.5 h under a hydrogen atmosphere, filtered over Celite, and washed with dichloromethane/ethanol (9:1).
  • the filtrate was concentrated, coevaporated with toluene and diisopropyl ether, and then dissolved in ethyl acetate, filtered over Celite, washed with ethyl acetate and concentrated again.
  • the residue was dissolved in hot diisopropyl ether, filtered, washed with diisopropyl ether, and concentrated for 7 h in vacuo. Yield: 17.12 g (92%)
  • Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (188 mg, 0.429 mmol) was added to the mixture, and stirring was carried out for 15 h at room temperature. The mixture was then concentrated in vacuo, the residue was taken up in ethyl acetate (20 ml) and saturated sodium hydrogen carbonate solution (10 ml), and the aqueous phase was extracted with ethyl acetate (20 ml). The combined organic phases were dried (Na 2 SO 4 ) and concentrated in vacuo.
  • Example compounds listed in the following table were prepared from the corresponding starting materials closely following the process described for Example 185.
  • the progress of the reaction was monitored in each case by thin-layer chromatography and, on the basis thereof, the reaction times for analogous reactions were adapted accordingly.
  • the reaction temperatures and the equivalent amounts of the reagents used can differ slightly in analogous reactions.
  • the starting materials used are commercially available or were prepared in the manner described.
  • the (S)-amino alcohol used was prepared as follows: Hydrogen bromide-tetrahydrofuran complex (3 eq., 1 M solution in tetrahydrofuran) was added dropwise to a suspension, cooled to 0° C., of the carboxylic acid (1 eq.) in tetrahydrofuran (4 ml/mmol), and the mixture was then stirred for 1 h at room temperature. The reaction mixture was then refluxed for 4 h and stirred for a further 15 h at room temperature. The mixture was cooled to 0° C. and 3 M sodium hydroxide solution was added, and then refluxing was carried out for 6 h.
  • Example compounds listed in the following table were prepared analogously to Example 133 from (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol, the corresponding sulfonyl chloride (R 1 SO 2 Cl) and the corresponding amine (R 5 R 6 NH).
  • DBU 1,8-diazabicyclo[5.4.0]-undec-7-ene
  • the reaction mixture was heated to room temperature and then stirred for 2 h at that temperature.
  • the phases were separated, and the aqueous phase was extracted with diethyl ether (2 ⁇ 30 ml).
  • the combined organic phases were washed with saturated sodium chloride solution (30 ml), dried (Na 2 SO 4 ) and concentrated in vacuo.
  • the crude product was filtered over silica gel using ethyl acetate and was used in the next step. Yield: 3.2 g (>99%).
  • Example compounds listed in the following table were prepared from the corresponding starting materials closely following the process described for Example 140.
  • the progress of the reaction was in each case monitored by thin-layer chromatography and, on the basis thereof, the reaction times in analogous reactions were adapted accordingly.
  • the reaction temperatures and equivalent amounts of the reagents used can differ in analogous reactions.
  • the amount of triethylamine used in step (v) in each case was adapted according to the stoichiometry of the amine hydrochloride ( ⁇ HCl) used.
  • the starting materials used are commercially available or were prepared in the manner described.
  • Example compounds listed in the following table were prepared from the corresponding starting materials closely following the process described for Example 201.
  • 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (acid structural unit S27) was synthesized analogously to the process described for Examples 202 and 210 for the preparation of the corresponding carboxylic acid from the corresponding amino alcohol, 4-methoxy-2,6-dimethylbenzene-1-sulfonyl chloride being prepared analogously to the process described for Example 167 (except that 2 eq. of chlorosulfonic acid were used).
  • diisopropylethylamine 2.5 eq.
  • HOBt N-hydroxybenzotriazole
  • EDCI N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • dichloromethane 5 ml/mmol
  • Example compounds listed in the following table were prepared from the corresponding sulfonyl chlorides closely following the process described for Example 202 (step (v)).
  • diisopropylethylamine 2.5 eq.
  • HOBt N-hydroxybenzotriazole
  • EDCI N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • AAV 1 Sulfonylation
  • Acid Structural Units (I) (AAV 1-AAV 3):
  • tert-butyl 2-((1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetate 180 ml of 50% sodium hydroxy solution and 180 ml of tert-butyl bromoacetate were added to a solution of 18 g of (1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methanol, and stirring was carried for 10 minutes. 1.815 g of tetra-n-butylammonium hydrogen sulfate were then added, and stirring was carried out for a further 45 minutes at room temperature.
  • Acid structural unit (Ia) (7.6 mmol) was reacted according to AAV4 with 4-(2-pyrrolidinoethyl)piperidine. The desired product was obtained in a yield of 71%. HPLC-MS, m/z 556.2 (MH + )
  • step A The title compound from step A (18.6 g) was dissolved in THF (190 ml), and the mixture was cooled to ⁇ 78° C. under a protecting gas atmosphere. Then 1.6 M n-BuLi in n-hexane (51 ml) was added sufficiently slowly that the temperature did not rise above ⁇ 70° C. The reaction mixture was stirred for 2 h at ⁇ 70° C., and then MeI (9.7 ml) was added. The reaction mixture was allowed to warm to 0° C. and was stirred for 3 h at that temperature. For working up, sat. NH 4 Cl (80 ml) was added at that temperature, and then the mixture was diluted with EtOAc (500 ml).
  • step B The title compound from step B (0.8 g) was suspended in 4 M HCl (31 ml), and the mixture was heated for 1-2 h at 110° C. It was then cooled to room temperature over a period of 15 h and concentrated completely; the residue obtained after coevaporation twice with DCM (2 ⁇ 30 ml) was dried under a high vacuum. The product so obtained was used in the next step without being purified further. 0.47 g, 70%.
  • step C The title compound from step C (0.46 g) was suspended in toluene (2.2 ml), and SOCl 2 (0.75 ml) and DMF (0.010 ml) were added to the resulting mixture. Heating was then carried out for 1 h at 90° C. until a solution was present. The solution was concentrated completely, and the residue was dried under a high vacuum. The product so obtained was used in the next step without being purified further.
  • step A The title compound from the preparation of 2-methylnaphthalene-1-sulfonyl chloride, step A (20 g) was dissolved in THF (213 ml), and the mixture was cooled to ⁇ 78° C. under a protecting gas atmosphere. Then 1.6 M n-BuLi in n-hexane (55 ml) was added sufficiently slowly that the temperature did not rise above ⁇ 70° C. The reaction mixture was stirred for 2 h at ⁇ 70° C., and then hexachloroethane (21 g) was added. The reaction mixture was allowed to warm to 0° C. and was stirred for 15 h at that temperature. For working up, sat.
  • step A The title compound from step A (3 g) was dissolved in EtOH (15.4 ml), and TFA (0.04 ml) was added. The resulting solution was refluxed for 5 h. After cooling, the mixture was concentrated and the residue was dissolved in DCM (20 ml) and washed with water (10 ml). After drying over MgSO 4 , complete concentration was carried out. The resulting product was used in the next step without being purified further. 2.2 g, 87%.
  • step 4 The title compound from Example 107, step 4 (1.0 g) was placed in DCM (19 ml); cooling to 0° C. was carried out, and Et 3 N (1.8 ml) was added. The title compound from step A (0.5 g) was then added rapidly at that temperature. Stirring was carried out at RT until TLC monitoring indicated that the reaction was complete. For working up, NH 4 Cl solution (10 ml) and water (10 ml) were added, and the organic phase was separated off. The aqueous phase was extracted with DCM (3 ⁇ 15 ml), and the combined organic phases were washed with water (10 ml) and sat. NaCl solution (10 ml).
  • Examples 157, 160, 173-176 and 191 were prepared closely following the process described for Example 179, except that the sulfonyl chlorides and amines mentioned in the following table were used. The preparation of sulfonyl chlorides that are not commercially available was carried out as described above.
  • Methylamine (350 ml of a 40% aqueous solution, 4.06 mol) was added to a solution of 4-(bromomethyl)benzonitrile (51.3 g, 262 mmol) in EtOH (500 ml). After 2 h, the solvent was removed in vacuo and CH 2 Cl 2 (500 ml) and aqueous saturated NaHCO 3 solution (400 ml) were added. The organic phase was separated off and extracted with aqueous saturated NaCl solution (250 ml), over Na 2 SO 4 , and the solvent was removed after filtration in vacuo.
  • Et 3 N 35.96 ml, 256 mmol was added to a solution of the amine (31.17 g, 213 mmol) in CH 2 Cl 2 (150 ml).
  • Benzyl chloroformate 36.37 ml, 256 mmol was then added dropwise at a temperature of 0° C.
  • the reaction mixture was stirred overnight at RT and washed with aqueous 0.1 M HCl (150 ml) and H 2 O (150 ml), dried over Na 2 SO 4 and filtered out, and the solvent was removed in vacuo.
  • the Boc-protected imidazoline (3.03 g, 7.15 mmol) was dissolved in absolute EtOH (60 ml) and hydrogenated under nitrogen for 10 min. with Pd/C (10%, 381 mg, 0.36 mmol) and hydrogen. After stirring for 2 h at RT, filtration over kieselguhr was carried out, followed by washing with EtOH. After removal of the solvent in vacuo, the product was used in the next step without being worked up further.
  • the agonistic or antagonistic action of substances can be determined on the bradykinin receptor 1 (B1R) of the species human and rat using the following assay.
  • B1R bradykinin receptor 1
  • the Ca 2+ influx through the channel is quantified with the aid of a Ca 2+ -sensitive dye (type Fluo-4, Molecular Probes Europe BV, Leiden, Netherlands) using a Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, USA).
  • CHO K1 cells Chinese hamster ovary cells (CHO K1 cells) which have been stably transfected with the human B1R gene (hB1R cells, Euroscreen s.a., Gosselies, Belgium) or with the B1R gene of the rat (rB1R cells, Axxam, Milan, Italy) are used.
  • the cells are plated out on black 96-well plates having a clear base (BD Biosciences, Heidelberg, Germany) in a density of 20,000-25,000 cells/well. The cells are incubated overnight at 37° C.
  • hB1R cells Nutrient Mixture Ham's F12, Gibco Invitrogen GmbH, Düsseldorf, Germany; rB1R cells: D-MEM/F12, Gibco Invitrogen GmbH, Düsseldorf, Germany), with 10 vol. % FBS (fetal bovine serum, Gibco Invitrogen GmbH, Düsseldorf, Germany).
  • FBS fetal bovine serum
  • HBSS buffer Hank's buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany
  • probenecid Sigma-Aldrich, Taufmün, Germany
  • 10 mM HEPES Sigma-Aldrich, Taufmün, Germany
  • BSA bovine serum albumin
  • gelatin Merck KGaA, Darmstadt, Germany
  • the plates After incubation for a further 20 minutes at room temperature, the plates are inserted into the FLIPR for Ca 2+ measurement.
  • the FLIPR protocol consists of 2 substance additions. Test substances (10 ⁇ M) are first pipetted onto the cells and the Ca 2+ influx is compared with the control (hB1R: Lys-Des-Arg 9 -bradykinin 0.5 nM; rB1R: Des-Arg 9 -bradykinin 100 nM). This gives the activation in %, based on the Ca 2+ signal after addition of Lys-Des-Arg 9 -bradykinin (0.5 nM) or Des-Arg 9 -bradykinin (100 nM).
  • B1R Antagonists Inhibition of the Bradykinin Receptor 1 (B1R)-Mediated Formation of IL-6 in Fibroblasts by Substances According to the Invention as B1R Antagonists
  • the pro-inflammatory cytokines TNF ⁇ lead in various cell types, such as, for example, fibroblasts, to an activation, which brings about inter alia enhanced expression of B1R.
  • a B1R agonist results in the formation of further pro-inflammatory cytokines, such as, for example, IL-6.
  • the chronification of inflammations is thereby promoted.
  • Treatment with a B1R antagonist should lead to inhibition of the B1R agonist-induced IL-6 formation.
  • a B1R antagonist identified in the FLIPR assay was tested in this respect.
  • the human fibroblast cell line IMR-90 (ATCC, CCL-186) was passaged in culture medium (Ham's F12 nutrient mixture, Gibco Invitrogen GmbH, Düsseldorf Germany with 10% FBS, fetal bovine serum, Gibco, Invitrogen GmbH, Düsseldorf Germany; 0.1 mM non-essential amino acids, Gibco, 11140-035, 1 mM sodium pyruvate, Euro Clone, ECM0542D; 1.5 g/l sodium bicarbonate, Euro Clone, ECM0980D) on 80 cm 2 bottles (Nunc; 178905) (ratio: 1:2 to 1:6; medium replaced every 3-4 days) and plated out for experiments on 96-well plates (Greiner bio-one; No. 655180) with 1 ⁇ 10 5 cells per well. The cells are incubated overnight at 37° C. and 5% CO 2 .
  • TNF ⁇ human, recombinant, expressed in E. coli , SIGMA-ALDRICH T6674, 10 ng/ml
  • TNF ⁇ human, recombinant, expressed in E. coli , SIGMA-ALDRICH T6674, 10 ng/ml
  • Lys-Des-Arg 9 -BK human B1R agonist Lys-Des-Arg 9 -bradykinin
  • the final concentrations of Lys-Des-Arg 9 -BK were 1000 nM or 10 nM.
  • Some IMR-90 stimulation batches additionally contained the B1R antagonist of Example 8 in a final concentration of 10 ⁇ M.
  • IL-6 content was determined by means of a commercially available IL-6 Elisa.
  • Elisa kit from: BIOSOURCE; CytoSetsTM, Art. No.: CHC 1264 Material: 96-well microplates: NUNC Brand Systems, Art. No.: 442404A
  • Coating application of primary antibody solution: 50 ⁇ l/well Incubation: covered plate overnight at RT, then tap the plate
  • Blocking application of blocking buffer: 300 ⁇ l/well; incubate plate for 2 hours at RT Washing: 3 ⁇ with 300 ⁇ l of washing solution/well Standard; samples; secondary antibody: application standard, samples per 50 ⁇ l/well immediate addition of the secondary antibody solution: application: 25 ⁇ l/well
  • Incubation shake covered plate for 2 h at RT Washing: 3 ⁇ with 300 ⁇ l of washing solution/well
  • Streptavidin application of streptavidin solution: 100 ⁇ l/well Incubation: covered plate 30 min.
  • Stimulation with TNF ⁇ in combination with Lys-Des-Arg 9 -BK results in an about 10- to 20-fold increase in IL-6 synthesis.
  • This activation of IL-6 formation is inhibited by the B1R antagonist of Example 8 in a dose-dependent manner.
  • the action of the relatively low dose of the agonist Lys-Des-Arg 9 -BK (10 nM) is eliminated almost completely, whereas a relatively high dose of Lys-Des-Arg 9 -BK (1000 nM) is still partially inhibited.
  • the inhibitory action of Example 8 is B1R-specific, because the activating effect of TNF ⁇ alone is not taken into account.
  • the formalin test (Dubuisson, D. and Dennis, S. G., 1977, Pain, 4, 161-174) represents a model for both acute and chronic pain.
  • a biphasic nociceptive reaction is induced in freely mobile test animals; the reaction is detected by observing three behaviour patterns which are clearly distinguishable from one another.
  • the 1st phase reflects a direct stimulation of the peripheral nocisensors with high spinal nociceptive input (acute pain phase); the 2nd phase reflects a spinal and peripheral hypersensitization (chronic pain phase).
  • acute pain phase a direct stimulation of the peripheral nocisensors with high spinal nociceptive input
  • 2nd phase reflects a spinal and peripheral hypersensitization (chronic pain phase).
  • chronic pain component phase 2 has been evaluated.
  • Formalin in a volume of 20 ⁇ l and a concentration of 1% is administered subcutaneously into the dorsal side of the right rear paw of each animal.
  • the specific changes in behavior, such as lifting, shaking or licking of the paw (score 3, Dubuisson & Dennis, 1977), are observed and recorded in the observation period of 21 to 24 minutes following the formalin injection.
  • ED 50 mean effective dose
  • the time of administration before the formalin injection was chosen in dependence on the mode of administration of the compounds according to the invention (intravenous: 5 min.).
  • Type of Example administration ED 50 value [mg/kg] 8 i.v. 12.8 97 i.v. 13.3 98 i.v. 13.6 193 i.v. 2.59

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WO2011125967A1 (ja) 2010-04-05 2011-10-13 塩野義製薬株式会社 カテコール基を有するセフェム化合物
US8680159B2 (en) 2010-09-22 2014-03-25 Gruenenthal Gmbh Bradykinin 1 receptor modulating compounds
WO2018212534A1 (en) 2017-05-17 2018-11-22 Legochem Biosciences, Inc. Novel compounds as autotaxin inhibitors and pharmaceutical compositions comprising the same
CN109810031A (zh) * 2017-11-21 2019-05-28 乳源瑶族自治县东阳光生物科技有限公司 非罗考昔中间体的制备方法
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