EP2262792A1 - Dérivés de sulfonamide substitués - Google Patents

Dérivés de sulfonamide substitués

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Publication number
EP2262792A1
EP2262792A1 EP09730791A EP09730791A EP2262792A1 EP 2262792 A1 EP2262792 A1 EP 2262792A1 EP 09730791 A EP09730791 A EP 09730791A EP 09730791 A EP09730791 A EP 09730791A EP 2262792 A1 EP2262792 A1 EP 2262792A1
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EP
European Patent Office
Prior art keywords
piperidin
ethoxy
methoxy
pyrrolidin
pyridin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09730791A
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German (de)
English (en)
Inventor
Stefan OBERBÖRSCH
Melanie Reich
Stefan Schunk
Michael Franz-Martin Engels
Ruth Jostock
Tieno Germann
Jean De Vry
Klaus Schiene
Sabine Hees
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Gruenenthal GmbH
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Gruenenthal GmbH
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Priority to EP09730791A priority Critical patent/EP2262792A1/fr
Publication of EP2262792A1 publication Critical patent/EP2262792A1/fr
Withdrawn legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
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Definitions

  • the present invention relates to substituted sulfonamide derivatives, processes for their preparation, medicaments containing these compounds and the use of substituted sulfonamide derivatives 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 B1 R on neuronal cells but also various peripheral cells such as fibroblasts, endothelial cells, granulocytes, macrophages and
  • Lymphocytes Lymphocytes.
  • IL-1 interleukin-1
  • TNF ⁇ tumor necrosis factor alpha
  • B1R-expressing cells may subsequently self secrete pro-inflammatory cytokines such as IL-6 and IL-8 (Hayashi et al., Eur Respir, J., 2000, 16, 452-458).
  • 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 (Stadnicki et al., Am J.
  • B1 R antagonists in acute and, in particular, chronic inflammatory diseases.
  • respiratory diseases bronchial asthma, allergies, COPD / chronic obstructive pulmonary disease, cystic fibrosis, etc.
  • inflammatory bowel disease ulcerative colitis, CD / Crohn's disease, etc.
  • neurological disorders 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.
  • B 1 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.
  • the invention relates to substituted sulfonamide derivatives of the general formula I.
  • Q is a single bond, -O- or -CH 2 -;
  • R 1 is aryl or heteroaryl, or is bonded via an alkylene group Ci -3 aryl or heteroaryl;
  • R 2 and R 3 are defined as described under (i) or (ii):
  • R 2 is H, C 1-6 -alkyl, C 3-8 -cycloalkyl, bicyclic 8-12-membered
  • Carbocyclyl, aryl or heteroaryl means 6 alkynylene group bonded C 3-8 cycloalkyl, bicyclic 8- to 12-membered carbocyclyl, CH (aryl) 2, aryl or heteroaryl - or a 1-6 alkylene group with a C, C 2 - 6 alkenylene or C 2 ;
  • R 3 is H, Ci- 6 alkyl, aryl or heteroaryl; or a C 1-6 - alkylene group, C 2 - 6 alkenylene or C 2 - 6 alkynylene group bonded aryl or heteroaryl;
  • R 8 is C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl or a Ci -3 alkylene group bonded via a C 3-8 cycloalkyl, aryl or Heteroaryl means;
  • R 4 is aryl, heteroaryl or an aryl or heteroaryl bonded through a C 1-6 alkylene group
  • CI_ R 5 and R 6 are independently H, 6 alkyl, C 3-8 -CyClOa I ky I, or a bonded via a Ci -3 alkylene C 3-8 -cycloalkyl, with the proviso that R 5 and R 6 do not represent H at the same time; or R 5 and R 6 together represent a substituted or unsubstituted 5 or 6-membered heteroaryl which, in addition to the N atom to which R 5 and R 6 are bonded, also contain at least one further heteroatom from the group N, O or S.
  • Aryl and heteroaryl can each be unsubstituted or monosubstituted or polysubstituted by identical or different radicals and the above radicals indicated C 1-6 alkyl, C 1-6 alkylene, C 2-6 -AlkenyIen and C 2-6 alkynylene, each may be branched or unbranched;
  • halogen is preferably the radicals F, Cl, Br and I, particularly preferably the radicals F, Cl and Br.
  • halide anion stands for fluoride, chloride, bromide and iodide.
  • C 1-6 -alkyl for the purposes of this invention comprises acyclic saturated hydrocarbon radicals having 1, 2, 3, 4, 5 or 6 C atoms which are branched or straight-chain (unbranched) and unsubstituted or mono- or polysubstituted, For example, 2-, 3-, 4- 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 2-6 alkenyl in the context of this invention comprises acyclic unsaturated hydrocarbon radicals having 2, 3, 4, 5 or 6 C atoms which are 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 may be substituted.
  • Alkenyl radicals may preferably be selected from the group consisting of vinyl, prop-1-enyl, allyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1, 3-dienyl, 2-methylprop-1-enyl, but-2-en-2-yl, but-1-en-2-yl, pentenyl and hexenyl.
  • alkenyl radicals can be selected from the group consisting of vinyl, prop-1-enyl, allyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1 , 3-dienyl, 2-methylprop-1-enyl, but-2-en-2-yl and but-1-en-2-yl.
  • C 3-8 -cycloalkyl means cyclic saturated hydrocarbons having 3, 4, 5, 6, 7 or 8 carbon atoms which are unsubstituted or mono- or polysubstituted on one or more ring members, for example 2, 3, 4 or 5, the same or different radicals may be substituted.
  • 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 monosubstituted or polysubstituted, for example 2, 3, 4 or 5 times, substituted, where the aryl substituents can be identical or different and in any desired 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, oxadiazolyl, isoxazoyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl,
  • bicyclic 8-12-membered carbocyclyl in the context of the present invention represents ring-shaped hydrocarbon compounds which consist of two fused ring systems, wherein the two ring systems together have 8-12 ring members and no heteroatoms
  • bicyclic 8-12-membered carbocycles are compounds which consist of an aromatic and a fused-on saturated ring system
  • General structure I can be carried out via any and possible ring member of the carbocyclyl radical, but preferably via a ring member of an unsaturated ring.
  • the bicyclic 8-12-membered carbocyclyl can be selected from the group end of 2,3-dihydro-1H-indenyl or 1, 2, 3, 4-tetrahydronaphthyl.
  • C 1-6 -alkylene group for the purposes of the present invention comprises acyclic saturated hydrocarbon radicals having 1, 2, 3, 4, 5 or 6 C atoms which are branched or straight-chain (unbranched) and unsubstituted or mono- or polysubstituted For example, 2-, 3-, 4- or 5-fold, may be substituted with the same or different radicals and linking a corresponding radical with the parent general structure.
  • 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 - (CH 2 ) 2 -CH 2 -, -CH (CHs) -CH 2 -CH 2 -, -CH 2 -CH (CHs ) -CH 2 -, -CH (CHs) -CH (CH 3 ) -, -CH (CH 2 CH 3 ) -CH 2 -, -C (CH 2 ) 2 -CH 2 -, -CH (CH 2 CH 2 (-C CH 3) (CH 2 CH 3) - - CH 3), -CH 2 - (CH 2) 3 -CH 2 -, -CH (CH 3) - CH 2 -CH 3),
  • C 2-6 alkenylene group in the context of the present invention comprises acyclic, mono- or polysubstituted, for example 2-, 3- or 4-membered, unsaturated hydrocarbon radicals having 2, 3, 4, 5 or 6 C atoms which branched or straight-chained (unbranched) and unsubstituted or mono- or polysubstituted, for example 2-, 3-, 4- or 5-fold, may be substituted by the same or different radicals and linking a corresponding radical with the parent general structure.
  • C 2-6 -alkynylene group for the purposes of the invention comprises acyclic, mono- or poly-substituted, for example 2-, 3- or 4-membered, unsaturated hydrocarbon radicals having 2, 3, 4, 5 or 6 carbon atoms which are branched - or straight-chain (unbranched) and unsubstituted or mono- or polysubstituted, for example 2-, 3-, 4- or 5-fold, may be substituted by the same or different radicals and linking a corresponding radical with the parent general structure.
  • the alkynylene groups have at least one C ⁇ C triple bond.
  • aryl or heteroaryl bonded via a C 1-6 -alkylene group, C 2-6 -alkenylene group or C 2-6 -alkynylene group in the context of the present invention means that the C 1-6 -alkylene groups, C 2-6 Alkenylene groups, C 2-6 - alkynylene groups and aryl or heteroaryl have the meanings defined above and the aryl or heteroaryl via a C 6 alkylene group, C 2 - 6 alkenylene or C 2 - 6 alkynylene group is attached to the general structure of higher. Examples include benzyl, phenethyl and phenylpropyl.
  • C 3-8 -CyClOa I ky I and heterocyclyl bonded via a C 1-6 -alkylene group, C 2-6 -alkenylene group or C 2-6 -alkynylene group means in the context of the present invention that the C 1-6 alkylene, C 2-6 alkenylene, C 2-6 - alkynylene, C 3 - 8 cycloalkyl and heterocyclyl are as defined above and C 3-8 cycloalkyl and heterocyclyl via a ⁇ -d-alkylene group, C 2- 6 - alkenylene group or C 2-6 alkynylene group is bonded to the general structure above.
  • alkyl alkenyl
  • alkylene alkenylene
  • alkynylene alkynylene
  • cycloalkyl substituted in the context of this invention, the substitution of a hydrogen radical by F, Cl, Br, I.
  • 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 -OC 1-3 -alkyl, unsubstituted C 1-6 -alkyl, F, Cl, Br, I, CF 3 , OCF 3 , OH, SH, phenyl, Naphthyl, furyl, thienyl and pyridinyl, in particular from the group consisting of F, Cl, Br, CF 3 , CH 3 and OCH 3 .
  • bicyclic 8- to 12-membered carbocyclyl in the context of this invention "substituted” is understood to mean the single or multiple substitution of hydrogen atoms of the corresponding ring systems of the bicyclic carbocyclyl.
  • Preferred substituents for aromatic ring members of the bicyclic 8- to 12-membered Carbocyclyls can can be selected from the group consisting of -O-Ci -3 alkyl, unsubstituted C 1-6 alkyl, F, Cl, Br, I, CF 3 , OCF 3 , OH, SH, phenyl, naphthyl, furyl, thienyl and pyridinyl, in particular from the group consisting of F, Cl, Br, CF 3 , CH 3 and OCH 3 .
  • 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-1, 6- benzo [d] isothiazol-3-one (saccharic acid), monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ - Lipoic acid, acetylglycine, hippuric acid, phosphoric acid, and / or
  • the radical R 1 is phenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl (benzothienyl); Benzooxazolyl, benzooxadiazolyl, pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazothiazolyl, carbazolyl, dibenzofuranyl or dibenzothiophenyl (dibenzothienyl), benzyl or phenethyl, preferred for phenyl, naphthyl, benzothiophenyl, benzooxadiazolyl, thiophenyl, pyridinyl, imidazothiazolyl or dibenzofuranyl particularly preferably represents phen
  • the radical R 1 is phenyl or naphthyl, where the phenyl or naphthyl is unsubstituted or mono- or polysubstituted, for example 2, 3, 4 or 5-fold, is substituted with the same or different radicals selected from the group consisting of methyl, methoxy, CF 3 , OCF 3 , F, Cl and Br.
  • the radical R 1 in the sulfonamide derivatives according to the invention 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, 2-chloro-6- (trifluoromethyl) phenyl, 2,6-dichloro-4-methoxyphenyl , 2-methylnaphthyl, 2-chloronaphthyl, 2-fluoronaphthyl, 2-chloro-4- (trifluoromethoxy) phenyl, 4-chloro-2,5-dimethylphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2,4- Dichlorophenyl, 2- (trifluoromethyl) phenyl
  • p and o are 1; p is 1 and o is O or p is 2 and o is 1.
  • Q is a single bond, m is 0 or 1 and n is 1 or 2; or Q is -O-, m is 1 or 2 and n is 1.
  • R 4 represents phenyl, a Ci -3 - bound alkylene phenyl; 2-, 3-, or 4-pyridinyl or bonded via a C 1-3 - alkylene 2-, 3-, or 4-pyridinyl, where the phenyl may be mono- or polysubstituted by F, Cl 1 or CF 3, respectively , In particular, the phenyl may be readily substituted in the 3- or 4-position, especially with F.
  • q is 1 or 2.
  • R 5 and R 6 including the N atom to which they are attached, may be selected from a group represent.
  • R 5 and R 6 together with the N-atom to which they are attached form a heteroaryl group selected from imidazolyl, in particular 1H-imidazol-1-yl, triazolyl, in particular 1H- [1,2 , 4] triazole-1 7 yl], tetrazolyl, pyrazolyl, benzimidazolyl, pyrrolyl or indolyl, where all these heteroaryl groups each unsubstituted, may be mono- or polysubstituted with identical or different groups, which may be selected in particular from the group consisting of F , Cl, Br, CF 3 , CH 3 and OCH 3 .
  • the heteroaryl group formed by R 5 and R 6 is selected from the group consisting of Imidazoly, in particular 1H-imidazol-1-yl, and triazolyl, in particular 1H- [1,2,4] triazol-1-yl].
  • R 2 is H 1 C 1-6 alkyl, C 3-6 cycloalkyl, 8- to 10-membered cycloalkyl benzanillatorss, CH (phenyl) 2, Aryl or heteroaryl; or R 2 represents a 2- 6 alkenylene group or C 2-6 via a C 1-6 alkylene group, C - alkynylene group bonded C 3 - 6 cycloalkyl, CH (phenyl) 2, aryl or heteroaryl, wherein the groups C - ⁇ -6 alkyl, C 3 - 8 in each case unsubstituted 6 cycloalkyl, C 2-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene to 10-membered benzanilltechnischators cycloalkyl, aryl, and heteroaryl or aryl, and heteroaryl, in particular mono- or polysubstituted, may
  • R 2 is H, substituted or unsubstituted C 1-6 -alkyl, 2,3-dihydro-1H-indenyl or cyclopropyl; or R 2 is CH (phenyl) 2, phenyl, pyridinyl or a via a C- ⁇ -6 alkylene group bonded phenyl or pyridinyl, wherein said phenyl or pyridinyl each being unsubstituted or mono- or polysubstituted by identical or different radicals, wherein the radicals are selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, methoxy, F, Cl, Br, I, CF 3 , OCF 3 and OH.
  • R 3 is H, C 1-6 -alkyl or aryl; or R 3 represents a via a C 1-6 alkylene, C 2-6 alkenylene or C 2- 6-alkynylene group bonded aryl, where the radicals Ci-e-alkyl, C 3-6 cycloalkyl, C 2- 6- alkylene, C 2-6 -alkenylene, C 2-6 - alkynylene or aryl may each be unsubstituted or substituted, the aryl may in particular be mono- or polysubstituted by identical or different radicals selected from the group consisting of Ci- ⁇ - Alkyl, C 1-6 alkyl-O-, F, Cl, Br, I, CF 3 , OCF 3 , OH and SH.
  • R 3 may be H or phenyl wherein the phenyl is in each case unsubstituted or monosubstituted or polysubstituted by identical or different radicals, where the substituents are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl, tert-butyl, methoxy, F, Cl, Br 1 I, CF 3 , OCF 3 and OH.
  • a, b and c independently of one another, are each O or 1;
  • R 9 , R 10 , R 11a , R 11b and R 11c are each H or two vicinal radicals of R 9 , R 10 , R 11a , R 11b and R 11c are a 5- or 6-membered fused aryl or form heteroaryl radical which may be unsubstituted or monosubstituted or polysubstituted by identical or different radicals.
  • the heterocycle (II) can be selected from
  • radicals R 9 and R 10 may together form a fused benzo group.
  • R is the corresponding radical of R, R 1D or R 11C ,
  • R is the corresponding radical of R 11b or R 11c
  • v and w are 1 and R 20 is C 1-6 -alkyl.
  • R 20 is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl or tert-butyl. It is particularly preferred that An " stands for iodide.
  • substituted sulfonamide derivatives according to the invention are compounds having the general formula Ia
  • X, Y or Z is N, CH; CF, C-Cl or C-CF 3 , provided that only one of X, Y or Z is other than CH, where X, Y and Z are preferably not simultaneously CH, and the radicals An ' .Q, R 1 , R 5 and R 6 , R 9 , R 10 , R 11a , R 11b and R 20 and the variables b, m, n, o, q, r, v and w have the respective meanings as in the preceding can take the described embodiments of the invention.
  • v, w and r are each 0.
  • v and w are 0 and r is 1.
  • substituted sulfonamide derivatives of the invention are compounds of general formula Ib
  • X, Y or Z is N, CH; CF, C-Cl or C-CF 3 , provided that only one of X, Y or Z is other than CH, where X, Y and Z are preferably not simultaneously CH, and the radicals An ' , Q, R 1 , R 5 and R 6 , R 9 , R 10 , R 11a R 11b and R 20 and the variables o, q, v and w may assume the respective meanings as in the preceding embodiments of the invention described above.
  • v, w and r are 0.
  • v and w are 0 and r is 1.
  • substituted sulfonamide derivatives according to the invention are compounds having the general formulas Ic, Id, Ie, If, Ig and Ih
  • r is preferably O or 1.
  • v is O
  • w is 0, r is 1 and q is 1.
  • R 1 is preferably phenyl or naphthyl, where the phenyl or naphthyl unsubstituted or singly or multiply selected, for example, 2-, 3-, 4- or 5-fold, with identical or different radicals from the group consisting of methyl, methoxy, CF 3 , OCF 3 , F, Cl and Br is substituted;
  • R 1 is 4-methoxy-2,6-dimethylphenyl, 4-chloro-2,5-dimethylphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-chloro-6-methylphenyl , 2-methyl-4-chlorophenyl, 2- (trifluoromethyl) phenyl, 3- (trifluoromethyl) phenyl, 1-naphthyl or 2-naphthyl.
  • R 2 is preferably selected from H, methyl, cyclopropyl, -CH (Ph) 2 , (pyridin-3-yl) methyl and 2,3-dihydro-1H-indene-1 yl;
  • the benzo group or the pheny groups in R 2 can be unsubstituted or substituted, preferably with a substituent selected from methyl, methoxy, CF 3 , F, Cl and Br.
  • R 3 is preferably selected from H or phenyl, where the phenyl group may be unsubstituted or substituted, preferably with a substituent selected from methyl, methoxy, CF 3 , F, Cl and Br.
  • R 9 , R 10 , R 11a and R 11b independently of one another, are each H or two vicinal radicals of R 9 , R 10 , R 11a and R 11b , preferably R 9 and R 10 , form an anellated benzo group which may be unsubstituted or mono- or polysubstituted by identical or different radicals, preferably with radicals independently selected from the group consisting of methyl, methoxy, CF 3 , F, Cl and Br.
  • (A * ) is a group selected from
  • o is 0, 1 or 2 and p is 0 or 1
  • q is 0, 1 or 2, preferably 1 or 2
  • X, Y and Z are N, CH; CF, C-Cl or C-CF 3 , provided that only one of X, Y or Z is any other than CH, with X, Y and Z preferably not being CH at the same time.
  • Y or Z, in particular Z 1 represent N or CF.
  • Y is N and X and Z are CH.
  • R 20 is methyl, ethyl, n-propyl, s-propyl, i-propyl, n-butyl, s-butyl, i-butyl or t-butyl, in particular methyl; and
  • An " represents a halide anion, especially iodide.
  • the partial structure S * is of the general formula I
  • radicals R 1 , R 2 and R 3 may assume the respective meanings as in the preceding embodiments of the invention described above.
  • the partial structure S * shown above is selected from the group consisting of
  • the radical R 1 can assume the respective meanings as in the preceding embodiments described according to the invention and the fused benzo group unsubstituted or as described above in connection with the term "aryl" substituted.
  • the sulfonamide derivatives according to the invention are 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 agonistic or antagonistic effect of substances can on the bradykinin receptor 1 (B1R) of the species human and rat using 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 -bradykinin (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 can act, for example, on the B1 R relevant in connection with various diseases, so that they are suitable as pharmaceutical active substance in medicaments.
  • Another object of the invention are therefore medicaments containing at least one inventive substituted sulfonamide derivative, and optionally suitable additives and / or adjuvants and / or optionally other active ingredients.
  • the medicaments according to the invention optionally contain suitable additives and / or adjuvants, such as carrier materials, fillers, solvents, diluents, dyes and / or binders and can be used as liquid dosage forms in the form of injection solutions, drops or juices, be administered 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, be administered 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
  • 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, readily reconstitutable dry preparations and sprays.
  • Sulfonamide derivatives according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of main-promoting agents, are suitable percutaneous administration preparations.
  • Orally or percutaneously applicable preparation forms can release the substituted sulfonamide derivatives according to the invention with a delay.
  • the substituted sulfonamide derivatives of 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, preferably 0.01 to 5 mg / kg of at least one substituted sulfonamide derivative according to the invention applied.
  • a substituted sulfonamide derivative according to the invention 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.
  • substituted sulfonamide derivatives of the invention may be used for the treatment and / or manufacture of a medicament for the treatment of pain, in particular acute, visceral, neuropathic, chronic pain or inflammatory pain.
  • Another object of the invention is therefore the use of a substituted sulfonamide derivative according to the invention treatment and / or for the manufacture of a medicament for the treatment of pain, in particular of acute, visceral, neuropathic, chronic pain or inflammatory pain.
  • Another object of the invention is the use of a substituted sulfonamide derivative according to the invention for the treatment and / or 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.
  • 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
  • a substituted sulfonamide derivative used as a pure diastereomer and / or Enantiomer is present as a racemate or as a non-equimolar or equimolar mixture of diastereomers and / or enantiomers.
  • Another object of the invention is a method for the treatment, in particular in one of the aforementioned indications, of a non-human mammal or human, which or a treatment of pain, especially chronic pain, requires by administering a therapeutically effective dose of a substituted sulfonamide derivative according to the invention , or 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 described in the following description, examples and claims.
  • the substituted sulfonamide derivatives according to the invention are prepared according to the method described below, wherein step 2 of the process shown below is required only for the synthesis of the N-oxide or alkyl or arylammonium compounds .:
  • the free amines (A) and the carboxylic acids (S) are converted into the compounds (P) according to the invention in an amide formation in the presence of at least one dehydrating agent and one organic base in an organic solvent.
  • dehydrating agents for example, sodium or magnesium sulfate, phosphorus oxide or reagents such as CDI 1 DCC (optionally polymer bound), TBTU, EDCI, PyBOP or PFPTFA can also be used in the presence of HOAt or HOBt.
  • organic bases for example, triethylamine, DIPEA or pyridine and as organic solvents THF, dichloromethane, diethyl ether, dioxane, DMF or acetonitrile can be used.
  • the temperature in the amide-forming step (1) is preferably between 0 and 50 ° C.
  • step 1 The compounds (P) thus obtained by step 1 can be converted into ammonium salts or N-oxides according to the invention in step 2 by alkylation with alkylhalides, for example methyl iodide, or oxidation with m-chloroperbenzoic acid, H 2 O 2, dimethyldioxirane, oxone or perhydrol.
  • alkylhalides for example methyl iodide, or oxidation with m-chloroperbenzoic acid, H 2 O 2, dimethyldioxirane, oxone or perhydrol.
  • an organic or inorganic base for example potassium carbonate, sodium carbonate, sodium bicarbonate, diisopropylethylamine, triethylamine, pyr
  • the sulfonylated amino alcohols B are used in an alkylation reaction with halogenated ester derivatives using tetrabutylammonium chloride or bromide or tetrabutylammonium hydrogensulfate in a phase transfer reaction using an organic solvent such as THF, toluene, benzene or xylene and inorganic bases such as potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or in the presence of an organic or inorganic base, conventional inorganic bases
  • Metal alcoholates such as sodium methoxide, sodium ethanolate, potassium tert-butylate, lithium or sodium bases such as lithium diisopropylamide, butyllithium, tert-butyl lithium, sodium methylate or metal hydrides such as potassium hydride, lithium hydride, sodium hydride, customary organic bases are diisopropylethylamine, triethylamine, in an organic solvent such as dichlor
  • an organic or inorganic base for example potassium carbonate, sodium bicarbonate, diisopropylethylamine, triethylamine, pyridine, dimethyla
  • mesylates or alternative Alkyl michsreagenzien optionally in the presence of an organic or inorganic base, for example sodium hydride, potassium carbonate, cesium carbonate, DBU or DIPEA preferably in an organic solvent such as dimethylformamide, acetone, THF, acetonitrile, dioxane or these solvents as mixtures, at a temperature of 0 0 C to reflux temperature, converted to the sulfonylated amino alcohols B.
  • an organic or inorganic base for example sodium hydride, potassium carbonate, cesium carbonate, DBU or DIPEA preferably in an organic solvent such as dimethylformamide, acetone, THF, acetonitrile, dioxane or these solvents as mixtures, at a temperature of 0 0 C to reflux temperature, converted to the sulfon
  • the ester derivatives C are ester cleaved 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 bicarbonate, potassium carbonate in organic solvents such as methanol, dioxane, Dichloromethane, THF, diethyl ether or these solvents as mixtures, at 0 0 C to room temperature, to the acid stages of the general formula D implemented.
  • organic acids such as trifluoroacetic acid or aqueous inorganic acids such as hydrochloric acid
  • aqueous inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate in organic solvents such as methanol, dioxane, Dichloromethane, THF, diethyl ether or these solvents as mixtures, at 0 0 C
  • an organic or inorganic base for example potassium carbonate, sodium carbonate, sodium bicarbonate, diisopropylethylamine, Triethylamine, pyridine, dimethylaminopyridine, diethylamine or DBU, preferably in an
  • the sulfonylated amines are then reacted in an alkylation reaction with methyl 2-bromoacetate or derivatives H in an alkylation reaction, if appropriate in the presence of an organic or inorganic base, for example sodium hydride, potassium carbonate, cesium carbonate, DBU or DIPEA, preferably in an organic solvent, for example dimethylformamide, acetone, THF, acetonitrile, dioxane or these solvents are reacted as mixtures to the sulfonylated Aminoestem I.
  • an organic or inorganic base for example sodium hydride, potassium carbonate, cesium carbonate, DBU or DIPEA
  • the sulfonylated aminoxides I are reacted in a reaction to a sulfonylated amino alcohols B, using metal hydrides as reducing agents such as LiAlH 4 , BH 3 x DMS or NaBH 4 in an organic solvent such as THF or diethyl ether.
  • metal hydrides as reducing agents such as LiAlH 4 , BH 3 x DMS or NaBH 4 in an organic solvent such as THF or diethyl ether.
  • the further method of method IV corresponds to the other methods.
  • the racemic (R and S configuration) or enantiomerically pure (R or S configuration) amino acid esters A or acids L are reduced to an aminoalcohol B 1 using metal hydrides as reducing agents such as LiAlH 4 , BF 3 -Etherat, BH 3 x DMS or NaBH 4 in an organic solvent such as THF or diethyl ether, at temperatures from 0 ° C to reflux temperature reacted.
  • metal hydrides as reducing agents such as LiAlH 4 , BF 3 -Etherat, BH 3 x DMS or NaBH 4 in an organic solvent such as THF or diethyl ether
  • an organic or inorganic base for example potassium carbonate, sodium bicarbonate, Diisopropylethylamine, triethylamine, pyridine, dimethylaminopyridine, diethylamine or DBU, preferably in an organic
  • the sulfonylated amino alcohols C are used in an alkylation reaction with halogenated ester derivatives using tetrabutylammonium chloride or bromide or tetrabutylammonium hydrogensulfate in a phase transfer reaction using an organic solvent such as THF, toluene, benzene or xylene and inorganic bases such as potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or in the presence of an organic or inorganic base
  • customary inorganic bases are metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butylate, lithium or sodium bases such as lithium diisopropylamide, butyllithium, tert-butyllithium, sodium methylate or metal hydrides such as potassium hydride, lithium hydride, sodium hydride
  • customary organic bases are diisopropylethylamine, triethylamine, in an organic
  • 3- (pyridin-2-yl) acrylic acid E is added to the step using dehydrating 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 F, at temperatures from room temperature to reflux temperature, esterified.
  • dehydrating 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 F, at temperatures from room temperature to reflux temperature, esterified.
  • organic solvents such as THF, diethyl ether, methanol, ethanol or dichloromethane F
  • the ester stages F and G are hydrogenated in a hydrogenation under conditions known to those skilled in the art in organic solvents such as THF
  • an organic or inorganic base for example potassium carbonate, sodium bicarbonate , Diisopropylethylamin, triethylamine, pyridine, diethylamine or DBU, preferably in an organic solvent such as acetonitrile, dichloromethane or tetrahydrofuran,
  • the ester derivatives D and I are ester cleaved 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 bicarbonate, potassium carbonate in organic solvents such as methanol, Dioxane, dichloromethane, THF, diethyl ether or these solvents as mixtures, at 0 0 C to room temperature, to the acid stages of the general formula J reacted.
  • organic acids such as trifluoroacetic acid or aqueous inorganic acids such as hydrochloric acid
  • aqueous inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate in organic solvents such as methanol, Dioxane, dichloromethane, THF, diethyl ether or these solvents as mixtures, at
  • Method IV the racemic (R and S configuration) or enantiomerically pure (R or S configuration) amino acids K are converted into organic solvents using dehydrating reagents such as inorganic acids such as H 2 SO 4 or phosphorus oxides or organic reagents such as thionyl chloride such as THF, diethyl ether, methanol, ethanol or dichloromethane to the amino esters H esterified.
  • dehydrating reagents such as inorganic acids such as H 2 SO 4 or phosphorus oxides
  • organic reagents such as thionyl chloride such as THF, diethyl ether, methanol, ethanol or dichloromethane
  • the carbonyl compound is reacted with organometallics, typically Li or Mg organyls (Grignard) in solvents such as toluene, benzene, hexane, pentane, THF or diethyl ether, optionally with the addition of, for example, CeCl 3 to the tertiary alcohol.
  • organometallics typically Li or Mg organyls (Grignard) in solvents such as toluene, benzene, hexane, pentane, THF or diethyl ether, optionally with the addition of, for example, CeCl 3 to the tertiary alcohol.
  • the tert. Alcohol in a suitable solvent such as, for example, ethanol, methanol, 2-butanone, DMSO, diethyl ether, water, benzene, toluene, THF 1 DCM, acetonitrile, acetone, DMF or pentane or a mixture of these solvents and with a suitable base, such as potassium hydroxide, sodium hydroxide, optionally in aqueous or alcoholic solution, potassium carbonate, potassium hexamethyldisilazane, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide or diisopropylethylamine, optionally with the addition of an adjuvant, such as 18-crown-6, 15-crown-5, terabutylammonium bromide or sulfate, benzyltriethylammonium chloride 1 -n-butyl-3-
  • a suitable base such as
  • the method of deprotection depends on the type of protecting group used. Suitable protecting groups are, for example, the Boc, Cbz, Fmoc or benzyl protecting group.
  • BOC protecting groups may be prepared by reaction with HCl in organic solvents such as dioxane, methanol, ethanol, acetonitrile or ethyl acetate, or by reaction with TFA or methanesulfonic acid in dichloromethane or THF at a temperature of 0 ° C. to 110 ° C. and a reaction time of 0.5 - 20h split off.
  • organic solvents such as dioxane, methanol, ethanol, acetonitrile or ethyl acetate
  • the Cbz protective group can be removed, for example, under acidic conditions.
  • This acid cleavage can be carried out, for example, by reaction with a HBr / glacial acetic acid mixture, a mixture of TFA in dioxane / water or HCl in methanol or ethanol.
  • Another method is the hydrogenolytic cleavage of the protective group under elevated pressure or without pressure with the aid of catalysts such as Pd on carbon, Pd (OH) 2 , PdCl 2 , Raney nickel or PtO 2 in solvents such as methanol, ethanol, 2-propanol , THF, acetic acid, ethyl acetate, chloroform optionally with the addition of HCl, formic acid or TFA.
  • the Fmoc protecting group is usually cleaved under basic conditions in solvents such as acetonitrile, DMF, THF, diethyl ether, methanol, ethanol, 1-octanethiol, DCM or chloroform.
  • Suitable bases are, for example, diethylamine, piperidine, 4-aminomethylpiperidine, pyrrolidine, DBU, NaOH or LiOH.
  • reagents such as Ag 2 O / Mel can also be used.
  • a benzylic protecting group can be cleaved off, for example, by catalytic hydrogenation.
  • Suitable catalysts are, for example, Pd on carbon, PtO 2 or Pd (OH) 2 .
  • the reaction may be carried out in solvents such as, for example, ethanol, methanol, 2-propanol, acetic acid, THF, or DMF, optionally with the addition of acids such as ammonium formate, maleic acid or formic acid, or in mixtures of the solvents.
  • A The carbonyl compound is reacted with organometallics, typically Li or Mg organyls (Grignard), in solvents such as toluene, benzene, hexane, pentane, THF or diethyl ether, optionally with the addition of, for example, CeCl 3 to the tertiary alcohol.
  • organometallics typically Li or Mg organyls (Grignard)
  • solvents such as toluene, benzene, hexane, pentane, THF or diethyl ether, optionally with the addition of, for example, CeCl 3 to the tertiary alcohol.
  • the tert. Alcohol in a suitable solvent such as ethanol, methanol, 2-butanone, DMSO, diethyl ether, water, benzene, toluene, THF, DCM, acetonitrile, acetone, DMF or pentane or a mixture of these solvents in the presence of a suitable base, such as for example, potassium hydroxide, sodium hydroxide, potassium carbonate, potassium hexamethyldisilazane, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide or diisopropylethylamine, optionally with the addition of an adjuvant, such as 18-crown-6, 15-crown-5, terabutylammonium bromide or sulfate , Benzyltriethylammoniumchlorid, 1-n-butyl-3-methylimidazolium tetra
  • a suitable base such
  • the aldehyde is converted to the alcohol in at least one solvent, preferably selected from the group consisting of THF, diethyl ether, toluene, methanol, ethanol or DCM with at least one suitable reducing agent, preferably sodium borohydride or lithium aluminum hydride.
  • the reaction can also be achieved by hydrogenolysis in the presence of a suitable catalyst.
  • catalysts for example, Pt on carbon, palladium on carbon, Raney nickel or Pt 2 O can be used.
  • the hydrogenolysis takes place in solvents such as acetic acid, methanol, ethanol, ethyl acetate, hexane, chloroform or mixtures of these solvents.
  • the alcohol is in at least one solvent, preferably selected from the group consisting of dichloromethane, dioxane, diethyl ether, tetrahydrofuran, acetonitrile and dimethylformamide, with methylsulfonyl chloride in the presence of at least one base, preferably selected from the group consisting of cesium carbonate, calcium carbonate, Potassium carbonate, triethylamine, diisopropylethylamine and pyridine, reacted to the methyl sulfonate.
  • solvent preferably selected from the group consisting of dichloromethane, dioxane, diethyl ether, tetrahydrofuran, acetonitrile and dimethylformamide
  • at least one base preferably selected from the group consisting of cesium carbonate, calcium carbonate, Potassium carbonate, triethylamine, diisopropylethylamine and pyridine, reacted to the methyl sulfonate
  • the methylsulfonate is in at least one solvent, preferably selected from the group consisting of dichloromethane, dioxane, diethyl ether, tetrahydrofuran, acetonitrile, toluene and dimethylformamide, with a suitable amine in the presence of a base, preferably selected from the group consisting of cesium carbonate, calcium carbonate , Potassium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, triethylamine, diisopropylethylamine and pyridine.
  • the deprotection method depends on the type of protecting group used. Suitable protecting groups are, for example, the Boc, Cbz, Fmoc or benzyl protecting group.
  • Pentane, THF or diethyl ether optionally with the addition of, for example
  • Reducing agents such as diisobutylaluminum hydride in organic solvent
  • Solvents such as THF, ether, toluene or benzene.
  • the aldehyde is in at least one solvent, preferably selected from the group consisting of THF, diethyl ether, toluene, methanol, ethanol or
  • reaction can also be carried out by hydrogenolysis in the presence of a suitable solvent
  • Catalyst can be achieved.
  • catalysts for example, Pt on carbon,
  • the substitution reaction of a CH-acidic compound to the piperidine derivative can be carried out in solvents such as, for example, methanol, ethanol, / -propanol, / -butanol, acetone,
  • Acetonitrile, DMF, DME, DMSO, toluene, benzene, THF or liquid NH 3 with addition bases such as, for example, potassium hydroxide, antrium hydroxide, sodium or potassium methoxide, ethanolate, - / - propylate, -f-butylate, lithium or sodium amide, lithium diisopropylamide, potassium carbonate, pyridine or elemental sodium and optionally with the addition of sodium or potassium iodide, HMPA, 1-butyl-3-methylimidazolinium hexafluorophosphate or 18-crown-6.
  • addition bases such as, for example, potassium hydroxide, antrium hydroxide, sodium or potassium methoxide, ethanolate, - / - propylate, -f-butylate, lithium or sodium amide, lithium diisopropylamide, potassium carbonate, pyridine or elemental sodium and optionally with the addition of sodium or potassium iodide,
  • the reduction of the carboxylic acid or of the carboxylic acid ester to the alcohol can be carried out with the aid of various reducing agents.
  • various reducing agents for example, LiBH 4 or NaBH 4 in solvents such as, for example, diethyl ether, toluene, THF, water, methanol, ethanol or mixtures of these solvents may also be used with the addition of auxiliary reagents such as, for example, boric acid esters.
  • auxiliary reagents such as, for example, boric acid esters.
  • borohydride it is also possible to use the Zn (BH 4 ) 2 in, for example, DME.
  • the reduction can also be carried out with BH 3 -Me 2 S complex in solvents such as THF or DCM.
  • the complex aluminum hydrides such as DIBAH or LAH in solvents such as diethyl ether, benzene, toluene, THF, DCM, DME, hexane or mixtures of these solvents to reduce the ester function to the alcohol are.
  • the nitrile can according to methods known in the art in the presence of a suitable acid, for example HCl, HBr, p-toluenesulfonic acid, trimethylsilyl chloride or H 2 SO 4 , in a suitable solvent, for example water, methanol, ethanol or mixtures of these solvents, to the corresponding carboxylic acid or the corresponding carboxylic acid ester are hydrolyzed.
  • a suitable acid for example HCl, HBr, p-toluenesulfonic acid, trimethylsilyl chloride or H 2 SO 4
  • a suitable solvent for example water, methanol, ethanol or mixtures of these solvents
  • the aldehyde can be prepared by methods known to the person skilled in the art in a Wittig reaction with the corresponding phosphonium compound, for example (methoxymethyl) triphenylphosphonium chloride, and a strong base, for example potassium tert-butoxide, n-butyllithium, s-butyllithium, phenyllithium, Lithium diisopropylamide or lithium hexamethyldisilazid, in organic solvents, for example, THF, diethyl ether, cyclohexane, toluene or corresponding Gmischen be implemented.
  • a strong base for example potassium tert-butoxide, n-butyllithium, s-butyllithium, phenyllithium, Lithium diisopropylamide or lithium hexamethyldisilazid
  • organic solvents for example, THF, diethyl ether, cyclohexane, tolu
  • the chemicals and solvents used were purchased commercially from conventional suppliers (e.g., Acros, Avocado, Aldrich, Bachern, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, etc.) or synthesized by methods known to those skilled in the art.
  • Step 1 To a solution of 3- (2-pyridyl) -acrylic acid (23.88 g, 160 mmol) in methanol (750 mL) was added H 2 SO 4 (12.8 mL, 240 mmol). The reaction was heated at reflux overnight and, after cooling to RT, poured into saturated aqueous NaHCO 3 solution (1000 ml). The methanol was removed on a rotary evaporator and the aqueous phase extracted twice with ethyl acetate (400 ml). The organic phase was washed with saturated NaCl solution (500 ml), over Na 2 SO 4 dried and concentrated. The crude product of the methyl 3- (pyridin-2-yl) acrylate was used without further purification in the next step. Yield: 22.19 g, 85%
  • Step 2 Methyl 3- (pyridin-2-yl) acrylate (22.15 g, 136 mmol) was dissolved in THF (300 mL) and chloroform (10.9 mL) and extracted with PtO 2 (3.08 g, 13.6 mmol, 0.1 eq.). under nitrogen atmosphere. The solution was first purged with nitrogen for 10 min and then stirred overnight under H 2 atmosphere (8 bar). After cooling, it was first rinsed again with nitrogen, the catalyst was removed by filtering through filter soil, rinsed with DCM and the filtrate was concentrated to dryness in vacuo. The methyl 3- (piperidin-2-yl) propionate hydrochloride was used without further purification in the next step. Yield: 27.95 g, 99%
  • Step 1 2-Methylaminoethanol 1 (1 eq, 79.9 mmol) was dissolved in 500 mL of dichloromethane and then dissolved successively with triethylamine (1.2 eq 95.9 mmol) and the sulfonyl chloride 2 (1.2 eq 95.9 mmol) in 60 mL of dichloromethane added. It was stirred for 4 h at room temperature (TLC control). Then the reaction mixture was washed with H 2 O (100 ml) and sat. NaHCOH solution (100 ml). After phase separation, the aqueous phase was extracted 3x with dichloromethane (250 ml).
  • Step-2 A mixture of Alcohol 3 (1 eq, 74.8 mmol), tert-butyl bromoacetate (2.1 eq, 157 mmol), tetrabutylammonium hydrogen sulfate (0.1 eq, 7.48 mmol), aqueous 50% NaOH solution and toluene were added Thoroughly mixed at room temperature for 3.5 h (TLC check!). The two phases were separated and the aqueous phase extracted 2x with 450 ml of diethyl ether. The combined organic phases were dried over Na 2 SO 4 and concentrated. The product 5 was obtained (67.3 mmol, 90%), which was used without further purification in the next stage.
  • Step 3 5 (1 eq, 67.3 mmol) was dissolved in dichloromethane (110 eq, 7400 mmol) and then TFA (20 eq, 1345 mmol) was added. It was stirred for 4 h at RT (TLC control). The reaction mixture was dried over magnesium sulfate, filtered off and completely concentrated. The residue was coevaporated 2x with toluene (300 ml). The residue was then washed 3x with diisopropyl ether, during which the diisopropyl ether was decanted off. The residue was taken up in dichloromethane and concentrated to dryness to give product S-07 (101.9 mmol, 151%).
  • the alcohol 2 (4.3 g, 37.2 mmol) was suspended in acetone (150 ml). K 2 CO 3 (10.27 g, 74.3 mmol) and 2- (trifluoromethyl) benzenesulfonyl chloride (7.10 g, 40.9 mmol) were then added. The mixture was stirred overnight at 50 0 C. The reaction mixture, after cooling to room temperature, was filtered and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (silica, heptane / ethyl acetate 2: 1) to give 8.95 g (75%) of the alcohol 8.
  • Ester 9 (11.57 g, 26.4 mmol) was stirred in aqueous 6 M NaOH (88 mL, 528 mmol), MeOH (85 mL) and THF (85 mL) for 30 min at room temperature. TLC (silica, heptane / The solution was then concentrated under reduced pressure and the resulting suspension acidified at 0 ° C. with aqueous 6 M HCl (120 ml) CH 2 Cl 2 (300 ml) was added and after phase separation The aqueous phase was extracted with CH 2 Cl 2 (100 mL) and the combined organic phases were dried (Na 2 SO 4 ) and concentrated to dryness under reduced pressure to give 9.89 g (98%) of acid S-10.
  • ester 19 (S-15) To a solution of ester 19 (12.00 g, 26.70 mmol) in MeOH (200 mL) and THF (200 mL) was added aqueous 4 M NaOH (200 mL, 800 mmol) and the reaction was stirred at room temperature. After 3 h, the organic solvents were evaporated and the aqueous phase was acidified with aqueous 6 M HCl (250 mL). The aqueous phase was extracted with CH 2 Cl 2 (200 ml) and the combined organic phases were dried over Na 2 SO 4 and concentrated to dryness to obtain the building block S-15 (11.27 g, '107%').
  • the synthesis of the acid building block S-16 was carried out in analogy to the synthesis of the building block (S-17) with naphthalene-2-sulfonyl chloride instead of 4-methoxy-2,6-dimethylbenzene-1-sulfonyl chloride.
  • the aqueous phase was extracted once with ethyl acetate. Thereafter, 2M HCl (aqueous) was added to the aqueous phase to reach a pH of 2. At this pH, the aqueous phase was extracted 4x with dichloromethane. The combined organic layers were dried over MgSO 4 , filtered off and concentrated to dryness to give (2) (13.13 g, 100%).
  • Step-1 Cyclopropylamine (5g, 1 equiv.) was taken up in ethanol (60 ml) and 2-bromoethanol (0.5 equiv.) Added. The resulting reaction mixture was heated to 60 ° C. for 16 h. The reaction mixture was concentrated under vacuum and used without further purification in the next step. Yield: 70%
  • Step-2 To a cold (O 0 C) solution of 2- (cyclopropylamino) ethanol (40 mmol, 1.1 equiv.) In dichloromethane (160 ml) and triethylamine (2.5 equiv.) was added a solution of 4-methoxy- 2,6-dimethylbenzenesulfonyl chloride (1 equiv) in dichloromethane (65 ml) was added dropwise at a temperature of 0 ° C. After complete addition, the reaction mixture was stirred for 90 minutes at room temperature. After this time, the reaction was complete (TLC). 75 ml of 0.5M HCl was added to the reaction mixture and stirred for 15 min. The organic phase was separated, washed with water, dried over Na 2 SO 4 and concentrated to dryness to give the clean product. Yield: 90%
  • Step-3 To a 0 0 C cold solution of sulfonamide just prepared (17:16 mmol) in toluene (100 ml) was added at 0 0 C tetrabutylammonium chloride (0:33 equiv.) And 35% NaOH solution (100 ml). To this cold reaction mixture was added dropwise tert-butyl bromoacetate (1.5 equiv.) At constant temperature. After complete addition, the reaction mixture was stirred for 90 minutes at room temperature. After this time, the reaction was complete (TLC). The organic phase was separated, washed with water until the pH was neutral, dried over Na 2 SO 4 and concentrated to dryness to obtain the neat product. Yield: 90%
  • Step-4 To a DCM solution (10 mL / mmol) of tert-butyl ester (. 1 equiv) was added at 0 0 C TFA (13 eq.) And stirred the reaction mixture for 2 h at room temperature. The solvent was distilled off and dried under reduced pressure to remove TFA residues. The crude acid was used directly in the synthesis library without further purification.
  • the synthesis of the building block S-29 was carried out in analogy to the synthesis of building block S-28.
  • the synthesis of the building block S-30 was carried out in analogy to the synthesis of building block S-28.
  • Step-1 To a cold (0 ° C) methanolic solution (60 ml) of 2- carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (25 mmol) was added thionyl chloride (3 ⁇ quiv.) And refluxed the reaction mixture for 16 h. The solvent was completely concentrated and the crude solid was used directly in the next step. Exploitation: 90%
  • Step-2 To a cold (0 0 C) solution of the ester just prepared (. 12 mmol, 1 equiv) in dichloromethane (100 ml) and triethylamine (. 2.5 equiv) was added a solution of 3-Trifluoromethylbenzene sulfonyl chloride (1 Equiv.) In dichloromethane (70 ml) at a constant temperature of 0 0 C added dropwise. After complete addition, the reaction mixture was stirred for 90 minutes at room temperature. The organic phase was separated, washed with water and sat. NaCl solution, dried over Na 2 SO 4 and concentrated under vacuum to obtain the crude product, which was clean enough to use this in the next step. Yield: 80%
  • Step-3 To the just obtained ester (12 mmol) was added, at room temperature, a mixture of THF-H 2 O (8: 2, 220 ml) and the reaction mixture was cooled to 0 ° C. To this cold reaction mixture was added LiOH (2 equiv.) And stirred for 16 h at room temperature. The solvent was evaporated completely under vacuum, the residue was dissolved in water, washed with dichloromethane and the aqueous phase carefully acidified with 1 (N) HCl. It was extracted with ethyl acetate, washed successively with water and sat. NaCl solution and finally dried over Na 2 SO 4 . Concentration of the organic phase gave the clean acid. Yield: 90%
  • Step 1 3-Piperidin-2-yl-propionic acid hydrochloride (5 g) was added with ethanol (200 ml) and saturated with HCl gas at 0 ° C. and the resulting reaction mixture was stirred for 16 h at room temperature (TLC control). , The solvent was completely stripped off under vacuum and the crude product was used directly in the next step without further purification. Yield: 90%
  • Step-3 To the just obtained sulfonamide (9 mmol) at room temperature was added a mixture of methanol-H 2 O (3: 1, 90 ml) and cooled to 0 ° C. To this cold reaction mixture was added LiOH (2 equiv.) And the resulting solution was stirred for 16 h at room temperature. The solvent was concentrated completely under vacuum, the residue was dissolved in water, washed with dichloromethane and the aqueous phase was carefully added with 1 (N) HCl acidified. It was extracted with ethyl acetate, washed successively with water and sat. NaCl solution and finally dried over Na 2 SO 4 . Concentration of the organic phase gave the clean acid. Yield: 80%
  • Step-1 To a cold (O 0 C) solution of 3-amino-3-phenylpropionic acid (54 mmol) in methanol (3 ml / mmol) was added dropwise thionyl chloride (3 equiv) and the resulting reaction mixture was refluxed for 12 h ( TLC). The solvent was completely concentrated and the residue was dried under reduced pressure. This was used directly in the next stage without further purification. Yield: 90%
  • Step-2 To a cold (O 0 C) suspension of the just obtained ester (32 mmol) in dichloromethane (200 ml) was added triethylamine (3 equiv.) And the resulting reaction mixture was treated with a solution of naphthalene-2-sulfonyl chloride ( 1.2 equiv.) In DCM (50 ml). The resulting reaction mixture was stirred for 3 h at room temperature (TLC control). It was diluted with DCM, washed with water and sat. NaCl solution and finally dried over Na 2 SO 4 . Concentration of the organic phase gave the crude product, which was purified by column chromatography (3: 7 ethyl acetate in hexane).
  • Step-3 The sulfonamide just obtained was added to a mixture of methanol-H 2 O (3: 1, 90 ml) at room temperature and cooled to 0 ° C. To this cold reaction mixture was added LiOH-H 2 O (2 equiv.) And the resulting solution was stirred for 16 h at room temperature. The solvent was concentrated completely under vacuum, the residue dissolved in water, washed with dichloromethane and the aqueous phase cautiously acidified with 1 (N) HCl. It was extracted with ethyl acetate, washed successively with water and sat. NaCl solution and finally dried over Na 2 SO- I . Concentration of the organic phase gave the clean acid. Yield: 80%
  • Step 1 To a solution of 3-bromopyridine (7.94 g, 1 eq.) In dry THF (1600 mL) at -70 ° C was added n-butyllithium (2 eq.) And stirred at this temperature for 1 h. Then, at -70 0 C a solution of N-Boc-piperidone (10 g, 1 eq.) In THF (400 ml) was added and stirred at this temperature for 2 (DC control) h. After completion of the reaction was first hydrolyzed with saturated ammonium chloride solution and then slowly warmed to RT. It was diluted with ethyl acetate. The organic phase was washed with sodium chloride solution and dried over Na 2 SO 4 .
  • Step 1 To a solution heated to 50 0 C NaOH (5:06 g, 126.5 mmol) in water (4:55 ml) was first pyrrolidine (6.95 ml) and then 3-chloropropanol (10 g, 106.3 mmol) was added slowly so that the solution did not warm above 70 ° C. After complete addition, the mixture was stirred for a further 90 minutes at this temperature, then cooled to 25 ° C and stirred for a further 16 h. After the reaction was saturated with NaOH, extracted with benzene and then the solvent removed on a rotary evaporator. The crude product was purified by distillation (98 ° C, 18 mm). Step 2.
  • Step 3 The tert -butyl 4-hydroxy-4- (pyridin-3-yl) piperidine-1-carboxylate (2g) was dissolved in benzene (20ml), sodium iodide (10eq) added at 25 ° C and stirred for 15 minutes at this temperature. It was then the corresponding chlorine compound (1.2 eq.) Was added and heated for 16 h under reflux. After completion of the reaction (TLC control) was cooled to 0 0 C and hydrolyzed with ice. The aqueous phase was extracted with ethyl acetate. The organic phase was then washed successively with water and saturated NaCl solution and dried over Na 2 SO 4 .
  • Step 1 To a solution of 3-bromopyridine (6.0 g, 1 eq.) In dry THF (600 ml) at -70 0 C n-butyl lithium (2 eq.) was added and stirred at this temperature for 1 h. Then, at -70 0 C a solution of N-benzylpiperidone (7.1 g, 1 eq.) In THF (100 ml) was added at this temperature and stirred for 2 h (TLC control). After completion of the reaction was first hydrolyzed with saturated ammonium chloride solution and then slowly heated to 25 0 C. It was diluted with ethyl acetate. The organic phase was washed with sodium chloride solution and dried over NaaSCu.
  • Step 2 Dissolve 1-benzyl-4- (pyridin-3-yl) -piperidin-4-ol (2 g) in benzene (20 mL), add sodium amide (10 eq) at 25 ° C and stir for 15 min stirred at this temperature. Then, 1- (2-chloroethyl) piperidine hydrochloride (1.2 eq.) was added and heated at reflux for 16 h. After completion of the reaction (TLC control) was cooled to 0 0 C and hydrolyzed with ice.
  • the aqueous phase was extracted with ethyl acetate.
  • the organic phase was then washed successively with water and saturated NaCl solution and dried over Na 2 SO 4 .
  • the solvent was removed on a rotary evaporator and the resulting Crude product purified by column chromatography (silica gel, DCM / methanol, 95: 5).
  • Step 3 To a solution of the benzylated compound (1.9 g) in methanol (3 ml / mmol) was added Pd (OH) 2 (50 wt.%). The mixture was under
  • Step-1 To a solution of 3-fluorophenyl magnesium bromide (15,075 mmol, 0.5 M) in THF (10 mmol) at 0 0 C, a solution of N-Boc piperidone (5.10 mmol) in THF. After complete addition, the reaction was stirred for 2 h at the same temperature (TLC control). Then with ges. Quenched NH 4 Cl solution, the reaction mixture was diluted with ethyl acetate and the organic phase was washed successively with water and sat. NaCl solution washed. The organic phase was dried over Na 2 SO 4 and finally concentrated under reduced pressure to give the crude product, which was purified by column chromatography (50% ethyl acetate in hexane). Yield: 40%
  • Step-2 To a benzene solution (200 ml) of the pyridine derivative from Step-1 (9.84 g, 35.3 mmol) was added dry, powdered KOH (9.9 g) 18-crown-6 (1.06 g) and 2-chloroethyl pyrrolidine hydrochloride (1.5 Equiv.) And the resulting mixture is refluxed for 16 h. It was then cooled to 25 ° C, diluted with ethyl acetate and the organic phase successively with water and sat. NaCl solution and finally dried over Na 2 SO 4 . Concentration of the organic phase under reduced pressure gave the crude product, which was characterized by Column chromatography (5% methanol in dichloromethane) was purified. Yield: 50%
  • Step-3 The just-obtained Boc-protected amine (1 eq., 25.7 mmol) was dissolved in methanol / THF (2: 1) and cooled to 0 ° C. At this temperature, acetyl chloride (5 eq., 128.7 mmol) was added. The reaction mixture was stirred for 3 h at room temperature (TLC control). After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the product A-07 (26.6 mmol, 103%) as an HCl salt.
  • Step-1 To a cold (-15 ° C) solution of diisopropylamine (31.38 mmol) in THF (50 mL) was added n-butyl lithium (31.38 mmol) and stirred for 30 min at this temperature. It was then cooled to -78 ° C and 2-chloro-3-iodopyridine (5 g, 20.9 mmol) in THF (10 mL) was added dropwise and the resulting reaction mixture was stirred at this temperature for an additional 1 h (TLC control). The reaction was quenched with water (10 ml), diluted with ethyl acetate, and the organic phase was washed successively with water and sat. NaCl Solution washed. Finally, it was dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step. Yield: Quantitative (raw)
  • Step-2 n-BuLi (26 mmol) was added to diethyl ether (17.5 mL) and to this was added slowly at -78 ° C a solution of 2-chloro-4-iodo-pyridine (21.7 mmol) in 17.5 mL diethyl ether. The resulting mixture was stirred at this temperature for 15 min and then N-Boc-piperidone (3.5 g, 17.5 mmol) in 35 ml of diethyl ether was added dropwise at -78 ° C. Stirring was continued for a further 45 minutes at this temperature, then quenched with water (50 mL), and the reaction was allowed to reach room temperature.
  • Step-3 To a benzene solution (260 ml) of the just-obtained pyridine derivative (13g, 41.98 mmol) was added dry, powdered KOH (11.74 g), 18-crown-6 (1.65 g) and N-2-chloroethylpyrrolidine hydrochloride (65 mmol ) and the resulting mixture is refluxed for 16 h. It was then cooled to 25 ° C, diluted with ethyl acetate and the organic phase was washed successively with water and sat. NaCl solution and finally dried over Na 2 SO 4 . Concentration of the organic phase under reduced pressure gave the crude product, which was purified by column chromatography (5% methanol in dichloromethane). Yield: 75%
  • Step-4 A solution of the just obtained chloro derivative (5 g) (12.2 mmol) in methanol (150 mL) was degassed with argon. To this was added 10% Pd-C (1g) and the resulting reaction mixture was hydrogenated at atmospheric pressure for 16 h (TLC and LCMS control). It was filtered through Celite, the residue washed with methanol and the combined organic phases evaporated to dryness to obtain the crude product, which was purified by column chromatography. Yield: 70% Step-5: The just-obtained Boc-protected amine (1 eq., 26.9 mmol) was dissolved in methanol and cooled to 0 ° C.
  • Step-1 To a THF solution of 4-fluorophenylmagnesium bromide (100.376 mmol, 0.5 M) at 0 ° C was added a solution of N-boc piperidone (10 g, 50.188 mmol) in THF (100 mL). After complete addition, the reaction mixture was stirred for 16 h at room temperature (TLC control). It was with ges. Quenched NH 4 Cl solution, the reaction mixture was diluted with ethyl acetate and the organic phase was washed successively with H 2 O and sat. Washed NaCl solution. The organic phase was dried over Na 2 SO 4 and finally concentrated in vacuo to give the crude product, which was purified by column chromatography (2% methanol in dichloromethane). Yield: 75.6%
  • Step-2 To a toluene solution (187 ml) of the product just obtained (11.0 g 37.288 mmol) was added dry, powdered KOH (10.44 g), 18-crown-6 (9,855 g) and 2-chloroethylpyrrolidine hydrochloride (1.5 equiv.). was added and the resulting reaction mixture was refluxed for 16 h. It was cooled to 25 ° C, diluted with ethyl acetate and the organic phase was washed successively with H 2 O and sat. Washed NaCl solution and finally dried over Na 2 SO 4 . The concentration The organic phase under vacuum gave the crude product, which was
  • Step-1 To a THF solution of 4-trifluoromethyl-phenyl magnesium bromide (100 376 mmol, 0.5 M) at 0 0 C, a solution of N-Boc piperidone (10 g, 50.188mmol) in THF (100 ml). After complete addition, the reaction mixture was stirred for 16 h at room temperature (TLC control). It was with ges. quenched aqueous NH 4 Cl solution, the reaction mixture was diluted with ethyl acetate and the organic phase was washed successively with H 2 O and sat. Washed NaCl solution. The organic phase was dried over Na 2 SO 4 and finally concentrated in vacuo to give the crude product, which was purified by column chromatography (2% methanol in dichloromethane). Yield: 54.8%
  • Step-2 To a toluene solution (94 ml) of the product just obtained (6.45 g, 18.69 mmol) were added dry, powdered KOH (5.23 g), 18-crown-6 (4.94 g) and 2-chloroethyl pyrrolidine hydrochloride (1.5 Equiv.) And the resulting reaction mixture was refluxed for 16 h. It was cooled to 25 ° C, diluted with ethyl acetate and the organic phase was washed successively with H 2 O and sat. Washed NaCl solution and finally dried over Na 2 SO 4 . Concentration of the organic phase under vacuum gave the crude product which was passed through Column chromatography (5% methanol in dichloromethane) was purified. Yield: 52%
  • the Boc-protected amine A-03 (1 eq., 12.7 mmol) was dissolved in methanol and cooled to 0 0 C. At this temperature, acetyl chloride (5 eq., 63.5 mmol) was added. The reaction mixture was stirred overnight at room temperature (TLC control). After completion of the reaction, the reaction mixture was completely concentrated under reduced pressure to obtain the product A-11 (14.0 mmol, 110%) as HCl salt.
  • Step 1 The Boc-protected amine building block (1 eq) at 0 0 C and TFA (20% in DCM, 5 ml / mmol) and then stirred for 3 hours at 25 ° C (TLC monitoring). After completion of the reaction, the solvent was carefully removed and used directly without further purification.
  • Step 2 To a solution of the appropriate acid moiety (0.7 eq.) In DCM (3 mL / mmol) was added EDCI (1.0 eq.), HOBt (0.7 eq.) And DIPEA (2 eq.) And the reaction mixture for Stirred at 25 ° C for 15 min.
  • the Boc-deprotected amine building block (1.0 eq.) was dissolved in DCM (2 mL / mmol), cooled in an ice bath and treated with DIPEA (2.5 eq). This mixture was added to the mixture of the acid component. The reaction mixture was stirred for 16 h at 25 ° C and then diluted with DCM. The organic phase was washed successively with ammonium chloride solution, sodium bicarbonate solution and sodium chloride solution and finally dried over Na 2 SO 4 . Purification was carried out on a parallel purification system from Biotage. Method B
  • the acid building blocks (S) were reacted in parallel with the amine (A) to give the example compounds (Ex).
  • the correlation of product to reagent, building block and method is shown in the synthesis matrix shown below.
  • the crude products of the parallel synthesis were analyzed by HPLC-MS and then purified by reverse phase HPLC-MS. The identity of the products could be detected by analytical HPLC-MS measurements.
  • Prep Pump Waters 2525; Make Up Pump: Waters 515; Auxiliary detector: Waters DAD 2487; MS detector: Waters Micromass ZQ; Injector / Fraction Collector: Waters Sample Manager 2767; Gradient: Initial: 60% Water 40% Methanol -> 12-14.5 min: 0% Water 100% Methanol -> 14.5-15 min: 60% Water 40% Methanol; Flow: 35 ml / min Column: Macherey-Nagel, C18 Gravity, 100x21 mm, 5 ⁇ . Individual examples were separated by means of a slightly modified variant of this method.
  • a solution of the acid (S) (100 ⁇ M) in 1 ml of dichloromethane is treated with a solution of 1, 1'-carbonyldiimidazole (150 uM) in 1 ml of dichloromethane and shaken for 1.5 hours at room temperature.
  • a solution of the amine (A) (150 uM) in Hünigs base (500 uM) and 1 ml of dichloromethane is added.
  • the reaction mixture was shaken for 18 hours at room temperature and finally concentrated.
  • the removal of the solvent was carried out under reduced pressure in vacuum centrifuges (GeneVac).
  • the final purification was carried out by HPLC-MS.
  • the final analysis was performed by LC-MS.
  • HPLC Waters Alliance 2795 with Waters 2998 PDA; MS: Micromass Quattro Micro TM API; Column: Waters Atlantis T3 ®, 3 .mu.m, 100 A, 2.1 x 30 mm; Column temperature: 40 ° C., eluent A: water + 0.1% formic acid; Eluent B: acetonitrile + 0.1% formic acid; Gradient: 0% B to 100% B in 8.8 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 / min; Ionization: ES +, 25V; Make up: 100 ⁇ L / min 70% methanol + 0.2% formic acid; UV: 200-400 nm
  • Example compounds listed in the table below were prepared from 3- (4- (2- (pyrrolidin-1-yl) ethoxy) piperidin-4-yl) pyridine dihydrochloride [amine D] by reaction with the corresponding carboxylic acids (acid building block) analogously to Example 46 was prepared.
  • Example 8 1- (4- (Pyridin-3-yl) -4- (2- (pyrrolidin-1-yl) ethoxy) piperidin-1-yl) -4- (1- (2- (trifluoromethyl) phenylsulfonyl) piperidin-2-yl) butan-1-one
  • reaction mixture was treated with water and ethyl acetate.
  • the phases were separated and the aqueous phase was extracted with ethyl acetate (1x).
  • the aqueous phase was adjusted to pH 2 with 2M HCl solution and then extracted 4 ⁇ with dichloromethane.
  • the combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure.
  • the crude product was obtained as a colorless oil (13.1 g) and used without further work-up in the next step.
  • reaction mixture was washed 3x with sat. Ammonium chloride solution and washed twice with sodium chloride solution. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The desired ester was obtained as a colorless solid (4.8 g) in a yield of 32% and used further without further purification.
  • Methyl 4- (1- (tert-butoxycarbonyl) piperidin-2-yl) butanoate (4.58 g, 16.05 mmol, 1 eq.) was dissolved in methanol (40 ml) and acetylchloride (5.7 ml, 80.2 mmol, 5 eq.). The mixture was stirred for 5 h at room temperature.
  • N-ethyl-diisopropylamine (9.6 mL, 56.50 mmol, 3 eq.) was then added slowly dropwise. The mixture was stirred at room temperature for 24 h. For workup, the reaction solution was acidified with 1 M aqueous HCl solution. The aqueous phase was saturated with sodium chloride and extracted 4x with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The residue (10.6 g) was purified by column chromatography [Alox Neutral (240 g) hexane / ethyl acetate 95: 5 ⁇ 93: 7 ⁇ 9: 1 ⁇ 8: 2]. The desired product was recovered in a yield of 61% (4.5 g) as an orange-brown oil.
  • Methyl 4- (1- (2- (trifluoromethyl) phenylsulfonyl) piperidin-2-yl) butanoate (3.5 g, 8.9 mmol, 1 eq.) was dissolved in water (25 mL) and methanol (35 mL) , With stirring, lithium hydroxide (1 g, 44.5 mmol, 5 eq.) was added. The mixture was stirred at room temperature for 24 h.
  • Example 9 4- (1- (2-Chloro-6-methylphenylsulfonyl) piperidin-2-yl) -1- (4- (pyridin-3-yl) -4- (2- (pyrrolidin-1-yl) ethoxy ) piperidin-1-yl) butan-1-one
  • the aqueous phase was saturated with sodium chloride and extracted 3x with dichloromethane.
  • the combined organic phases were dried with magnesium sulfate and concentrated under reduced pressure.
  • the residue (10.6 g) was purified by column chromatography [Alox Neutral (240 g) hexane / ethyl acetate 98: 2 ⁇ 92: 8 ⁇ 9: 1 ⁇ 8: 2].
  • the desired product was recovered in a yield of 93% (3.9 g) as a yellow oil.
  • Methyl 4- (1- (2-chloro-6-methylphenylsulfonyl) piperidin-2-yl) butanoate (2.7 g, 7.3 mmol, 1 eq.) was dissolved in water (20 ml) and methanol (30 ml). solved. With stirring, lithium hydroxide (0.87 g, 36.5 mmol, 5 eq.) was added. The mixture was stirred at room temperature for 24 h. For workup, the methanol was removed under reduced pressure. The residue was taken up in ethyl acetate and acidified with dilute HCl solution. The aqueous phase was extracted 2x with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product (3 g) was used without further purification in the next step.
  • 1,2-Dibromoethane (6.8 ml) was added to mCPBA (112 mg, 2 eq) and the mixture cooled to 0 ° C.
  • 2-Chloro-N-cyclopropyl-N- [2- [2- [4- (3-fluorophenyl) -4- (2-pyrrolidin-1-yl-ethoxy) -piperidin-1-yl] -2-oxo ethoxy] ethyl] -6-methylbenzenesulfonic acid amide
  • Example 62 (200 mg, 1 eq) was dissolved in dichloromethane (20 ml) and added dropwise to the reaction mixture.
  • the desired target compound was prepared from (S) -2 - ((1- (4-methoxy-2,6-dimethylphenylsulfonyl) piperidin-2-yl) methoxy) acetic acid under reaction conditions analogously to the procedure described for Example 61 (see below).
  • the reaction mixture was stirred for 16 h at 25 0 C.
  • the mixture was concentrated on a rotary evaporator to dryness, the residue taken up in dichloromethane, washed with water and sat. Sodium chloride solution and dried over sodium sulfate.
  • the organic phase was concentrated and the crude product by column chromatography (5% methanol in
  • Step 1 The reaction was carried out under N 2 atmosphere. A solution of 2,4-dichlorobenzenesulfonyl chloride (15.0 g, 61.1 mmol) in DCM (40 ml) was added dropwise at 0 ° C. within 10 min to a solution of diphenylmethanamine (11.2 g, 61.1 mmol) and triethylamine (8.49 ml, 61.1 mmol) in DCM (100 ml). It was stirred overnight at RT and then the organic phase with KHSCv solution (0.5 M, 2 x 100 ml), sat. NaCl solution washed. The precipitated solid was filtered and the filtrate concentrated. The residue was taken up in DCM (25 ml) again. The resulting solid was filtered, washed with DCM and dried on filter paper. Yield: 22.24 g, 93%.
  • Step 2 The reaction was carried out under N 2 atmosphere. A solution of the sulfonic acid amide (21.29 g, 54.3 mmol) in acetone (400 ml) was heated to reflux. K 2 CO 3 (8.25 g, 59.7 mmol) was added and stirred for 20 min. Subsequently, ethyl bromoacetate (10.31 ml, 109 mmol) was added and stirred for 5 h. The LCMS control showed that the reaction was not complete. It was cooled to RT and over the weekend at this temperature touched. The subsequent LCMS control showed complete conversion. The solids were filtered off and the filtrate was i. Vak. concentrated to dryness. The resulting oil was crystallized from diisopropyl ether / heptane. Yield: 20.45 g, 81%.
  • Step 3 The reaction was carried out under N 2 atmosphere. A solution of LiBH 4 in THF (2 M, 21.86 ml, 43.7 mmol) was added dropwise to a solution of the ester from Step 2 (20.3 'g, 43.7 mmol) in dry THF (20 ml). The reaction mixture was stirred at RT overnight, then heated to 40 ° C. for 3 h, cooled again to RT and stirred at RT over the weekend. As the reaction was not complete, additional LiBH 4 in THF (2M, 4.0 mL, 8.0 mmol) was added dropwise. It was heated again for 5 h at 40 0 C then cooled to RT and stirred at RT overnight. After LCMS control, sales were almost complete.
  • Step 4 To a solution of the alcohol from Step 3 (15.05 g, 34.54 mmol) and Bu 4 NCI (2.7 g, 9.72 mmol) in DCM (200 mL) was added aqueous NaOH (35%, 200 mL) followed by te / t Butyl bromoacetate (7.64 ml, 51.7 mmol) was added. The reaction mixture was stirred at RT for 2 h. Since the conversion was not complete (TLC check), additional te / t-butyl bromoacetate (3.82 ml, 25.9 mmol) was added and stirred again at RT for 2 h.
  • Step 5 NaOH (10.0 g, 250.7 mmol) was added to a solution of the ester from step
  • Step 1 A solution of the 4-methoxy-2,6-dimethylbenzene-1-sulfonyl chloride (8.0 g, 34.1 mmol) in DCM (75 mL) was added dropwise at 0 ° C to a solution of pyridine-3-ylmethanamine (3.48 mL) , 34.1 mmol) and triethylamine (5.23 ml, 37.5 mmol) in DCM (150 ml). It was stirred overnight at RT and then the organic phase was washed with sat. NaCl solution (250 ml), dried over Na 2 SO 4 and concentrated. The crude product was used without further purification.
  • Step 2 To a solution of the sulfonamide (11.85 g, max 34.1 mmol) and Bu 4 NCI (3.13 g, 11.25 mmol) in DCM (100 mL) was added at 0 ° C aqueous NaOH (35%, 78 mL) and 10 min reaction time terf-butyl bromoacetate (5.46 ml, 37.5 mmol). The reaction mixture was stirred at RT for 2 h. After completion of the reaction (TLC control), the phases were separated and the organic phase washed with water (3 x 200 ml), dried over Na 2 SO 4 and concentrated. The crude product was purified by column chromatography (silica gel, DCM / methanol 99: 1). Yield: 12.02 g, 84% (two stages)
  • Step 3 A solution of the ester from Step 2 (12.0 g, 28.5 mmol) in dry THF (100 mL) was added dropwise to a stirred and cooled solution of LAH (2 M in THF 1 28.5 ml, 57.1 mmol) in dry THF (50 ml). The reaction mixture was stirred at 0 ° C. for 15 min. Subsequently, Na 2 SO 4 10 H 2 O was added until no gas evolution was observed. The reaction mixture was filtered through a narrow bed of Na 2 SO 4 and the filtrate was concentrated to dryness. The crude product was used without further purification. Yield: 9.44 g, 94%
  • Step 4 To a solution of the alcohol from Step 3 (9:44 g, 26.9 mmol) and Bu 4 NCl (2.47g, 8.89 mmol) in DCM (100 ml) at 0 0 C aqueous NaOH (35%, 61.6 ml) and after 10 min reaction time te / t-butyl bromoacetate (4.12 ml, 28.3 mmol) was added. The reaction mixture was stirred at RT for 2 h. After completion of the reaction (TLC control), the phases were separated and the organic phase washed with water (3 x 200 ml), dried over Na 2 SO 4 and concentrated. The crude product was purified by column chromatography (silica gel, DCM / methanol 99: 1). Yield: 7.35 g, 59%
  • Step 5 NaOH (6M, 77 mL, 465 mmol) was added to a solution of the ester from Step 4 (10.79 g, 23.23 mmol) in a mixture of methanol (80 mL), THF (80 mL) and water (15 ml). The reaction mixture was stirred at RT for 2 h. Subsequently, the solvent was removed on Rotatioinsverdampfer. The residue was taken at 0 0 C in aqueous HCl solution (6 M, 82 ml) and with DCM (2 x 150 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated. The crude product was used without further purification. Yield: 9.1 g, 96%.
  • Step 1 The reaction was carried out under N 2 atmosphere. A solution of 2,4-dichlorobenzenesulfonyl chloride (18.4 g, 74.9 mmol) in DCM (50 mL) was added dropwise at 0 ° C. to a solution of 1-aminoindan (10.0 g, 75 mmol) and triethylamine (15.7 mL, 113 mmol). in DCM (50 ml). The mixture was then stirred at RT for 1 h. After completion of the reaction (TLC check), the organic phase with KHSO 4 solution (0.5 M, 3 x 50 ml), sat. NaCl solution, dried over Na 2 SO 4 and concentrated. The crude product was used without further purification. Yield: 24.56 g, 96%
  • Step 2 The reaction was carried out under N 2 atmosphere. To a solution of the sulfonic acid amide (12.21 g, 35.7 mmol) and ethyl bromoacetate (10.92 g, 71.4 mmol) in acetone (100 mL) was added K 2 CO 3 (5.42 g, 39.2 mmol). The reaction was heated at reflux for 4 h. After completion of the reaction (TLC monitoring), the solution was cooled to RT and filtered. The filtrate was i. Vak. concentrated to dryness.
  • the crude product was purified by column chromatography (silica gel, heptane / ethyl acetate, 4: 1, the crude product was taken up in ethyl acetate and added to the column). Step 3.
  • the reaction was carried out under N 2 atmosphere.
  • a solution of LiBH 4 in THF (2M, 16.18ml, 32.4mmol) was added dropwise to a solution of the ester from Step 2 (12.19g, 29.4mmol) in dry THF (100ml).
  • the reaction mixture was stirred at RT overnight.
  • additional LiBH 4 in THF (2M, 7.36 mL, 14.71 mmol
  • Step 4 To a solution of the alcohol from Step 3 (10.03 g, 26.0 mmol) and Bu 4 NCI (2.17 g, 7.81 mmol) in DCM (100 mL) was added aqueous NaOH (35%, 100 mL) followed by tert. Butyl bromoacetate (11.51 ml, 78 mmol) was added. The reaction mixture was stirred for 1 h at RT. After completion of the reaction (TLC), the phases were separated and the organic phase washed with water (3 x 100 ml), dried over Na 2 SO 4 and concentrated. The crude product was purified by column chromatography (silica gel, heptane / ethyl acetate 4: 1). Yield: 11.53 g, 89%
  • Step 5 NaOH (9.22g, 231mmol) was added to a solution of the ester from Step 4 (11.53g, 23.04mmol) in a mixture of methanol (90ml), THF (40ml) and water (10ml) , The reaction mixture was stirred for 1 h at RT. Subsequently, most of the solvent was removed. It was first DCM (500 ml) and then at 0 0 C KHSO 4 (0.5 M, 500 ml). To improve the phase separation was sat. Add NaCl solution. The aqueous phase was then extracted with DCM. The combined organic phases were dried over Na 2 SO 4 and the cloudy solution i. Vak. concentrated.
  • the reaction mixture was diluted with dichloromethane, washed with water and sat.
  • Tetrahydrofuran was completely evacuated and refluxed in a sealed flask for 24 h.
  • the reaction mixture was diluted with ethyl acetate and successively with water and sat. Sodium chloride solution washed.
  • the organic phase was dried over sodium sulfate and concentrated.
  • the crude product was purified by column chromatography (Alox). Yield: 11%
  • the amine building block [amine J] corresponds to the product of step 4 of the synthesis of the amine building block A-08 described above in connection with the parallel synthesis.
  • the agonistic or antagonistic effect of substances can be determined on the bradykinin receptor 1 (B1 R) of the human and rat species with the following assay.
  • Ca 2+ influx through the channel is monitored using a Ca 2+ -sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden Netherlands) in the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, USA ).
  • FLIPR Fluorescent Imaging Plate Reader
  • CHO K1 cells Chinese hamster ovary cells (CHO K1 cells) stably transfected with the human B1R gene (hB1R cells) or the rat B1R gene (rB1R cells) are used. For functional studies, these cells are plated on black 96-well plates with a clear bottom (BD Biosciences, Heidelberg, Germany or Greiner, Frickenhausen, Germany) at a density of 20,000-35,000 cells / well.
  • hB1R cells Nutrient Mixture Ham's F12, Gibco Invitrogen GmbH, Düsseldorf, Germany or DMEM, Sigma-Aldrich, Taufkirchen, Germany; rB1R 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.
  • 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 agonistic or antagonistic action of the compounds according to the invention on the bradykinin receptor 1 (B1 R) of the human and rat species was determined as described above.
  • Antagonists lead to a suppression of Ca 2+ influx. % Inhibition was calculated compared to the maximum achievable inhibition.

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Abstract

L'invention concerne des dérivés de sulfonamide substitués, des procédés de fabrication de ces composés, des médicaments contenant ces composés et l'utilisation de dérivés de sulfonamide substitués pour la fabrication de médicaments.
EP09730791A 2008-04-08 2009-04-08 Dérivés de sulfonamide substitués Withdrawn EP2262792A1 (fr)

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EP08006957 2008-04-08
EP09730791A EP2262792A1 (fr) 2008-04-08 2009-04-08 Dérivés de sulfonamide substitués
PCT/EP2009/002578 WO2009124733A1 (fr) 2008-04-08 2009-04-08 Dérivés de sulfonamide substitués

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CN101553481A (zh) * 2006-09-29 2009-10-07 格吕伦塔尔有限公司 取代的磺酰胺衍生物
US8404741B2 (en) * 2010-02-19 2013-03-26 Bristol-Myers Squibb Company Glycine chroman-6-sulfonamides for use as inhibitors of diacylglycerol lipase
HUP1000598A2 (en) 2010-11-05 2012-09-28 Richter Gedeon Nyrt Indole derivatives
JP2014159375A (ja) * 2011-06-15 2014-09-04 Takeda Chem Ind Ltd アゼパン化合物
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AU755498B2 (en) * 1997-05-22 2002-12-12 G.D. Searle & Co. 3(5)-heteroaryl substituted pyrazoles as p38 kinase inhibitors
FR2822827B1 (fr) * 2001-03-28 2003-05-16 Sanofi Synthelabo Nouveaux derives de n-(arylsulfonyl) beta-aminoacides comportant un groupe aminomethyle substitue, leur procede de preparation et les compositions pharmaceutiques en contenant
WO2004087700A1 (fr) * 2003-03-25 2004-10-14 Laboratoires Fournier S.A. Derives du benzenesulfonamide, leur procede de preparation et leur utilisation de la douleur
CA2521937A1 (fr) * 2003-04-10 2004-10-28 Amgen, Inc. Composes bicycliques presentant une affinite pour les recepteurs de la bradykinine et compositions pharmaceutiques en contenant
WO2004092164A1 (fr) * 2003-04-10 2004-10-28 Amgen, Inc. Derives amines cycliques et leur utilisation dans le traitement de troubles lies a l'inflammation induits par la bradykinine
WO2007140383A2 (fr) 2006-05-30 2007-12-06 Neurogen Corporation Sulfonamides spirocycliques et composés apparentés
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WO2008024692A1 (fr) 2006-08-23 2008-02-28 Neurogen Corporation Sulfones de n-oxyde aryle et sulfoxydes
CN101553481A (zh) * 2006-09-29 2009-10-07 格吕伦塔尔有限公司 取代的磺酰胺衍生物
JP5406722B2 (ja) * 2006-10-16 2014-02-05 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング ブラジキニン１受容体モジュレータとしての置換されたスルホンアミド誘導体
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US8318769B2 (en) 2012-11-27
RU2503674C2 (ru) 2014-01-10
WO2009124733A1 (fr) 2009-10-15
RU2010145013A (ru) 2012-05-20
IL208519A0 (en) 2010-12-30
CN102056919B (zh) 2014-03-12
US20090264400A1 (en) 2009-10-22
AU2009235634B2 (en) 2013-04-18
JP2011517459A (ja) 2011-06-09
AU2009235634B8 (en) 2013-05-23
CN102056919A (zh) 2011-05-11
MX2010011095A (es) 2010-11-05
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AU2009235634A8 (en) 2013-05-23
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