EP2155678A1 - Neue bradykinin-b1-antagonisten - Google Patents

Neue bradykinin-b1-antagonisten

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Publication number
EP2155678A1
EP2155678A1 EP08736022A EP08736022A EP2155678A1 EP 2155678 A1 EP2155678 A1 EP 2155678A1 EP 08736022 A EP08736022 A EP 08736022A EP 08736022 A EP08736022 A EP 08736022A EP 2155678 A1 EP2155678 A1 EP 2155678A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
pain
alkynyl
alkenyl
optionally substituted
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Withdrawn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
EP08736022A
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English (en)
French (fr)
Inventor
James Madden
David Hallett
Steven Taylor
Gurubaran Raju
Xiaolu Wang
Mark Gemkow
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Evotec OAI AG
Original Assignee
Evotec Neurosciences GmbH
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Publication date
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Priority to EP08736022A priority Critical patent/EP2155678A1/de
Publication of EP2155678A1 publication Critical patent/EP2155678A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to Bradykinin Bl antagonists, pharmaceutical compositions thereof, the preparation of such compounds as well as the production and use as medicament, especially for treatment of inflammation-related disorders including inflammatory pain, and neuropathic pain.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • aspirin, ibuprofen, and indomethacin are moderately effective against inflammatory pain but they are also renally toxic, and high doses tend to cause gastrointestinal irritation, ulceration, bleeding, confusion and increased cardiovascular risk.
  • Vioxx was withdrawn from the market in 2004, due to a risk of myocardial infarction and stroke.
  • Patients treated with opioids frequently experience confusion and constipation, and long-term opioid use is associated with tolerance and dependence.
  • Local anaesthetics such as lidocaine and mixelitine simultaneously inhibit pain and cause loss of normal sensation.
  • local anaesthetics are associated with adverse cardiovascular effects.
  • Kinins are proinflammatory peptides that mediate vascular and pain responses to tissue injury, with functions in cardiovascular homeostasis, contraction or relaxation of smooth muscle, inflammation and nociception. They exert most of their effects by interacting with two classes of G-protein-coupled receptors called Bradykinin receptor 1 and 2 (Bl and B2).
  • Bl and B2 G-protein-coupled receptors
  • the classification of the kinin receptors was originally achieved by means of pharmacological studies originally carried out at the end of the 1970s. During the 1990s, the existence of kinin Bl and B2 receptors was further confirmed through cloning and genetic deletion studies (McEachern et al. 1991; Menke et al. 1994). The past 30 years of research on the kinin system has indicated that both Bl and B2 receptors are involved in pain and inflammation (for reviews see Leeb-Lundberg et al. 2005; Moreau et al. 2005; Chen and Johnson 2007).
  • B2 receptors are widely expressed in a constitutive manner throughout most mammalian tissues.
  • Bl receptors are not constitutively expressed to a great extent under normal conditions, but are up-regulated under different inflammatory conditions such as asthma, arthritis and osteoarthritis, sepsis and type-1 diabetes, as well as by some neuropathological diseases such as epilepsy, stroke and multiple sclerosis. Therefore, Bl receptors have been suggested to have a pivotal role in several chronic diseases involving inflammation, inflammatory pain and neuropathic pain (Campos et al. 2006).
  • Bl receptor activation in inflammation and pain processes is supported by the demonstration that Bl receptor knockout mice have a largely decreased response to nociceptive and pro-inflammatory stimuli (Ferreira et al. 2001; Ferreira et al. 2005).
  • the therapeutic interest of Bl receptor blockage is supported further by the pharmacological properties of Bl antagonists in many inflammatory and neuropathic pain models (Gougat et al. 2004; Fox et al. 2005).
  • Bl receptor expression is induced under disease conditions clearly raises the possibility that therapeutic use of Bl receptor antagonists should be devoid of undesired side effects.
  • non-peptide Bl antagonists with long-lasting efficacy and oral bioavailability, which would represent a new treatment paradigm for inflammation and pain, should clearly be advantageous over the existing treatment strategies.
  • Such agents are provided in the present invention.
  • Bradykinin antagonists are described in WO-A 2006/132837, US-A 2005/234044 and Expert Opin. Ther. Targets 11 (2007), 21-35.
  • an object of the present invention is to provide a new class of compounds as Bradykinin Bl antagonists which may be effective in the treatment of Bl receptor related diseases. Accordingly, the present invention provides compounds of formula (I)
  • R 1 is H; methyl; ethyl; n-propyl; i-propyl; or cyclopropyl, wherein methyl; ethyl; n- propyl; i-propyl; and cyclopropyl are optionally substituted with one or more halogen, which are the same or different;
  • X 1 is CR 6 R 6a ; O; S; S(O); or S(O) 2 ;
  • R 6 , R 6a are independently selected from the group consisting of H; and halogen;
  • X 2 is O; S; or N(R 7 );
  • R 2 ; R 3 ; R 4 ; R 5 ; R 7 are independently selected from the group consisting of H; methyl; ethyl; n-propyl; i-propyl; and cyclopropyl, wherein methyl; ethyl; n-propyl; i-propyl; and cyclopropyl are optionally substituted with one or more halogen, which are the same or different;
  • R 2 , R 3 or R 4 , R 5 are joined together with the carbon atom to which they are attached to give a cyclopropyl, which is optionally substituted with one or more halogen, which are the same or different;
  • n 1 or 2;
  • n 0; 1 or 2;
  • X 3 is phenyl or a 5- or 6-membered aromatic heterocycle, wherein X 3 is substituted in 2-position relative to the sulfonamide group in formula (I) with R 8 and is optionally substituted with one or more R 9 , which are the same or different;
  • R 8 ; R 9 are independently selected from the group consisting of halogen; CN; COOR 10 ;
  • OR 10 C(O)N(R 10 R 10a ); S(O) 2 N(R 10 R 10a ); S(O)N(R 10 R 10a ); S(O) 2 R 10 ; N(R 10 )S(O) 2 N(R 10a R 10b ); SR 10 ; N(R 10 R 10a ); NO 2 ; OC(O)R 10 ; N(R 10 )C(O)R 10a ; N(R 10 )S(O) 2 R 10a ;N(R 10 )S(O)R 10a ; N(R 1 °)C (O)N(R 10a R 10b ); N(R 10 )C(O)OR 10a ; OC(O)N(R 10 R 10a ); C(O)R 10 ; Ci -6 alkyl; C 2 .
  • Ci -6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl are optionally substituted with one or more R 11 , which are the same or different;
  • R 8 and R 9 in 2-position relative to R 8 are joined together with the atoms to which they are attached to form benzo; or a 5- or 6-membered aromatic heterocyle; wherein benzo; and the 5- or 6-membered aromatic heterocyle; are optionally substituted with one or more R 12 , which are the same or different;
  • R 9 two adjacent R 9 are joined together with the atoms to which they are attached to form benzo; or a 5- or 6-membered aromatic heterocyle; wherein benzo; and the 5- or 6-membered aromatic heterocyle; are optionally substituted with one or more R 12 , which are the same or different;
  • R 12 is independently selected from the group consisting of halogen; CN; COOR 10 ;
  • OR 10 C(O)N(R 10 R 10a ); S(O) 2 N(R 10 R 10a ); S(O)N(R 10 R 10a ); S(O) 2 R 10 ; N(R 10 )S(O) 2 N(R 10a R 10b ); SR 10 ; N(R 10 R 10a ); NO 2 ; OC(O)R 10 ; N(R 10 )C(O)R 10a ;
  • R 10 , R 1Oa , R 10b are independently selected from the group consisting of H; T; Ci_ 6 alkyl;
  • R 11 , R 13 are independently selected from the group consisting of halogen; C(O)R 14 ; CN; COOR 14 ; OR 14 ; C(O)N(R 14 R 14a ); S(O) 2 N(R 14 R 14a ); S(O)N(R 14 R 14a ); S(O) 2 R 14 ; N(R 14 )S(O) 2 N(R 14a R 14b ); SR 14 ; N(R 14 R 14a ); NO 2 ; OC(O)R 14 ; N(R 14 )C(O)R 14a ; N(R 14 )S(O) 2 R 14a ; N(R 14 )S(O)R 14a ; N(R 14 )S(O)R 14a ; N(R 14 )S(O)R 14a ; N(R 14 )S(O)R 14a ; N(R 14 )S(O)R 14a ; N(R 14 )S(O)R 14
  • R 14 , R 14a , R 14b are independently selected from the group consisting of H; T 1 ; Ci_ 6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl, wherein Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl are optionally substituted with one or more R 15 , which are independently selected from the group consisting of halogen; C(O)R 16 ; CN; COOR 16 ; OR 16 ; C(O)N(R 16 R 16a );
  • R 16 , R 16a , R 16b are independently selected from the group consisting of H; Ci_ 6 alkyl;
  • Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl wherein Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
  • T, T 1 are independently selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; adamantyl; C 3 _ 7 cycloalkyl; 4 to 7 membered heterocyclyl; and 9 to 11 membered heterobicyclyl, wherein T, T 1 are optionally substituted with one or more R 17 , which are independently selected from the group consisting of halogen; CN; C(O)R 18 ; COOR 18 ; OR 18 ; C(O)N(R 18 R 18a ); S(O) 2 N(R 18 R 18a ); S(O)N(R 18 R 18a ); S(O) 2 R 18 ; N(R 18 )S(O) 2 N(R 18a R 18b ); SR 18 ; N(R 18 R 18a ); NO 2 ; OC(O)R 18 ; N(R 18 )C(O)R 18
  • N(R 18 )C(O)N(R 18a R 18b ); N(R 18 )C(O)OR 18a ; OC(O)N(R 18 R 18a ); oxo ( 0), where the ring is at least partially saturated; Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl, wherein Ci _ 6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
  • R 18 , R 18a , R 18b are independently selected from the group consisting of H; Ci_ 6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl, wherein Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
  • X 4 is OR 19 or NR 19 R 19a ;
  • R 19 , R 19a are independently selected from the group consisting of H; T 2 ; Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl, wherein Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl are optionally substituted with one or more R 20 , which are the same or different;
  • R 19 , R 19a are joined together with the nitrogen to which they are attached to from a 4 to 7 membered heterocycle or 9 to 11 membered heterobicycle, wherein the 4 to 7 membered heterocycle or 9 to 11 membered heterobicycle is optionally substituted with one or more R 21 , which are the same or different;
  • T 2 is independently selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; adamantyl; C 3 _ 7 cycloalkyl; 4 to 7 membered heterocyclyl; and 9 to 11 membered heterobicyclyl, wherein T 2 is optionally substituted with one or more R 22 , which are the same or different;
  • R 21 , R 22 are independently selected from the group consisting of halogen; CN;
  • C 1-10 alkyl C 2-10 alkenyl; C 2-10 alkynyl; and T 3 , wherein C 1-10 alkyl; C 2-10 alkenyl; and
  • C 2 - 1 0 alkynyl are optionally substituted with one or more R 24 , which are the same or different;
  • R 23 , R 23a , R 23b are independently selected from the group consisting of H; T 3 ; Ci_ 6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl, wherein Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl are optionally substituted with one or more R 25 , which are the same or different;
  • R 20 is independently selected from the group consisting of halogen; CN; C(O)R 26 ;
  • R 24 , R 25 are independently selected from the group consisting of halogen; CN; C(O)R 26 ; COOR 26 ; OR 26 ; C(O)R 26 ; C(O)N(R 26 R 26a ); S(O) 2 N(R 26 R 26a );
  • R 26 , R 26a , R 26b are independently selected from the group consisting of H; T 3 ; Ci_ 6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl, wherein Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl are optionally substituted with one or more R 28 , which are the same or different;
  • R 27 , R 28 are independently selected from the group consisting of halogen; CN;
  • R 29 , R 29a , R 29b are independently selected from the group consisting of H; Ci_ 6 alkyl; C 2 -6 alkenyl; C 2 -6 alkynyl; and T 4 wherein Ci_6 alkyl; C 2 -6 alkenyl; and C 2 -6 alkynyl are optionally substituted with one or more R 31 , which are the same or different;
  • T 3 ; T 4 are independently selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; adamantyl; C 3 _ 7 cycloalkyl; 4 to 7 membered heterocyclyl; and 9 to 11 membered heterobicyclyl, wherein T 3 , T 4 are optionally substituted with one or more R 32 , which are the same or different;
  • R 33 , R 33a , R 33b are independently selected from the group consisting of H; Ci_ 6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl, wherein Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl are optionally substituted with one or more halogen, which are the same of different;
  • T 5 is phenyl; C3_7 cycloalkyl; or 4 to 7 membered heterocyclyl, wherein T 5 is optionally substituted with one or more R 36 , which are the same or different;
  • R 30 ; R 31 ; R 34 are independently selected from the group consisting of halogen; CN;
  • R 35 , R 35a , R 35b are independently selected from the group consisting of H; Ci_ 6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl, wherein Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl are optionally substituted with one or more halogen, which are the same of different.
  • R 36 is independently selected from the group consisting of halogen; CN; COOR 37 ; OR 37 ; C(O)N(R 37 R 37a ); S(O) 2 N(R 37 R 37a ); S(O)N(R 37 R 37a ); S(O) 2 R 37 ; N(R 37 )S(O) 2 N(R 37a R 37b ); SR 37 ; N(R 37 R 37a ); NO 2 ; OC(O)R 37 ; N(R 37 )C(O)R 37a ; N(R 37 )S(O) 2 R 37a ; N(R 37 )S(O)R 37a ; N(R 37 )C(O)N(R 37a R 37b ); N(R 37 )C(O)OR 37a ;
  • OC(O)N(R 37 R 37a ); oxo ( 0), where the ring is at least partially saturated; C(O)R 37 ; Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl, wherein Ci_6 alkyl; C 2 _6 alkenyl; and C 2 _6 alkynyl are optionally substituted with one or more halogen, which are the same or different; R 37 , R 37a , R 37b are independently selected from the group consisting of H; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same of different.
  • variable or substituent can be selected from a group of different variants and such variable or substituent occurs more than once the respective variants can be the same or different.
  • Alkyl means a straight-chain or branched saturated aliphatic acyclic hydrocarbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent.
  • Alkenyl means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon double bond. Each hydrogen of an alkenyl carbon may be replaced by a substituent.
  • Alkynyl means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon triple bond. Each hydrogen of an alkynyl carbon may be replaced by a substituent.
  • Ci_ 4 alkyl means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or e.g.
  • Ci_6 alkyl means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: Ci_ 4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl; tert-butyl, n-pentyl, n-hexyl, or e.g.
  • Ci_6 alkyl carbon when two moieties of a molecule are linked by the alkyl group.
  • Each hydrogen of a Ci_6 alkyl carbon may be replaced by a substituent.
  • Ci_io alkyl means an alkyl chain having 1 to 10 carbon atoms, e.g. if present at the end of a molecule: Ci_4 alkyl, Ci_6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl; tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-hexyl or e.g.
  • Each hydrogen of a C 2 -6 alkenyl carbon may be replaced by a substituent.
  • Each hydrogen of a C 2 -6 alkynyl carbon may be replaced by a substituent.
  • C 3 _ 7 cycloalkyl or “C 3 _ 7 cycloalkyl ring” means a cyclic alkyl chain having 3 - 7 carbon atoms, e.g. cyclopropyl, cyclo butyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent.
  • Halogen means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.
  • Examples for a 4 to 7 membered heterocycles are azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydro furan, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyr
  • Examples for a 9 to 11 membered heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine.
  • 9 to 11 membered heterobicycle also includes spiro structures of two rings like l,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles like 8-aza-bicyclo[3.2. ljoctane.
  • heterocycles examples include furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, pyranium, pyridine, pyridazine, pyrimidine, triazole, tetrazole.
  • Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given below, with all combinations of preferred substituent definitions being a subject of the present invention.
  • the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts as well as their isotopic derivatives.
  • Preferred compounds according to the present invention are those having a stereochemistry as given in formula (Ia)
  • R 1 to R 5 and X 1 to X 4 , n and m have the meaning as indicated above.
  • the substituents R 1 to R 5 and X 1 to X 4 of the formula (I) independently have the following meaning. Hence, one or more of the substituents R 1 to R 5 and X 1 to X 4 can have the preferred or more preferred meanings given below.
  • R 1 is H or methyl, more preferred R 1 is H.
  • X 1 is O; CH 2 ; or CF 2 .
  • X 2 is O.
  • R 2 , R 3 , R 4 , R 5 are H.
  • n 1
  • n is 1 or 2, more preferred m is 1.
  • X 3 is selected from the group consisting of
  • X 3 is selected from the group consisting of
  • R , r R> 9 and R , 12 have the meaning as indicated above.
  • R , R > 9 , R , 12 are independently selected from the group consisting of halogen; CN; OR 10 ; NO 2 ; phenyl; and Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more halogen; or phenyl and wherein R 10 is H; or Ci_ 6 alkyl, which is optionally substituted with phenyl or one or more halogen, which are the same or different.
  • More preferred R 8 , R 9 , R 12 are independently selected from the group consisting of F; Cl; Br; I; CN; OCH 3 ; NO 2 ; CH 3 ; CH 2 CH 3 ; CH(CH 3 ) 2 ; and CF 3 .
  • X 4 is NR 19 R 19a , wherein R 19 , R 19a have the meaning as indicated above.
  • R 19a is selected from the group consisting of H; and Ci_6 alkyl.
  • R 19 is selected from the group consisting of T 2 ; and Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more R 20 and wherein T 2 and R 20 have the meaning as indicated above. More preferred Ci_6 alkyl is substituted with one R 20 and wherein R 20 has the meaning as indicated above.
  • R 19 , R 19a are joined together with the nitrogen to which they are attached to form a piperazinyl; a homopiperazinyl; or a thiazolidinyl ring, wherein the ring is optionally substituted with one or more R 21 and wherein R 21 has the meaning as indicated above. More preferred the ring is substituted with one R 21 and wherein R 21 has the meaning as indicated above.
  • R 20 is selected from the group consisting of T 2 ; and N(R 26 R 26a ), wherein R 26 , R 26a have the meaning as indicated above.
  • R 26 , R 26a are independently selected from the group consisting of H; and Ci_6 alkyl.
  • R 21 is selected from the group consisting of Ci_io alkyl; C 2 _io alkenyl; C 2 _io alkynyl; and T 3 , wherein Ci_io alkyl; C 2 _io alkenyl; and C 2 _io alkynyl are optionally substituted with one or more R 24 and wherein T 3 and R 24 have the meaning as indicated above. More preferred, Ci_io alkyl; C 2 _io alkenyl; and C 2 _io alkynyl are optionally substituted with one R 24 and wherein R 24 has the meaning as indicated above.
  • R 24 is selected from the group consisting of T 3 ; CN; N(R 26 R 26a ); and C(O)N(R 26 R 26a ) and wherein R 26 , R 26a have the meaning as indicated above.
  • T 2 and T 3 are independently selected from the group consisting of phenyl; cyclopentyl; cyclohexyl; tetralinyl; pyrrolidinyl; imidazolyl; piperidyl; pyridyl; mopholinyl; thiophenyl; and benzodioxolanyl, wherein T 2 is optionally substituted with one or more R 22 and T 3 is optionally substituted with one or more R 32 .
  • T 2 is optionally substituted with up to 3 R 22 , which are the same or different and T 3 is optionally substituted with up to 3 R 32 , which are the same or different.
  • R 22 , R 32 are independently selected from the group consisting of halogen; CN; OCi_6 alkyl; Ci_ 6 alkyl; C 2 - 6 alkenyl; and C 2 - 6 alkynyl.
  • these individual compounds are not excluded as far as compounds of formula (I) are used in pharmaceutical compositions, as a medicament, for the manufacture of a medicament, in a method controlling, delaying or preventing in mammalian patient in need of treatment one or more conditions or prepared in a process for the preparation according to the present invention.
  • Prodrugs of the compounds of the invention are also within the scope of the present invention.
  • “Prodrug” means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically.
  • Examples of a prodrug are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterified or amidated.
  • These compounds can be produced from compounds of the present invention according to well-known methods.
  • Metabolites of compounds of formula (I) are also within the scope of the present invention.
  • tautomerism like e.g. keto-enol tautomerism
  • compounds of general formula (I) may occur
  • the individual forms like e.g. the keto and enol form, are comprised separately and together as mixtures in any ratio.
  • stereoisomers like e.g. enantiomers, cis/trans isomers, conformers and the like.
  • Iso topic labeled compounds of formula (I) are also within the scope of the present invention.
  • Methods for isotope labeling are known in the art.
  • Preferred isotopes are those of the elements H, C, N, O and S.
  • isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases.
  • enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue.
  • any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials.
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • Compounds of the formula (I) which contain one or more basic groups i.e.
  • acids which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • the respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • the present invention provides compounds of general formula (I) as Bradykinin Bl antagonists.
  • There utilities are described in detail in the utility section of WO-A 2006/132837, page 8, line 9 to page 12, line 2, which paragraph is herewith incorporated by reference.
  • compounds of the present inventions may be useful for the treatment or prophylaxis of pain and inflammation including visceral pain (like pancreatitis, interstitial cystitis, renal colic, prostatitis, chronic pelvic pain), neuropathic pain (including postherpetic neuralgia, acute zoster pain, nerve injury, the "dynias", including vulvodynia, phantom limb pain, root avulsions, radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, carpal tunnel syndrome, ulnar neuropathy, tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia), central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system including but not limited to stroke, multiple sclerosis, spinal cord injury), and postsurgical pain syndromes (including postmastectomy syndrome, postthoracotomy syndrome, stump pain)), bone and joint pain (osteoarthritis), spine
  • hyperglycemia diuresis, proteinuria and increased nitrite and kallikrein urinary excretion
  • spasm of the gastrointestinal tract or uterus liver disease, multiple sclerosis, cardiovascular disease, including atherosclerosis, congestive heart failure, myocardial infarct
  • neurodegenerative diseases including Parkinson's and Alzheimers disease, epilepsy, septic shock, headache including cluster headache, migraine including prophylactic and acute use, stroke, closed head trauma, cancer, sepsis, gingivitis, osteoporosis, benign prostatic hyperplasia and hyperactive bladder.
  • compounds of the present invention may be useful for the treatment or prophylaxis of obesity. Accordingly, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use as a medicament.
  • the compounds of the present invention can be used for the manufacture of a medicament for the treatment or prophylaxis of pain and inflammation including visceral pain (like pancreatitis, interstitial cystitis, renal colic, prostatitis, chronic pelvic pain), neuropathic pain (including postherpetic neuralgia, acute zoster pain, nerve injury, the "dynias", including vulvodynia, phantom limb pain, root avulsions, radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, carpal tunnel syndrome, ulnar neuropathy, tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia), central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system including but not limited to stroke, multiple sclerosis, spinal cord injury), and postsurgical pain syndromes (including postmastectomy syndrome, postthoracotomy syndrome, stump pain), bone and joint pain (osteoste
  • hyperglycemia diuresis, proteinuria and increased nitrite and kallikrein urinary excretion
  • spasm of the gastrointestinal tract or uterus liver disease, multiple sclerosis, cardiovascular disease, including atherosclerosis, congestive heart failure, myocardial infarct
  • neurodegenerative diseases including Parkinson's and Alzheimers disease, epilepsy, septic shock, headache including cluster headache, migraine including prophylactic and acute use, stroke, closed head trauma, cancer, sepsis, gingivitis, osteoporosis, benign prostatic hyperplasia, hyperactive bladder; and obesity.
  • the present invention also provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment one or more conditions selected from the group consisting of pain and inflammation including visceral pain (like pancreatitis, interstitial cystitis, renal colic, prostatitis, chronic pelvic pain), neuropathic pain (like postherpetic neuralgia, acute zoster pain, nerve injury, the "dynias", including vulvodynia, phantom limb pain, root avulsions, radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, carpal tunnel syndrome, ulnar neuropathy, tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia), central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system including but not limited to stroke, multiple sclerosis, spinal cord injury), and postsurgical pain syndromes (including postmastectomy syndrome, postthoracoto
  • hyperglycemia diuresis, proteinuria and increased nitrite and kallikrein urinary excretion
  • spasm of the gastrointestinal tract or uterus liver disease, multiple sclerosis, cardiovascular disease, including atherosclerosis, congestive heart failure, myocardial infarct
  • neurodegenerative diseases including Parkinson's and Alzheimers disease, epilepsy, septic shock, headache including cluster headache, migraine including prophylactic and acute use, stroke, closed head trauma, cancer, sepsis, gingivitis, osteoporosis, benign prostatic hyperplasia, hyperactive bladder; and obesity.
  • the present invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.
  • “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like one or more compounds of formula (I) not being the first compound in the composition or other Bradykinin Bl antagonists.
  • the active ingredients may be comprised in one or more different pharmaceutical compositions (combination of pharmaceutical compositions).
  • the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally, for example, as liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of formula (I) are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • compound of formula (I) may be prepared starting from compounds of formula (IV). Accordingly, another aspect of the present invention is a process for the preparation of a compound according to the present invention, comprising the steps of
  • the potency to inhibit the Bradykinin Bl receptors was determined for the compounds of this invention in a cell-based fluorescent calcium-mobilization assay.
  • the assay measures the ability of test compounds to inhibit Bradykinin Bl receptor agonist-induced increase of intracellular free Ca 2+ in cell lines expressing Bl.
  • calcium indicator -loaded cells are pre-incubated in the absence or presence of different concentrations of test compounds followed by the stimulation with a selective Bl receptor agonist peptide.
  • the change of the intracellular Ca 2+ concentration is monitored with a specifically designed fluorescent plate reader (FlexStation, Molecular Devices).
  • CHO-Kl cell line expressing human Bl was purchased from Euroscreen (Gosselies, Belgium, with reference name hBl-Dl).
  • CHO-Kl cell lines expressing rat Bl or mouse Bl were established in the following way: the full-length receptor-coding cDNA clones were obtained by PCR performed on rat or mouse brain cDNAs. The respective cDNAs were cloned into an expression vector under the control of a CMV promotor. The resultant plasmids were introduced into CHO-Kl cells with liposome technology (FuGENE; Roche Diagnostics, Basel), according to the standard protocols described by the manufacturer.
  • Cell lines expressing a Bradykinin receptor were selected in the culture medium containing 400 ⁇ g/ml
  • G418 Sigma. From selected cell populations, monoclonal cell lines were isolated by single cell cloning. The expression of Bradykinin receptors was confirmed by immunofluorescence staining of the cells, as well as by calcium flux assay.
  • Human Bl -expressing cells were grown in Nutrient Mixture Ham's F 12 (Sigma) containing 10% Foetal bovine serum (Sigma) and 400 ⁇ g/ml G418 (Sigma), 5 ⁇ g/ml puromycim (Sigma); Rat Bl and mouse Bl -expressing cells were grown in DMEM/F12 medium (Sigma) containing 10% Foetal bovine serum (Sigma) and 400 ⁇ g/ml G418 (Sigma).
  • 80% confluent cells were detached from the culture vessels with Versene (Gibco; for human Bl cell- line) or with Ix trypsin-EDTA solution (Sigma; for rodent Blcell-line), and seeded into 384-well plates (Cell binding Surface; Corning, NY; #3683) at a density of 15,000 cells per well for human Bl or at a density of 20,000 cells per well for rodent Bl.
  • Cells were seeded in a volume of 50 ⁇ l in medium without antibiotics and incubated overnight in a humidified atmosphere with 5% CO 2 at 37°C.
  • Agonist plates contained the Bl agonist Lys-(Des-Arg)-Bradykinin (Bachem, Brackley) at 3.5x EC90 in assay buffer with 1% DMSO.
  • the addition of agonist 20 ⁇ l per well to the assay plate was carried out on the FlexStation while continuously monitoring Ca 2+ -dependent fluorescence at 538nm.
  • the integrated values, normalized with the background fluorescence, were plotted against the logarithm of the antagonist concentrations.
  • typical EC50 values for the Bl agonist Lys-(Des-Arg)-Bradykinin were the following: 2 nM (human), 250 nM (rat) and 10 nM (mouse); typical IC50 values for the Bl antagonist Lys-(Des-Arg-Leu)-Bradykinin (Bachem, Brackley) were 0.5 nM (human), 12 nM (rat) or 15 nM (mouse).
  • an active compound was selected from those that exhibited an IC50 value against human Bl of ⁇ l ⁇ M. Based on their levels of potency, the selected compounds are grouped in the present invention as below:
  • IMR-90 human fetal lung fibroblasts cells were obtained from the American Type Culture Collection (Rockville, MD). The fibroblasts were cultured in complete growth media comprised of Dulbecco's modified Eagle's medium (DMEM; Life Technologies, Grand Island, NY) containing 10% fetal bovine serum (Sigma, St. Louis, MO), 50 IU/ml penicillin, 50 ⁇ g/ml streptomycin, 4mM L-glutamine, and 1% nonessential amino acids (Life Technologies). The cells were maintained in a humidified atmosphere in 5% CO 2 at 37°C and were subcultured by incubating with 0.05% trypsin / 0.5mM EDTA (Life Technologies) at a ratio of 1 :3, weekly.
  • DMEM Dulbecco's modified Eagle's medium
  • fetal bovine serum Sigma, St. Louis, MO
  • 50 IU/ml penicillin 50 ⁇ g/ml streptomycin
  • 4mM L-glutamine 4mM
  • IMR-90 cells were washed once with growth medium excluding foetal bovine serum before being incubated at 37°C for 6hr in the presence of the Bl receptor agonist Lys-(Des-Arg)-Bradykinin (Bachem California, Torrance, CA) at 10OnM.
  • the cells after exposure to the receptor agonist were rinsed in PBS, followed by two incubations in 0.05M glycine-HCl, pH 3.0 for 6 and 0.5 min, and then two brief rinses in PBS, in order to remove surface receptor-bound agonist. Binding assays were performed at 25°C in duplicate six-well dishes in a final volume of 1.25 ml.
  • IMR-90 cells were incubated for 60 min in the presence of 0.5nM [ 3 H] Lys-(Des-Arg)-Bradykinin (91-105 Ci/mmol; PerkinElmer, Boston) and test compounds at 4 concentrations (lO ⁇ M, l ⁇ M O.l ⁇ M and O.Ol ⁇ M) in binding buffer that was comprised of 2OmM HEPES, pH 7.4, 125mM N- methyl-D-glucamine, 5mM KCl, 0.14 g/1 bacitracin and ImM 1,10-phenanthroline.
  • Nonspecific binding was defined as the amount of radiolabeled ligand bound in the presence of lO ⁇ M (Des-Arg-Leu.)-Bradykinin (Bachem California, Torrance, CA). After incubation, the assay buffer was removed and the cells were washed with 2 x 4 ml of ice-cold PBS. The cells were then lysed with 0.05% sodium dodecyl sulfate. Specific binding was expressed in femtomoles per milligram of protein, and protein was determined using a Bio-Rad kit (Bio- Rad Laboratories, Richmond, CA). All assay plates were carried out in duplicate and the variation between wells was ⁇ 8%. For data analysis, IC50 values were determined by a non-linear, least squares regression analysis using Data Analysis Toolbox (MDL Information Systems, San Leandro, CA, USA).
  • rings of human umbilical vein denuded of endothelium were suspended in 20-ml organ baths filled with an oxygenated (95% O 2 and 5% CO 2 ) and pre-warmed (37°C) physiological salt solution of the following composition: 118mM NaCl, 4.7mM KCl, 1.2mM
  • Hoe 140 (l ⁇ M), benextramine (l ⁇ M), propranolol (l ⁇ M), pyrilamine (l ⁇ M), atropine (l ⁇ M), methysergide (l ⁇ M), mergetpa (l ⁇ M) and captopril (l ⁇ M) were also present throughout the experiments to block the bradykinin B 2 , ⁇ -adrenergic, ⁇ -adrenergic, histamine
  • the tissues were connected to force transducers (FT03, Grass Instruments) for isometric tension recordings. They were stretched to a resting tension of 2g, washed several times then allowed to equilibrate overnight. The experiments were carried out using semi-automated isolated organ systems possessing eight organ baths, with multi-channel data acquisition (Grass model 7D orLinseis GmbH model L2005).
  • the tissues were contracted with a high K + solution (8OmM KCl) to obtain a control response. Following washings and recovery of the basal tension, the tissues were exposed to a sub- maximal concentration of the reference agonist Lys-(Des-Arg)-Bradykinin (0.03 ⁇ M) to obtain a contractile response either in the absence or presence of increasing concentrations of a test compound or the reference antagonist Lys-(Des-Arg-Leu)-Bradykinin, each added 30 min prior to Lys-(Des-Arg)-Bradykinin. Only one compound concentration was tested in each tissue.
  • the title compound was prepared following the general procedure A using piperidine-2- ethanol (58.1 g, 0.45 mol), DIPEA (235 mL, 1.35 mol), DMAP (54.9 g, 0.45 mol), DCM (1000 mL), TBDMSCl (88.2 g, 0.59 mol) in DCM (250 mL) and benzyl chloroformate (92.5 g, 0.54 mol).
  • the title product was obtained as a colourless oil No further purification was required. Yield: 231 g.
  • the title compound was prepared following general procedure B using crude benzyl 2-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)piperidine-l-carboxylate (231 g, 0.45 mol) in THF (500 rnL) and TBAF.2H2O (IM in THF, 500 mL). The title compound was obtained as a colourless oil. No further purification was required. Yield: 150 g.
  • the title compound was prepared following general procedure C for etherification with tert- butylbromoacetate using crude benzyl 2-(hydroxymethyl)piperidine-l-carboxylate (175.75 g, 0.5 mol), TBAI (cat, 5 g) in toluene (1000 mL); 25 % w/v NaOH (1000 mL); and tert- butylbromoacetate (202.0 mL, 1.51 mol). Purification by dry flash column chromatography eluting with 0-20% EtOAc in heptanes afforded the title compound as a colourless solid. Yield: 72.71 g, 40 %.
  • the title compound was prepared following the general procedure C using crude benzyl 2-(2- hydroxyethyl)piperidine-l-carboxylate (146 g, 0.45 mol), TBAI (cat 5.5 g) in toluene (1100 mL); NaOH (aq., 25% (w/v), 1150 rnL); and tert-butylbromoacetate (205 mL, 1.53 mol). Purification by dry flash column chromatography eluting with 0-25% EtOAc in heptanes afforded the title compound as a colourless solid (77 g, 71 %).
  • the title compound was prepared following general procedure D using benzyl 2-[(2-tert- butoxy-2-oxoethoxy)methyl]piperidine-l-carboxylate (55.95 g, 0.15 mol) and 10 % Pd/C (cat, 5 g) in ethanol (550 mL). This yielded the title compound as a colourless oil. Yield: 32 g, 93 %.
  • the title compound was prepared following general procedure D using benzyl 2-[2-(2-tert- butoxy-2-oxoethoxy)ethyl]piperidine-l-carboxylate (35 g, 92.7 mmol) and 10 % Pd/C (cat, 5 g) in ethanol (350 mL). This afforded the title compound as a colourless oil. Yield: 24 g, 107 %.
  • the title compound was prepared following general procedure E using tert-butyi (piperidin-2- ylmethoxy)acetate (1.960 g, 8.55 mmol) in DCE (118 mL), 2-cyanobenzenesulfonyl chloride (2.585 g, 12.82 mmol), and aqueous K 2 CO 3 (1.0 M, 34 mL). Purification by Biotage column chromatography eluting with 10-100 % DCM in heptanes) afforded the title compound as a pale yellow oil. Yield: 2.003 g, 59 %.
  • the organic layer was washed with 2 mL water; in all other cases the organic layer was washed with 2 mL aqueous 10 % w/v citric acid solution.
  • the organic layer was separated from the mixtures and filtered through a Na 2 SO 4 plug into a 48 x 5 mL plate.
  • the master plates were concentrated in vacuo using a Genevac.
  • the title compound was prepared according to general procedure B by using 2-( ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ methyl)- 1 - [(4-methoxy-2 ,6-dimethylphenyl)sulfonyl]piperidine (4.27 g, 10 mmol) and 1 M TBAF solution in THF (10 mL). The crude product required no further purification. Yield: 3.34 g, quantitative.
  • the title compound was prepared according to general procedure C using tert-butyl 3- (hydroxymethyl)morpholine-4-carboxylate (0.43 g, 2.0 mmol), tert-butylbromoacetate (0.58 g, 3.0 mmol), TBAI (20 mg, cat), toluene (4 mL) and 35 % w/v aqueous NaOH solution (4 mL). The title compound was obtained and no further purification was required. Yield: 0.66 g, 99 %
  • the title compound was prepared according to general procedure K using ⁇ [4-(tert- butoxycarbonyl)morpholin-3-yl]methoxy ⁇ acetic acid (10 g, 36 mmol), CDI (5.89 g, 36 mmol) and l-(l-methylpiperidin-4-yl)piperazine (6.65 g, 36 mmol).
  • the title compound was obtained as a brown oil. Yield: 11.8 g, 74 %
  • the title compound was prepared according to general procedure H using (25)-piperidine-2- carboxylic acid (0.5 g, 3.87 mmol) in MeOH (10.0 mL) and 2.0 M TMSdiazomethane in heptanes (6.0 mL) at ambient temperature. The title compound was obtained as a white solid. Yield: 0.55 g, 99 %.
  • the title compound was prepared according to general procedure C using [(2S)- 1 -[(4- methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl ⁇ methanol (0.2 g, 0.64 mmol), TBAI (10 mg, cat), toluene (2.0 mL), 35 % w/v NaOH solution (2 mL) and tert-butyl bromoacetate (0.19 g, 0.96 mmol).
  • the crude product was absorbed onto a pad of silica, washed with heptanes and eluted with EtOAc to afford the title compound. Yield: 0.22 g, 80 %.
  • the title compound was prepared according to general procedure F using tert-butyi ([(2S)-I- [(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl ⁇ methoxy)acetate (0.2 g, 0.47 mmol) and a 1 :3 mixture of TFA/DCM (4 mL).
  • the title compound did not require any further purification. Yield: 0.167 g, quantitative.
  • the title compound was prepared according to general procedure K using ( ⁇ (25)-l-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl ⁇ methoxy)acetic acid (74 mg, 0.20 mmol), THF (1.5 mL), CDI (32 mg, 0.20 mmol) and l-(l-methylpiperidin-4-yl)piperazine (42 mg, 0.23 mmol). A portion of the crude product was purified using prep method 3.
  • the title compound was prepared according to general procedure C using te/t-butyl (25)-2-(2- hydroxyethyl)piperidine-l-carboxylate (2.17 g, 10.0 mmol), TBAI (100 mg, cat), toluene (22 rnL), 35 % w/v NaOH solution (22 rnL) and tert-butyl bromoacetate (2.93 g, 15.0 mmol).
  • the crude product was purified by FCC eluting with 0-5 % MeOH in DCM to afford the title compound. Yield: 2.67 g, 77 %.
  • the title compound was prepared according to general procedure K using (2- ⁇ (25)-l-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl ⁇ ethoxy)acetic acid (0.25 g, 0.65 mmol), THF (5 mL), CDI (0.10 g, 0.65 mmol) and l-(l-methylpiperidin-4-yl)piperazine (0.11 g, 0.59 mmol). A portion of the crude product was purified using prep method 3.
  • the title compound was prepared according to general procedure C using [(3i?)-4- benzylmorpholin-3-yl]methanol (13.0 g, 62.7 mmol), TBAI (100 mg, cat), toluene (130 mL), 35 % w/v NaOH solution (130 mL) and t ⁇ t-butyl bromoacetate (12.8 g, 65.8 mmol).
  • the crude product was purified by flash column chromatography, eluting with 10-35 % EtO Ac/heptanes to afford the title compound as a clear oil that solidified on standing. Yield: 13.8 g, 68 %.
  • the title compound was prepared according to general procedure F using tert-butyl ( ⁇ (3S)-4- [(2-methylphenyl)sulfonyl]morpholin-3-yl ⁇ methoxy)acetate (0.23 mmol) and a 1 :3 mixture of TFA/DCM (1 mL). The title compound required no further purification.
  • the title compound was prepared according to general procedure K using ( ⁇ (35)-4-[(2- methylphenyl)sulfonyl]morpholin-3-yl ⁇ methoxy)acetic acid (0.23 mmol), THF (1 mL), CDI (37 mg, 0.23 mmol), and l-(l-methylpiperidin-4-yl)piperazine (42 mg, 0.23 mmol). This afforded the title compound, a portion of which was purified using prep methods 2 or 3.
  • the title compound was prepared in a method analogous to general procedure D using ethyl l-(diphenylmethyl)-4,4-difluoropiperidine-2-carboxylate (496 mg, 1.38 mmol), EtOH (20 mL), 10% Pd/C (50 mg, cat) and hydrogen. The mixture was stirred overnight, and filtered through Celite. The filtrate was concentrated in vacuo, and the crude mixture taken up in 10% w/v aqueous citric acid (10 mL) and Et 2 O (10 mL). The aqueous phase was separated and washed with Et 2 O (2 x 10 mL).
  • the title compound was prepared according to general procedure C using ⁇ 4,4-difluoro-l-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl ⁇ methanol (274 mg, 784 ⁇ mol), TBAI (7 mg, cat) and tert-butyi bromoacetate (174 ⁇ L, 1.18 mmol) in DCM (2.5 mL) and 35% w/v NaOH solution (2.5 mL). The residue was purified using flash column chromatography eluting with 10-20 % EtOAc in heptanes to afford the title compound. Yield: 222 mg, 61 %
  • the title compound was prepared according to general procedure F using tert-butyl ( ⁇ 4,4- difluoro-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl ⁇ methoxy)acetate (222 mg, 479 ⁇ mol) and a 1 :5 mixture of TFA and DCM. This afforded the title compound which required no further purification. Yield: 195 mg, 100 %
  • Ethyl (25)-4-oxo-l-[(lR)-l-phenylethyl]piperidine-2-carboxylate (1.0 g, 3.63 mmol) was dissolved in DCM (1.0 mL) and stirred under N 2 prior to addition of deoxofluor (50 %, 2.3 mL, 6.17 mmol). EtOH (21 ⁇ L) was added and the reaction stirred at ambient temperature under N 2 overnight. The solution was then poured into saturated aqueous NaHCO 3 solution (10 mL) and after effervescence had ceased the mixture was extracted with DCM (2 x 10 mL).
  • the title compound was prepared according to general procedure T using ethyl (25)-4,4-difluoro-l- [(lR)-l-phenylethyl]piperidine-2-carboxylate (4.61 g, 15.5 mmol), THF (2.5 mL) and 1.0 M solution of LiAlH 4 in THF (31 mL, 31 mmol) This afforded the title compound which required no further purification.
  • the title compound was prepared according to general procedure C using ⁇ (25)-4,4-difluoro-l-[(lR)- l-phenylethyl]piperidin-2-yl ⁇ methanol (3.33 g, 13.1 mmol), TBAI (120 mg, cat), tert-butyl bromoacetate (2.9 mL, 19.7 mmol) in DCM (35 mL) and 35% w/v NaOH solution (35 mL).
  • the product was purified using flash column chromatography eluting with 10-20 % EtOAc in heptanes to afford the title compound. Yield: 4.81 g, 100 %.
  • the title compound was prepared according to general procedure S using tert-butyl ⁇ [(2S)-4,4- difluoropiperidin-2-yl]methoxy ⁇ acetate (481 mg, 1.81 mmol), 2,6-dimethyl-4-methoxybenzene-l- sulfonyl chloride (426 mg, 1.81 mmol), DIPEA (315 ⁇ L, 1.81 mmol) and DMAP (22 mg, 0.18 mmol) in DCM (5 mL). This afforded the title compound, which was purified using flash column chromatography, eluting with 10 % EtOAc in heptanes. Yield: 463 mg, 55 %.
  • the title compound was prepared according to general procedure K using ( ⁇ (25)-4,4-difluoro-l-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl ⁇ methoxy)acetic acid (160 mg, 0.39 mmol), THF (1.5 mL), CDI (79 mg, 488 ⁇ mol) and l-(l-methylpiperidin-4-yl)piperazine (71 mg, 0.39 mmol). A portion of the crude product was purified using preparative HPLC using method 3.
  • the title compound was prepared according to general procedure S using methyl thiomorpholine- 3-carboxylate (3.00 g, 17.1 mmol), DIPEA (6.0 mL, 34.2 mmol), DMAP (209 mg, 1.71 mmol) and DCM (40 mL). The residue was purified using FCC eluting with 0-20 % EtOAc in heptanes. Yield: 5.86 g, 92 %
  • the title compound was prepared according to general procedure C using ⁇ 4-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]thiomorpholin-3-yl ⁇ methanol (5.36 g, 16.2 mmol), TBAI (150 mg, 405 ⁇ mol), tert-butyl bromoacetate (3.6 mL, 24.3 mmol), DCM (110 mL) and 35% w/v NaOH solution (110 mL). The crude product was purified using FCC eluting with 0-20 % EtOAc in heptanes.
  • the title compound was prepared according to general procedure F using tert-butyl ( ⁇ 4-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]thiomorpholin-3-yl ⁇ methoxy)acetate (2.50 g, 5.61 mmol) and a 9: 1 mixture of TFA/DCM. This afforded the title compound which required no further purification.
  • the title compound was prepared according to general procedure K using ( ⁇ 4-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]thiomorpholin-3-yl ⁇ methoxy)acetic acid (1.00 g, 2.56 mmol), , CDI (417 mg, 2.56 mmol), l-(l-methylpiperidin-4-yl)piperazine (424 mg, 2.31 mmol) and THF (15 mL) instead of DCE.
  • the crude product was purified using FCC eluting with 0.5:5:95 NH 4 OH/MeOH/DCM to 1: 10:90 NH 4 OH /MeOH/DCM. Yield: 1.18 g, 82 %
  • the title compound was prepared according to general procedure F using tert-butyl ( ⁇ 4-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]-l,l-dioxidothiomorpholin-3-yl ⁇ methoxy)acetate (187 mg, 391 ⁇ mol) and a 9: 1 mixture of DCM/TFA (0.4 mL). This afforded the title compound that required no further purification.
  • the title compound was prepared according to general procedure K using ( ⁇ 4-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]-l,l-dioxidothiomorpholin-3-yl ⁇ methoxy)acetic acid (148 mg, 351 ⁇ mol), CDI (57 mg, 351 ⁇ mol), l-(l-methylpiperidin-4-yl)piperazine (58 mg, 316 ⁇ mol) and THF (3 mL) instead of DCE. A portion of the crude product was purified using preparative HPLC using method 3.
  • the title compound was prepared according to general procedure S using methyl (3R)- thiomorpholine-3-carboxylate (980 mg), 2,6-dimethyl-4-methoxybenzene-l-sulfonyl chloride (1.55 g, 6.6 mmol), DIPEA (3.1 mL, 18.2 mmol), DMAP (73 mg, 0.6 mmol) and DCM (40 mL). This afforded the title compound, which was purified by FCC eluting with 10-30 % EtOAc in heptanes. Yield: 813 mg, 37 %.
  • the title compound was prepared according to general procedure T using methyl (3i?)-4-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]thiomorpholine-3-carboxylate (500 mg, 1.39 mmol), 2.3 M LiAlH 4 in THF (0.86 mL) and THF (5 mL). This afforded the title compound which required no further purification. Yield: 453 mg, 98 %.
  • the title compound was prepared according to general procedure C using ⁇ (3i?)-4-[(4-methoxy- 2,6-dimethylphenyl)sulfonyl]thiomorpholin-3-yl ⁇ methanol (453 mg, 1.37 mmol), tert-butyl bromoacetate (401 mg, 2.06 mmol), TBAI (13 mg, cat), DCM (5 mL) and 35 % w/v aqueous NaOH (6 mL). This afforded the title compound, which required no further purification. Yield: 511 mg, 84 %.
  • the title compound was prepared according to general procedure K using tert-butyl ( ⁇ (3i?)-4-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]- 1 , 1 -dioxidothiomorpholin-3-yl ⁇ methoxy)acetate (300 mg, 0.628 mmol) and 1 :9 TFA/DCM (5 mL). This afforded the title compound, which required no further purification. Yield: 220 mg, 93 %.
  • the title compound was prepared according to general procedure K using ( ⁇ (3i?)-4-[(4-Methoxy- 2,6-dimethylphenyl)sulfonyl]-l,l-dioxidothiomorpholin-3-yl ⁇ methoxy)acetic acid (100 mg, 0.24 mmol), CDI (47 mg, 0.29 mmol), l-(l-methylpiperidin-4-yl)piperazine (48 mg, 0.26 mmol) and DCE (2 mL).
  • the crude product was purified using prep method 3. Yield: 16 mg, 11 %
  • the title compound was prepared in a manner analogous to general procedure D using ethyl cis- 1 - (diphenylmethyl)-6-methyl-l,2,3,6-tetrahydropyridine-2-carboxylate (2.68 g, 7.99 mmol), EtOH (30 mL), 10 % Pd/C (cat., 268 mg) and hydrogen. The mixture was stirred overnight, and filtered through Celite. The filtrate was concentrated in vacuo, and the crude mixture taken up in 10% w/v aqueous citric acid (50 mL) and Et 2 O (25 mL).
  • the title compound was prepared according to general procedure T using ethyl c ⁇ -l-[(4-methoxy- 2,6-dimethylphenyl)sulfonyl]-6-methylpiperidine-2-carboxylate (468 mg, 1.27 mmol), THF (4.5 mL) and 2.3 M solution Of LiAlH 4 in THF (1.1 mL, 2.53 mmol.
  • the title compound was obtained as a clear oil. Yield: 237 mg, 57 %
  • the title compound was prepared according to general procedure C using ⁇ c ⁇ -l-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]-6-methylpiperidin-2-yl ⁇ methanol (240 mg, 733 ⁇ mol), TBAI (7 mg, 18.3 ⁇ mol), tert-butyl bromoacetate (162 ⁇ L, 1.10 mmol), DCM (2.5 mL) instead of toluene and 35 % w/v NaOH (2.5 mL).
  • the crude product was purified using FCC eluting with 10-30 % EtOAc in heptanes to afford the title compound. Yield: 240 mg, 74 %
  • the title compound was prepared according to general procedure K using ( ⁇ c ⁇ -l-[(4-methoxy- 2,6-dimethylphenyl)sulfonyl]-6-methylpiperidin-2-yl ⁇ methoxy)acetic acid (196 mg, 512 ⁇ mol), THF (2.5 mL), CDI (83 mg, 512 ⁇ mol) and l-(l-methylpiperidin-4-yl)piperazine (94 mg, 512 ⁇ mol) in. A portion of the crude mixture was purified using preparative HPLC using method 3.

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EP08736022A 2007-04-12 2008-04-09 Neue bradykinin-b1-antagonisten Withdrawn EP2155678A1 (de)

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