WO2018104307A1 - Aromatic sulfonamide derivatives and their use as anatagon i sts or negative allosteric modulators of p2x4 - Google Patents

Aromatic sulfonamide derivatives and their use as anatagon i sts or negative allosteric modulators of p2x4 Download PDF

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WO2018104307A1
WO2018104307A1 PCT/EP2017/081533 EP2017081533W WO2018104307A1 WO 2018104307 A1 WO2018104307 A1 WO 2018104307A1 EP 2017081533 W EP2017081533 W EP 2017081533W WO 2018104307 A1 WO2018104307 A1 WO 2018104307A1
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acetamide
alkyl
sulfamoylphenyl
pain
phenyl
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PCT/EP2017/081533
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French (fr)
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Stefan Werner
Stefanie MESCH
Nico Braeuer
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Bayer Pharma Aktiengesellschaft
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • C07D213/34—Sulfur atoms to which a second hetero atom is attached
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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]
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/40—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
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    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/61—Halogen atoms or nitro radicals
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • 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
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

  • the invention relates to substituted aromatic sulfonamides of formula (I) as described and defined herein, pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease.
  • the present invention as described and defined herein, relates to pharmaceutical compositions and combinations comprising an active ingredient which is an antagonist or a negative allosteric modulator of P2X4.
  • a pharmaceutical composition for the treatment or prophylaxis of a disease in particular in mammals, such as but not limited to diseases associated with pain, or for the treatment or prophylaxis of pain or neuronal damage and inflammation in the brain or spinal cord or arthritis or spondylitis syndromes (acute and chronic), inflammatory-induced pain, neuropathic pain, pelvic pain, cancer-associated pain, endometriosis-associated pain as well as endometriosis as such, cancer as such, multiple sclerosis as such, spinal cord or ischemic brain injury as such, as a sole agent or in combination with other active ingredients.
  • diseases associated with pain or for the treatment or prophylaxis of pain or neuronal damage and inflammation in the brain or spinal cord or arthritis or spondylitis syndromes (acute and chronic), inflammatory-induced pain, neuropathic pain, pelvic pain, cancer-associated pain, endometriosis-associated pain as well as endometriosis as such, cancer as such, multiple sclerosis as such, spinal cord or
  • Chronic inflammatory pain such as in, but not limited to, conditions of endometriosis and adenomyosis, arises as a consequence of inflammatory responses mounted by the immune system following tissue damage or local cell death and generally persists long after the initial injury has healed. Since a large percentage of patients with inflammatory diseases do not respond adequately to currently available anti-inflammatory treatments or analgesic drugs or suffer from intolerable side effects, investigation of alternative treatments for inflammatory conditions / disorders is warranted.
  • Adenosine triphosphate ATP is widely recognized as an important neurotransmitter implicated in various physiological and pathophysiological roles by acting through different subtypes of purinergic receptors (Burnstock 1993, Drug Dev Res 28:196-206; Burnstock 201 1 , Prog Neurobiol 95:229-274). To date, seven members of the P2X family have been cloned, comprising P2X1 -7 (Burnstock 2013, Front Cell Neurosci 7:227).
  • the P2X4 receptor is a ligand-gated ion channel that is expressed on a variety of cell types largely known to be involved in inflammatory/ immune processes specifically including monocytes, macrophages, mast cells and microglia cells (Wang et al., 2004, BMC Immunol 5:16; Brone et al., 2007 Immunol Lett 1 13:83-89).
  • P2X4 Activation of P2X4 by extracellular ATP is known, amongst other things, to lead to release of pro-inflammatory cytokines and prostaglandins (PGE2) (Bo et al., 2003 Cell Tissue Res 313:159-165; Ulmann et al., 2010, EMBO Journal 29:2290-2300; de Ribero Vaccari et al., 2012, J Neurosci 32:3058-3066). Numerous lines of evidence in the literature using animal models implicate P2X4 receptor in nociception and pain.
  • PGE2X4 receptor Numerous lines of evidence in the literature using animal models implicate P2X4 receptor in nociception and pain.
  • mice lacking the P2X4 receptor do not develop pain hypersensitivity in response to numerous inflammatory challenges such as complete Freunds Adjuvant, carrageenan or formalin (Ulmann et al., 2010, EMBO Journal 29:2290-2300).
  • mice lacking the P2X4R do not develop mechanical allodynia after peripheral nerve injury, indicating an important role of P2X4 also in neuropathic pain conditions (Tsuda et al., 2009, Mol Pain 5:28; Ulmann et al., 2008, J Neurocsci 28:1 1263- 1 1268).
  • P2X4 is considered as a critically important mediator of inflammatory diseases such as, respiratory diseases (e.g. asthma, COPD), lung diseases including fibrosis, cancer and atherosclerosis (Burnstock et al., 2012 Pharmacol Rev. 64:834-868).
  • respiratory diseases e.g. asthma, COPD
  • lung diseases including fibrosis, cancer and atherosclerosis
  • EP 2 597 088 A1 describes P2X4 receptor antagonists and in particular a diazepine derivative of formula (III) or a pharmacologically acceptable salt thereof. Said document further disclosed the use of P2X4 receptor antagonist diazepine derivatives represented by the formula (I), (II), (III), or its pharmacologically acceptable salt, which shows P2X4 receptor antagonism, being effective as an agent for prevention or treatment of nociceptive, inflammatory, and neuropathic pain.
  • EP 2 597 088 A1 describes P2X4 receptor antagonists being effective as a preventive or therapeutic agent for pain caused by various cancers, diabetic neuritis, viral diseases such as herpes, and osteoarthritis.
  • the preventive or therapeutic agent according to EP 2 597 088 A1 can also be used in combination with other agents such as opioid analgesic (e.g., morphine, fentanyl), sodium channel inhibitor (e.g., novocaine, lidocaine), or NSAIDs (e.g., aspirin, ibuprofen).
  • opioid analgesic e.g., morphine, fentanyl
  • sodium channel inhibitor e.g., novocaine, lidocaine
  • NSAIDs e.g., aspirin, ibuprofen
  • the P2X4 receptor antagonist used for pain caused by cancers can be also used in combination with a carcinostatic such as a chemotherapic. Further P2X4 receptor antagonists and their use are disclosed in WO2013105608, WO2015005467 and WO2015005468.
  • WO2015/088564 and WO2015/088565 provide P2X4 receptor modulating compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. Said P2X4 receptor modulating compounds are useful for the treatment, prevention, and/or management of various disorders, including but not limited to, chronic pain, neuropathy, inflammatory diseases and central nervous system disorders.
  • substituted aromatic sulfonamides of general formula (I) as described and defined herein and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, particularly to the use of substituted aromatic sulfonamides of general formula (I) for the treatment or prophylaxis of diseases associated with pain, or for the treatment or prophylaxis of pain syndromes (acute and chronic), inflammatory-induced pain, neuropathic pain, pelvic pain, cancer-associated pain, endometriosis-associated pain as well as endometriosis as such, cancer as such, and proliferative diseases as such like endometriosis, as a sole agent or in combination with other active ingredients.
  • inhibitors of P2X4 of the current invention represent valuable compounds that should complement therapeutic options either as single agents or in combination with other drugs.
  • the present invention relates to a compound of formula (I)
  • R 11 which together represent a methylendioxy group to form a 5-membered ring; represents hydrogen, cyano, nitro, halogen, Ci-C2-alkyl or Ci-C2-haloalkyl; represents hydrogen, halogen, Ci-C2-alkyl or Ci-C2-haloalkyl; represents hydrogen, halogen, Ci-C2-alkyl or Ci-C2-haloalkyl,
  • R 2a , R 2b and R 2c represents hydrogen;
  • R 3 represents hydrogen or fluoro;
  • R 4 represents hydrogen, fluoro, methyl or OH
  • R 5 represents hydrogen or Ci-C3-alkyl
  • R 6 represents hydrogen, halogen, cyano, nitro, OH, Ci-C4-alkyl, C1-C4- haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy or F3CS-;
  • R 6a and R 6b are the same or different and represent, independently from each
  • R 6a hydrogen, halogen, hydroxy, nitro, cyano, Ci-C4-alkyl, C3-C6-cycloalkyl,
  • Ci-C4-haloalkyl Ci-C4-alkoxy, Ci-C4-haloalkoxy, HO-(C2-C4-alkoxy)-, (Ci-C 4 -alkoxy)-(C 2 -C 4 -alkoxy)-, R 9 R 10 N-, R 8 -C(0)-NH-, R 8 -C(0)-,
  • R 6b hydrogen, halogen, hydroxy, nitro, cyano, Ci-C4-alkyl, C3-C6-cycloalkyl,
  • Ci-C 4 -haloalkyl Ci-C 4 -haloalkoxy, HO-(C 2 -C 4 -alkoxy)-,
  • R 6a and R 6b adjacent to each other together represent a group selected from
  • R 7a , R 7b and R 7c are the same or different and represent, independently from each other, hydrogen, hydroxy, halogen, Ci-C4-alkyl or Ci-C4-haloalkyl;
  • R 8 represents, independently from each respective occurence, hydrogen
  • Ci-C6-alkyl Ci-C4-alkoxy-Ci-C4-alkyl, C3-C6-cycloalkyl or Ci-C4-haloalkyl;
  • R 9 and R 10 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-methyl,
  • R 11 represents, independently from each other, halogen, hydroxy, nitro, cyano, Ci-C4-alkyl, C 2 -C4-alkenyl, Ci-C4-haloalkyl, Ci-C6-hydroxyalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, (Ci-C4-alkoxy)-(Ci-C4-alkyl)-,
  • R 12 represents Ci-C 6 -alkyl, Ci-C 4 -haloalkyl, (Ci-C 4 -alkoxy)-(Ci-C 4 -alkyl)-,
  • the invention relates to a compound of formula (I), in which:
  • R 1 represents a group selected from:
  • R 2 represents phenyl, heteroaryl, 2-oxopyridin-1 (2H)-yl or R 12 0-, wherein said phenyl or heteroaryl groups are optionally substituted one to three times with R 11 , being, independently from each other, the same or different, or
  • R 2a represents hydrogen or halogen
  • R 2b and R 2c represents hydrogen
  • R 3 ;R 4 ;R 5 represents hydrogen
  • R 6 represents hydrogen, halogen, Ci-C4-alkyl, Ci-C4-haloalkyl
  • R 6a and R 6b are the same or different and represent, independently from each
  • R 7a , R 7b and R 7c represent hydrogen
  • R 8 represents, independently from each respective occurence, hydrogen, d-Ce-alkyl
  • R 9 and R 10 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-methyl, or together with the nitrogen atom to which they are attached form a
  • R 11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl,
  • R 12 represents Ci-C 6 -alkyl, Ci-C 4 -haloalkyl, (Ci-C 4 -alkoxy)-(Ci-C 4 -alkyl)-,
  • R 1 represents a group selected from:
  • R 2 represents phenyl, heteroaryl, 2-oxopyridin-1 (2H)-yl or R 12 0-, wherein said phenyl or heteroaryl groups are optionally substituted one to three times with R 11 , being, independently from each other, the same or different;
  • R 2a represents hydrogen or halogen
  • R 2b and R 2 represents hydrogen
  • R 3 ; R 4 ; R 5 represents hydrogen
  • R 6 represents hydrogen, halogen, trifluoromethyl
  • R 6a and R 6b are the same or different and represent, independently from each
  • R 6a hydrogen, halogen
  • R 7a and R 7b represent hydrogen; R 8 represents hydrogen;
  • R 9 and R 10 are the same or different and represent, independently from each other, hydrogen, cyclopropylmethyl or together with the nitrogen atom to which they are attached form a
  • R 11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R 8 -0-C(0)-, R 9 R 10 N-C(O)-cyclopropyl or tetrahydro-2H-pyran-2- yi;
  • R 12 represents Ci-C6-alkyl, Ci-C4-haloalkyl, methoxy-(Ci-C4-alkyl)-, phenyl, phenylmethyl, pyridylmethyl, (1 -methylpiperidin-4-yl)methyl, (CH3)2N-C(0)- CH 2 -; wherein said phenyl groups are optionally substituted one to two times with halogen, methyl or trifluoromethyl, being, independently from each other, the same or different; or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
  • the invention relates to a compound of formula (I), in which:
  • R 1 represents a group selected from:
  • R 2 represents phenyl, pyridyl, pyrazolyl, isoxazolyl, 2-oxopyridin-1 (2H)-yl or R 12 0-, wherein said phenyl, pyridyl, pyrazolyl or isoxazolyl groups are optionally substituted one to two times with R 11 , being, independently from each other, the same or different;
  • R 2a ; R 2b ; R 2c represent hydrogen
  • R 3 ; R 4 ; R 5 represents hydrogen
  • R 6 represents hydrogen, fluoro or chloro
  • R 6a represents hydrogen or fluoro
  • R 6b represents hydrogen
  • R 7a and R 7b represent hydrogen
  • R 8 represents hydrogen
  • R 9 and R 10 are different and represent hydrogen and cyclopropyl-methyl or together with the nitrogen atom to which they are attached form a
  • R 11 represents, independently from each other, fluoro, chloro, methyl
  • R 12 represents C2-C5-alkyl, C2-C4-haloalkyl, phenyl, phenylmethyl, 2- pyridylmethyl; wherein said phenyl groups are optionally substituted one to two times with fluoro, chloro or methyl, being, independently from each other, the same or different; or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
  • R 1 represents
  • R 6 represents hydrogen, halogen, Ci-C4-alkyl, Ci-C4-haloalkyl
  • R 6a represents hydrogen or halogen
  • R 6b hydrogen
  • the invention refers to compounds of formula (I) as described supra, in which:
  • R 6 represents hydrogen or halogen
  • R 6a represents hydrogen or halogen
  • R 6b hydrogen
  • R 6 represents hydrogen, fluoro or chloro
  • R 6a represents hydrogen, fluoro or chloro; R 6b hydrogen.
  • the invention refers further to compounds of formula (I) as described supra, wherein:
  • R 1 represents a group selected from:
  • R 7a and R 7b represent hydrogen, fluoro, or chloro.
  • R 2 represents phenyl, heteroaryl, 2-oxopyridin-1 (2H)-yl or R 12 0-,
  • phenyl or heteroaryl groups are optionally substituted one to three times with R 11 , being, independently from each other, the same or different;
  • R 11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R 8 -0-C(0)-, R 9 R 10 N-C(O)-, C 3 -C 6 -cycloalkyl or 4- to 6-membered heterocycloalkyl;
  • R 8 in the occurrence defining R 11 represents, hydrogen
  • Ci-C6-alkyl Ci-C4-alkoxy-Ci-C4-alkyl, C3-C6-cycloalkyl or Ci-C4-haloalkyl;
  • R 9 and R 10 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-methyl,
  • R 12 represents Ci-C 6 -alkyl, Ci-C 4 -haloalkyl, (Ci-C 4 -alkoxy)-(Ci-C 4 -alkyl)-,
  • R 2 represents phenyl, pyridyl, pyrazolyl, isoxazolyl, 2-oxopyridin-1 (2H)-yl or R 12 0-,
  • phenyl, pyridyl, isoxazolyl, or pyrazolyl groups are optionally substituted one to three times with R 11 , being, independently from each other, the same or different,;
  • R 11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R 8 -0-C(0)-, R 9 R 10 N-C(O)-, C 3 -C 6 -cycloalkyl or 4- to 6-membered heterocycloalkyl;
  • R 8 in the occurrence defining R 11 represents, hydrogen
  • R 12 represents Ci-C 6 -alkyl, Ci-C 4 -haloalkyl, (Ci-C 4 -alkoxy)-(Ci-C 4 -alkyl)-,
  • R 2 represents phenyl, pyridyl, pyrazolyl, isoxazolyl, 2-oxopyridin-1 (2H)-yl or R 12 0-, wherein said phenyl, pyridyl, isoxazolyl or pyrazolyl groups are optionally substituted one to three times with R 11 , being, independently from each other, the same or different;
  • R 11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R 8 -0-C(0)-, R 9 R 10 N-C(O)-, C 3 -C 6 -cycloalkyl or 4- to 6-membered heterocycloalkyl;
  • R 8 in the present occurrence defining R 11 represents, hydrogen
  • Ci-C6-alkyl Ci-C4-alkoxy-Ci-C4-alkyl, C3-C6-cycloalkyl or Ci-C4-haloalkyl;
  • R 9 and R 10 are are different and represent hydrogen and cyclopropyl-methyl or together with the nitrogen atom to which they are attached form a
  • R 12 represents C2-C5-alkyl, C2-C4-haloalkyl, phenyl, phenylmethyl, 2- pyridylmethyl; wherein said phenyl groups are optionally substituted one to two times with fluoro, chloro or methyl, being, independently from each other, the same or different.
  • R 3 represents hydrogen
  • R 4 represents hydrogen, methyl or OH.
  • R 3 represents hydrogen
  • R 4 represents hydrogen
  • R 3 represents fluoro; and represents fluoro. According to a more particular aspect of the present invention compounds of formula (I) as described supra are those in which:
  • R 5 represents hydrogen
  • a compound of formula (I) is one in which:
  • R 1 represents a group selected from:
  • R 6 represents hydrogen or halogen
  • R 6a represents hydrogen or halogen
  • R 6b hydrogen
  • R 2 represents phenyl, pyridyl, isoxazolyl, pyrazolyl, 2-oxopyridin-1 (2H)-yl or R 12 0-,
  • phenyl, pyridyl, isoxazolyl, or pyrazolyl groups are optionally substituted one to three times with R 11 , being, independently from each other, the same or different;
  • R 11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R 8 -0-C(0)-, R 9 R 10 N-C(O)-, C 3 -C 6 -cycloalkyl or 4- to 6-membered heterocycloalkyl;
  • R 8 in the occurrence defining R 11 represents, hydrogen
  • Ci-C6-alkyl Ci-C4-alkoxy-Ci-C4-alkyl, C3-C6-cycloalkyl or Ci-C4-haloalkyl;
  • R 9 and R 10 are are different and represent hydrogen and cyclopropyl-methyl or together with the nitrogen atom to which they are attached form a
  • R 12 represents C2-C5-alkyl, C2-C4-haloalkyl, phenyl, phenylmethyl, 2- pyridylmethyl; wherein said phenyl groups are optionally substituted one to two times with fluoro, chloro or methyl, being, independently from each other, the same or different; other, the same or different;
  • R 2a ; R 2b ; R 2c represent hydrogen
  • R 3 ; R 4 , and R 5 represents hydrogen
  • One aspect of the invention are compounds of formula (I) as described in the examples, as characterized by their names in the title and their structures as well as the subcombinations of all residues specifically disclosed in the compounds of the examples.
  • R 2 , R 2a , R 2b and R 2c are as defined above as substituents of the general formula (I) of the invention.
  • formulae 15a, 15b, 16a and 16b are those in which:
  • R 2 represents phenyl, pyridyl, isoxazolyl, pyrazolyl, 2-oxopyridin-1 (2H)-yl or
  • R 12 0- wherein said phenyl, pyridyl, isoxazolyl, or pyrazolyl groups are optionally substituted one to three times with R 11 , being, independently from each other, the same or different;
  • R 11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R 8 -0-C(0)-, R 9 R 10 N-C(O)-, C 3 -C 6 -cycloalkyl or 4- to 6-membered heterocycloalkyl;
  • R 8 in the present occurrence defining R 11 represents, hydrogen
  • Ci-C6-alkyl Ci-C4-alkoxy-Ci-C4-alkyl, C3-C6-cycloalkyl or Ci-C4-haloalkyl;
  • R 9 and R 10 are are different and represent hydrogen and cyclopropyl-methyl or together with the nitrogen atom to which they are attached form a
  • R 12 represents C2-C5-alkyl, C2-C4-haloalkyl, phenyl, phenylmethyl, 2- pyridylmethyl; wherein said phenyl groups are optionally substituted one to two times with fluoro, chloro or methyl, being, independently from each other, the same or different;
  • R 2a ; R 2b ; R 2c represent hydrogen
  • Another aspect of the invention relates to the use of any of the intermediates described herein for preparing a compound of formula (I) as defined herein or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
  • a further aspect of the invention are compounds of formula (I) which are present as their salts.
  • the present invention covers compounds of general formula (I) which are disclosed in the Example section of this text, infra.
  • the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
  • Another embodiment of the invention are compounds according to the claims as disclosed in the Claims section wherein the definitions are limited according to the preferred or more preferred definitions as disclosed below or specifically disclosed residues of the exemplified compounds and subcombinations thereof.
  • Constituents which are optionally substituted as stated herein, may be substituted, unless otherwise noted, one or more times, independently from one another at any possible position.
  • each definition is independent.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , X and/or Y occur more than one time in any compound of formula (I) each definition of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , X and Y is independent.
  • a constituent be composed of more than one part, e.g. Ci-C4-alkoxy-Ci-C4-alkyl-
  • the position of a possible substituent can be at any of these parts at any suitable position.
  • a hyphen at the beginning of the constituent marks the point of attachment to the rest of the molecule.
  • the substitutent could be at any suitable position of the ring, also on a ring nitrogen atom if suitable.
  • a constituent composed of more than one part and comprising several chemical residues e.g. Ci -C 4 -a I koxv-Ci -C 4 -a I kyl or phenyl-Ci-C 4 -alkyl, should be read from left to right with the point of attachment to the rest of the molecule on the last part (in the example mentioned previously on the Ci-C 4 -alkyl residue)
  • halogen halogen
  • halogen atom halo- or Hal-
  • fluorine fluoro
  • chlorine chloro
  • bromine bromine
  • iodine atom preferably a fluorine or chlorine atom.
  • Ci-C4-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3 or 4 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, particularly 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl”), e.g. a methyl, ethyl, n-propyl- or iso-propyl group.
  • Ci-C4-haloalkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C4-alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F.
  • Said Ci-C4-haloalkyl group is, for example, -CF 3 , -CHF 2 , -CH 2 F, -CF2CF3, or-CH 2 CF 3 .
  • Ci-C4-alkoxy is to be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term “alkyl” is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert- butoxy or sec-butoxy group, or an isomer thereof.
  • Ci-C4-haloalkoxy is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci-C4-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F.
  • Said Ci-C4-haloalkoxy group is, for example, -OCF3, -OCHF2, -OCH2F, -OCF2CF3, or -OCH 2 CF 3 .
  • Ci-C4-hydroxyalkyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C4-alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a hydroxy group, e.g. a hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2- hydroxypropyl, 2,3-dihydroxypropyl, 1 ,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1 -hydroxy-2-methyl-propyl group.
  • a hydroxymethyl e.g. a hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2- hydroxypropyl, 2,3-dihydroxypropyl, 1 ,3-d
  • Ci-C4-alkoxy-Ci-C4-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a Ci-C4-alkoxy group, as defined supra, e.g. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, iso-propoxyalkyl, butoxyalkyl, iso-butoxyalkyl, tert-butoxyalkyl or sec-butoxyalkyl group, in which the term "Ci-C4-alkyl" is defined supra, or an isomer thereof.
  • C3-C6-cycloalkyl is to be understood as meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms ("C3-C6- cycloalkyl").
  • Said C3-C6-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or a bicyclic hydrocarbon ring.
  • said heterocycloalkyl can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "5- to 6-membered heterocycloalkyl").
  • said heterocycloalkyl can be a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, for example.
  • said heterocycloalkyl can be benzo fused.
  • heteroaryl is understood as preferably meaning a monovalent, monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur.
  • said ring system can be benzocondensed.
  • heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl; or azocinyl, indoli
  • the heteroarylic radical include all the possible isomeric forms thereof, e.g. the positional isomers thereof.
  • the term pyridyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • the heteroaryl group is a pyridyl group.
  • said nitrogen atom-containing ring can be partially unsaturated, i.e. it can contain one or more double bonds, such as, without being limited thereto, a 2,5- dihydro-1 H-pyrrolyl, 4H-[1 ,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1 ,4]thiazinyl ring, for example, or, it may be benzo-fused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.
  • C1-C4 as used throughout this text, e.g. in the context of the definition of "Ci- C4-alkyl”, “Ci-C4-haloalkyl", “Ci-C4-alkoxy”, or “Ci-C4-haloalkoxy” is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 4, i.e. 1 , 2, 3 or 4 carbon atoms. It is to be understood further that said term “C1-C4" is to be interpreted as any sub-range comprised therein, e.g.
  • C3-C6 as used throughout this text, e.g. in the context of the definition of "C3-C6-cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3-C6” is to be interpreted as any sub-range comprised therein, e.g. C3-C6 , C4-C5 , C3-C5 , C3-C4 , C4-C6, C5-C6 ; particularly C3-C6.
  • the R 9 R 10 N-C(O)- group include, for example, -C(0)NH 2 , -C(0)N(H)CH 3 , -C(0)N(CH 3 ) 2 , -C(0)N(H)CH 2 CH 3 , -C(0)N(CH 3 )CH 2 CH 3 or -C(0)N(CH 2 CH 3 ) 2 .
  • the R 9 R 10 N- group includes, for example, -NH 2 , -N(H)CH 3 , -N(CH 3 ) 2 , -N(H)CH 2 CH 3 and -N(CH 3 )CH 2 CH 3 .
  • R 9 R 10 N- when R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, NH, NR a in which R a represents a Ci-C6-alkyl- or Ci-C6-haloalkyl- group, particularly a CH 3 , or S and being optionally substituted, one to three times, independently from each other, with halogen or Ci-C4-alkyl, particularly a CH 3 .
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • the term "one or more”, e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning “one, two, three, four or five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or two".
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
  • isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 CI, 82 Br, 123 l, 124 l, 125 l, 129 l and 131 1, respectively.
  • isotopic variations of a compound of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of this invention may contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms may be present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres.
  • asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful.
  • the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, or E- or Z-isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • the compounds of the present invention may exist as tautomers.
  • any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1 H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1 H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1 H, 2H and 4H tautomers, namely:
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N-oxides.
  • the present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • polar solvents in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1 -19.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1 -amino-2,3,4- butantriol.
  • basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
  • diamyl sulfates long chain halides such as decyl, lauryl
  • acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • the salts include water-insoluble and, particularly, water-soluble salts.
  • bioprecursors or pro-drugs are covered by the invention.
  • Said biological system is e.g. a mammalian organism, particularly a human subject.
  • the bioprecursor is, for example, converted into the compound of formula (I) or a salt thereof by metabolic processes.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio.
  • pharmacokinetic profile means one single parameter or a combination thereof including permeability, bioavailability, exposure, and pharmacodynamic parameters such as duration, or magnitude of pharmacological effect, as measured in a suitable experiment.
  • Compounds with improved pharmacokinetic profiles can, for example, be used in lower doses to achieve the same effect, may achieve a longer duration of action, or a may achieve a combination of both effects.
  • An allosteric modulator is a substance which indirectly influences (modulates) the effects of an agonist or inverse agonist at a target protein, for example a receptor. Allosteric modulators bind to a site distinct from that of the orthosteric agonist binding site. Usually they induce a conformational change within the protein structure. A negative modulator (NAM) reduces the effects of the orthosteric ligand, but is inactive in the absence of the orthosteric ligand.
  • NAM negative modulator
  • the compounds of the present invention have surprisingly been found to effectively be active as an antagonist or a negative allosteric modulator of P2X4.
  • a compound according to the invention is used for the manufacture of a medicament.
  • a further aspect of the invention is the use of the compounds according to formula (I), (la) or (lb) for the treatment or prophylaxis of a disease
  • the invention relates to a compound of general formula (I) (la) or (lb), or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease.
  • the invention further relates to a method for using the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer to treat mammalian and human disorders and diseases, which include but are not limited to:
  • gynecological diseases including primary and secondary dysmenorrhea, dyspareunia, vulvudynia, endometriosis and adenomyosis; endometriosis- associated pain; endometriosis-associated symptoms, wherein said symptoms are in particular abdominal pain, dysmenorrhea, dyspareunia, dysuria, dyschezia or pelvic hypersensitivity;
  • urinary tract disease states including those associated with bladder outlet obstruction; urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyperreactivity; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive urinary bladder and symptoms related to overactive urinary bladder wherein said symptoms are in particular increased urinary frequency, nocturia, urinary urgency or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, in particular interstitial cystitis; idiopathic bladder hypersensitivity; kidney disease as hyperprostaglandin E syndrome, classic Bartter syndrome;
  • cancer cancer, cancer-related pain and cancer cachexia
  • respiratory disorders including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, interstitial pulmonary fibrosis, bronchospasm, chronic chough, refractory chronic cough, ideopahtic chronic cough;
  • gastrointestinal disorders including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea- dominant IBS; gastroesophageal reflux, gastrointestinal distension, Crohn's disease and the like;
  • fatty liver disorders in particular NASH (Non-Alcoholic Steato-Hepatitis); fibrotic diseases including lung fibrosis, heart fibrosis, kidney fibrosis and fibrosis of other organs; metabolic syndrome including, for example, insulin resistance, hypertension, refractory hypertension, dyslipoproteinaemia and obesity, diabetes mellitus, in particular Diabetes type II, myocardial infarction; atherosclerosis; lipid disorders;
  • neurodegenerative disorders such as Alzheimer's disease, Multiple Sclerosis, Parkinson's disease, brain ischemia, traumatic brain injury, spinal cord injury;
  • heart disorders including ischemia reperfusion injury, cardiac ischemia,
  • the present invention further relates to a method for using the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, to treat pain-associated mammalian disorders and diseases, which include but not limited to
  • pain-associated diseases or disorders selected from the group consisting of hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome), gout, arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis), burning mouth syndrome, burns, migraine or cluster headaches, nerve injury, traumatic nerve injury, post-traumatic injuries (including fractures and sport injuries), neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgias, HIV and HIV treatment-induced neuropathy, pruritus; impaired wound healing and disease of the skeleton like degeneration of the joints.
  • hyperalgesia allodynia
  • functional bowel disorders such as irritable bowel syndrome
  • arthritis such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis
  • burning mouth syndrome burns
  • the present invention relates to a method for using the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, to treat mammalian and human disorders and diseases, which are associated with pain or pain syndromes that are in particular:
  • pain syndromes including hyperalgesia, allodynia, acute and chronic inflammatory and neuropathic pain, preferably inflammatory pain, low back pain, surgical pain, visceral pain, dental pain, periodontitis, premenstrual pain, endometriosis- associated pain, pain associated with fibrotic diseases, central pain, pain due to burning mouth syndrome, pain due to burns, pain due to migraine, cluster headaches, pain due to nerve injury, pain due to neuritis, neuralgias, pain due to poisoning, pain due to ischemic injury, pain due to interstitial cystitis, cancer pain, pain due to viral, parasitic or bacterial infections, pain due to traumatic nerve-injury, pain due to post-traumatic injuries (including fractures and sport injuries), pain due to trigeminal neuralgia, pain associated with small fiber neuropathy, pain associated with diabetic neuropathy, postherpetic neuralgia, chronic lower back pain, neck pain phantom limb pain, pelvic pain syndrome, chronic pelvic pain, neuroma pain,
  • inflammation is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including, inter alia, acute, chronic, ulcerative, fibrotic, allergic and auto-immune disaeses, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, necrosis, endometriosis and other forms of inflammation known to those skilled in the art.
  • the term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever.
  • the compounds of the present invention may also be useful in the treatment, viral infections (e.g.
  • influenza e.g. melanoma, breast cancer, colon cancer, lung cancer and prostate cancer
  • malignancies e.g. melanoma, breast cancer, colon cancer, lung cancer and prostate cancer
  • arthritis osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile onset rheumatoid arthritis, rheumatic fever, ankylosing spondylitis
  • Compounds of the invention are also expected to be useful in the treatment of conditions associated or causing bone loss in a subject. Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases.
  • the compounds according to the invention are useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, lowere back and neck pain, dysmenorrhea, headache, migraine (acute and prophylactic treatment), toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, juvenile rheumatoid arthritis, degenerative joint diseases (osteoarthritis), acute gout and ankylosing spondylitis, acute, subacute and chronic musculoskeletal pain syndromes such as bursitis, burns, injuries, and pain following surgical (post-operative pain) and dental procedures as well as the preemptive treatment of surgical pain.
  • the pain may be mild pain, moderate pain, severe pain, musculoskeletal pain, complex regional pain syndrome, neuropathic pain, back pain such as acute visceral pain, neuropathies, acute trauma, chemotherapy— induced mononeuropathy pain states, polyneuropathy pain states (such as diabetic peripheral neuropathy and/ or chemotherapy induced neuropathy), autonomic neuropathy pain states, pheriphaeral nervous system (PNS) lesion or central nervous system (CNS) lesion or disease related pain states, polyradiculopathies of cervical, lumbar or sciatica type, cauda equina syndrome, piriformis syndrome, paraplegia, quadriplegia, pain states related to various Polyneuritis conditions underlying various infections, chemical injuries, radiation exposure, underlying disease or deficiency conditions (such as beriberi, vitamin deficiencies, hypothyroidism, porphyria, cancer, HIV, autoimmune disease such as multiple sclerosis and spinal-cord injury, fibromyalgia, nerve injury, ischaemia, neuro
  • the invention relates also to a method for using the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, to treat conditions treatable by inhibition of prostanoid- induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of relevance to use in treatment of dysmenorrhea premature labor and asthma.
  • the present invention relates to a method for the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, to treat cancer and hyperproliferative disorders.
  • Hyperproliferative discorders include, but are not limited to, for example: psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias.
  • BPH benign prostate hyperplasia
  • solid tumours such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • Those disorders also include lymphomas, sarcomas, and leukaemias.
  • breast cancers include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, and ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
  • Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
  • Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, and renal pelvis, ureter, urethral and human papillary renal cancers.
  • Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • a preferred embodiment of the present invention relates to a method for using the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, to treat a gynaecological disease, preferably dysmenorrhea, dyspareunia, vulvodynia or endometriosis, endometriosis-associated pain, or other endometriosis-associated symptoms, wherein said symptoms are in particular acute and chronic abdominal pain, dysmenorrhea, dyspareunia, dysuria, or dyschezia.
  • a gynaecological disease preferably dysmenorrhea, dyspareunia, vulvodynia or endometriosis, endometriosis-associated pain, or
  • Another preferred embodiment of the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat a urinary tract disease, in particular overactive bladder or cystitis, preferably interstitial cystitis.
  • Another preferred embodiment of the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat a respiratory disorder, preferably cough, in particular chronic cough.
  • Another preferred embodiment of the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat a neurodegenerative disorders, preferably ischemic brain injury, spinal cord injury and Multiple Sclerosis.
  • a neurodegenerative disorders preferably ischemic brain injury, spinal cord injury and Multiple Sclerosis.
  • Another preferred embodiment of the present invention relates to a method for using of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, to treat arthritis, in particular rheumatoid arthritis and ankylosing spondylitis (Burnstock et al., 2012 Pharmacol Rev. 64:834-868).
  • treating or “treatment” as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a gynaecological disease or a disease associated with undesired proliferation like endometriosis or cancer.
  • a disease or disorder such as a gynaecological disease or a disease associated with undesired proliferation like endometriosis or cancer.
  • the diseases treated with said method are gynaecological disorders, more preferably dysmenorrhea, dyspareunia or endometriosis, endometriosis-associated pain, or other endometriosis-associated symptoms, wherein said symptoms are in particular acute and chonic abdominal pain, dysmenorrhea, dyspareunia, dysuria, or dyschezia.
  • Further diseases, which can be treated with said method are osteoarthritis, diabetic neuropathy, burning mouth syndrome, gastroesophageal reflux, migraine disorders, chronic cough, asthma, pruritus, irritable bowel disease, overactive urinary bladder, prostatic hyperplasia, interstitial cystitis.
  • the method of treating the diseases mentioned above is not limited to the treatment of said disease but also includes the treatment of pain related to or associated with said diseases.
  • the compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of genitourinary, gastrointestinal, respiratory or pain-related disease, condition or disorder.
  • compositions of the compounds of the invention are provided.
  • This invention also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease.
  • the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier or auxiliary and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I) and a pharmaceutically acceptable auxiliary for the treatment of a disease mentioned supra, especially for the treatment of haematological tumours, solid tumours and/or metastases thereof.
  • a pharmaceutically acceptable carrier or auxiliary is preferably a carrier that is non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • Carriers and auxiliaries are all kinds of additives assisting to the composition to be suitable for administration.
  • a pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts the intended influence on the particular condition being treated.
  • the compounds of the present invention can be administered with pharmaceutically- acceptable carriers or auxiliaries well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, subcutaneously, intra uterine and the like.
  • the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatine type containing auxiliaries, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
  • the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatine, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, colouring agents, and flavouring agents such as peppermint, oil of wintergreen, or cherry flavouring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • binders such as acacia, corn starch or gelatine
  • disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid
  • Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavouring and colouring agents described above, may also be present.
  • the pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (1 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
  • the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate ; one or more colouring agents ; one or more flavouring agents ; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavouring and colouring agents.
  • the compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1 -dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfact
  • Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates ; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates ; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers ; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
  • suitable detergents include cationic detergents,
  • compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile- lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • compositions may be in the form of sterile injectable aqueous suspensions.
  • suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia ; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can be used in the preparation of injectables.
  • composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are, for example, cocoa butter and polyethylene glycol.
  • Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.
  • a mechanical delivery device It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device.
  • the construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art.
  • Direct techniques for administration, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier.
  • One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,01 1 ,472, issued April 30, 1991.
  • compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
  • Commonly used pharmaceutical ingredients that can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid) ; alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine) ; adsorbents (examples include but are not limited to powdered cellulose and activated charcoa)l ; aerosol propellants (examples include but are not limited to carbon dioxide, CCI2F2, air displacement agents - examples include but are not limited to nitrogen and argon ; antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylpara
  • FD&C Red No. 20 FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red
  • clarifying agents include but are not limited to bentonite
  • emulsifying agents include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate
  • encapsulating agents include but are not limited to gelatin and cellulose acetate phthalate
  • flavourants examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
  • humectants include but are not limited to glycerol, propylene glycol and sorbitol
  • levigating agents include but are not limited to bentonite
  • emulsifying agents include but are not limited to
  • compositions according to the present invention can be illustrated as follows:
  • Sterile i.v. solution A 5 mg/ml solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/ml with sterile 5% dextrose and is administered as an i.v. infusion over about 60 minutes.
  • a sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lyophilised powder, (ii) 32- 327 mg/ml sodium citrate, and (iii) 300 - 3000 mg Dextran 40.
  • the formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/ml, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/ml, and is administered either IV bolus or by IV infusion over 15 - 60 minutes.
  • Intramuscular suspension The following solution or suspension can be prepared, for intramuscular injection:
  • Hard Shell Capsules A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
  • Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
  • Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 1 1 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
  • Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
  • the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • "drug holidays" in which a patient is not dosed with a drug for a certain period of time may be beneficial to the overall balance between pharmacological effect and tolerability.
  • a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
  • a preferred oral unit dosage for a administration of the compounds of the present invention includes but is not limited to 0.1 mg/kg to about 10 mg/kg body weight one to three times a day to once a week.
  • the average daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • a "fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity.
  • a "fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • Another example of a "fixed combination” is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
  • a non-fixed combination or "kit of parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit.
  • One example of a non-fixed combination or kit of parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately.
  • the components of the non-fixed combination or kit of parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • the compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the present invention relates also to such combinations.
  • Those combined pharmaceutical agents can be other agents having antiproliferative, antinociceptive and/or antiinflammatory effects such as for example for the treatment of haematological tumours, solid tumours and/or metastases thereof and/or agents for the treatment of different pain syndromes and/or undesired side effects.
  • the present invention relates also to such combinations.
  • anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225- 1287, (1996), which is hereby incorporated by reference, especially (chemotherapeutic) anti-cancer agents as defined supra.
  • the compounds of the present invention can be combined with known hormonal therapeutic agents.
  • the compounds of the present invention can be administered in combination or as co-medication with hormonal contraceptives.
  • Hormonal contraceptives can be administered via oral, subcutaneous, transdermal, intrauterine or intravaginal route, for example as Combined Oral Contraceptives (COCs) or Progestin-Only-Pills (POPs) or hormone-containing devices like implants, patches or intravaginal rings.
  • COCs Combined Oral Contraceptives
  • POPs Progestin-Only-Pills
  • hormone-containing devices like implants, patches or intravaginal rings.
  • COCs include but are not limited to birth control pills or a birth control method that includes a combination of an estrogen (estradiol) and a progestogen (progestin).
  • the estrogenic part is in most of the COCs ethinyl estradiol.
  • Some COCs contain estradiol or estradiol valerate.
  • Said COCs contain the progestins norethynodrel, norethindrone, norethindrone acetate, ethynodiol acetate, norgestrel, levonorgestrel, norgestimate, desogestrel, gestodene, drospirenone, dienogest, or nomegestrol acetate.
  • Birth control pills include for example but are not limited to Yasmin, Yaz, both containing ethinyl estradiol and drospirenone; Microgynon or Miranova containing levonorgestrel and ethinyl estradiol; Marvelon containing ethinyl estradiol and desogestrel; Valette containing ethinyl estradiol and dienogest; Belara and Enriqa containing ethinyl estradiol and chlormadinonacetate; Qlaira containing estradiol valerate and dienogest as active ingredients; and Zoely containing estradiol and normegestrol.
  • POPs are contraceptive pills that contain only synthetic progestogens (progestins) and do not contain estrogen. They are colloquially known as mini pills.
  • POPs include but are not limited to Cerazette containing desogestrel; Microlut containing levonorgestrel and Micronor containing norethindrone.
  • Progeston-Only forms are intrauterine devices (lUDs), for example Mirena containing levonorgestrel, or injectables, for example Depo-Provera containing medroxyprogesterone acetate, or implants, for example Implanon containing etonogestrel.
  • lUDs intrauterine devices
  • injectables for example Depo-Provera containing medroxyprogesterone acetate
  • implants for example Implanon containing etonogestrel.
  • hormone-containing devices with contraceptive effect which are suitable for a combination with the compounds of the present invention are vaginal rings like Nuvaring containing ethinyl estradiol and etonogestrel, or transdermal systems like contraceptive patches, for example Ortho-Evra containing ethinyl estradiol and norelgestromin or Apleek (Lisvy) containing ethinyl estradiol and gestodene.
  • a preferred embodiment of the present invention is the administration of a compound of general formula (I) in combination with a COC or a POP or other Progestin-Only forms as well as vaginal rings or contraceptive patches as mentioned above.
  • the compounds of the present invention can be combined with therapeutic agents or active ingredients, that are already approved or that are still under development for the treatment and/ or prophylaxis of diseases which are related to or mediated by P2X4.
  • the compounds of the present invention can be administered in combination or as co-medication with any substance that can be applied as therapeutic agent in the following indications:
  • Urinary tract disease states including those associated with bladder outlet obstruction; urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyperreactivity; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive urinary bladder and symptoms related to overactive urinary bladder wherein said symptoms are in particular increased urinary frequency, nocturia, urinary urgency or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, in particular interstitial cystitis; idiopathic bladder hypersensitivity; kidney disease as hyperprostaglandin E syndrome, classic Bartter syndrome
  • the compounds of the present invention can be administered in combination or as co-medication in addition to behavioral therapy like diet, lifestyle or bladder training with anticholinergics like oxybutynin, tolterod
  • the compounds of the present invention can be administered in combination or as co-medication in addition to behavioral therapy like diet, lifestyle or bladder training with pentosans like elmiron; antidepressants like amitriptyline, imipramine; or antihistamines like loratadine.
  • the compounds of the present invention can be administered in combination or as co-medication with any substance that can be applied as therapeutic agent in the following indications:
  • dysmenorrhea including primary and secondary; dyspareunia; endometriosis; endometriosis-associated pain; endometriosis-associated symptoms, wherein said symptoms are in particular acute and chronic abdominal pain, dysmenorrhea, dyspareunia, dysuria, or dyschezia.
  • the compounds of the present invention can be administered in in combination with ovulation inhibiting treatment, in particular COCs as mentioned above or contraceptive patches like Ortho- Evra or Apleek (Lisvy); or with progestogenes like dienogest (Visanne); or with GnRH analogous, in particular GnRH agonists and antagonists, for example leuprorelin, nafarelin, goserelin, cetrorelix, abarelix, ganirelix, degarelix; or with androgens: danazol.
  • ovulation inhibiting treatment in particular COCs as mentioned above or contraceptive patches like Ortho- Evra or Apleek (Lisvy); or with progestogenes like dienogest (Visanne); or with GnRH analogous, in particular GnRH agonists and antagonists, for example leuprorelin, nafarelin, goserelin, cetrorelix, abare
  • the compounds of the present invention can be administered in combination or as co-medication with any substance that can be applied as therapeutic agent in the following indications:
  • pain-associated diseases or disorders like hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome) and arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis), burning mouth syndrome, burns, migraine or cluster headache, nerve injury, traumatic nerve injury, post-traumatic injuries (including fractures and sport injuries), neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, viral, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgias, HIV and HIV treatment-induced neuropathy.
  • the compounds of the present invention can be combined with other pharmacological agents and compounds that are intended to treat inflammatory diseases, inflammatory pain or general pain conditions.
  • the compounds of the present invention can be administered in combination with inhibitors of the P2X purinoceptor family (e,g, P2X3 and P2X7), with inhibitors of IRAK4, with inhibitors of PTGES and with antagonists of the prostanoid EP4 receptor.
  • the compounds of the present invention can be administered in combination with pharmacological endometriosis agents, intended to treat inflammatory diseases, inflammatory pain or general pain conditions and/or interfering with endometriotic proliferation and endometriosis associated symptoms, namely with inhibitors of Aldo-keto- reductase1 C3 (AKR1 C3) and with functional blocking antibodies of the prolactin receptor.
  • pharmacological endometriosis agents intended to treat inflammatory diseases, inflammatory pain or general pain conditions and/or interfering with endometriotic proliferation and endometriosis associated symptoms, namely with inhibitors of Aldo-keto- reductase1 C3 (AKR1 C3) and with functional blocking antibodies of the prolactin receptor.
  • the compounds of the present invention can be combined with other pharmacological agents and compounds that are intended for the treatment, prevention or management of cancer.
  • the compounds of the present invention can be administered in combination with 131 1-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate,amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, b
  • the compounds of the present invention can be combined with active ingredients, which are well known for the treatment of cancer-related pain and chronic pain.
  • active ingredients which are well known for the treatment of cancer-related pain and chronic pain.
  • Such combinations include, but are not limited to step II opiods like codeine phosphate, dextropropoxyphene, dihydro-codeine,Tramadol), step III opiods like morphine, fentanyl, buprenorphine, oxymorphone, oxycodone and hydromorphone; and other medications used for the treatment of cancer pain like steroids as Dexamethasone and methylprednisolone; bisphosphonates like Etidronate, Clodronate, Alendronate, Risedronate, and Zoledronate; tricyclic antidepressants like Amitriptyline, Clomipramine, Desipramine, Imipramine and Doxepin; class I antiarrhythmics like mexiletine and lidocaine; anticonvulsants like carbamaze
  • interconversion of substituents for example of residues R 1 , R 2 , R 2a , R 2b , R 2c , R 3 , R 4 , R 5 , R 6 , R 6a , R 6b , R 7a , R 7b , R 7c , R 8 , R 9 , R 10 , R 11 or R 12 can be achieved before and/or after the exemplified transformations.
  • These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, late-stage functionalization chemistry, substitution or other reactions known to the person skilled in the art.
  • These transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art.
  • Scheme 1 General procedures for the preparation of compounds of general formula (I) corresponding to formula 9; R 1 , R 3 , R 4 - R 5 and R 12 are as defined in the description and claims of this invention; W corresponds to either an amine with hydrogen and/or a protecting group PG (e.g. (dimethylamino)methylene, 2,4-dimethoxybenzyl); LG corresponds to a leaving group (e.g. nitro, chloride, fluoride, tosyl).
  • PG e.g. (dimethylamino)methylene, 2,4-dimethoxybenzyl
  • LG corresponds to a leaving group (e.g. nitro, chloride, fluoride, tosyl).
  • Electron poor benzene systems with a leaving group LG e.g. nitro, chloride, fluoride, tosyl
  • LG e.g. nitro, chloride, fluoride, tosyl
  • a nucleophilic aromatic substitution reaction with an alcohol or substituted phenol (R 12 OH) under basic conditions (e.g. potassium carbonate, cesium carbonate) in a suitable solvent (e.g. DMF, acetonitrile), elevated temperature might be necessary.
  • Selective reduction of one nitro group can be acieved with sodium hydrosulfide hydrate in a protic solvent (e,g, methanol/water) yielding aniline derivatives with general formula 3.
  • diazotation conditions e.g.
  • anilines 3 can be converted to sulfonyl chlorides 4.
  • the corresponding sulfonamides 5 can be obtained from 4 by reaction with ammonia or any amine in aprotic solvents such as dichloromethane and acetonitrile. Subsequent reduction under hydrogenation conditions, in polar solvents such as ethanol or tetrahydrofuran in the presence of for example Pd-, Pt-, Fe- or Sn- based catalysts yield the aniline derivatives with general formula 6 or 7.
  • acylation to the corresponding amides 8 or 9 can be achieved for example by reaction with acyl chlorides or by standard peptide bond formation using all known procedures, such as reaction of the corresponding carboxylic acid in the presence of a coupling reagent e.g. HATU.
  • a coupling reagent e.g. HATU.
  • For W a protected amino function subsequent deprotection with e.g. trifluoroacetic acid (TFA) results in compounds of general formula 9.
  • TFA trifluoroacetic acid
  • Substituent R 5 (if different from hydrogen) can be introduced by alkylation chemistry in presence of a base.
  • aniline 10 perform first the above described
  • the corresponding anilines 16 can be obtained from intermediates 15 by reduction under hydrogenation conditions, in polar solvents such as ethanol or tetrahydrofuran in the presence of for example Pd-, Pt-, Fe- or Sn- based catalysts.
  • Subsequent acylation to the corresponding amides 17 can be achieved for example by reaction with acyl chlorides or by standard peptide bond formation using all known procedures, such as reaction of the corresponding carboxylic acid in the presence of a coupling reagent e.g. HATU.
  • a coupling reagent e.g. HATU.
  • For W equals a protecting group subsequent deprotection with e.g. trifluoroacetic acid (TFA), results in compounds of general formula 18a.
  • TFA trifluoroacetic acid
  • Substituent R 5 (if different from hydrogen) can be introduced by alkylation in presence of a base.
  • compounds of general formula 22 can be obtained by deprotecting sulfonamides 20, followed by copper-catalyzed cross-coupling reactions known to the person skilled in the art (e.g. copper (I) iodide, a base as potassium carbonate, a ligand as (1 S,2S)-/V,/V-dimethylcyclohexane-1 ,2-diamine and a solvent as DMF and/or toluene).
  • copper (I) iodide e.g. copper (I) iodide, a base as potassium carbonate, a ligand as (1 S,2S)-/V,/V-dimethylcyclohexane-1 ,2-diamine and a solvent as DMF and/or toluene.
  • the compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as chromatography on a suitable support material.
  • reverse phase preparative HPLC of compounds of the present invention which possess a sufficiently basic or acidic functionality may result in the formation of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
  • Salts of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. Additionally, the drying process during the isolation of compounds of the present invention may not fully remove traces of cosolvents, especially such as formic acid or trifluoroacetic acid, to give solvates or inclusion complexes. The person skilled in the art will recognise which solvates or inclusion complexes are acceptable to be used in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base, solvate, inclusion complex) of a compound of the present invention as isolated as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
  • Salts of the compounds of formula (I) according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
  • a suitable solvent for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol
  • the acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom.
  • the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts.
  • pharmaceutically unacceptable salts which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.
  • hydrochlorides and the process used in the example section are especially preferred.
  • Pure diastereomers and pure enantiomers of the compounds and salts according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis.
  • Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to a person skilled in the art. Preferably, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxilliary agent, resolving the diastereomers obtained and removing the chiral auxilliary agent. As chiral auxilliary agents, for example, chiral acids can be used to separate enantiomeric bases such as e.g.
  • mandelic acid and chiral bases can be used to separate enantiomeric acids by formation of diastereomeric salts.
  • diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids or chiral alcohols, respectively, as chiral auxilliary agents.
  • diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures.
  • enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation.
  • One preferred aspect of the invention is the process for the preparation of the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer according to the examples, as well as the intermediates used for their preparation.
  • compounds of the formula (I) can be converted into their salts, or, optionally, salts of the compounds of the formula (I) can be converted into the free compounds.
  • Corresponding processes are customary for the skilled person. EXPERIMENTAL PART
  • PoraPakTM a HPLC column obtainable from Waters
  • NMR peak forms in the following specific experimental descriptions are stated as they appear in the spectra, possible higher order effects have not been considered.
  • Reactions employing microwave irradiation may be run with a Biotage Initator® microwave oven optionally equipped with a robotic unit.
  • the reported reaction times employing microwave heating are intended to be understood as fixed reaction times after reaching the indicated reaction temperature.
  • the compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent.
  • the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. from Separtis such as Isolute® Flash silica gel or Isolute® Flash NH2 silica gel in combination with a Isolera® autopurifier (Biotage) and eluents such as gradients of e.g. hexane/ethyl acetate or DCM/methanol.
  • Separtis such as Isolute® Flash silica gel or Isolute® Flash NH2 silica gel in combination with a Isolera® autopurifier (Biotage) and eluents such as gradients of e.g. hexane/ethyl acetate or DCM/methanol.
  • the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
  • a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc) of a compound of the present invention as isolated as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
  • W NHPG or NPG
  • Bromide A (e.g. 90 ⁇ ) was dissolved in DMF (0.5 - 2.0 mL in case of 90 ⁇ scale) and boronic acid (1.2 - 1 .5 eq) was added followed by addition of catalyst bis(triphenylphosphine)palladium(ll) dichloride (CAS 23965-03-2) (0.15 eq) and aqueous potassium carbonate solution (1 M, 0.2 mL) and the reaction mixture was heated at 120 °C in the microwave for 45 minutes. The reaction mixture was filtered over Celite and washed with DCM. Afterwards the mixture was concentrated in vacuo and the crude was taken onto the next step.
  • boronic acid 1.2 - 1 .5 eq
  • aqueous potassium carbonate solution (1 M, 0.2 mL
  • Protected sulfonamide C (e.g. 240 ⁇ ) was dissolved in dichloromethane (1 .0 -3.0 mL in case of 240 ⁇ scale), trifluoroacetic acid (50 eq) was added and the reaction mixture was stirred at room temperature until TLC showed consumption of starting material.
  • the reaction mixture was concentrated in vacuo, ethyl acetate or DCM and water were added to the crude and the phases were separated. The organic phase was dried and the solvent was removed under reduced pressure.
  • the crude was purified as indicated in the examples. Purification without aqueous extraction was also possible but made e.g. the HPLC purification more difficult.
  • Aniline E (e.g. 2.4 mmol) and the corresponding acid (1 .2 eq) were dissolved in DMF (15 mL) and HATU (1.6 - 2.0 eq) and ⁇ /,/V-diisopropylethylamine (5.0 eq) were added successively.
  • the reaction was heated at 50 °C for 16h. Afterwards 1 .2 eq of acid and 2.0 eq of HATU were added and stirring at 50°C was continued for 16h. Then, the solvent was removed under reduced pressure and the crude was partitioned between water and DCM. The combined organic phases were dried over a Whatmanfilter and the solvent was removed under reduced pressure. The crude was taken without further purification to the next step.
  • Nitro compound G (1 .0 eq, e.g. 885 ⁇ ) was dissolved in ethanol (10 mL) / THF (10 mL) and palladium on charcoal (10% loading, 1 .0 eq) was added. The reaction is evacuated and flushed with hydrogen (1 bar). After stirring at room temperature for 1 h, the reaction was evacuated three times and flushed with hydrogen and stirring was continued for 4h. Then, the reaction mixture was filtered over Celite and washed with THF. The solvent was removed under reduced pressure and the crude was taken without further purification to the next step.
  • Nitro compound G (1 .0 eq, e.g. 1 .08 mmol) was dissolved in 1 ,4-dioxane (5.2 mL) and stannous chloride dihydrate (5.0 eq, 5.41 mmol) was added. The reaction was heated at 70 °C until TLC indicated consumption of starting material. After cooling to room temperature, the mixture was filtered over silica gel and the solvent was removed under reduced pressure. Afterwards, the crude was suspended in DCM and filtered again over silica gel. After removing the solvent, the crude was taken onto the next steps without further purification.
  • Aniline I (e.g. on 0.46 mmol scale, 1.00 equiv), the corresponding acid (1.0 equiv), DIPEA (2.0 equiv) and T3P (1 .0 mL in case of 0.46 mmol scale) were dissolved in DCM (3 mL in case of 0.46 mmol scale). It was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo, then redissolved in DMF and filtered. The filtrate was purified with preparative HPLC. The collected fractions were evaporated and lyophilized.
  • the aqueous phase was extracted three times with ethyl acetate.
  • the combined organic phases were dried over a Whatmanfilter and the solvent was removed under reduced pressure.
  • the crude title compound was taken without further purification to the next step (5 g, 100% yield, 97% purity).
  • 3,5-Dinitrophenyl amine (5 g, 27.3 mmol, 1.00 equiv) was added in one portion to a well stirred solution of concentrated HCI (20 mL) and water (20 mL) and the mixture was cooled to -10 °C before a solution of NaN0 2 (2.072 g, 30.0 mmol, 1.10 equiv) in water (5 mL) was added dropwise at such a rate that the temperature did not exceed -5°C. The mixture was stirred for 45 min at -10°C after the addition.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.
  • the title compound was prepared according to GP 5.

Abstract

Substituted aromatic sulfonamides of formula (I), pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease.

Description

AROMATIC SULFONAMIDE DERIVATIVES AND THEIR USE AS ANATAGON I STS
OR NEGATIVE ALLOSTERIC MODULATORS OF P2X4
FIELD OF APPLICATION OF THE INVENTION
The invention relates to substituted aromatic sulfonamides of formula (I) as described and defined herein, pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease. The present invention, as described and defined herein, relates to pharmaceutical compositions and combinations comprising an active ingredient which is an antagonist or a negative allosteric modulator of P2X4. The use of such compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular in mammals, such as but not limited to diseases associated with pain, or for the treatment or prophylaxis of pain or neuronal damage and inflammation in the brain or spinal cord or arthritis or spondylitis syndromes (acute and chronic), inflammatory-induced pain, neuropathic pain, pelvic pain, cancer-associated pain, endometriosis-associated pain as well as endometriosis as such, cancer as such, multiple sclerosis as such, spinal cord or ischemic brain injury as such, as a sole agent or in combination with other active ingredients.
BACKGROUND OF THE INVENTION
Chronic inflammatory pain such as in, but not limited to, conditions of endometriosis and adenomyosis, arises as a consequence of inflammatory responses mounted by the immune system following tissue damage or local cell death and generally persists long after the initial injury has healed. Since a large percentage of patients with inflammatory diseases do not respond adequately to currently available anti-inflammatory treatments or analgesic drugs or suffer from intolerable side effects, investigation of alternative treatments for inflammatory conditions / disorders is warranted.
Adenosine triphosphate ATP is widely recognized as an important neurotransmitter implicated in various physiological and pathophysiological roles by acting through different subtypes of purinergic receptors (Burnstock 1993, Drug Dev Res 28:196-206; Burnstock 201 1 , Prog Neurobiol 95:229-274). To date, seven members of the P2X family have been cloned, comprising P2X1 -7 (Burnstock 2013, Front Cell Neurosci 7:227). The P2X4 receptor is a ligand-gated ion channel that is expressed on a variety of cell types largely known to be involved in inflammatory/ immune processes specifically including monocytes, macrophages, mast cells and microglia cells (Wang et al., 2004, BMC Immunol 5:16; Brone et al., 2007 Immunol Lett 1 13:83-89). Activation of P2X4 by extracellular ATP is known, amongst other things, to lead to release of pro-inflammatory cytokines and prostaglandins (PGE2) (Bo et al., 2003 Cell Tissue Res 313:159-165; Ulmann et al., 2010, EMBO Journal 29:2290-2300; de Ribero Vaccari et al., 2012, J Neurosci 32:3058-3066). Numerous lines of evidence in the literature using animal models implicate P2X4 receptor in nociception and pain. Mice lacking the P2X4 receptor do not develop pain hypersensitivity in response to numerous inflammatory challenges such as complete Freunds Adjuvant, carrageenan or formalin (Ulmann et al., 2010, EMBO Journal 29:2290-2300). In addition, mice lacking the P2X4R do not develop mechanical allodynia after peripheral nerve injury, indicating an important role of P2X4 also in neuropathic pain conditions (Tsuda et al., 2009, Mol Pain 5:28; Ulmann et al., 2008, J Neurocsci 28:1 1263- 1 1268).
Besides the prominent role of P2X4 in acute and chronic pain-related diseases (Trang and Salter, 2012, Purinergic Signalling 8:621 -628; Burnstock , 2013 Eur J Pharmacol 716:24-40), P2X4 is considered as a critically important mediator of inflammatory diseases such as, respiratory diseases (e.g. asthma, COPD), lung diseases including fibrosis, cancer and atherosclerosis (Burnstock et al., 2012 Pharmacol Rev. 64:834-868).
EP 2 597 088 A1 describes P2X4 receptor antagonists and in particular a diazepine derivative of formula (III) or a pharmacologically acceptable salt thereof. Said document further disclosed the use of P2X4 receptor antagonist diazepine derivatives represented by the formula (I), (II), (III), or its pharmacologically acceptable salt, which shows P2X4 receptor antagonism, being effective as an agent for prevention or treatment of nociceptive, inflammatory, and neuropathic pain. In more detail, EP 2 597 088 A1 describes P2X4 receptor antagonists being effective as a preventive or therapeutic agent for pain caused by various cancers, diabetic neuritis, viral diseases such as herpes, and osteoarthritis. The preventive or therapeutic agent according to EP 2 597 088 A1 can also be used in combination with other agents such as opioid analgesic (e.g., morphine, fentanyl), sodium channel inhibitor (e.g., novocaine, lidocaine), or NSAIDs (e.g., aspirin, ibuprofen). The P2X4 receptor antagonist used for pain caused by cancers can be also used in combination with a carcinostatic such as a chemotherapic. Further P2X4 receptor antagonists and their use are disclosed in WO2013105608, WO2015005467 and WO2015005468.
"Discovery and characterization of novel, potent and selective P2X4 receptor antagonists for the treatment of pain" was presented at the Society for Neuroscience Annual Meeting 2014 (Carrie A Bowen et al.; poster N. 241 .1 ) Said poster describes the methods to identify novel, potent and selective small-molecule antagonists that inhibit P2X4 across species, and how to evaluate selected compounds in experimental models of neuropatic and inflammatory pain. In particular a method for human, rat, mouse P2X4R Flipr-based screening, a human P2X4R electrophysiology assay, a suitable mouse neuropathy model and a mouse inflammation model were described.
WO2015/088564 and WO2015/088565 provide P2X4 receptor modulating compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. Said P2X4 receptor modulating compounds are useful for the treatment, prevention, and/or management of various disorders, including but not limited to, chronic pain, neuropathy, inflammatory diseases and central nervous system disorders.
There is no reference in the state of the art about substituted aromatic sulfonamides of general formula (I) as described and defined herein and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, particularly to the use of substituted aromatic sulfonamides of general formula (I) for the treatment or prophylaxis of diseases associated with pain, or for the treatment or prophylaxis of pain syndromes (acute and chronic), inflammatory-induced pain, neuropathic pain, pelvic pain, cancer-associated pain, endometriosis-associated pain as well as endometriosis as such, cancer as such, and proliferative diseases as such like endometriosis, as a sole agent or in combination with other active ingredients.
Therefore, the inhibitors of P2X4 of the current invention represent valuable compounds that should complement therapeutic options either as single agents or in combination with other drugs.
DESCRIPTION OF THE INVENTION
The present invention relates to a compound of formula (I)
Figure imgf000005_0001
Figure imgf000005_0002
wherein * indicates the point of attachment of said group with the rest of the molecule; represents phenyl, heteroaryl, 2-oxopyridin-1 (2H)-yl, R9R10N(C=O)- or R120-, wherein said phenyl or heteroaryl groups are optionally substituted one to three times with R11 , being, independently from each other, the same or different, or
substituted with two adjacent substituents R11 which together represent a methylendioxy group to form a 5-membered ring; represents hydrogen, cyano, nitro, halogen, Ci-C2-alkyl or Ci-C2-haloalkyl; represents hydrogen, halogen, Ci-C2-alkyl or Ci-C2-haloalkyl; represents hydrogen, halogen, Ci-C2-alkyl or Ci-C2-haloalkyl,
wherein not less than one of R2a, R2b and R2c represents hydrogen; R3 represents hydrogen or fluoro;
R4 represents hydrogen, fluoro, methyl or OH;
R5 represents hydrogen or Ci-C3-alkyl;
R6 represents hydrogen, halogen, cyano, nitro, OH, Ci-C4-alkyl, C1-C4- haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy or F3CS-;
R6a and R6b are the same or different and represent, independently from each
other, respectively
R6a hydrogen, halogen, hydroxy, nitro, cyano, Ci-C4-alkyl, C3-C6-cycloalkyl,
Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, HO-(C2-C4-alkoxy)-, (Ci-C4-alkoxy)-(C2-C4-alkoxy)-, R9R10N-, R8-C(0)-NH-, R8-C(0)-,
R8-0-C(0)-, R9R10N-C(O)- or (Ci-C4-alkyl)-S02-;
R6b hydrogen, halogen, hydroxy, nitro, cyano, Ci-C4-alkyl, C3-C6-cycloalkyl,
Ci-C4-haloalkyl, Ci-C4-haloalkoxy, HO-(C2-C4-alkoxy)-,
(Ci-C4-alkoxy)-(C2-C4-alkoxy)-, R9R10N-, R8-C(0)-NH-, R8-C(0)-,
R8-0-C(0)-, R9R10N-C(O)- or (Ci-C4-alkyl)-S02-; or
R6a and R6b adjacent to each other together represent a group selected from
-0-CH2-CH2-, -0-CH2-0- or -0-CH2-CH2-0-;
R7a, R7b and R7c are the same or different and represent, independently from each other, hydrogen, hydroxy, halogen, Ci-C4-alkyl or Ci-C4-haloalkyl;
R8 represents, independently from each respective occurence, hydrogen,
Ci-C6-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, C3-C6-cycloalkyl or Ci-C4-haloalkyl;
R9 and R10 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-methyl,
C2-C4-haloalkyl or (CH3)2N-Ci-C4-alkyl or together with the nitrogen atom to which they are attached form a
4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a C2-C6-alkyl or Ci-C6-haloalkyl group and being optionally substituted, one to three times, independently from each other, with halogen or Ci-C4-alkyl;
R11 represents, independently from each other, halogen, hydroxy, nitro, cyano, Ci-C4-alkyl, C2-C4-alkenyl, Ci-C4-haloalkyl, Ci-C6-hydroxyalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, (Ci-C4-alkoxy)-(Ci-C4-alkyl)-,
(Ci-C4-haloalkoxy)-(Ci-C4-alkyl)-, R9R10N-(Ci-C4-alkyl)-, R9R10N-,
R8-C(0)-NH-, R8-C(0)-, R8-0-C(0)-, R9R10N-C(O)-, (Ci-C4-alkyl)-S-, (Ci-C4-alkyl)-SC>2-, C3-C6-cycloalkyl or 4- to 6-membered heterocycloalkyl;
R12 represents Ci-C6-alkyl, Ci-C4-haloalkyl, (Ci-C4-alkoxy)-(Ci-C4-alkyl)-,
phenyl, heteroaryl, phenyl-Ci-C4-alkyl, heteroaryl-Ci-C4-alkyl, 4- to 6- membered heterocycloalkyl-(Ci-C4-alkyl)-, R9R10N-C(O)-(Ci-C4-alkyl)-; wherein said phenyl or heteroaryl groups are optionally substituted one to three times with R11, being, independently from each other, the same or different, or
substituted with two adjacent substituents R11 which together represent a methylendioxy group to form a 5-membered ring; or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
In another embodiment the invention relates to a compound of formula (I), in which:
R1 represents a group selected from:
Figure imgf000007_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;
R2 represents phenyl, heteroaryl, 2-oxopyridin-1 (2H)-yl or R120-, wherein said phenyl or heteroaryl groups are optionally substituted one to three times with R11, being, independently from each other, the same or different, or
substituted with two adjacent substituents R11 which together represent a methylendioxy group to form a 5-membered ring;
R2a represents hydrogen or halogen; R2b; and R2c represents hydrogen; R3;R4;R5 represents hydrogen;
R6 represents hydrogen, halogen, Ci-C4-alkyl, Ci-C4-haloalkyl;
R6a and R6b are the same or different and represent, independently from each
other, hydrogen or halogen;
R7a, R7b and R7c represent hydrogen;
R8 represents, independently from each respective occurence, hydrogen, d-Ce-alkyl;
R9 and R10 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-methyl, or together with the nitrogen atom to which they are attached form a
4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C6-alkyl or C2-C6-haloalkyl group and being optionally substituted, one to three times, independently from each other, with halogen or Ci-C4-alkyl;
R11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl,
R8-0-C(0)-, R9R10N-C(O)-, Cs-Ce-cycloalkyl or 4- to 6-membered heterocycloalkyl;
R12 represents Ci-C6-alkyl, Ci-C4-haloalkyl, (Ci-C4-alkoxy)-(Ci-C4-alkyl)-,
phenyl, heteroaryl, phenyl-Ci-C4-alkyl, heteroaryl-Ci-C4-alkyl, 4- to 6- membered heterocycloalkyl-(Ci-C4-alkyl)-, R9R10N-C(O)-(Ci-C4-alkyl)-; wherein said phenyl or heteroaryl groups are optionally substituted one to three times with R11, being, independently from each other, the same or different, or
substituted with two adjacent substituents R11 which together represent a methylendioxy group to form a 5-membered ring; or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
In a preferred embodiment the invention relates to a compound of formula (I), in which: R1 represents a group selected from:
Figure imgf000009_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;
R2 represents phenyl, heteroaryl, 2-oxopyridin-1 (2H)-yl or R120-, wherein said phenyl or heteroaryl groups are optionally substituted one to three times with R11, being, independently from each other, the same or different;
R2a represents hydrogen or halogen; R2b and R2 represents hydrogen;
R3; R4; R5 represents hydrogen;
R6 represents hydrogen, halogen, trifluoromethyl;
R6a and R6b are the same or different and represent, independently from each
other, respectively
R6a hydrogen, halogen;
R6b hydrogen;
R7a and R7b represent hydrogen; R8 represents hydrogen;
R9 and R10 are the same or different and represent, independently from each other, hydrogen, cyclopropylmethyl or together with the nitrogen atom to which they are attached form a
5-membered nitrogen containing heterocyclic ring, being optionally substituted, one to three times, independently from each other, with halogen; R11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R8-0-C(0)-, R9R10N-C(O)-cyclopropyl or tetrahydro-2H-pyran-2- yi;
R12 represents Ci-C6-alkyl, Ci-C4-haloalkyl, methoxy-(Ci-C4-alkyl)-, phenyl, phenylmethyl, pyridylmethyl, (1 -methylpiperidin-4-yl)methyl, (CH3)2N-C(0)- CH2-; wherein said phenyl groups are optionally substituted one to two times with halogen, methyl or trifluoromethyl, being, independently from each other, the same or different; or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
In a preferred embodiment the invention relates to a compound of formula (I), in which:
R1 represents a group selected from:
Figure imgf000010_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;
R2 represents phenyl, pyridyl, pyrazolyl, isoxazolyl, 2-oxopyridin-1 (2H)-yl or R120-, wherein said phenyl, pyridyl, pyrazolyl or isoxazolyl groups are optionally substituted one to two times with R11, being, independently from each other, the same or different;
R2a; R2b; R2c represent hydrogen;
R3; R4; R5 represents hydrogen;
R6 represents hydrogen, fluoro or chloro; R6a represents hydrogen or fluoro;
R6b represents hydrogen; R7a and R7b represent hydrogen; R8 represents hydrogen;
R9 and R10 are different and represent hydrogen and cyclopropyl-methyl or together with the nitrogen atom to which they are attached form a
5-membered nitrogen containing heterocyclic ring, being optionally substituted, one to two times, with fluoro;
R11 represents, independently from each other, fluoro, chloro, methyl,
difluoromethyl, trifluoromethyl, R8-0-C(0)-, R9R10N-C(O)-, cyclopropyl or tetrahydro-2H-pyran-2-yl;
R12 represents C2-C5-alkyl, C2-C4-haloalkyl, phenyl, phenylmethyl, 2- pyridylmethyl; wherein said phenyl groups are optionally substituted one to two times with fluoro, chloro or methyl, being, independently from each other, the same or different; or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
In particular the invention refers further to compounds of formula (I) as described supra, wherein:
R1 represents
Figure imgf000011_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;
R6 represents hydrogen, halogen, Ci-C4-alkyl, Ci-C4-haloalkyl;
R6a represents hydrogen or halogen; R6b hydrogen; According to a further alternative the invention refers to compounds of formula (I) as described supra, in which:
Figure imgf000012_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;
R6 represents hydrogen or halogen;
R6a represents hydrogen or halogen; R6b hydrogen.
According to a further alternative the invention refers to compounds of formula (I) as described supra, in which:
Figure imgf000012_0002
wherein * indicates the point of attachment of said group with the rest of the molecule;
R6 represents hydrogen, fluoro or chloro;
R6a represents hydrogen, fluoro or chloro; R6b hydrogen. In particular the invention refers further to compounds of formula (I) as described supra, wherein:
R1 represents a group selected from:
Figure imgf000012_0003
wherein * indicates the point of attachment of said group with the rest of the molecule; R7a and R7b represent hydrogen, fluoro, or chloro.
In particular the invention refers further to compounds of formula (I) as described supra, wherein:
R2 represents phenyl, heteroaryl, 2-oxopyridin-1 (2H)-yl or R120-,
wherein said phenyl or heteroaryl groups are optionally substituted one to three times with R11, being, independently from each other, the same or different;
wherein
R11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R8-0-C(0)-, R9R10N-C(O)-, C3-C6-cycloalkyl or 4- to 6-membered heterocycloalkyl;
R8 in the occurrence defining R11, represents, hydrogen,
Ci-C6-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, C3-C6-cycloalkyl or Ci-C4-haloalkyl;
R9 and R10 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-methyl,
Ci-C4-haloalkyl or (CH3)2N-Ci-C4-alkyl or together with the nitrogen atom to which they are attached form a
4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C6-alkyl or C2-C6-haloalkyl group and being optionally substituted, one to three times, independently from each other, with halogen or Ci-C4-alkyl;
and wherein
R12 represents Ci-C6-alkyl, Ci-C4-haloalkyl, (Ci-C4-alkoxy)-(Ci-C4-alkyl)-,
phenyl, heteroaryl, phenyl-Ci-C4-alkyl, heteroaryl-Ci-C4-alkyl, 4- to 6- membered heterocycloalkyl-(Ci-C4-alkyl)-, R9R10N-C(O)-(Ci-C4-alkyl)-; wherein said phenyl or heteroaryl groups are optionally substituted one to three times with R11, being in this specific occurrence of R12, independently from each other, the same or different, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R8-0-C(0)-, R9R10N-C(O)-, C3-C6-cycloalkyl or
substituted with two adjacent substituents R11 which together represent a methylendioxy group to form a 5-membered ring; Compounds of formula (I) according to the invention are those in which:
R2 represents phenyl, pyridyl, pyrazolyl, isoxazolyl, 2-oxopyridin-1 (2H)-yl or R120-,
wherein said phenyl, pyridyl, isoxazolyl, or pyrazolyl groups are optionally substituted one to three times with R11, being, independently from each other, the same or different,;
wherein
R11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R8-0-C(0)-, R9R10N-C(O)-, C3-C6-cycloalkyl or 4- to 6-membered heterocycloalkyl;
R8 in the occurrence defining R11, represents, hydrogen,
Ci-C6-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, C3-C6-cycloalkyl or Ci-C4-haloalkyl; R9 and R10 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-methyl,
Ci-C4-haloalkyl or (CH3)2N-Ci-C4-alkyl or together with the nitrogen atom to which they are attached form a
4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C6-alkyl or Ci-C6-haloalkyl group and being optionally substituted, one to three times, independently from each other, with halogen or Ci-C4-alkyl;
and wherein
R12 represents Ci-C6-alkyl, Ci-C4-haloalkyl, (Ci-C4-alkoxy)-(Ci-C4-alkyl)-,
phenyl, heteroaryl, phenyl-Ci-C4-alkyl, heteroaryl-Ci-C4-alkyl, 4- to 6- membered heterocycloalkyl-(Ci-C4-alkyl)-, R9R10N-C(O)-(Ci-C4-alkyl)-; wherein said phenyl or heteroaryl groups are optionally substituted one to three times with R11, being in this specific occurrence of R12, independently from each other, the same or different, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R8-0-C(0)-, R9R10N-C(O)-, C3-C6-cycloalkyl or
substituted with two adjacent substituents R11 which together represent a methylendioxy group to form a 5-membered ring.
More particularly compounds of formula (I) according to the invention are those in which:
R2 represents phenyl, pyridyl, pyrazolyl, isoxazolyl, 2-oxopyridin-1 (2H)-yl or R120-, wherein said phenyl, pyridyl, isoxazolyl or pyrazolyl groups are optionally substituted one to three times with R11, being, independently from each other, the same or different;
wherin
R11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R8-0-C(0)-, R9R10N-C(O)-, C3-C6-cycloalkyl or 4- to 6-membered heterocycloalkyl;
R8 in the present occurrence defining R11, represents, hydrogen,
Ci-C6-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, C3-C6-cycloalkyl or Ci-C4-haloalkyl;
R9 and R10 are are different and represent hydrogen and cyclopropyl-methyl or together with the nitrogen atom to which they are attached form a
5-membered nitrogen containing heterocyclic ring, being optionally substituted, one to two times, with fluoro;; and wherein
R12 represents C2-C5-alkyl, C2-C4-haloalkyl, phenyl, phenylmethyl, 2- pyridylmethyl; wherein said phenyl groups are optionally substituted one to two times with fluoro, chloro or methyl, being, independently from each other, the same or different.
According to a further aspect of the present invention compounds of formula (I) as described supra are those in which:
R3 represents hydrogen; and
R4 represents hydrogen, methyl or OH.
According to a further aspect of the present invention compounds of formula (I) as described supra are those in which:
R3 represents hydrogen; and
R4 represents hydrogen.
According to a further aspect of the present invention compounds of formula (I) as described supra are those in which:
R3 represents fluoro; and represents fluoro. According to a more particular aspect of the present invention compounds of formula (I) as described supra are those in which:
R5 represents hydrogen.
According to a more particular aspect of the present invention a compound of formula (I) is one in which:
R1 represents a group selected from:
Figure imgf000016_0001
wherein * indicates the point of attachment of said group with the rest of the
molecule; R6 represents hydrogen or halogen; R6a represents hydrogen or halogen; and R6b hydrogen;
R2 represents phenyl, pyridyl, isoxazolyl, pyrazolyl, 2-oxopyridin-1 (2H)-yl or R120-,
wherein said phenyl, pyridyl, isoxazolyl, or pyrazolyl groups are optionally substituted one to three times with R11, being, independently from each other, the same or different;
wherin
R11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R8-0-C(0)-, R9R10N-C(O)-, C3-C6-cycloalkyl or 4- to 6-membered heterocycloalkyl;
R8 in the occurrence defining R11, represents, hydrogen,
Ci-C6-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, C3-C6-cycloalkyl or Ci-C4-haloalkyl;
R9 and R10 are are different and represent hydrogen and cyclopropyl-methyl or together with the nitrogen atom to which they are attached form a
5-membered nitrogen containing heterocyclic ring, being optionally substituted, one to two times, with fluoro; and wherein
R12 represents C2-C5-alkyl, C2-C4-haloalkyl, phenyl, phenylmethyl, 2- pyridylmethyl; wherein said phenyl groups are optionally substituted one to two times with fluoro, chloro or methyl, being, independently from each other, the same or different; other, the same or different;
R2a; R2b; R2c represent hydrogen;
R3; R4, and R5 represents hydrogen
or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said
compound, or a salt of said N-oxide, tautomer or stereoisomer.
One aspect of the invention are compounds of formula (I) as described in the examples, as characterized by their names in the title and their structures as well as the subcombinations of all residues specifically disclosed in the compounds of the examples.
Another aspect of the present invention are intermediates according to formulae 15a, 15b, 16a and 16b
Figure imgf000017_0001
15a 15b 16a 16b wherein R2, R2a, R2b and R2c are as defined above as substituents of the general formula (I) of the invention.
According to a particular form of embodiment of the present invention, formulae 15a, 15b, 16a and 16b are those in which:
R2 represents phenyl, pyridyl, isoxazolyl, pyrazolyl, 2-oxopyridin-1 (2H)-yl or
R120-, wherein said phenyl, pyridyl, isoxazolyl, or pyrazolyl groups are optionally substituted one to three times with R11, being, independently from each other, the same or different;
wherin R11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R8-0-C(0)-, R9R10N-C(O)-, C3-C6-cycloalkyl or 4- to 6-membered heterocycloalkyl;
R8 in the present occurrence defining R11, represents, hydrogen,
Ci-C6-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, C3-C6-cycloalkyl or Ci-C4-haloalkyl;
R9 and R10 are are different and represent hydrogen and cyclopropyl-methyl or together with the nitrogen atom to which they are attached form a
5-membered nitrogen containing heterocyclic ring, being optionally substituted, one to two times, with fluoro; and wherein
R12 represents C2-C5-alkyl, C2-C4-haloalkyl, phenyl, phenylmethyl, 2- pyridylmethyl; wherein said phenyl groups are optionally substituted one to two times with fluoro, chloro or methyl, being, independently from each other, the same or different;
R2a; R2b; R2c represent hydrogen;
Specific intermediates for the synthesis of compounds of formula (I) according to present invention are:
1 3-Bromo-/V-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide
3 3-Amino-5-bromo-/V-(2,4-dimethoxybenzyl)benzenesulfonamide
4 /V-{3-Bromo-5-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2- chlorophenyl)acetamide
Another aspect of the invention relates to the use of any of the intermediates described herein for preparing a compound of formula (I) as defined herein or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
Preferred intermediates are the Intermediate Examples as disclosed below.
A further aspect of the invention are compounds of formula (I) which are present as their salts.
It is to be understood that the present invention relates to any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I) supra.
More particularly still, the present invention covers compounds of general formula (I) which are disclosed in the Example section of this text, infra. In accordance with another aspect, the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
Another embodiment of the invention are compounds according to the claims as disclosed in the Claims section wherein the definitions are limited according to the preferred or more preferred definitions as disclosed below or specifically disclosed residues of the exemplified compounds and subcombinations thereof.
Definitions
Constituents which are optionally substituted as stated herein, may be substituted, unless otherwise noted, one or more times, independently from one another at any possible position. When any variable occurs more than one time in any constituent, each definition is independent. For example, when R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, X and/or Y occur more than one time in any compound of formula (I) each definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, X and Y is independent.
Should a constituent be composed of more than one part, e.g. Ci-C4-alkoxy-Ci-C4-alkyl-, the position of a possible substituent can be at any of these parts at any suitable position. A hyphen at the beginning of the constituent marks the point of attachment to the rest of the molecule. Should a ring be substituted the substitutent could be at any suitable position of the ring, also on a ring nitrogen atom if suitable.
Furthermore, a constituent composed of more than one part and comprising several chemical residues, e.g. Ci -C4-a I koxv-Ci -C4-a I kyl or phenyl-Ci-C4-alkyl, should be read from left to right with the point of attachment to the rest of the molecule on the last part (in the example mentioned previously on the Ci-C4-alkyl residue)
The term "comprising" when used in the specification includes "consisting of".
If it is referred to "as mentioned above" or "mentioned above" within the description it is referred to any of the disclosures made within the specification in any of the preceding pages. "suitable" within the sense of the invention means chemically possible to be made by methods within the knowledge of a skilled person.
The terms as mentioned in the present text have preferably the following meanings:
The term "halogen", "halogen atom", "halo-" or "Hal-" is to be understood as meaning a fluorine (fluoro), chlorine (chloro), bromine or iodine atom, preferably a fluorine or chlorine atom.
The term "Ci-C4-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3 or 4 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, particularly 1 , 2 or 3 carbon atoms ("Ci-C3-alkyl"), e.g. a methyl, ethyl, n-propyl- or iso-propyl group.
The term "Ci-C4-haloalkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C4-alkyl" is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F. Said Ci-C4-haloalkyl group is, for example, -CF3, -CHF2, -CH2F, -CF2CF3, or-CH2CF3.
The term "Ci-C4-alkoxy" is to be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term "alkyl" is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert- butoxy or sec-butoxy group, or an isomer thereof.
The term "Ci-C4-haloalkoxy" is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci-C4-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F. Said Ci-C4-haloalkoxy group is, for example, -OCF3, -OCHF2, -OCH2F, -OCF2CF3, or -OCH2CF3.
The term "Ci-C4-hydroxyalkyl" is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C4-alkyl" is defined supra, and in which one or more hydrogen atoms is replaced by a hydroxy group, e.g. a hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2- hydroxypropyl, 2,3-dihydroxypropyl, 1 ,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1 -hydroxy-2-methyl-propyl group.
The term "Ci-C4-alkoxy-Ci-C4-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a Ci-C4-alkoxy group, as defined supra, e.g. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, iso-propoxyalkyl, butoxyalkyl, iso-butoxyalkyl, tert-butoxyalkyl or sec-butoxyalkyl group, in which the term "Ci-C4-alkyl" is defined supra, or an isomer thereof.
The term "C3-C6-cycloalkyl" is to be understood as meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms ("C3-C6- cycloalkyl"). Said C3-C6-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or a bicyclic hydrocarbon ring.
The term "4- to 6-membered heterocycloalkyl" or "4- to 6-membered heterocyclic ring", is to be understood as meaning a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4 or 5 carbon atoms, and one or more heteroatom-containing groups selected from C(=0), O, S, S(=0), S(=0)2, NH, NRa, in which Ra represents a Ci-C6-alkyl- or Ci-C6-haloalkyl- group ; it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom.
Particularly, said heterocycloalkyl can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "5- to 6-membered heterocycloalkyl").
Particularly, without being limited thereto, said heterocycloalkyl can be a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, for example. Optionally, said heterocycloalkyl can be benzo fused.
The term "heteroaryl" is understood as preferably meaning a monovalent, monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl" group), particularly 5, 6, 9 or 10 ring atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur. In addition said ring system can be benzocondensed. Particularly, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl; or azocinyl, indolizinyl, purinyl, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl or oxepinyl.
In general, and unless otherwise mentioned, the heteroarylic radical include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some illustrative non-restricting example, the term pyridyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl. Preferably, the heteroaryl group is a pyridyl group.
As mentioned supra, said nitrogen atom-containing ring can be partially unsaturated, i.e. it can contain one or more double bonds, such as, without being limited thereto, a 2,5- dihydro-1 H-pyrrolyl, 4H-[1 ,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1 ,4]thiazinyl ring, for example, or, it may be benzo-fused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.
The term "C1-C4", as used throughout this text, e.g. in the context of the definition of "Ci- C4-alkyl", "Ci-C4-haloalkyl", "Ci-C4-alkoxy", or "Ci-C4-haloalkoxy" is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 4, i.e. 1 , 2, 3 or 4 carbon atoms. It is to be understood further that said term "C1-C4" is to be interpreted as any sub-range comprised therein, e.g. C1-C4 , C2-C4 , C3-C4 , C1-C2, C1-C3 , particularly Ci- C2 , C1-C3 , C1-C4, in the case of "Ci-C6-haloalkyl" or "Ci-C4-haloalkoxy" even more particularly C1-C2.
Further, as used herein, the term "C3-C6", as used throughout this text, e.g. in the context of the definition of "C3-C6-cycloalkyl", is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term "C3-C6" is to be interpreted as any sub-range comprised therein, e.g. C3-C6 , C4-C5 , C3-C5 , C3-C4 , C4-C6, C5-C6 ; particularly C3-C6. The R9R10N-C(O)- group include, for example, -C(0)NH2, -C(0)N(H)CH3, -C(0)N(CH3)2, -C(0)N(H)CH2CH3, -C(0)N(CH3)CH2CH3 or -C(0)N(CH2CH3)2.
The R9R10N- group includes, for example, -NH2, -N(H)CH3, -N(CH3)2, -N(H)CH2CH3 and -N(CH3)CH2CH3. In the case of R9R10N-, when R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, NH, NRa in which Ra represents a Ci-C6-alkyl- or Ci-C6-haloalkyl- group, particularly a CH3, or S and being optionally substituted, one to three times, independently from each other, with halogen or Ci-C4-alkyl, particularly a CH3.
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.
Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.
As used herein, the term "one or more", e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning "one, two, three, four or five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or two".
The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 11C, 13C, 14C, 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36CI, 82Br, 123l, 124l, 125l, 129l and 1311, respectively. Certain isotopic variations of a compound of the invention, for example, those in which one or more radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.
By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of this invention may contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.
Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
In order to limit different types of isomers from each other reference is made to lUPAC Rules Section E (Pure Appl Chem 45, 1 1 -30, 1976).
The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, or E- or Z-isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
Further, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1 H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1 H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1 H, 2H and 4H tautomers, namely:
Figure imgf000026_0001
1 H-tautomer 2H-tautomer 4H-tautomer
The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.
The present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.
Further, the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1 -19.
A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para- toluenesulfonic, methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.
Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1 -amino-2,3,4- butantriol. Additionally, basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
Those skilled in the art will further recognise that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown.
Unless specified otherwise, suffixes to chemical names or structural formulae such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCI", "x CF3COOH", "x Na+", for example, are to be understood as not a stoichiometric specification, but solely as a salt form.
This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates with (if defined) unknown stoichiometric composition.
The salts include water-insoluble and, particularly, water-soluble salts.
Furthermore, derivatives of the compounds of formula (I) and the salts thereof which are converted into a compound of formula (I) or a salt thereof in a biological system (bioprecursors or pro-drugs) are covered by the invention. Said biological system is e.g. a mammalian organism, particularly a human subject. The bioprecursor is, for example, converted into the compound of formula (I) or a salt thereof by metabolic processes.
Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio.
In the context of the properties of the compounds of the present invention the term "pharmacokinetic profile" means one single parameter or a combination thereof including permeability, bioavailability, exposure, and pharmacodynamic parameters such as duration, or magnitude of pharmacological effect, as measured in a suitable experiment. Compounds with improved pharmacokinetic profiles can, for example, be used in lower doses to achieve the same effect, may achieve a longer duration of action, or a may achieve a combination of both effects.
It has now been found, and this constitutes the basis of the present invention, that said compounds of the present invention have surprising and advantageous properties. In particular, compounds according to the present invention have surprisingly been found to effectively be active as an antagonist or a negative allosteric modulator of P2X4.
An allosteric modulator is a substance which indirectly influences (modulates) the effects of an agonist or inverse agonist at a target protein, for example a receptor. Allosteric modulators bind to a site distinct from that of the orthosteric agonist binding site. Usually they induce a conformational change within the protein structure. A negative modulator (NAM) reduces the effects of the orthosteric ligand, but is inactive in the absence of the orthosteric ligand.
Commercial utility and medical indications
As mentioned supra, the compounds of the present invention have surprisingly been found to effectively be active as an antagonist or a negative allosteric modulator of P2X4.
A compound according to the invention is used for the manufacture of a medicament.
A further aspect of the invention is the use of the compounds according to formula (I), (la) or (lb) for the treatment or prophylaxis of a disease
Furthermore, the invention relates to a compound of general formula (I) (la) or (lb), or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease.
The invention further relates to a method for using the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer to treat mammalian and human disorders and diseases, which include but are not limited to:
• genitourinary, gastrointestinal, respiratory, proliferative and pain-related diseases, conditions and disorders;
gynecological diseases including primary and secondary dysmenorrhea, dyspareunia, vulvudynia, endometriosis and adenomyosis; endometriosis- associated pain; endometriosis-associated symptoms, wherein said symptoms are in particular abdominal pain, dysmenorrhea, dyspareunia, dysuria, dyschezia or pelvic hypersensitivity;
urinary tract disease states including those associated with bladder outlet obstruction; urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyperreactivity; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive urinary bladder and symptoms related to overactive urinary bladder wherein said symptoms are in particular increased urinary frequency, nocturia, urinary urgency or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, in particular interstitial cystitis; idiopathic bladder hypersensitivity; kidney disease as hyperprostaglandin E syndrome, classic Bartter syndrome;
cancer, cancer-related pain and cancer cachexia;
epilepsy, partial and generalized seizures;
• respiratory disorders including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, interstitial pulmonary fibrosis, bronchospasm, chronic chough, refractory chronic cough, ideopahtic chronic cough;
• gastrointestinal disorders including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea- dominant IBS; gastroesophageal reflux, gastrointestinal distension, Crohn's disease and the like;
• fatty liver disorders, in particular NASH (Non-Alcoholic Steato-Hepatitis); fibrotic diseases including lung fibrosis, heart fibrosis, kidney fibrosis and fibrosis of other organs; metabolic syndrome including, for example, insulin resistance, hypertension, refractory hypertension, dyslipoproteinaemia and obesity, diabetes mellitus, in particular Diabetes type II, myocardial infarction; atherosclerosis; lipid disorders;
• neurodegenerative disorders such as Alzheimer's disease, Multiple Sclerosis, Parkinson's disease, brain ischemia, traumatic brain injury, spinal cord injury;
pruritus.
heart disorders including ischemia reperfusion injury, cardiac ischemia,
The present invention further relates to a method for using using the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, to treat pain-associated mammalian disorders and diseases, which include but not limited to
pain-associated diseases or disorders selected from the group consisting of hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome), gout, arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis), burning mouth syndrome, burns, migraine or cluster headaches, nerve injury, traumatic nerve injury, post-traumatic injuries (including fractures and sport injuries), neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgias, HIV and HIV treatment-induced neuropathy, pruritus; impaired wound healing and disease of the skeleton like degeneration of the joints.
Furthermore, the present invention relates to a method for using using the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, to treat mammalian and human disorders and diseases, which are associated with pain or pain syndromes that are in particular:
• pain syndromes (including hyperalgesia, allodynia, acute and chronic inflammatory and neuropathic pain), preferably inflammatory pain, low back pain, surgical pain, visceral pain, dental pain, periodontitis, premenstrual pain, endometriosis- associated pain, pain associated with fibrotic diseases, central pain, pain due to burning mouth syndrome, pain due to burns, pain due to migraine, cluster headaches, pain due to nerve injury, pain due to neuritis, neuralgias, pain due to poisoning, pain due to ischemic injury, pain due to interstitial cystitis, cancer pain, pain due to viral, parasitic or bacterial infections, pain due to traumatic nerve-injury, pain due to post-traumatic injuries (including fractures and sport injuries), pain due to trigeminal neuralgia, pain associated with small fiber neuropathy, pain associated with diabetic neuropathy, postherpetic neuralgia, chronic lower back pain, neck pain phantom limb pain, pelvic pain syndrome, chronic pelvic pain, neuroma pain, complex regional pain syndrome, fibromyalgia, myofascial disorders, pain associated with gastrointestinal distension, chronic arthritic pain and related neuralgias, and pain associated with cancer, Morphine-resistant pain, pain associated with chemotherapy, HIV and HIV treatment-induced neuropathy; and pain associated with diseases or disorders selected from the group consisting of abdominal pain such as functional bowel disorders, irritable bowel syndrome, inflammatory bowl disease and selected from the group of arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis). Compounds of the invention are thus expected to be useful in the treatment of inflammation. The term "inflammation" is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including, inter alia, acute, chronic, ulcerative, fibrotic, allergic and auto-immune disaeses, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, necrosis, endometriosis and other forms of inflammation known to those skilled in the art. The term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever. The compounds of the present invention may also be useful in the treatment, viral infections (e.g. influenza, common cold, herpes zoster, hepatitis C and HIV), bacterial infections, fungal infections, surgical or dental procedures, malignancies (e.g. melanoma, breast cancer, colon cancer, lung cancer and prostate cancer), arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile onset rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, stroke, diabetes mellitus, autoimmune diseases, allergic disorders, rhinitis, ulcers, mild to moderately active ulcerative colitis, familial adenomatous polyposis, coronary heart disease, sarcoidosis and any other disease with an inflammatory component.
Compounds of the invention are also expected to be useful in the treatment of conditions associated or causing bone loss in a subject. Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases.
Based on the P2X4 antagonising activity the compounds according to the invention are useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, lowere back and neck pain, dysmenorrhea, headache, migraine (acute and prophylactic treatment), toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, juvenile rheumatoid arthritis, degenerative joint diseases (osteoarthritis), acute gout and ankylosing spondylitis, acute, subacute and chronic musculoskeletal pain syndromes such as bursitis, burns, injuries, and pain following surgical (post-operative pain) and dental procedures as well as the preemptive treatment of surgical pain. The pain may be mild pain, moderate pain, severe pain, musculoskeletal pain, complex regional pain syndrome, neuropathic pain, back pain such as acute visceral pain, neuropathies, acute trauma, chemotherapy— induced mononeuropathy pain states, polyneuropathy pain states (such as diabetic peripheral neuropathy and/ or chemotherapy induced neuropathy), autonomic neuropathy pain states, pheriphaeral nervous system (PNS) lesion or central nervous system (CNS) lesion or disease related pain states, polyradiculopathies of cervical, lumbar or sciatica type, cauda equina syndrome, piriformis syndrome, paraplegia, quadriplegia, pain states related to various Polyneuritis conditions underlying various infections, chemical injuries, radiation exposure, underlying disease or deficiency conditions (such as beriberi, vitamin deficiencies, hypothyroidism, porphyria, cancer, HIV, autoimmune disease such as multiple sclerosis and spinal-cord injury, fibromyalgia, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, overactive bladder, pelvic hypersensitivity, urinary incontinence, cystitis, stomach, duodenal ulcer, muscle pain, pain due to colicky and referred pain. Compounds of thepresent invention may also be useful for the treatment or prevention of hemophilic arthropathy and Parkinson's disease.
The invention relates also to a method for using the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, to treat conditions treatable by inhibition of prostanoid- induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of relevance to use in treatment of dysmenorrhea premature labor and asthma.
The present invention relates to a method for the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, to treat cancer and hyperproliferative disorders. Hyperproliferative discorders include, but are not limited to, for example: psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias.
Examples of breast cancers include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, and ductal carcinoma in situ, and lobular carcinoma in situ.
Examples of cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma. Examples of brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, and renal pelvis, ureter, urethral and human papillary renal cancers.
Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
Head-and-neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
A preferred embodiment of the present invention relates to a method for using the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, to treat a gynaecological disease, preferably dysmenorrhea, dyspareunia, vulvodynia or endometriosis, endometriosis-associated pain, or other endometriosis-associated symptoms, wherein said symptoms are in particular acute and chronic abdominal pain, dysmenorrhea, dyspareunia, dysuria, or dyschezia.
Another preferred embodiment of the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat a urinary tract disease, in particular overactive bladder or cystitis, preferably interstitial cystitis.
Another preferred embodiment of the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat a respiratory disorder, preferably cough, in particular chronic cough.
Another preferred embodiment of the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat a neurodegenerative disorders, preferably ischemic brain injury, spinal cord injury and Multiple Sclerosis.
Another preferred embodiment of the present invention relates to a method for using of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, to treat arthritis, in particular rheumatoid arthritis and ankylosing spondylitis (Burnstock et al., 2012 Pharmacol Rev. 64:834-868).
These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
The term "treating" or "treatment" as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a gynaecological disease or a disease associated with undesired proliferation like endometriosis or cancer.
Preferably, the diseases treated with said method are gynaecological disorders, more preferably dysmenorrhea, dyspareunia or endometriosis, endometriosis-associated pain, or other endometriosis-associated symptoms, wherein said symptoms are in particular acute and chonic abdominal pain, dysmenorrhea, dyspareunia, dysuria, or dyschezia. Further diseases, which can be treated with said method, are osteoarthritis, diabetic neuropathy, burning mouth syndrome, gastroesophageal reflux, migraine disorders, chronic cough, asthma, pruritus, irritable bowel disease, overactive urinary bladder, prostatic hyperplasia, interstitial cystitis.
Preferably, the method of treating the diseases mentioned above is not limited to the treatment of said disease but also includes the treatment of pain related to or associated with said diseases.
The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of genitourinary, gastrointestinal, respiratory or pain-related disease, condition or disorder.
Pharmaceutical compositions of the compounds of the invention
This invention also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease.
Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier or auxiliary and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention.
Another aspect of the invention is a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I) and a pharmaceutically acceptable auxiliary for the treatment of a disease mentioned supra, especially for the treatment of haematological tumours, solid tumours and/or metastases thereof.
A pharmaceutically acceptable carrier or auxiliary is preferably a carrier that is non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. Carriers and auxiliaries are all kinds of additives assisting to the composition to be suitable for administration.
A pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts the intended influence on the particular condition being treated. The compounds of the present invention can be administered with pharmaceutically- acceptable carriers or auxiliaries well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, subcutaneously, intra uterine and the like.
For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatine type containing auxiliaries, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatine, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, colouring agents, and flavouring agents such as peppermint, oil of wintergreen, or cherry flavouring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavouring and colouring agents described above, may also be present. The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate ; one or more colouring agents ; one or more flavouring agents ; and one or more sweetening agents such as sucrose or saccharin.
Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavouring and colouring agents.
The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1 -dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants.
Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates ; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates ; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers ; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile- lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia ; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.
The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.
A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol.
Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.
It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for administration, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,01 1 ,472, issued April 30, 1991.
The compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al., "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-31 1 ; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1 " PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349 ; and Nema, S. et al., "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997, 51 (4), 166-171.
Commonly used pharmaceutical ingredients that can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid) ; alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine) ; adsorbents (examples include but are not limited to powdered cellulose and activated charcoa)l ; aerosol propellants (examples include but are not limited to carbon dioxide, CCI2F2,
Figure imgf000041_0001
air displacement agents - examples include but are not limited to nitrogen and argon ; antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate) ; antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal) ; antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite) ; binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene- butadiene copolymers) ; buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate); carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection); chelating agents (examples include but are not limited to edetate disodium and edetic acid); colourants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red) ; clarifying agents (examples include but are not limited to bentonite) ; emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate) ; encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate), flavourants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin) ; humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol) ; levigating agents (examples include but are not limited to mineral oil and glycerin) ; oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil) ; ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment) ; penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas), plasticizers (examples include but are not limited to diethyl phthalate and glycerol) ; solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation) ; stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax) ; suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)) ; surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate) ; suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum) ; sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose) ; tablet anti-adherents (examples include but are not limited to magnesium stearate and talc) ; tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch) ; tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch) ; tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac) ; tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate) ; tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross- linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch) ; tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc) ; tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate) ; tablet/capsule opaquants (examples include but are not limited to titanium dioxide) ; tablet polishing agents (examples include but are not limited to carnuba wax and white wax) ; thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin) ; tonicity agents (examples include but are not limited to dextrose and sodium chloride) ; viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth) ; and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).
Pharmaceutical compositions according to the present invention can be illustrated as follows:
Sterile i.v. solution: A 5 mg/ml solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/ml with sterile 5% dextrose and is administered as an i.v. infusion over about 60 minutes.
Lvophilised powder for i.v. administration: A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lyophilised powder, (ii) 32- 327 mg/ml sodium citrate, and (iii) 300 - 3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/ml, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/ml, and is administered either IV bolus or by IV infusion over 15 - 60 minutes.
Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection:
50 mg/ml of the desired, water-insoluble compound of this invention
5 mg/ml sodium carboxymethylcellulose
4 mg/ml TWEEN 80
9 mg/ml sodium chloride
9 mg/ml benzyl alcohol
Hard Shell Capsules: A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 1 1 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
Immediate Release Tablets/Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
Dose and administration
Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of disorders and/ or disease, which are influenced by P2X4, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions. The effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. A preferred oral unit dosage for a administration of the compounds of the present invention includes but is not limited to 0.1 mg/kg to about 10 mg/kg body weight one to three times a day to once a week. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
Combination Therapies
The term "combination" in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combination or kit of parts.
A "fixed combination" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity. One example of a "fixed combination" is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
A non-fixed combination or "kit of parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit. One example of a non-fixed combination or kit of parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately. The components of the non-fixed combination or kit of parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. The present invention relates also to such combinations. Those combined pharmaceutical agents can be other agents having antiproliferative, antinociceptive and/or antiinflammatory effects such as for example for the treatment of haematological tumours, solid tumours and/or metastases thereof and/or agents for the treatment of different pain syndromes and/or undesired side effects. The present invention relates also to such combinations.
Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225- 1287, (1996), which is hereby incorporated by reference, especially (chemotherapeutic) anti-cancer agents as defined supra.
For example, the compounds of the present invention can be combined with known hormonal therapeutic agents.
In particular, the compounds of the present invention can be administered in combination or as co-medication with hormonal contraceptives. Hormonal contraceptives can be administered via oral, subcutaneous, transdermal, intrauterine or intravaginal route, for example as Combined Oral Contraceptives (COCs) or Progestin-Only-Pills (POPs) or hormone-containing devices like implants, patches or intravaginal rings.
COCs include but are not limited to birth control pills or a birth control method that includes a combination of an estrogen (estradiol) and a progestogen (progestin). The estrogenic part is in most of the COCs ethinyl estradiol. Some COCs contain estradiol or estradiol valerate.
Said COCs contain the progestins norethynodrel, norethindrone, norethindrone acetate, ethynodiol acetate, norgestrel, levonorgestrel, norgestimate, desogestrel, gestodene, drospirenone, dienogest, or nomegestrol acetate.
Birth control pills include for example but are not limited to Yasmin, Yaz, both containing ethinyl estradiol and drospirenone; Microgynon or Miranova containing levonorgestrel and ethinyl estradiol; Marvelon containing ethinyl estradiol and desogestrel; Valette containing ethinyl estradiol and dienogest; Belara and Enriqa containing ethinyl estradiol and chlormadinonacetate; Qlaira containing estradiol valerate and dienogest as active ingredients; and Zoely containing estradiol and normegestrol. POPs are contraceptive pills that contain only synthetic progestogens (progestins) and do not contain estrogen. They are colloquially known as mini pills.
POPs include but are not limited to Cerazette containing desogestrel; Microlut containing levonorgestrel and Micronor containing norethindrone.
Other Progeston-Only forms are intrauterine devices (lUDs), for example Mirena containing levonorgestrel, or injectables, for example Depo-Provera containing medroxyprogesterone acetate, or implants, for example Implanon containing etonogestrel.
Other hormone-containing devices with contraceptive effect which are suitable for a combination with the compounds of the present invention are vaginal rings like Nuvaring containing ethinyl estradiol and etonogestrel, or transdermal systems like contraceptive patches, for example Ortho-Evra containing ethinyl estradiol and norelgestromin or Apleek (Lisvy) containing ethinyl estradiol and gestodene.
A preferred embodiment of the present invention is the administration of a compound of general formula (I) in combination with a COC or a POP or other Progestin-Only forms as well as vaginal rings or contraceptive patches as mentioned above.
Furthermore, the compounds of the present invention can be combined with therapeutic agents or active ingredients, that are already approved or that are still under development for the treatment and/ or prophylaxis of diseases which are related to or mediated by P2X4.
For the treatment and/ or prophylaxis of urinary tract diseases, the compounds of the present invention can be administered in combination or as co-medication with any substance that can be applied as therapeutic agent in the following indications:
Urinary tract disease states including those associated with bladder outlet obstruction; urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyperreactivity; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive urinary bladder and symptoms related to overactive urinary bladder wherein said symptoms are in particular increased urinary frequency, nocturia, urinary urgency or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, in particular interstitial cystitis; idiopathic bladder hypersensitivity; kidney disease as hyperprostaglandin E syndrome, classic Bartter syndrome For the treatment and/ or prophylaxis of overactive bladder and symptoms related to overactive bladder, the compounds of the present invention can be administered in combination or as co-medication in addition to behavioral therapy like diet, lifestyle or bladder training with anticholinergics like oxybutynin, tolterodine, propiverine, solifenacin, darifenacin, trospium, fesoterdine; β-3 agonists like mirabegron; neurotoxins like onabutolinumtoxin A; or antidepressants like imipramine, duloxetine.
For the treatment and/ or prophylaxis of interstitial cystitis, the compounds of the present invention can be administered in combination or as co-medication in addition to behavioral therapy like diet, lifestyle or bladder training with pentosans like elmiron; antidepressants like amitriptyline, imipramine; or antihistamines like loratadine.
For the treatment and/ or prophylaxis of gynaecological diseases, the compounds of the present invention can be administered in combination or as co-medication with any substance that can be applied as therapeutic agent in the following indications:
dysmenorrhea, including primary and secondary; dyspareunia; endometriosis; endometriosis-associated pain; endometriosis-associated symptoms, wherein said symptoms are in particular acute and chronic abdominal pain, dysmenorrhea, dyspareunia, dysuria, or dyschezia.
For the treatment and/ or prophylaxis of dysmenorrhea, including primary and secondary; dyspareunia; endometriosis and endometriosis-associated pain, the compounds of the present invention can be administered in in combination with ovulation inhibiting treatment, in particular COCs as mentioned above or contraceptive patches like Ortho- Evra or Apleek (Lisvy); or with progestogenes like dienogest (Visanne); or with GnRH analogous, in particular GnRH agonists and antagonists, for example leuprorelin, nafarelin, goserelin, cetrorelix, abarelix, ganirelix, degarelix; or with androgens: danazol.
For the treatment and/ or prophylaxis of diseases, which are associated with pain, or pain syndromes, the compounds of the present invention can be administered in combination or as co-medication with any substance that can be applied as therapeutic agent in the following indications:
pain-associated diseases or disorders like hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome) and arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis), burning mouth syndrome, burns, migraine or cluster headache, nerve injury, traumatic nerve injury, post-traumatic injuries (including fractures and sport injuries), neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, viral, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgias, HIV and HIV treatment-induced neuropathy.
The compounds of the present invention can be combined with other pharmacological agents and compounds that are intended to treat inflammatory diseases, inflammatory pain or general pain conditions.
In addition to well-known medicaments which are already approved and on the market, the compounds of the present invention can be administered in combination with inhibitors of the P2X purinoceptor family (e,g, P2X3 and P2X7), with inhibitors of IRAK4, with inhibitors of PTGES and with antagonists of the prostanoid EP4 receptor.
In particular, the compounds of the present invention can be administered in combination with pharmacological endometriosis agents, intended to treat inflammatory diseases, inflammatory pain or general pain conditions and/or interfering with endometriotic proliferation and endometriosis associated symptoms, namely with inhibitors of Aldo-keto- reductase1 C3 (AKR1 C3) and with functional blocking antibodies of the prolactin receptor.
The compounds of the present invention can be combined with other pharmacological agents and compounds that are intended for the treatment, prevention or management of cancer.
In particular, the compounds of the present invention can be administered in combination with 131 1-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate,amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib , crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, lanreotide, lapatinib, lasocholine, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, romidepsin, romiplostim, romurtide, roniciclib , samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.
Furthermore, the compounds of the present invention can be combined with active ingredients, which are well known for the treatment of cancer-related pain and chronic pain. Such combinations include, but are not limited to step II opiods like codeine phosphate, dextropropoxyphene, dihydro-codeine,Tramadol), step III opiods like morphine, fentanyl, buprenorphine, oxymorphone, oxycodone and hydromorphone; and other medications used for the treatment of cancer pain like steroids as Dexamethasone and methylprednisolone; bisphosphonates like Etidronate, Clodronate, Alendronate, Risedronate, and Zoledronate; tricyclic antidepressants like Amitriptyline, Clomipramine, Desipramine, Imipramine and Doxepin; class I antiarrhythmics like mexiletine and lidocaine; anticonvulsants like carbamazepine, Gabapentin, oxcarbazepine, phenytoin, pregabalin, topiramate, alprazolam, diazepam, flurazepam, pentobarbital and phenobarbital.
Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art.
The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.
As will be appreciated by persons skilled in the art, the invention is not limited to the particular embodiments described herein, but covers all modifications of said embodiments that are within the spirit and scope of the invention as defined by the appended claims.
The following examples illustrate the invention in greater detail, without restricting it. Further compounds according to the invention, of which the preparation is not explicitly described, can be prepared in an analogous way. The compounds, which are mentioned in the examples and the salts thereof represent preferred embodiments of the invention as well as a claim covering all subcombinations of the residues of the compound of formula (I) as disclosed by the specific examples.
The term "according to" within the experimental section is used in the sense that the procedure referred to is to be used "analogously to".
SYNTHESIS OF COMPOUNDS
The following schemes and general procedures illustrate general synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is obvious to the person skilled in the art that the order of transformations as exemplified in Schemes 1 , 2 and 3 can be modified in various ways. The order of transformations exemplified in Schemes 1 , 2 and 3 is therefore not intended to be limiting. In addition, interconversion of substituents, for example of residues R1, R2, R2a, R2b, R2c, R3, R4, R5, R6, R6a, R6b, R7a, R7b, R7c, R8, R9, R10, R11 or R12 can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, late-stage functionalization chemistry, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art.
All reagents used for the preparation of the compounds of the invention are commercially available, known in the literature or can be prepared as described.
Figure imgf000055_0001
Figure imgf000055_0002
Scheme 1: General procedures for the preparation of compounds of general formula (I) corresponding to formula 9; R1, R3, R4- R5 and R12 are as defined in the description and claims of this invention; W corresponds to either an amine with hydrogen and/or a protecting group PG (e.g. (dimethylamino)methylene, 2,4-dimethoxybenzyl); LG corresponds to a leaving group (e.g. nitro, chloride, fluoride, tosyl).
Compounds of general formula 9 can by synthesized as depicted in Scheme 1.
Electron poor benzene systems with a leaving group LG (e.g. nitro, chloride, fluoride, tosyl ) like 1 can undergo a nucleophilic aromatic substitution reaction with an alcohol or substituted phenol (R12OH) under basic conditions (e.g. potassium carbonate, cesium carbonate) in a suitable solvent (e.g. DMF, acetonitrile), elevated temperature might be necessary. Selective reduction of one nitro group can be acieved with sodium hydrosulfide hydrate in a protic solvent (e,g, methanol/water) yielding aniline derivatives with general formula 3. Under diazotation conditions (e.g. sodium nitrite/HCI/water plus thionyl chloride/copper(l)chloride/water or acetic acid/sulphur dioxide/copper(l)chloride/water) anilines 3 can be converted to sulfonyl chlorides 4. The corresponding sulfonamides 5 can be obtained from 4 by reaction with ammonia or any amine in aprotic solvents such as dichloromethane and acetonitrile. Subsequent reduction under hydrogenation conditions, in polar solvents such as ethanol or tetrahydrofuran in the presence of for example Pd-, Pt-, Fe- or Sn- based catalysts yield the aniline derivatives with general formula 6 or 7. Subsequent acylation to the corresponding amides 8 or 9 can be achieved for example by reaction with acyl chlorides or by standard peptide bond formation using all known procedures, such as reaction of the corresponding carboxylic acid in the presence of a coupling reagent e.g. HATU. For W equals a protected amino function subsequent deprotection with e.g. trifluoroacetic acid (TFA) results in compounds of general formula 9. Substituent R5 (if different from hydrogen) can be introduced by alkylation chemistry in presence of a base.
Obviousely one can also start with aniline 10, perform first the above described
diazotation chemistry to sulfonyl chloride 11 and sulfonamide 12 and then conduct the nucleophilic aromatic substitution reaction to intermediate 5.
Figure imgf000057_0001
Figure imgf000057_0002
15 20
Figure imgf000057_0003
Figure imgf000057_0004
18a R2a = H
18b R2a = Br
Scheme 2: General procedures for the preparation of compounds of general formula (I) corresponding to formula 18a (R2a= H) or 18b (R2a= Br); R R3, R4 and R5 are as defined in the description and claims of this invention; R2 corresponds to (substituted) aryl or heteroaryls as defined in the description and claims of this invention; W corresponds to either an amine with hydrogen and/or a protecting group PG (e.g.,
(dimethylamino)methylene, 2, 4-dimethoxybenzyl). Compounds of general formula 18a or 18b can by synthesized as depicted in Scheme 2. Starting from corresponding sulfonyl chlorides 13 C-connected aryl and heteroaryl derivatives can be prepared after forming protected sulfonamide 14. Transformation of the protected sulfonamides 14 into aryl/heteroaryl compounds of general formula 15 can be achieved e.g. by Suzuki cross-coupling reaction known to the person skilled in the art with the corresponding boronic acid (or ester or a mixture of both) under palladium catalysis in protic (e.g. isopropanol, DMF) or aprotic solvents. The corresponding anilines 16 can be obtained from intermediates 15 by reduction under hydrogenation conditions, in polar solvents such as ethanol or tetrahydrofuran in the presence of for example Pd-, Pt-, Fe- or Sn- based catalysts. Subsequent acylation to the corresponding amides 17 can be achieved for example by reaction with acyl chlorides or by standard peptide bond formation using all known procedures, such as reaction of the corresponding carboxylic acid in the presence of a coupling reagent e.g. HATU. For W equals a protecting group subsequent deprotection with e.g. trifluoroacetic acid (TFA), results in compounds of general formula 18a.
Alternatively, starting from intermediates 14, reduction under hydrogenation conditions, in polar solvents such as ethanol or tetrahydrofuran in the presence of for example Pt- , Fe- or Sn- based catalysts yields anilines 19. The corresponding amides 20 can be obtained by reaction with acyl chlorides or by standard peptide bond formation using all known procedures. Subsequent arylation / heteroarylation using e.g. palladium catalyzed cross- couplings gives access to intermediates 17, which after deprotection yield final products with general formula 18a. Halogenation, e.g. bromination in cone, acetic acid of 18a (R2a= H) yields compounds of general formula 18b.
Substituent R5 (if different from hydrogen) can be introduced by alkylation in presence of a base.
Figure imgf000058_0001
Scheme 3: General procedures for the preparation of compounds of general formula (I) corresponding to formula 22; R1, R2a, R3 and R4 are as defined in the description and claims of this invention; W corresponds to either an amine with hydrogen and/or a protecting group PG (e.g., (dimethylamino)methylene, 2,4-dimethoxybenzyl).
As depicted in Scheme 3, compounds of general formula 22 can be obtained by deprotecting sulfonamides 20, followed by copper-catalyzed cross-coupling reactions known to the person skilled in the art (e.g. copper (I) iodide, a base as potassium carbonate, a ligand as (1 S,2S)-/V,/V-dimethylcyclohexane-1 ,2-diamine and a solvent as DMF and/or toluene).
The compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as chromatography on a suitable support material. Furthermore, reverse phase preparative HPLC of compounds of the present invention which possess a sufficiently basic or acidic functionality, may result in the formation of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. Salts of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. Additionally, the drying process during the isolation of compounds of the present invention may not fully remove traces of cosolvents, especially such as formic acid or trifluoroacetic acid, to give solvates or inclusion complexes. The person skilled in the art will recognise which solvates or inclusion complexes are acceptable to be used in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base, solvate, inclusion complex) of a compound of the present invention as isolated as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
Salts of the compounds of formula (I) according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art. Especially preferred are hydrochlorides and the process used in the example section.
Pure diastereomers and pure enantiomers of the compounds and salts according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis.
Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to a person skilled in the art. Preferably, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxilliary agent, resolving the diastereomers obtained and removing the chiral auxilliary agent. As chiral auxilliary agents, for example, chiral acids can be used to separate enantiomeric bases such as e.g. mandelic acid and chiral bases can be used to separate enantiomeric acids by formation of diastereomeric salts. Furthermore, diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids or chiral alcohols, respectively, as chiral auxilliary agents. Additionally, diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures. Alternatively, enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation.
One preferred aspect of the invention is the process for the preparation of the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer according to the examples, as well as the intermediates used for their preparation.
Optionally, compounds of the formula (I) can be converted into their salts, or, optionally, salts of the compounds of the formula (I) can be converted into the free compounds. Corresponding processes are customary for the skilled person. EXPERIMENTAL PART
Abbreviations
The following table lists the abbreviations used in this paragraph and in the Intermediate Examples and Examples section as far as they are not explained within the text body.
Abbreviation Meaning
AcOH acetic acid (ethanoic acid)
aq. aqueous
boc t-butoxycarbonyl
br broad
CI chemical ionisation
d doublet
DAD diode array detector
DBU 1 ,8-Diazabicyclo(5.4.0)undec-7-ene
DCM dichloromethane
dd double-doublet
DIPEA diisopropylethylamine
DMF /V,/V-dimethylformamide
DMSO dimethyl sulfoxide
ELSD Evaporative Light Scattering Detector
EtOAc ethyl acetate
EtOH ethanol
eq. equivalent
ESI electrospray (ES) ionisation
HATU 1 -[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate
HPLC high performance liquid chromatography
LC-MS liquid chromatography mass spectrometry
m multiplet
MeCN acetonitrile
MeOH methanol
MS mass spectrometry
MTBE methyl tert-butylether
NMR nuclear magnetic resonance spectroscopy : chemical shifts (δ) are given in ppm. The chemical shifts were
corrected by setting the DMSO signal to 2.50 ppm unless otherwise stated.
P pentet
PDA Photo Diode Array
PoraPak™; a HPLC column obtainable from Waters
q quartet
r.t. or rt room temperature
Rt retention time (as measured either with HPLC or UPLC) in minutes
s singlet
SM starting material
SQD Single-Quadrupol-Detector
t triplet
td dublett of a triplet
T3P Propylphosphonic anhydride
TEA triethylamine
THF tetrahydrofuran
UPLC ultra performance liquid chromatography
Other abbreviations have their meanings customary per se to the skilled person.
The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.
Specific Experimental Descriptions
NMR peak forms in the following specific experimental descriptions are stated as they appear in the spectra, possible higher order effects have not been considered. Reactions employing microwave irradiation may be run with a Biotage Initator® microwave oven optionally equipped with a robotic unit. The reported reaction times employing microwave heating are intended to be understood as fixed reaction times after reaching the indicated reaction temperature. The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. from Separtis such as Isolute® Flash silica gel or Isolute® Flash NH2 silica gel in combination with a Isolera® autopurifier (Biotage) and eluents such as gradients of e.g. hexane/ethyl acetate or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia. In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc) of a compound of the present invention as isolated as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
The percentage yields reported in the following examples are based on the starting component that was used in the lowest molar amount. Most reaction conditions were not optimized for yield. Air and moisture sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Commercial grade reagents and solvents were used without further purification. The term "concentrated in vacuo" refers to use of a Buchi rotary evaporator at a minimum pressure of approximately 15 mm of Hg. All temperatures are reported uncorrected in degrees Celsius (°C).
In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. All publications mentioned herein are incorporated by reference in their entirety. Analytical LC-MS and UPLC-MS conditions
LC-MS and UPLC-MS data given in the subsequent specific experimental descriptions refer (unless otherwise noted) to the following conditions:
Method A
Instrument: Waters Acquity UPLC-MS SingleQuad; column: Acquity UPLC BEH C18 1 .7 μηη, 50x2.1 mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1 .6 min 1 -99% B, 1 .6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm.
Method B
Instrument: Waters Acquity UPLC-MS SingleQuad; column: Acquity UPLC BEH C18 1 .7 μηη, 50x2.1 mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1 .6 min 1 -99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm.
Method C
Instrument: Shimadzu LCMS-2020; column: Kinetex 2.6u XB-C18, 50x3.0 mm; eluent A: water/0.1 % formic acid, eluent B: acetonitrile/0.05% formic acid; gradient: 0-2.0 min 10- 100% B, 2.0-2.7 min 100% B; flow: 1 .5 mL/min; temperature: 40°C; DAD scan: 190-400 nm.
Method D
Instrument: Shimadzu LCMS-2020; column: Waters XBridge shield RP18 2.5u, 50x3.0 mm; eluent A: water/0.05% ammonia water, eluent B: acetonitrile; gradient: 0-2.0 min 5- 100% B, 2.0-2.7 min 100% B; flow: 1 .0 mL/min; temperature: 40°C; DAD scan: 190-400 nm.
Method E
Instrument: Shimadzu LCMS-2020; column: Kinetex 2.6u XB-C18, 50x3.0 mm; eluent A: water/0.1 % formic acid, eluent B: acetonitrile/0.05% formic acid; gradient: 0-4.0 min 10- 80% B, 4.0-4.7 min 100% B; flow: 1 .5 mL/min; temperature: 40°C; DAD scan: 190-400 nm. Flash column chromatography conditions
"Purification by (flash) column chromatography" as stated in the subsequent specific experimental descriptions refers to the use of a Biotage Isolera purification system. For technical specifications see "Biotage product catalogue" on www.biotage.com.
General Experimental Procedures
Figure imgf000065_0001
W = NHPG or NPG
PG = Protecting Group
A B
General procedure GP1.1
Bromide A (e.g. 90 μηηοΙ) was dissolved in DMF (0.5 - 2.0 mL in case of 90 μηηοΙ scale) and boronic acid (1.2 - 1 .5 eq) was added followed by addition of catalyst bis(triphenylphosphine)palladium(ll) dichloride (CAS 23965-03-2) (0.15 eq) and aqueous potassium carbonate solution (1 M, 0.2 mL) and the reaction mixture was heated at 120 °C in the microwave for 45 minutes. The reaction mixture was filtered over Celite and washed with DCM. Afterwards the mixture was concentrated in vacuo and the crude was taken onto the next step.
General procedure GP1.2
Bromide A (with Z = R1R3R4CCONH) (180 μιτιοΙ) and boronic acid (2.0 eq) were dissolved in DMF (0.7 mL) and Pd(dppf)CI2 - DCM complex (CAS 95464-05-4) (0.2 eq) was added, followed by addition of aqueous sodium carbonate solution (1 M, 0.45 mL). The reaction was heated at 120 °C for 1 h in the microwave. Afterwards, the mixture was filtered over Celite and the solvent was removed under reduced pressure. The crude was purified by column chromatography on silica gel (Isolera, gradient: ethyl acetate / hexane).
Figure imgf000066_0001
General procedure GP2.1
Protected sulfonamide C (e.g. 240 μηηοΙ) was dissolved in dichloromethane (1 .0 -3.0 mL in case of 240 μηηοΙ scale), trifluoroacetic acid (50 eq) was added and the reaction mixture was stirred at room temperature until TLC showed consumption of starting material. The reaction mixture was concentrated in vacuo, ethyl acetate or DCM and water were added to the crude and the phases were separated. The organic phase was dried and the solvent was removed under reduced pressure. The crude was purified as indicated in the examples. Purification without aqueous extraction was also possible but made e.g. the HPLC purification more difficult.
Figure imgf000066_0002
PG = Protecting Group
General procedure GP3.1
The corresponding carboxylic acid (e.g. 489 μηηοΙ) and aniline E (1 .3 eq) were dissolved in DMF (3.9 ml) and HATU (1.3 eq) and Λ/,/V-diisopropylethylamine (5.0 eq) were added successively. The reaction was heated at 50 °C for 4h. Afterwards the solvent was removed under reduced pressure and the crude was partitioned between water and ethyl acetate. The combined organic phases were dried over a Whatmanfilter and the solvent was removed under reduced pressure. The crude was taken without further purification to the next step.
General procedure GP3.2
Aniline E (e.g. 2.4 mmol) and the corresponding acid (1 .2 eq) were dissolved in DMF (15 mL) and HATU (1.6 - 2.0 eq) and Λ/,/V-diisopropylethylamine (5.0 eq) were added successively. The reaction was heated at 50 °C for 16h. Afterwards 1 .2 eq of acid and 2.0 eq of HATU were added and stirring at 50°C was continued for 16h. Then, the solvent was removed under reduced pressure and the crude was partitioned between water and DCM. The combined organic phases were dried over a Whatmanfilter and the solvent was removed under reduced pressure. The crude was taken without further purification to the next step.
Figure imgf000067_0001
PG = Protecting Group G H
General procedure GP4.1
Nitro compound G (1 .0 eq, e.g. 885 μηηοΙ) was dissolved in ethanol (10 mL) / THF (10 mL) and palladium on charcoal (10% loading, 1 .0 eq) was added. The reaction is evacuated and flushed with hydrogen (1 bar). After stirring at room temperature for 1 h, the reaction was evacuated three times and flushed with hydrogen and stirring was continued for 4h. Then, the reaction mixture was filtered over Celite and washed with THF. The solvent was removed under reduced pressure and the crude was taken without further purification to the next step.
General procedure GP4.2
Nitro compound G (1 .0 eq, e.g. 1 .08 mmol) was dissolved in 1 ,4-dioxane (5.2 mL) and stannous chloride dihydrate (5.0 eq, 5.41 mmol) was added. The reaction was heated at 70 °C until TLC indicated consumption of starting material. After cooling to room temperature, the mixture was filtered over silica gel and the solvent was removed under reduced pressure. Afterwards, the crude was suspended in DCM and filtered again over silica gel. After removing the solvent, the crude was taken onto the next steps without further purification.
Figure imgf000068_0001
J
General Procedure GP5
Aniline I (e.g. on 0.46 mmol scale, 1.00 equiv), the corresponding acid (1.0 equiv), DIPEA (2.0 equiv) and T3P (1 .0 mL in case of 0.46 mmol scale) were dissolved in DCM (3 mL in case of 0.46 mmol scale). It was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo, then redissolved in DMF and filtered. The filtrate was purified with preparative HPLC. The collected fractions were evaporated and lyophilized.
Synthesis of Intermediates Intermediate 1
3-Bromo-A/-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide
Figure imgf000068_0002
3-Bromo-5-nitrobenzenesulfonyl chloride (5.00 g, 16.6 mmol) was dissolved in dichloromethane (48 mL) and sodium bicarbonate (2.80 g, 33.3 mmol) was added, followed by slow addition of 1 -(2,4-dimethoxyphenyl)methanamine (2.7 mL, 18 mmol). The reaction is slightly exothermic and was stirred for 30 min at room temperature. Afterwards, DCM and water were added and the phases were separated. The organic phase was washed three times with water and brine. The organic phase was dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The crude was suspended in diethylether and filtered. The residue was washed with ether and dried to yield 7.49 g (104% yield, 92% purity) of the title compound.
LC-MS (Method B): Rt = 1 .27 min; MS (ESIneg): m/z = 431 [M-H]"
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.60 (s, 3H), 3.68 (s, 3H), 4.03 (s, 2H), 6.21 (d, 1 H), 6.32 (dd, 1 H), 7.04 (d, 1 H), 8.06 (t, 1 H), 8.07 - 8.1 1 (m, 1 H), 8.15 - 8.23 (m, 1 H), 8.49 (s, 1 H).
Intermediate 2
3-(3-Chlorophenoxy)-W-[(2,4-dimethoxyphenyl)methyl]-5-nitro-benzenesulfonami
Figure imgf000069_0001
A mixture of 1 ,3,5-trinitrobenzene (34.6 g, 163 mmol), 3-chlorophenol (20.9 g, 163 mmol), potassium carbonate (44.9 g, 325 mmol) and DMF (170 mL) was stirred for 3h at 60 °C and further 3h at 90 °C. After cooling to RT the mixture was poured in water (1 L) and the product was extracted with dichloromethane (5x200 mL). The organic phase was washed with 5% NaOH and 5% HCI. After drying over sodium sulfate the solvent was evaporated in vacuum and the residue was stirred with dibutyl ether (600 mL) and charcoal (10 g) for 30 min. After filtration the solution was concentrated in vacuum and cooled for 30 min. in ice-salt mixture. The separated crystals were filtered with suction, washed 3 times with small amounts of cold (-10 °C) diethyl ether and dried in vacuum over P2O5 to give 1 -(3- chlorophenoxy)-3,5-dinitro-benzene as yellow crystalline solid, (16.5 g, 55.9 mmol, 34 %, LCMS: 100 %)
1 -(3-Chlorophenoxy)-3,5-dinitro-benzene (16.3 g 55.3 mmol) was dissolved in warm methanol (260 mL) and the flask was equipped with a reflux condenser. Under stirring a solution of NaSH«H20 (Riedel 13590, purity 90%, 7.60 g, 92.3 mmol) in H20-MeOH (8 mL-20 mL) was quickly poured into the flask. After subsiding the very vigorous reaction the mixture was refluxed for 1 h then the methanol was evaporated in vacuo. The residue was washed with water and dried over P2O5 in vacuum to give 3-(3- chlorophenoxy)-5-nitro-aniline as yellow crystalline solid, (13.5 g, 51 .0 mmol, 92 %, LCMS: 92.0 %).
Thionyl chloride (136 mL) was added to water (817 mL) under ice cooling and stirred at RT for 18h. Copper(l)chloride was added at -3 °C and stored at same temp (solution I). Sodium nitrite (7.10 g; 103 mmol) dissolved in water (10 mL) was added drop wise over 30 minutes to a cooled solution (-5 °C) of 3-(3-chlorophenoxy)-5-nitro-aniline (22.7 g; 85.8 mmol) in cc. HCI (100 mL). While stirring at -5 °C for a further 1 h it was poured into the solution I at same temp. The reaction mixture was stirred at 0 °C for 1 h and slowly warmed to RT and stirred for 1 h. The product was extracted with ether (3x300 mL), dried over MgSC>4 and the solvent was evaporated to give 3-(3-chlorophenoxy)-5-nitro- benzenesulfonyl chloride as brown oil (28.2 g, 81 .0 mmol, 94%, LCMS shows 56% of the sulfonyl chloride and 12% of its sulphonic acid in the crude mixture) which was used in next step without further purification.
3-(3-Chlorophenoxy)-5-nitro-benzenesulfonyl chloride (27.3 g, 78.4 mmol) was dissolved in dichloromethane (273 mL) and (2,4-dimethoxyphenyl)methanamine (13 mL, 86.2 mmol) and triethyamine (12 mL, 86.2 mmol) were added while the mixture was cooled in ice bath and stirred for 30 min. The resulting solution was washed with 1 N HCI solution (100 mL) and sat. NaHCC>3 solution (100 mL) and dried over MgS04. The volume was reduced in vacuum to half of the original and hexane (150 mL) was added while the solution was seeded with seeding crystal. The resulting suspension was stirred in ice for 1 h then filtered washed with 1 :1 mixture of hexane and dichloromethane (2x20 mL) finally hexane (20 mL) to give 3-(3-chlorophenoxy)-/V-[(2,4-dimethoxyphenyl)methyl]-5-nitro- benzenesulfonamide as yellow solid (17.24 g, 36.0 mmol, 46 % yield, m.p.: 132.5 - 133.0 °C).
LC-MS (Method A): Rt = 1 .43 min; MS (ESIneg): m/z = 478 [M-H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.61 (s, 3H), 3.66 (s, 3H), 3.99 (s, 2H), 6.26 - 6.35 (m, 2H), 6.99 (s, 1 H), 7.13 (ddd, 1 H), 7.31 (t, 1 H), 7.38 (ddd, 1 H), 7.49 - 7.62 (m, 2H), 7.86 (t, 1 H), 7.98 - 8.06 (m, 1 H), 8.21 - 8.35 (m, 1 H).
Intermediate 3
3-Amino-5-bromo-A/-(2,4-dimethoxybenzyl)benzenesulfonamide
Figure imgf000071_0001
Ammonium chloride (3.39 g, 63.4 mmol) and iron powder (3.54 g, 63.4 mmol) were added to water (150 ml_). Afterwards, a solution of 3-bromo-/V-(2,4-dimethoxybenzyl)-5- nitrobenzenesulfonamide (5.47 g, 12.7 mmol) in THF (75 mL) / methanol (75 mL) was added and the reaction mixture was heated at 80 °C for 90 minutes. After cooling to room temperature the reaction mixture was filtered over Celite and the solvent was concentrated under reduced pressure. The crude was partitioned between water and ethyl acetate and the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over a Whatmanfilter and the solvent was removed under reduced pressure. The crude title compound was taken without further purification to the next step (5 g, 100% yield, 97% purity).
LC-MS (Method A): Rt = 1.10 min; MS (ESIpos): m/z = 401 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.69 (s, 3H), 3.72 (s, 3H), 3.85 (d, 2H), 5.85 (s, 2H), 6.39 - 6.48 (m, 2H), 6.85 - 6.89 (m, 1 H), 6.92 (dt, 2H), 7.09 (d, 1 H), 7.77 (t, 1 H).
Intermediate 4
W-{3-Bromo-5-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2- chlorophenyl)acetamide
Figure imgf000071_0002
3-Amino-5-bromo-/V-(2,4-dimethoxybenzyl)benzenesulfonamide (5.00 g, 12.5 mmol) and (2-chlorophenyl)acetic acid (2.55 g, 15.0 mmol) were dissolved in DMF (100 mL) followed by addition of Λ/,/V-diisopropylethylamine (1 1 mL, 62 mmol) and HATU (6.16 g, 16.2 mmol). The reaction mixture was heated at 50°C for 16h. Afterwards, the solvent was removed under reduced pressure and the crude was partitioned between water and ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over a Whatmanfilter and the solvent was removed under reduced pressure. The crude was purified by chromatography on silica gel (Biotage, 45% ethyl acetate / 55% hexane) to yield 3.76 g (54% yield) of the title compound.
LC-MS (Method B): Rt = 1.31 min; MS (ESIneg): m/z = 551 [M-H]"
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.63 (s, 3H), 3.70 (s, 3H), 3.86 (s, 2H), 3.91 (d, 2H), 6.34 - 6.43 (m, 2H), 7.04 (d, 1 H), 7.23 - 7.37 (m, 2H), 7.38 - 7.50 (m, 3H), 7.86 - 8.07 (m, 3H), 10.62 (s, 1 H).
Intermediate 5
3-Amino-5-(3-chlorophenoxy)-W-(2,4-dimethoxybenzyl)benzenesulfonamide
Figure imgf000072_0001
Ammonium chloride (1 .12 g, 20.9 mmol) and iron powder (1 .17 g, 20.9 mmol) were suspended in water (40 ml). Afterwards a solution of 3-(3-chlorophenoxy)-/V-(2,4- dimethoxybenzyl)-5-nitrobenzenesulfonamide (2.00 g, 4.18 mmol) in THF/MeOH (20 mL/ 20 mL) was added and the reaction mixture was stirred at 80 °C for 3h. Afterwards the reaction was filtered over Celite and the solvent was removed under reduced pressure. The crude was partitioned between water and DCM, the phases were separated and the aqueous phase was extracted with DCM three times. The combined organic phases were dried over a Whatmanfilter and the solvent was removed under reduced pressure to yield the title compound (2.25 g) which was taken without further purification to the next step. LC-MS (Method B): Rt = 1 .31 min; MS (ESIneg): m/z = 447 [M-H]"
Intermediate 6
3-Amino-W-(2,4-dimethoxybenzyl)-5-(pyridin-3-yl)benzenesulfonamide
Figure imgf000073_0001
According to GP1 .1 and GP4.1 3-bromo-/V-(2,4-dimethoxybenzyl)-5- nitrobenzenesulfonamide (500 mg, 1.16 mmol) and pyridin-3-ylboronic acid (214 mg, 1.74 mmol) were converted to the title compound (390 mg, 1 10 % yield, 70% purity, 2 steps). The intermediate obtained after GP1.1 was purified via column chromatography on silica gel (Biotage, gradient ethyl acetate / hexane), the crude after GP4.1 was taken onto the next step without further purification.
LC-MS (Method B): Rt = 0.95 min; MS (ESIpos): m/z = 400 [M+H]+
Intermediate 7
3-Amino-W-(2,4-dimethoxybenzyl)-5-(1 -methyl-1 H^yrazol-4-yl)benzenesulfonamide
Figure imgf000073_0002
C H 3
According to GP1 .1 and GP4.1 3-bromo-/V-(2,4-dimethoxybenzyl)-5- nitrobenzenesulfonamide (650 mg, 1 .51 mmol) and (1 -methyl-1 /-/-pyrazol-4-yl)boronic acid (285 mg, 2.26 mmol) were converted to the title compound (509 mg, 90 % purity, 90 % yield over 2 steps). The crude after GP1 .1 was purified via column chromatography on silica gel (Biotage, gradient ethyl acetate / hexane), the crude after GP4.1 was taken onto the next step without further purification.
LC-MS (Method B): Rt = 0.91 min; MS (ESIpos): m/z = 403 [M+H]+
Intermediate 8
5-Amino-3'-chloro-yV-(2,4-dimethoxybenzyl)biphenyl -3 -sulfonamide
Figure imgf000074_0001
According to GP1 .1 and GP4.2 3-bromo-/V-(2,4-dimethoxybenzyl)-5- nitrobenzenesulfonamide (550 mg, 1.28 mmol) and (3-chlorophenyl)boronic acid (299 mg, 1 .91 mmol) were converted to the title compound (503 mg, 107% yield, 77% purity). The intermediate obtained after GP1 .1 was purified via column chromatography on silica gel (Biotage, gradient ethyl acetate / hexane), the crude after GP4.2 was taken onto the next step without further purification.
LC-MS (Method B): Rt = 1 .27 min; MS (ESIneg): m/z = 431 [M-H]" Intermediate 9
3'-{[(2-Chlorophenyl)acetyl]amino}-5'-[(2,4-dimethoxybenzyl)sulfamoyl]-6- fluorobiphenyl-3-carbox lic acid
Figure imgf000074_0002
According to GP1 .1 /V-{3-bromo-5-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2- chlorophenyl)acetamide (500 mg, 903 μηηοΙ) and 3-(dihydroxyboranyl)-4-fluorobenzoic acid (299 mg, 1 .62 mmol) were converted to the title compound (1 .00 g) and the crude was used without further purification in the next step.
LC-MS (Method B): Rt = 0.74 min; MS (ESIneg): m/z = 61 1 [M-H]"
Intermediate 10
3,5-Dinitrobenzenesulfonyl chloride
Figure imgf000075_0001
3,5-Dinitrophenyl amine (5 g, 27.3 mmol, 1.00 equiv) was added in one portion to a well stirred solution of concentrated HCI (20 mL) and water (20 mL) and the mixture was cooled to -10 °C before a solution of NaN02 (2.072 g, 30.0 mmol, 1.10 equiv) in water (5 mL) was added dropwise at such a rate that the temperature did not exceed -5°C. The mixture was stirred for 45 min at -10°C after the addition. While the diazotization reaction proceeded, a separate well-stirred solution of AcOH (6.67 mL) and water (30 mL) was saturated with SO2 by bubbling the gas into the solution until all gas introduced emerged to the surface. CuCI (0.676 g, 6.83 mmol, 0.25 equiv) was added to the solution and the introduction of SO2 was continued until the yellow-green suspension became blue-green. The SO2/CUCI mixture was then cooled to 10°C before being treated with the diazotization reaction mixture in portions over a 20 min period. The foaming that occurred upon addition was disrupted with a few drops of Et.20. After the addition was complete, the dark red mixture was poured into ice-water (100 mL) and stirred until the ice melted before being filtered. The collected solid was dried in air to afford 3,5-dinitrobenzenesulfonyl chloride (6.01 g, crude) as a red solid that was used directly in the next step.
Intermediate 11
3,5-Dinitrobenzenesulfonamide
Figure imgf000075_0002
Into a 250 mL 3-necked round-bottom flask was placed a solution of 3,5-dinitrobenzenesulfonyl chloride (6.01 g, crude) in tetrahydrofuran (100 mL). The pH value of the solution was adjusted to 9 with NH4OH (25% aq.) at 0°C. The reaction was then diluted by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3x100 mL). The organic layers were combined, washed with 50 mL of brine, then dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/hexane (1/5-1/1 ). The collected fractions were combined and concentrated under vacuum. This resulted in 1 .5 g (22% yield in 2 steps) of 3,5-dinitrobenzenesulfonamide as a yellow solid.
Intermediate 12
3-[(4-Fluorobenzyl)oxy]-5-nitrobenzenesulfonamide
Figure imgf000076_0001
A solution of 3,5-dinitrobenzenesulfonamide (1 1 .8 g, 48 mmol, 1 .0 equiv), (4- fluorophenyl)methanol (12.1 g, 96 mmol, 2.0 equiv) and K2CO3 (13.2 g, 96 mmol, 2.0 equiv) in DMF (100 mL) was heated to 80 °C for 72 h. The reaction mixture was cooled to room temperature and neutralized by 0.5 M HCI to pH = 8, then it was extracted with ethyl acetate (3 x 250 mL). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuum to afford the crude product. Further purification by column chromatography (PE/EA= 6/1 to 2/1 ) afford the title compound (3.5 g, 26%) as a white solid.
Intermediate 13
3-Amino-5-[(4-fluorobenzyl)ox benzenesulfonamide
Figure imgf000076_0002
Into a 250 mL 3-necked round-bottom flask was placed a solution of 3-(4- fluorobenzyloxy)-5-nitrobenzenesulfonamide (3.5 g, 10.7 mmol, 1.0 equiv) in EtOH/HCI (40 mL, 3/1 ). SnCI2-2H20 (4.4 g, 21.4 mmol, 2.0 equiv) was added in 3 batches. The resulting solution was stirred 2 h while the temperature was maintained at 50°C in an oil bath. The reaction mixture was cooled to room temperature and neutralized by 4N NaOH (aq.) to pH = 8, then extracted with ethyl acetate (3 x 250 mL). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuum to afford the crude product. Further purification by column chromatography (PE/EA= 3/1 to 1/1 ) afforded the title compound (2.5 g, 80 %) as a white solid.
MS (ESpos): m/z = 297 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: 7.55 - 7.43 (m, 2H), 7.29 - 7.17 (m, 2H), 7.14 (s, 2H), 6.66 (s, 1 H), 6.61 (s, 1 H), 6.35 (s, 1 H), 5.55 (s, 2H), 5.02 (s, 2H).
Intermediate 14
3-Amino-5-ethoxybenzenesulfonamide
Figure imgf000077_0001
Intermediate 14 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 217 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: 7.1 1 (s, 2H), 6.63 (s, 1 H), 6.51 (s, 1 H), 6.26 (s, 1 H), 5.50 (s, 2H), 4.05 - 3.93 (m, 2H), 1.35 - 1 .29 (m, 3H).
Intermediate 15
3-Amino-5-(2-fluoro-2-methyl ropoxy)benzenesulfonamide
Figure imgf000077_0002
Intermediate 15 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 263 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: 7.12 (s, 2H), 6.66 (s, 1 H), 6.56 (s, 1 H), 6.31 (s, 1 H), 5.55 (s, 2H), 3.94 (d, 2H), 1 .46 (s, 3H), 1 .38 (s, 3H).
Intermediate 16
3-Amino-5-(2,2,2-trifluoroethoxy)benzenesulfonamide
Figure imgf000078_0001
Intermediate 16 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 271 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: 7.16 (s, 2H), 6.73 (s, 1H), 6.61 (s, 1H), 6.36 (s, 1H), 5.66 (s, 2H), 4.72-4.64 (q, 2H).
Intermediate 17
3-Amino-5-[(1-methylpiperidin-4- l)methoxy]benzenesulfonamide
Figure imgf000078_0002
Intermediate 17 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 300 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: 7.11 (s, 2H), 6.63 (s, 1H), 6.52 (s, 1H), 6.27 (s, 1H), 5.51 (s, 2H), 3.75 (d, 2H), 2.77 (d, 2H), 2.53 (m,1H), 2.10 (s, 3H), 1.90-1.82 (m, 2H), 1.69-1.64 (m, 2H), 1.37-1.12 (m, 2H).
Intermediate 18
3-Amino-5-isobutoxybenzenesulfonamide
Figure imgf000078_0003
Intermediate 18 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 245 [M+H]+ 1H-NMR (300MHz, DMSO-d6) δ [ppm]: 7.10 (s, 2H), 6.63 (s, 1 H), 6.52 (s, 1 H), 6.28 (s, 1 H), 5.50 (s, 2H), 3.68 (d, 2H), 2.00 (dt, 1 H), 0.97 (d, 6H).
Intermediate 19
3-Amino-5-(2,2-dimethylpropox benzenesulfonamide
Figure imgf000079_0001
Intermediate 19 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 259 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: 7.10 (s, 2H), 6.62 (s, 1 H), 6.53 (s, 1 H), 6.29 (s, 1 H), 5.50 (s, 2H), 3.56 (s, 2H), 0.99 (s, 9H).
Intermediate 20
3-Amino-5-(3-methylbutoxy benzenesulfonamide
Figure imgf000079_0002
Intermediate 20 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 259 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: 7.10 (s, 2H), 6.63 (s, 1 H), 6.52 (s, 1 H), 6.28 (s, 1 H), 5.50 (s, 2H), 3.93 (t, 2H), 1 .77 (m, 1 H), 1.60 (m, 2H), 0.93 (d, 6H).
Intermediate 21
3-Amino-5-(2-methoxy-2-meth lpropoxy)benzenesulfonamide
Figure imgf000079_0003
Intermediate 21 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 275 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: 7.1 1 (s, 2H), 6.64 (s, 1 H), 6.55 (s, 1 H), 6.30 (s, 1 H), 5.53 (s, 2H), 3.32 (s, 2H), 3.16 (s, 3H), 1.20 (s, 6H).
Intermediate 22
3-Amino-5-[(3-methylbenzyl)ox ]benzenesulfonamide
Figure imgf000080_0001
Intermediate 22 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 293 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: δ 7.34 - 7.14 (m, 6H), 6.66 (s, 1 H), 6.64 (s, 1 H), 6.35 (s, 1 H), 5.55 (s, 2H), 5.00 (s, 2H), 2.33 (s, 3H).
Intermediate 23
3-Amino-5-[(2-fluoro-4-meth lbenzyl)oxy]benzenesulfonamide
Figure imgf000080_0002
Intermediate 23 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 31 1 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: δ 7.43 - 7.38 (m, 1 H), 7.04-7.18 (m, 4H), 6.64 (s, 1 H), 6.61 (s, 1 H), 6.35 (s, 1 H), 5.55 (s, 2H), 5.02 (s, 2H), 2.33 (s, 3H).
Intermediate 24
3-Amino-5-phenoxybenzenesulfonamide
Figure imgf000081_0001
Intermediate 44 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 265 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: δ 7.49 - 7.35 (m, 2H), 7.23 - 7.12 (m, 3H), 7.10 - 6.99 (m, 2H), 6.78 (s, 1 H), 6.52 (s, 1 H), 6.31 (s, 1 H), 5.70 (s, 2H).
Intermediate 25
3-Amino-5-(4-fluorophenoxy)benzenesulfonamide
Figure imgf000081_0002
Intermediate 25 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 283 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: δ 7.32 - 7.16 (m, 4H), 7.16 - 7.03 (m, 2H), 6.77 (s, 1 H), 6.48 (s, 1 H), 6.28 (s, 1 H), 5.70 (s, 2H).
Intermediate 26
3-Amino-5-(3-fluorophenoxy)benzenesulfonamide
Figure imgf000081_0003
Intermediate 26 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 283 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: δ 7.46-7.41 (m, 1 H), 7.22 (s, 2H), 7.12 - 6.93 (m, 3H), 6.91 (s, 1 H), 6.56 (s, 1 H), 6.37 (s, 1 H), 5.76 (s, 2H).
Intermediate 27
3-Amino-5-(3-methylphenoxy)benzenesulfonamide
Figure imgf000082_0001
Intermediate 27 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 279 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: δ 7.29 (m, 1 H), 7.19 (s, 2H), 7.04 - 6.94 (m, 1 H), 6.94 - 6.73 (m, 2H), 6.51 (s,1 H), 6.49 (s,1 H), 6.30 (s, 1 H), 5.69 (s, 2H), 2.31 (s, 3H).
Intermediate 28
3-Amino-5-[3-(trifluoromethyl) henoxy]benzenesulfonamide
Figure imgf000082_0002
Intermediate 28 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 333 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: δ 7.66 (m, 1 H), 7.53 (m, 1 H), 7.35 (m, 2H), 7.23 (s, 2H), 6.85 (s, 1 H), 6.57 (s, 1 H), 6.36 (s, 1 H), 5.79 (s, 2H).
Intermediate 29
3-Amino-5-(2,4-dichlorophenox benzenesulfonamide
Figure imgf000082_0003
Intermediate 29 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 333 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: δ 7.81 (s, 1 H), 7.50 (d, 1 H), 7.27 - 7.17 (m, 3H), 6.79 (s, 1 H), 6.47 (s, 1 H), 6.24 (s, 1 H), 5.76 (s, 2H).
Intermediate 30
2-(3-Amino-5-sulfamoylphenoxy)-yV,yV-dimethylacetamide
Figure imgf000083_0001
Intermediate 30 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 274 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: 7.15 (br, 2H), 6.63 (s, 1 H), 6.49 (s, 1 H), 6.23 (s, 1 H), 5.55 (s, 2H), 4.73(s, 2H), 2.95 (s, 3H), 2.82 (s, 3H)
Intermediate 31
3-Amino-5-(pyridin-2-ylmethox benzenesulfonamide
Figure imgf000083_0002
Intermediate 31 was prepared in analogy to Intermediates 12 and 13
MS (ESpos): m/z = 280 [M+H]+
1H-NMR (300MHz, DMSO-d6) δ [ppm]: 8.63-8.54 (m, 1 H), 7.91 -7.79 (m,1 H), 7.53-7.44 (m, 1 H), 7.41 -7.30 (m, 1 H), 7.17 (s, 2H), 6.66 (s, 1 H), 6.63 (s, 1 H), 6.36 (s, 1 H), 5.60 (s, 2H), 5.12 (s, 2H).
Synthesis of Examples
Example 1
2-(2-Chlorophenyl)-A/-[3-(5-chloropyridin-3-yl)-5-sulfamoylphenyl]acetamide
Figure imgf000083_0003
CI According to GP1 .1 and GP2.1 /V-{3-bromo-5-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2- (2-chlorophenyl)acetamide (50.0 mg, 90.3 μηιοΙ) and (5-chloropyridin-3-yl)boronic acid (17.0 mg, 108 μηηοΙ) were converted without purification of the to the title compound. After aqueous work-up, the product was obtained after preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) followed by crystallization from methanol. The filtrate was concentrated and crystallization was repeated (10.0 mg, 95% purity, 9% yield over 2 steps).
LC-MS (Method A): Rt = 1.08 min; MS (ESIpos): m/z = 436 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.91 (s, 2H), 7.20 - 7.39 (m, 2H), 7.40 - 7.62 (m, 4H), 7.88 (s, 1 H), 8.13 (s, 1 H), 8.20 (d, 2H), 8.71 (d, 1 H), 8.82 (s, 1 H), 10.70 (s, 1 H).
Example 2
2-(2-Chlorophenyl)-/V-[3-(1 -cyclopropyl-1 H-pyrazol-4-yl)-5- sulfamoylphenyljacetamide
Figure imgf000084_0001
According to GP1 .1 and GP2.1 /V-{3-bromo-5-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2- (2-chlorophenyl)acetamide (100 mg, 181 μηιοΙ) and 1 -cyclopropyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (54.9 mg, 235 μηηοΙ) were converted without purification of the intermediates to the title compound. The pure product was obtained by chromatography on silica gel (Biotage, gradient ethyl acetate / hexane) followed by crystallization in diethyl ether (5.20 mg, 95% purity, 6% yield over 2 steps).
LC-MS (Method B): Rt = 0.93 min; MS (ESIpos): m/z = 431 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 0.91 - 1 .02 (m, 2H), 1 .04 - 1 .15 (m, 2H), 3.77 (tt, 1 H), 3.87 (s, 2H), 7.21 - 7.38 (m, 4H), 7.41 - 7.50 (m, 2H), 7.69 (t, 1 H), 7.76 (d, 1 H), 7.91 - 8.00 (m, 2H), 8.22 (s, 1 H), 10.51 (s, 1 H).
Example 3
2-(2-Chlorophenyl)-yV-[3-(3,5-dimethyl-1 ,2-oxazol-4-yl)-5-sulfamoylphenyl]acetamide
Figure imgf000085_0001
According to GP1 .2 and GP2.1 /V-{3-bromo-5-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2- (2-chlorophenyl)acetamide (100 mg, 181 μηηοΙ) and (3,5-dimethyl-1 ,2-oxazol-4-yl)boronic acid (50.9 mg, 361 μηηοΙ) were converted to the title compound. The pure product was obtained after preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (13.0 mg, 95% purity, 56% yield over 2 steps).
LC-MS (Method B): Rt = 0.96 min; MS (ESIpos): m/z = 420 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 2.26 (s, 3H), 2.45 (s, 3H), 3.89 (s, 2H), 7.27 - 7.37 (m, 2H), 7.41 - 7.56 (m, 5H), 7.81 (t, 1 H), 8.14 (t, 1 H), 10.41 - 10.79 (m, 1 H).
Example 4
2-(2-Chlorophenyl)-W-{3-[1 -(difluoromethyl)-1 H-pyrazol-4-yl]-5- sulfamoylphenyl}acetamide
Figure imgf000085_0002
According to GP1 .1 and GP2.1 /V-{3-bromo-5-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2- (2-chlorophenyl)acetamide (125 mg, 226 μηιοΙ) and 1 -(difluoromethyl)-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (82.6 mg, 339 μηηοΙ) were converted without purification of the intermediates to the title compound. The pure product was obtained after preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (21 .7 mg, 95% purity, 20% yield).
LC-MS (Method B): Rt = 0.94 min; MS (ESIpos): m/z = 441 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.90 (s, 2H), 7.28 - 7.36 (m, 2H), 7.39 (s, 2H), 7.43 - 7.49 (m, 2H), 7.68 - 8.01 (m, 2H), 8.04 (dt, 2H), 8.20 (s, 1 H), 8.72 (s, 1 H), 10.62 (s, 1 H).
Example 5
3'-{[(2-Chlorophenyl)acetyl]amino}-6-fluoro-5'-sulfamoylbiphenyl-3-carboxylic acid O
Figure imgf000086_0001
According to GP2.1 3'-{[(2-chlorophenyl)acetyl]amino}-5'-[(2,4-dimethoxybenzyl) sulfamoyl]-6-fluorobiphenyl-3-carboxylic acid was to the title compound. The pure product was obtained after preparative HPLC (Waters XBridge C18 5μ 100x30mm,
acetonitrile/water + 0.1 % formic acid) (16.8 mg, 95% purity, 18% yield).
LC-MS (Method B): Rt = 0.56 min; MS (ESIpos): m/z = 463 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.90 (s, 2H), 7.28 - 7.38 (m, 2H), 7.41 - 7.55 (m, 5H), 7.73 (s, 1 H), 8.01 - 8.08 (m, 2H), 8.10 (dd, 1 H), 8.24 (s, 1 H), 10.70 (s, 1 H), 12.70 - 13.86 (m, 1 H).
Example 6
3'-{[(2-Chlorophenyl)acetyl]amino}-yV-(cyclopropylmethyl)-6-fluoro-5'- sulfamoylbiphenyl-3-carboxamide
O
Figure imgf000086_0002
According to GP3.1 and GP2.1 3'-{[(2-chlorophenyl)acetyl]amino}-5'-[(2,4- dimethoxybenzyl)sulfamoyl]-6-fluorobiphenyl-3-carboxylic acid (300 mg, 489 μηηοΙ) and 1 - cyclopropylmethanamine (55 μΙ, 640 μηηοΙ) were converted without purification of the intermediate to the title compound. The pure product was obtained after preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (27.7 mg, 95% purity, 10% yield over 2 steps).
LC-MS (Method B): Rt = 1 .05 min; MS (ESIneg): m/z = 514 [M-H]"
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 0.16 - 0.29 (m, 2H), 0.37 - 0.50 (m, 2H), 0.96 - 1 .09 (m, 1 H), 3.15 (t, 2H), 3.89 (s, 2H), 7.23 - 7.38 (m, 2H), 7.42 - 7.64 (m, 5H), 7.71 (d, 1 H), 7.88 - 8.12 (m, 3H), 8.22 (t, 1 H), 8.70 (t, 1 H), 10.66 (s, 1 H). Example 7
2-(2-Chlorophenyl)-yV-{5'-[(3,3-difluoropyrrolidin-1 -yl)carbonyl]-2'-fluoro-5- sulfamoylbiphenyl-3-yl}acetamide
O
Figure imgf000087_0001
According to GP3.1 and GP2.1 3'-{[(2-chlorophenyl)acetyl]amino}-5'-[(2,4- dimethoxybenzyl)sulfamoyl]-6-fluorobiphenyl-3-carboxylic acid (300 mg, 489 μηηοΙ) and 3,3-difluoropyrrolidine hydrochloride (1 :1 ) (91 .3 mg, 636 μηηοΙ) were converted without purification of the intermediate to the title compound. The pure product was obtained after preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (10.0 mg, 5% purity, 4% yield over 2 steps).
LC-MS (Method B): Rt = 1 .04 min; MS (ESIneg): m/z = 550 [M-H]"
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 2H overlapped by solvent/water, 3.64 - 3.76 (m, 2H), 3.85 - 3.97 (m, 4H), 7.14 - 7.37 (m, 2H), 7.42 - 7.52 (m, 5H), 7.70 (s, 3H), 7.93 - 8.09 (m, 1 H), 8.14 - 8.30 (m, 1 H), 10.65 (s, 1 H).
Example 8
2-(2-Chlorophenyl)-yV-{3-sulfamoyl-5-[1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazol-5- yl]phenyl}acetamide
O
Figure imgf000087_0002
According to GP1 .1 and GP2.1 /V-{3-bromo-5-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-
(2-chlorophenyl)acetamide (100 mg, 181 μηηοΙ) and 1 -(tetrahydro-2/-/-pyran-2-yl)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (100 mg, 361 μηιοΙ) were converted without purification of the intermediates to the title compound. The pure compound was obtained after crystallisation in DCM followed by purification of the filtrate by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (3.40 mg, 95% purity, 2% yield over 2 steps).
LC-MS (Method B): Rt = 1.05 min; MS (ESIpos): m/z = 475 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 1.50 - 1 .61 (m, 2H), 1.63 - 1 .78 (m, 1 H), 1.89 - 2.03 (m, 2H), 2.07 - 2.24 (m, 1 H), 3.60 - 3.74 (m, 1 H), 3.89 (s, 2H), 3.92 - 4.00 (m, 1 H), 5.46 (dd, 1 H), 6.71 (d, 1 H), 7.29 - 7.37 (m, 2H), 7.41 (s, 2H), 7.44 - 7.52 (m, 2H), 7.95 (t, 1 H), 8.00 (d, 1 H), 8.1 1 (t, 1 H), 8.24 (t, 1 H), 10.61 (s, 1 H).
Example 9
2-(2-Chlorophenyl)-yV-[3-(1 H-pyrazol-5-yl)-5-sulfamoylphenyl]acetamide
O
Figure imgf000088_0001
The title compound was isolated from the deprotection of 2-(2-chlorophenyl)-/V-{3- sulfamoyl-5-[1 -(tetrahydro-2/-/-pyran-2-yl)-1 /-/-pyrazol-5-yl]phenyl}acetamide under the reaction conditions GP 2.1. The pure product was obtained after crystallization from DCM (precipitate, 33.4 mg, 95% purity, 28% yield).
LC-MS (Method B): Rt = 0.83 min; MS (ESIpos): m/z = 391 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.87 (s, 2H), 6.64 (d, 1 H), 7.25 - 7.34 (m, 2H), 7.37 (s, 2H), 7.42 - 7.48 (m, 2H), 7.80 (d, 1 H), 7.94 (t, 1 H), 8.08 (t, 1 H), 8.20 (d, 1 H), 10.56 (s, 1 H).
Example 10
yV-[3-(3-Chlorophenoxy)-5-sulfamoylphenyl]-2-[4-(trifluoromethyl)phenyl]acetamide
Figure imgf000088_0002
According to GP3.2 and GP2.1 3-amino-5-(3-chlorophenoxy)-/V-(2,4- dimethoxybenzyl)benzenesulfonamide (1 .08 g, 2.41 mmol) and [4- (trifluoromethyl)phenyl]acetic acid (589 mg, 2.89 mmol) were converted without purification of the intermediate to the title compound. The pure product was obtained after preparative HPLC (Chromatorex C-18 Ι Ομηι, 125x30mm, acetonitrile/water + 0.1 % aqueous ammonia (32%)) (90.0 mg, 99% purity, 3% yield over 2 steps).
LC-MS (Method A): Rt = 1.31 min; MS (ESIpos): m/z = 485 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.79 (s, 2H), 7.06 - 7.1 1 (m, 1 H), 7.12 (dd, 1 H), 7.23 (s, 1 H), 7.29 - 7.33 (m, 1 H), 7.44 - 7.58 (m, 6H), 7.70 (d, 2H), 7.90 (t, 1 H), 10.65 (s, 1 H).
Example 11
2-(2-Chloro-6-fluorophenyl)-yV-[3-(3-chlorophenoxy)-5-sulfamoylphenyl]acetamide
Figure imgf000089_0001
According to GP3.2 and GP2.1 3-amino-5-(3-chlorophenoxy)-/V-(2,4- dimethoxybenzyl)benzenesulfonamide (200 mg, 446 μηηοΙ) and (2-chloro-6- fluorophenyl)acetic acid (101 mg, 535 μηηοΙ) were converted without purification of the intermediate to the title compound. The pure product was obtained after two preparative HPLC runs (Chromatorex C-18 Ι Ομηη, 125x30mm, acetonitrile/water + 0.1 % aqueous ammonia (32%)) (13.0 mg, 95% purity, 3% yield over 2 steps).
LC-MS (Method A): Rt = 1.25 min; MS (ESIpos): m/z = 469 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.90 (d, 2H), 7.09 (ddd, 1 H), 7.12 (dd, 1 H), 7.22 - 7.28 (m, 2H), 7.31 (ddd, 1 H), 7.33 - 7.41 (m, 2H), 7.41 - 7.51 (m, 4H), 7.90 (t, 1 H), 10.74 (s, 1 H).
Example 12
2-(4-Bromophenyl)-yV-[3-(3-chlorophenoxy)-5-sulfamoylphenyl]acetamide
Figure imgf000090_0001
According to GP3.2 and GP2.1 3-amino-5-(3-chlorophenoxy)-/V-(2,4- dimethoxybenzyl)benzenesulfonamide (1 .13 g, 2.51 mmol) and (4-bromophenyl)acetic acid (647 mg, 3.01 mmol) were converted to the title compound. The pure product was obtained after column chromatography on silica gel (Biotage, gradient ethyl acetate / hexane) followed by preparative HPLC (Chromatorex C-18 Ι Ομηη, 125x30mm, acetonitrile/water + 0.1 % aqueous ammonia (32%)) (20.0 mg, 95% purity, 3% yield over 2 steps).
LC-MS (Method B): Rt = 1 .27 min; MS (ESIneg): m/z = 493 [M-H]"
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.64 (s, 2H), 7.08 (ddd, 1 H), 7.1 1 (dd, 1 H), 7.21 - 7.24 (m, 1 H), 7.25 - 7.33 (m, 3H), 7.37 (br s, 2H), 7.45 - 7.55 (m, 4H), 7.89 (t, 1 H), 10.58 (s, 1 H).
Example 13
yV-[3-(3-Chlorophenoxy)-5-sulfamoylphenyl]-2-[2-chloro-4- (trifluoromethyl)phenyl]acetamide
O
Figure imgf000090_0002
According to GP3.2 and GP2.1 3-amino-5-(3-chlorophenoxy)-/V-(2,4- dimethoxybenzyl)benzenesulfonamide (1 .13 g, 2.51 mmol) and [2-chloro-4- (trifluoromethyl)phenyl]acetic acid (755 mg, 95 % purity, 3.01 mmol) were converted to the title compound. The intermediate obtained after GP3.2 was purified by column chromatography on silica gel (gradient ethyl acetate / hexane). Pure product was obtained after preparative HPLC (Chromatorex C-18 10μηι, 125x30mm, acetonitrile/water + 0.1 % formic acid) (35.0 mg, 95% purity, 7% yield over 2 steps).
LC-MS (Method A): Rt = 1 .38 min; MS (ESIneg): m/z = 517 [M-H]"
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.98 (s, 2H), 7.02 - 7.17 (m, 2H), 7.24 (t, 1 H), 7.31 (ddd, 1 H), 7.37 - 7.58 (m, 4H), 7.65 - 7.79 (m, 2H), 7.84 - 7.96 (m, 2H), 10.71 (s, 1 H).
Example 14
yV-[4-Bromo-3-(3-chlorophenoxy)-5-sulfamoylphenyl]-2-[4- (trifluoromethyl)phenyl]acetamide
O
Figure imgf000091_0001
Starting material /V-[3-(3-chlorophenoxy)-5-sulfamoylphenyl]-2-[4-(trifluoromethyl)- phenyl]acetamide was prepared as described for Example 10.
N-[3-(3-Chlorophenoxy)-5-sulfamoylphenyl]-2-[4-(trifluoromethyl)phenyl]acetamide (100 mg,0.21 mmol) was dissolved in cone, acetic acid (13 mL) and bromine (12 μΙ_, 0.23 mmol, 1 .1 eq) was added into the solution. The reaction was stirred for 24h at room temperature. Afterwards aq. sodium thiosulfate solution was added followed by ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over a Whatmanfilter and the solvent was removed under reduced pressure. The pure product was obtained after preparative HPLC (Chromatorex C-18 Ι Ομηη, 125x30mm, acetonitrile/water + 0.1 % formic acid) (13.0 mg, 95% purity, 1 1 % yield).
LC-MS (Method A): Rt = 1.37 min; MS (ESIpos): m/z = 563 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.77 (s, 2H), 6.98 (ddd, 1 H), 7.15 (t, 1 H), 7.28 (ddd, 1 H), 7.45 (t, 1 H), 7.52 (d, 2H), 7.63 (d, 1 H), 7.66 - 7.75 (m, 4H), 8.16 (d, 1 H), 10.73 (s, 1 H).
Example 15
2-Phenyl-yV-[3-(pyridin-3-yl)-5-sulfamoylphenyl]acetamide
Figure imgf000092_0001
According to GP3.2 and GP2.1 3-amino-/V-(2,4-dimethoxybenzyl)-5-(pyridin-3- yl)benzenesulfonamide (130 mg, 325 μηιοΙ) and (phenylacetic acid (53.2 mg, 391 μηιοΙ) were converted without purification of the intermediates to the title compound. The pure product was obtained after preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (17.7 mg, 95% purity, 14% yield over 2 steps).
LC-MS (Method B): Rt = 0.76 min; MS (ESIpos): m/z = 368 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.69 (s, 2H), 7.23 - 7.27 (m, 1 H), 7.31 - 7.46 (m, 6H), 7.52 - 7.57 (m, 1 H), 7.81 (t, 1 H), 8.01 - 8.06 (m, 1 H), 8.09 (t, 1 H), 8.18 (t, 1 H), 8.63 (dd, 1 H), 8.82 - 8.85 (m, 1 H), 10.61 (s, 1 H).
Example 16
2-(2-Chlorophenyl)-yV-[3-(pyridin-3-yl)-5-sulfamoylphenyl]acetamide
O
Figure imgf000092_0002
According to GP3.2 and GP2.1 3-amino-/V-(2,4-dimethoxybenzyl)-5-(pyridin-3- yl)benzenesulfonamide (130 mg, 325 μηηοΙ) and (2-chlorophenyl)acetic acid (66.6 mg, 391 μηηοΙ) were converted without purification of the intermediates to the title compound. The pure product was obtained after preparative HPLC (32.8 mg, 95% purity, 24% yield over 2 steps).
LC-MS (Method B): Rt = 0.83 min; MS (ESIpos): m/z = 402 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.89 (s, 2H), 7.28 - 7.35 (m, 2H), 7.41 (s, 2H), 7.45 (dt, 2H), 7.49 - 7.61 (m, 1 H), 7.82 (t, 1 H), 8.00 - 8.05 (m, 1 H), 8.10 (t, 1 H), 8.18 (t, 1 H), 8.63 (dd, 1 H), 8.78 - 8.90 (m, 1 H), 10.67 (s, 1 H). Example 17
yV-[3-(1 -Methyl-1 H-pyrazol-4-yl)-5-sulfamoylphenyl]-2-phenylacetamide
O
Figure imgf000093_0001
C H 3
According to GP3.2 and GP2.1 3-amino-/V-(2,4-dimethoxybenzyl)-5-(1 -methyl-1 /-/-pyrazol- 4-yl)benzenesulfonamide (165 mg, 410 μηηοΙ) and phenylacetic acid (67.0 mg, 492 μηηοΙ) were converted without purification of the intermediates to the title compound. The pure product was obtained after preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (18.6 mg (95% purity, 15% yield over 2 steps).
LC-MS (Method B): Rt = 0.76 min; MS (ESIpos): m/z = 371 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.65 (s, 2H), 3.86 (s, 3H), 7.21 - 7.28 (m, 1 H), 7.28 - 7.38 (m, 6H), 7.65 (t, 1 H), 7.78 (d, 1 H), 7.88 (t, 1 H), 7.94 (t, 1 H), 8.10 (s, 1 H), 10.49 (s, 1 H).
Example 18
2-(2-Chlorophenyl)-yV-[3-(1 -methyl-1 H-pyrazol-4-yl)-5-sulfamoylphenyl]acetamide
O
Figure imgf000093_0002
C H 3
According to GP3.2 and GP2.1 3-amino-/V-(2,4-dimethoxybenzyl)-5-(1 -methyl-1 /-/-pyrazol- 4-yl)benzenesulfonamide (165 mg, 410 μηηοΙ) and (2-chlorophenyl)acetic acid (83.9 mg, 492 μηηοΙ) were converted without purification of the intermediates to the title compound. The pure product was obtained after preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (40.4 mg, 95% purity, 31 % yield over 2 steps).
LC-MS (Method B): Rt = 0.83 min; MS (ESIpos): m/z = 405 [M+H]+ 1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.87 (s, 5H), 7.30 - 7.36 (m, 4H), 7.42 - 7.47 (m, 2H), 7.67 (t, 1 H), 7.77 (d, 1 H), 7.92 (t, 1 H), 7.95 (t, 1 H), 8.13 (s, 1 H), 10.53 (s, 1 H).
Example 19
2-(2-Chlorophenyl)-yV-(3'-chloro-5-sulfamoylbiphenyl-3-yl)acetamide
O
Figure imgf000094_0001
According to GP3.2 and GP2.1 5-amino-3'-chloro-/V-(2,4-dimethoxybenzyl)biphenyl-3- sulfonamide (166 mg, 383 μηιοΙ) and (2-chlorophenyl)acetic acid (78.5 mg, 460 μηιοΙ) were converted without purification of the intermediates to the title compound. The pure product was obtained after preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (28.0 mg, 95 % purity, 14 % yield over 2 steps). LC-MS (Method A): Rt = 1 .22 min; MS (ESIpos): m/z = 435 [M+H]+
1H-NMR (400MHz, CD3OD) δ [ppm]: 3.96 (s, 2H), 7.25 - 7.37 (m, 2H), 7.41 - 7.53 (m, 4H), 7.56 - 7.65 (m, 1 H), 7.69 (t, 1 H), 7.89 (t, 1 H), 8.08 (t, 1 H), 8.22 (t, 1 H).
Example 20
yV-(3'-Chloro-5-sulfamoylbiphenyl-3-yl)-2-phenylacetamide
O
Figure imgf000094_0002
According to GP3.2 and GP2.1 5-amino-3'-chloro-/V-(2,4-dimethoxybenzyl)biphenyl-3- sulfonamide (166 mg, 383 μηηοΙ) and phenylacetic acid (62.6 mg, 460 μηηοΙ) were converted without purification of the intermediates to the title compound. The pure product was obtained after preparative HPLC (Waters XBridge C18 5μ 100x30mm,
acetonitrile/water + 0.1 % formic acid) (2.00 mg, 95% purity, 1 % yield over 2 steps).
LC-MS (Method A): Rt = 1 .17 min; MS (ESIpos): m/z = 401 [M+H]+ 1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.69 (s, 2H), 7.22 - 7.28 (m, 1 H), 7.30 - 7.38 (m, 4H), 7.40 (s, 2H), 7.49 - 7.53 (m, 1 H), 7.56 (t, 1 H), 7.60 (s, 1 H), 7.68 (t, 1 H), 7.80 (t, 1 H), 8.07 - 8.13 (m, 1 H), 8.16 (s, 1 H), 10.59 (s, 1 H).
Example 21
yV-[3-(3-Chlorophenoxy)-5-sulfamoylphenyl]-2-phenylacetamide
Figure imgf000095_0001
According to GP3.2 and GP2.1 3-amino-5-(3-chlorophenoxy)-/V-(2,4- dimethoxybenzyl)benzenesulfonamide (150 mg, 334 μηηοΙ) and phenylacetic acid (54.6 mg, 401 μηηοΙ) were converted without purification of the intermediates. In this specific case the amide coupling according to GP3.2 was repeated after aqueous work-up before the deprotection. Pure title compound (25.0 mg, 95% purity, 16% yield over 2 steps) was obtained after preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.2% aqueous ammonia (32%)).
LC-MS (Method B): Rt = 1.15 min; MS (ESIpos): m/z = 434 [M+H20]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.65 (s, 2H), 7.06 - 7.12 (m, 2H), 7.21 - 7.36 (m,
7H), 7.43 (s, 2H), 7.45 - 7.50 (m, 1 H), 7.51 (t, 1 H), 7.91 (s, 1 H), 10.56 (s, 1 H).
Example 22
yV-[3-(3-Chlorophenoxy)-5-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide
O
Figure imgf000095_0002
According to GP3.2 and GP2.1 3-amino-5-(3-chlorophenoxy)-/V-(2,4- dimethoxybenzyl)benzenesulfonamide (800 mg, 1.78 mmol) and (2-chlorophenyl)acetic acid (365 mg, 2.14 mmol) were converted without purification of the intermediates to the title compound. The pure product was obtained after preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (12.0 mg, 95% purity, 8% yield over 2 steps). LC-MS (Method B): Rt = 1.19 min; MS (ESIpos): m/z = 451 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.83 (s, 2H), 7.07 (ddd, 1 H), 7.10 - 7.12 (m, 1 H), 7.21 (t, 1 H), 7.26 - 7.33 (m, 3H), 7.37 - 7.47 (m, 5H), 7.47 - 7.51 (m, 1 H), 7.90 (t, 1 H), 10.60 (s, 1 H).
Example 23
W-[3-(2-Fluoro-2-methyl ropoxy)-5-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide
Figure imgf000096_0001
The title compound was prepared according to GP 5.
51.4 mg, 0.129 mmol, 100% purity
LC-MS (Method C): Rt = 1 .29 min; MS (ESIneg): m/z = 397 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 1 .43 (d, 6H), 3.75 (s, 2H), 4.03 (d, 2H), 7.09 - 7.23 (m, 3H), 7.24 - 7.45 (m, 4H), 7.54 (t, 1 H), 7.66 (t, 1 H), 10.52 (s, 1 H).
Example 24
2-(2-Fluorophenyl)-A/-[3- 3-methylbutoxy)-5-sulfamoylphenyl]acetamide
Figure imgf000096_0002
The title compound was prepared according to GP 5.
60.9 mg, 0.154 mmol, 99 % purity
LC-MS (Method C): Rt = 1 .46 min; MS (ESIneg): m/z = 393 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 0.93 (d, 6H), 1.63 (q, 2H), 1.78 (m, 1 H), 3.74 (s, 2H), 4.01 (t, 2H), 7.06 (s, 1 H), 7.13 - 7.22 (m, 2H), 7.28 - 7.43 (m, 4H), 7.47 (t, 1 H), 7.64 (t, 1 H), 10.48 (s, 1 H).
Example 25
A/-{3-[(3-Methylbenzyl)oxy]-5-sulfamoylphenyl}-2-(pyridin-3-yl)acetamide
Figure imgf000097_0001
The title compound was prepared according to GP 5.
82.1 mg, 0.200 mmol, 93 % purity
LC-MS (Method C): Rt = 0.93 min; MS (ESIneg): m/z = 410 [M-HJ
1H-NMR (300MHz, DMSO-de) δ [ppm]: 2.32 (s, 3H), 3.72 (s, 2H), 5.07 (s, 2H), 7.1 1 - 7.40 (m, 8H), 7.54 (t, 1 H), 7.68 (br t, 1 H), 7.75 (br dt, 1 H), 8.47 (br dd 1 H), 8.53 (br s, 1 H), 10.53 (s, 1 H).
Example 26
2-(2-Fluorophenyl)-W-[3- ridin-2-ylmethoxy)-5-sulfamoylphenyl]acetamide
Figure imgf000097_0002
The title compound was prepared according to GP 5.
33.3 mg, 0.0802 mmol, 99 % purity
LC-MS (Method D): Rt = 1 .60 min; MS (ESIneg): m/z = 414 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.75 (s, 2H), 5.20 (s, 2H), 7.12 - 7.23 (m, 3H), 7.27 - 7.43 (m, 5H), 7.47 - 7.54 (m, 2H), 7.73 (t, 1 H), 7.85 (td, 1 H), 8.59 (dq, 1 H), 10.52 (s, 1 H).
Example 27
yV-[3-(3-Fluorophenoxy)-5-sulfamo lphenyl]-2-(2-fluorophenyl)acetamide
Figure imgf000097_0003
The title compound was prepared according to GP 5. 46.5 mg, 0.1 1 1 mmol, 94 % purity
LC-MS (Method E): Rt = 2.61 min; MS (ESIneg): m/z = 417 [M-HJ
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.74 (s, 2H), 6.94 (dd, 1 H), 7.03 (dt, 1 H), 7.07 - 7.22 (m, 4H), 7.28 - 7.53 (m, 6H), 7.90 (t, 1 H), 10.61 (s, 1 H).
Example 28
2-(2-Fluorophenyl)-A/-[3- 2-methylpropoxy)-5-sulfamoylphenyl]acetamide
The title compound was prepared according to GP 5.
84.7 mg, 0.223 mmol, 99 % purity
LC-MS (Method C): Rt = 1 .38 min; MS (ESIneg): m/z = 379 [M-HJ
1H-NMR (300MHz, DMSO-de) δ [ppm]: 0.98 (d, 6H), 1 .96 - 2.08 (m, 1 H), 3.74 (s, 2H), 3.75 (d, 2H), 7.06 (dd, 1 H), 7.14 - 7.22 (m, 2H), 7.28 - 7.43 (m, 4H), 7.49 (t, 1 H), 7.63 (t, 1 H), 10.48 (s, 1 H).
Example 29
A/-{3-[(4-Fluorobenzyl)ox -5-sulfamoylphenyl}-2-(2-fluorophenyl)acetamide
Figure imgf000098_0002
The title compound was prepared according to GP 5.
34.7 mg, 0.0802 mmol, 100 % purity
LC-MS (Method C): Rt = 1 .40 min; MS (ESIneg): m/z = 431 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.76 (s, 2H), 5.1 1 (s, 2H), 7.14 - 7.43 (m, 9H), 7.49 - 7.58 (m, 3H), 7.69 (t, 1 H), 10.53 (s, 1 H).
Example 30
A/-{3-[(4-Fluorobenzyl)oxy]-5-sulfamoylphenyl}-2-(pyridin-3-yl)acetamide
Figure imgf000099_0001
The title compound was prepared according to GP 5.
42.2 mg, 0.102 mmol, 99 % purity
LC-MS (Method C): Rt = 0.86 min; MS (ESIneg): m/z = 414 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.72 (s, 2H), 5.10 (s, 2H), 7.15 (dd, 1 H), 7.19 - 7.28 (m, 2H), 7.33 - 7.40 (m, 3H), 7.48 - 7.56 (m, 3H), 7.67 (t, 1 H), 7.74 (dt, 1 H), 8.47 (br dd, 1 H), 8.52 (br dd, 1 H), 10.54 (s, 1 H).
Example 31
2-(2-Fluorophenyl)-yV-(3-phenox -5-sulfamoylphenyl)acetamide
Figure imgf000099_0002
The title compound was prepared according to GP 5.
62.6 mg, 0.156 mmol, 100 % purity
LC-MS (Method C): Rt = 1 .36 min; MS (ESIneg): m/z = 399 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.73 (s, 2H), 7.07 - 7.51 (m, 13H), 7.87 (d, 1 H), 10.59 (s, 1 H).
Example 32
yV-{3-[(2-Fluoro-4-methylbenzyl)oxy]-5-sulfamoylphenyl}-2-(2- fluorophenyl)acetamide
Figure imgf000100_0001
The title compound was prepared according to GP 5.
44.2 mg, 0.0990 mmol, 100 % purity
LC-MS (Method C): Rt = 1 .47 min; MS (ESIneg): m/z = 445 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 2.34 (s, 3H), 3.76 (s, 2H), 5.1 1 (s, 2H), 7.03 - 7.23 (m, 5H), 7.29 - 7.47 (m, 5H), 7.54 (t, 1 H), 7.71 (t, 1 H), 10.52 (s, 1 H).
Example 33
yV-[3-(4-Fluorophenoxy)-5-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide
N H 2
Figure imgf000100_0002
The title compound was prepared according to GP 5.
46.8 mg, 0.1 12 mmol, 96 % purity
LC-MS (Method C): Rt = 1 .39 min; MS (ESIneg): m/z = 417 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.73 (s, 2H), 7.05 (t, 1 H), 7.12 - 7.21 (m, 4H), 7.26 - 7.45 (m, 7H), 7.85 (t, 1 H), 10.58 (s, 1 H). Example 34
2-(2-Fluorophenyl)-yV-{3-[(3-methylbenzyl)oxy]-5-sulfamoylphenyl}acetamide
Figure imgf000100_0003
The title compound was prepared according to GP 5.
41.6 mg, 0.0971 mmol, 100 % purity LC-MS (Method C): Rt = 1 .46 min; MS (ESIneg): m/z = 427 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 2.32 (s, 3H), 3.75 (s, 2H), 5.07 (s, 2H), 7.12 - 7.43 (m, 1 1 H), 7.54 (t, 1 H), 7.68 (br s, 1 H), 10.52 (s, 1 H).
Example 35
A/-[3-(4-Fluorophenoxy)-5-sulfamo lphenyl]-2-(pyridin-3-yl)acetamide
Figure imgf000101_0001
The title compound was prepared according to GP 5.
75.3 mg, 0.188 mmol, 93 % purity
LC-MS (Method E): Rt = 1 .28 min; MS (ESIneg): m/z = 400 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.70 (s, 2H), 7.06 (dd, 1 H), 7.13 - 7.22 (m, 2H), 7.25 - 7.47 (m, 6H), 7.72 (dt, 1 H), 7.85 (t, 1 H), 8.46 (dd, 1 H), 8.50 (s, 1 H), 10.59 (s, 1 H).
Example 36
2-(2-Fluorophenyl)-A/-[3-sulfamo l-5-(2,2,2-trifluoroethoxy)phenyl]acetamide
Figure imgf000101_0002
The title compound was prepared according to GP 5.
93.0 mg, 0.229 mmol, 99 % purity
LC-MS (Method C): Rt = 1 .28 min; MS (ESIneg): m/z = 405 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.76 (s, 2H), 4.80 (q, 2H), 7.13 - 7.22 (m, 3H), 7.28 - 7.43 (m, 4H), 7.58 (t, 1 H), 7.75 (t, 1 H), 10.59 (s, 1 H).
Example 37
A/-[3-(2-Fluoro-2-methylpropoxy)-5-sulfamoylphenyl]-2-(pyridin-3-yl)acetamide
Figure imgf000102_0001
The title compound was prepared according to GP 5.
44.2 mg, 0.1 16 mmol, 96 % purity
LC-MS (Method C): Rt = 0.70 min; MS (ESIneg): m/z = 380 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 1.43 (d, 6H), 3.72 (s, 2H), 4.03 (d, 2H), 7.1 1 (t, 1 H), 7.32 - 7.40 (m, 3H), 7.53 (t, 1 H), 7.65 (t, 1 H), 7.74 (dt, 1 H), 8.45 - 8.49 (dd, 1 H), 8.53 (d, 1 H), 10.53 (s, 1 H).
Example 38
A/-(3-Ethoxy-5-sulfamoyl henyl)-2-(2-fluorophenyl)acetamide
Figure imgf000102_0002
The title compound was prepared according to GP 5.
69.7 mg, 0.198 mmol, 99 % purity
LC-MS (Method C): Rt = 1 .16 min; MS (ESIneg): m/z = 351 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 1.34 (t, 3H), 3.74 (s, 2H), 4.04 (q, 2H), 7.05 (dd, 1 H), 7.13 - 7.23 (m, 2H), 7.28 - 7.42 (m, 4H), 7.45 (t, 1 H), 7.65 (t, 1 H), 10.48 (s, 1 H).
Example 39
A/-{3-[(2-Fluoro-4-meth lbenzyl)oxy]-5-sulfamoylphenyl}-2-(pyridin-3-yl)acetamide
Figure imgf000102_0003
The title compound was prepared according to GP 5. 33.7 mg, 0.0785 mmol, 97 % purity
LC-MS (Method C): Rt = 1 .16 min; MS (ESIneg): m/z = 351 [M-HJ
1H-NMR (300MHz, DMSO-de) δ [ppm]: 2.34 (s, 3H), 3.73 (s, 2H), 5.1 1 (s, 2H), 7.03 - 7.19 (m, 3H), 7.32 - 7.48 (m, 4H), 7.53 (t, 1 H), 7.67 - 7.78 (m, 2H), 8.47 (dd, 1 H), 8.52 (d, 1 H), 10.54 (s, 1 H).
Example 40
yV-[3-(3-Fluorophenoxy)-5-sulfamo lphenyl]-2-(pyridin-3-yl)acetamide
Figure imgf000103_0001
The title compound was prepared according to GP 5.
37.3 mg, 0.0929 mmol, 96 % purity
LC-MS (Method C): Rt = 0.85 min; MS (ESIneg): m/z = 400 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.71 (s, 2H), 6.94 (dd, 1 H), 6.99 - 7.15 (m, 3H), 7.35 (dd, 1 H), 7.41 - 7.54 (m, 4H), 7.72 (dt, 1 H), 7.89 (t, 1 H), 8.44 - 8.53 (m, 2H), 10.62 (s, 1 H).
Example 41
yV-[3-(2-Methylpropoxy)-5-sulfamo lphenyl]-2-(pyridin-3-yl)acetamide
Figure imgf000103_0002
The title compound was prepared according to GP 5.
78.0 mg, 0.215 mmol, 99 % purity
LC-MS (Method C): Rt = 0.80 min; MS (ESIneg): m/z = 362 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 0.98 (d, 6H), 1 .97 - 2.08 (m, 1 H), 3.71 (s, 2H), 3.75 (d, 2H), 7.06 (dd, 1 H), 7.32 (s, 2H), 7.36 (dd, 1 H), 7.48 (t, 1 H), 7.63 (t, 1 H), 7.74 (dt, 1 H), 8.47 (dd, 1 H), 8.52 (d, 1 H), 10.50 (s, 1 H). Example 42
yV-[3-(3-Methylbutoxy)-5-sulfamo lphenyl]-2-(pyridin-3-yl)acetamide
Figure imgf000104_0001
The title compound was prepared according to GP 5.
94.8 mg, 0.251 mmol, 98 % purity
LC-MS (Method C): Rt = 0.89 min; MS (ESIneg): m/z = 376 [M-HJ
1H-NMR (300MHz, DMSO-de) δ [ppm]: 0.87 - 0.99 (m, 6H), 1.63 (q, 2H), 1 .70 - 1 .85 (m, 1 H), 3.71 (s, 2H), 4.00 (t, 2H), 7.06 (t, 1 H), 7.32 (s, 2H), 7.36 (dd, 1 H), 7.46 (t, 1 H), 7.63 (t, 1 H), 7.74 (dt, 1 H), 8.46 (m, 1 H), 8.52 (d, 1 H), 10.49 (s, 1 H).
Example 43
2-(3-{[(2-fluorophenyl)acet l]amino}-5-sulfamoylphenoxy)-N,yV-dimethylacetamide
Figure imgf000104_0002
The title compound was prepared according to GP 5.
32.3 mg, 0.0789 mmol, 99 % purity
LC-MS (Method C): Rt = 0.94 min; MS (ESIneg): m/z = 408 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 2.85 (s, 3H), 2.99 (s, 3H), 3.75 (s, 2H), 4.85 (s, 2H), 7.04 (t, 1 H), 7.14 - 7.23 (m, 2H), 7.28 - 7.43 (m, 5H), 7.73 (t, 1 H), 10.49 (s, 1 H).
Example 44
yV-[3-(2,4-Dichlorophenoxy)-5-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide
Figure imgf000104_0003
The title compound was prepared according to GP 5.
57.1 mg, 0.122 mmol, 99 % purity
LC-MS (Method C): Rt = 1 .55 min; MS (ESIneg): m/z = 467 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.73 (s, 2H), 7.04 (dd, 1 H), 7.13 - 7.21 (m, 2H), 7.28 - 7.38 (m, 3H), 7.40 (t, 1 H), 7.44 (s, 2H), 7.53 (dd, 1 H), 7.85 - 7.89 (m, 2H), 10.59 (s, 1 H).
Example 45
A/-[3-(2,4-Dichlorophenox -5-sulfamoylphenyl]-2-(pyridin-3-yl)acetamide
Figure imgf000105_0001
The title compound was prepared according to GP 5.
74.7 mg, 0.165 mmol, 95 % purity
LC-MS (Method C): Rt = 1 .02 min; MS (ESIneg): m/z = 450 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.70 (s, 2H), 7.04 (dd, 1 H), 7.29 - 7.48 (m, 5H), 7.53 (dd, 1 H), 7.72 (dt, 1 H), 7.86 (t, 2H), 8.46 (dd, 1 H), 8.50 (d, 1 H), 10.60 (s, 1 H).
Example 46
A/-(3-Phenoxy-5-sulfamo lphenyl)-2-(pyridin-3-yl)acetamide
Figure imgf000105_0002
The title compound was prepared according to GP 5.
37.1 mg, 0.0968 mmol, 95 % purity
LC-MS (Method C): Rt = 0.80 min; MS (ESIneg): m/z = 382 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.70 (s, 2H), 7.06 - 7.14 (m, 3H), 7.23 (t, 1 H), 7.35 (ddd, 1 H), 7.39 - 7.50 (m, 5H), 7.72 (dt, 1 H), 7.86 (t, 1 H), 8.46 (dd, 1 H), 8.50 (d, 1 H), 10.59 (s, 1 H). Example 47
2-(Pyridin-3-yl)-W-[3-(pyridin-2- lmethoxy)-5-sulfamoylphenyl]acetamide
Figure imgf000106_0001
The title compound was prepared according to GP 5.
40.5 mg, 0.102 mmol, 96 % purity
LC-MS (Method E): Rt = 0.84 min; MS (ESIneg): m/z = 397 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.72 (s, 2H), 5.20 (s, 2H), 7.18 (t, 1 H), 7.33 - 7.40 (m, 4H), 7.48 - 7.54 (m, 2H), 7.70 - 7.77 (m, 2H), 7.85 (td, 1 H), 8.47 (dd, 1 H), 8.52 (d, 1 H), 8.59 (ddd, 1 H), 10.53 (s, 1 H). Example 48
2-(pyridin-3-yl)-A/-[3-sulfamo l-5-(2,2,2-trifluoroethoxy)phenyl]acetamide
Figure imgf000106_0002
The title compound was prepared according to GP 5.
92.1 mg, 0.237 mmol, 94 % purity
LC-MS (Method C): Rt = 0.69 min; MS (ESIneg): m/z = 388 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.73 (s, 2H), 4.80 (q, 2H), 7.18 (dd, 1 H), 7.32 - 7.43 (m, 3H), 7.57 (t, 1 H), 7.71 - 7.78 (m, 2H), 8.47 (dd, 1 H), 8.53 (d, 1 H), 10.60 (s, 1 H).
Example 49
A/-(3-Ethoxy-5-sulfamoylphenyl)-2-(pyridin-3-yl)acetamide
Figure imgf000107_0001
The title compound was prepared according to GP 5.
54.5 mg, 0.153 mmol, 99 % purity
LC-MS (Method C): Rt = 0.54 min; MS (ESIneg): m/z = 334 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 1 .34 (t, 3H), 3.72 (s, 2H), 4.05 (q, 2H), 7.05 (t, 1 H), 7.34 (s, 2H), 7.37 (dd, 1 H), 7.45 (t, 1 H), 7.65 (s, 1 H), 7.74 (dt, 1 H), 8.47 (dd, 1 H), 8.53 (d, 1 H), 10.51 (s, 1 H).
Example 50
yV-[3-(3-Methylphenox -5-sulfamoylphenyl]-2-(pyridin-3-yl)acetamide
Figure imgf000107_0002
The title compound was prepared according to GP 5.
30.3 mg, 0.0762 mmol, 90 % purity
LC-MS (Method C): Rt = 1 .01 min; MS (ESIneg): m/z = 396 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 2.32 (s, 3H), 3.70 (s, 2H), 6.86 - 6.95 (m, 2H), 7.02 - 7.10 (m, 2H), 7.29 - 7.46 (m, 5H), 7.72 (br d, 1 H), 7.87 (br s, 1 H), 8.44 - 8.53 (m, 2H), 10.59 (s, 1 H).
Example 51
2-(2-Fluorophenyl)-yV-[3- 3-methylphenoxy)-5-sulfamoylphenyl]acetamide
Figure imgf000107_0003
The title compound was prepared according to GP 5. 60.4 mg, 0.146 mmol, 96 % purity
LC-MS (Method C): Rt = 1 .55 min; MS (ESIneg): m/z = 413 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 2.32 (s, 3H), 3.73 (s, 2H), 6.86 - 6.96 (m, 2H), 7.01 - 7.10 (m, 2H), 7.12 - 7.21 (m, 2H), 7.28 - 7.46 (m, 6H), 7.87 (br s, 1 H), 10.56 (s, 1 H).
Example 52
2-(2-Fluorophenyl)-A/-{3-[(1 -methylpiperidin-4-yl)methoxy]-5- sulfamoylphenyl}acetamide
Figure imgf000108_0001
The title compound was prepared according to GP 5.
44.9 mg, 0.103 mmol, 100 % purity
LC-MS (Method C): Rt = 0.85 min; MS (ESIneg): m/z = 434 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 1 .23 - 1 .36 (m, 2H), 1.72 (br d, 2H), 1.86 (br t, 2H), 2.15 (s, 3H), one signal overlapped by solvent, 2.77 (br d, 2H), 3.74 (s, 2H), 3.83 (d, 2H), 7.06 (t, 1 H), 7.14 - 7.22 (m, 2H), 7.28 - 7.43 (m, 4H), 7.48 (t, 1 H), 7.64 (t, 1 H), 10.47 (s,
1 H).
Example 53
A/-[3-(2,2-Dimethylpropox -5-sulfamoylphenyl]-2-(pyridin-3-yl)acetamide
Figure imgf000108_0002
The title compound was prepared according to GP 5.
67.3 mg, 0.178 mmol, 97 % purity
LC-MS (Method C): Rt = 1 .00 min; MS (ESIneg): m/z = 376 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 1 .00 (s, 9H), 3.64 (s, 2H), 3.71 (s, 2H), 7.08 (t, 1 H), 7.31 (s, 2H), 7.37 (dd, 1 H), 7.51 (t, 1 H), 7.62 (t, 1 H), 7.72 - 7.76 (m, 1 H), 8.47 (dd, 1 H), 8.53 (d, 1 H), 10.49 (s, 1 H). Example 54
2-(Pyridin-3-yl)-W-{3-sulfamo l-5-[3-(trifluoromethyl)phenoxy]phenyl}acetamide
Figure imgf000109_0001
The title compound was prepared according to GP5.
85.7 mg, 0.190 mmol, 93 % purity
LC-MS (Method C): Rt = 1 .09 min; MS (ESIneg): m/z = 450 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.72 (s, 2H), 7.15 (s, 1 H), 7.33 - 7.54 (m, 6H), 7.58 - 7.63 (m, 1 H), 7.66 - 7.75 (m, 2H), 7.92 (s, 1 H), 8.47 (br d, 1 H), 8.51 (s, 1 H), 10.63 (s, 1 H). Example 55
2-(2-Fluorophenyl)-yV-{3-sulfamo l-5-[3-(trifluoromethyl)phenoxy]phenyl}acetamide
Figure imgf000109_0002
The title compound was prepared according to GP 5.
39.6 mg, 0.0845 mmol, 97 % purity
LC-MS (Method C): Rt = 1 .09 min; MS (ESIneg): m/z = 467 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 3.74 (s, 2H), 7.12 - 7.22 (m, 3H), 7.27 - 7.54 (m, 7H), 7.61 (br d, 1 H), 7.69 (br t, 1 H), 7.92 (t, 1 H), 10.61 (s, 1 H).
Example 56
2-(2-Fluorophenyl)-yV-[3-(2-methoxy-2-methylpropoxy)-5-sulfamoylphenyl]acetamide
Figure imgf000110_0001
The title compound was prepared according to GP 5.
99.5 mg, 0.242 mmol, 99 % purity
LC-MS (Method C): Rt = 1 .31 min; MS (ESIneg): m/z = 409 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 1 .22 (s, 6H), 3.16 (s, 3H), 3.75 (s, 2H), 3.85 (s, 2H), 7.10 (br s, 1 H), 7.14 - 7.23 (m, 2H), 7.28 - 7.44 (m, 4H), 7.53 (br s, 1 H), 7.64 (br s, 1 H), 10.50 (s, 1 H).
Example 57
W-[3-(2-Methoxy-2-meth lpropoxy)-5-sulfamoylphenyl]-2-(pyridin-3-yl)acetamide
Figure imgf000110_0002
The title compound was prepared according to GP 5.
30.4 mg, 0.0773 mmol, 100 % purity
LC-MS (Method C): Rt = 0.71 min; MS (ESIneg): m/z = 392 [M-H]"
1H-NMR (300MHz, DMSO-de) δ [ppm]: 1 .22 (s, 6H), 3.16 (s, 3H), 3.73 (s, 2H), 3.85 (s, 2H), 7.1 1 (br s, 1 H), 7.32 (br s, 2H), 7.38 (dd, 1 H), 7.52 (br s, 1 H), 7.64 (br s, 1 H), 7.76 (br d, 1 H), 8.48 (br d, 1 H), 8.54 (br s, 1 H), 10.52 (s, 1 H).
Example 58
2-(2-Chlorophenyl)-A/-[3-(2-oxopyridin-1 (2H)-yl)-5-sulfamoylphenyl]acetamide
Figure imgf000111_0001
/V-{3-Bromo-5-[(2,4-dimethoxybenzyl)sufe (90 mg, 0.163 mmol), pyridin-2(1 /-/)-one (21.6 mg, 0.228 mmol), copper (I) iodide (1 .6 mg, 0.008 mmol) and potassium carbonate (44.9 mg, 355 mg) were added to a dry vial that was flushed with argon. Then, toluene (1 mL) and dimethylformamide (3.5 mL) were added, followed by addition of (1 S,2S)-/V,/V-dimethylcyclohexane-1 ,2-diamine (2.2 mg, 0.016 mmol). The reaction mixture was stirred at 120°C overnight. Pyridin-2(1 /-/)-one (9 mg), potassium carbonate (15 mg) and (1 S,2S)-/V,/V'-dimethylcyclohexane-1 ,2-diamine (two drops) were added and stirring at 120°C was continued overnight. Further ten drops (1 S,2S)-/V,/V-dimethylcyclohexane-1 ,2-diamine were added and stirring was continued over a weekend. After cooling to room temperature, any solid was removed by filtration. The filtrate was extracted with water and ethyl acetate. The organic phase was reextracted with ethyl acetate and the combined organic phases were dried over sodium sulfate and were concentrated in vacuo to give crude 2-(2-chlorophenyl)-/V-{3-[(2,4- dimethoxybenzyl)sulfamoyl]-5-(2-oxopyridin-1 (2/-/)-yl)phenyl}acetamide.
The crude intermediate from the previous step was redissolved in dichloromethane (5 mL) and trifluoroacetic acid (903 mg, 7.92 mmol) was added. After stirring at room temperature for 2 hours, water was added. The aqueous phase was reextracted with dichloromethane and the combined organic phases were dried over sodium sulfate and were concentrated. Purification by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) gave the title compound (6 mg, 0.0144 mmol, 9 % yield over 2 steps, 85 % purity).
LC-MS (Method A): Rt = 0.89 min; MS (ESIpos): m/z = 418 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.88 (s, 2H), 6.35 (td, 1 H), 6.50 (d, 1 H), 7.25 - 7.55 (m, 8H), 7.62 - 7.68 (m, 1 H), 7.84 (t, 1 H), 8.18 (t, 1 H), 10.74 (s, 1 H).
Example 59
yV-(3'-Chloro-5-sulfamoylbiphenyl-3-yl)-2-(pyridin-2-yl)acetamide
Figure imgf000112_0001
According to GP3.2 and GP2.1 5-amino-3'-chloro-/V-(2,4-dimethoxybenzyl)biphenyl-3- sulfonamide (166 mg, 383 μηηοΙ) and pyridin-2-ylacetic acid (63.1 mg, 460 μηηοΙ) were converted without purification of the intermediates to the title compound. The pure product was obtained after preparative HPLC (Waters XBridge C18 5μ 100x30mm,
acetonitrile/water + 0.2% aqueous ammonia (32%)) (13.1 mg, 95 % purity, 8 % yield over 2 steps).
LC-MS (Method B): Rt = 0.95 min; MS (ESIpos): m/z = 402 [M+H]+
1H-NMR (400MHz, DMSO-d6) δ [ppm]: 3.89 (s, 2H), 7.26 - 7.30 (m, 1 H), 7.38 - 7.44 (m, 3H), 7.49 - 7.62 (m, 3H), 7.67 (t, 1 H), 7.77 (td, 1 H), 7.80 (t, 1 H), 8.10 (t, 1 H), 8.17 (t, 1 H), 8.50 (dd, 1 H), 10.64 (s, 1 H).
Example 60
W-[3-(1 -Methyl-1 H^yrazol-4-yl)-5-sulfamoylphenyl]-2-(pyridin-2-yl)acetamide
Figure imgf000112_0002
H 3
According to GP3.2 and GP2.1 3-amino-/V-(2,4-dimethoxybenzyl)-5-(1 -methyl-1 H-pyrazol- 4-yl)benzenesulfonamide (165 mg, 410 μηηοΙ) and pyridin-2-ylacetic acid (67.5 mg, 492 μηηοΙ) were converted without purification of the intermediates to the title compound. The pure product was obtained after preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.2% aqueous ammonia (32%)). The HPLC fractions were dissolved in DCM and methanol was added until a clear solution was obtained. The organic phase was washed with brine. The organic phase was dried over Whatmanfilter and the solvent was removed under reduced pressure. The residue was was purified by column chromatography on a Biotage Isolera system (silica gel) to yield the title compound (1.1 mg, 95 % purity, 1 % yield over 2 steps).
LC-MS (Method B): Rt = 0.58 min; MS (ESIpos): m/z = 372 [M+H]+
1H-NMR (400MHz, CD3OD) δ [ppm]: 3.85 - 4.05 (m, 5H), 7.29 - 7.43 (m, 1 H), 7.48 - 7.60 (m, 1 H), 7.81 (t, 1 H), 7.84 - 7.89 (m, 2H), 7.98 - 8.01 (m, 1 H), 8.02 - 8.06 (m, 2H), 8.47 - 8.65 (m, 1 H).
BIOLOGICAL ASSAYS
The following assays can be used to illustrate the commercial utility of the compounds according to the present invention.
Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average (avg) values or as median values, wherein
- the average value, also referred to as the arithmetic mean value, represents the sum of the obtained values divided by the number of values obtained, and
- the median value represents the middle number of the group of obtained values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.
When no meaningful calculation of average values or median values is possible due to the existence of measurement values falling outside the detection range of the assay
(indicated by < or > in the tables below) all individual measurement values are indicated. Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.
IN VITRO STUDIES
Human P2X4 HEK Cell FLIPR Assay
HEK293 cells stably expressing human P2X4 were plated in poly-D-lysine-coated 384- well plates at a seeding density of 30000 cells/well and incubated overnight. P2X4 function was assessed by measuring intracellular calcium changes using the calcium- chelating dye Fluo8-AM (Molecular Devices) on a fluorescent imaging plate reader (FLEX/FLIPR station; Molecular Devices). On the day of the assay, the medium was removed and the cells were incubated for 30 min at 37°C and 5% CO2 in 30 μΙ_ of dye buffer (Hank's balanced salt solution, 10 mM HEPES, 1 .8 mM CaC , 1 mM MgC , 2 mM probenecid, 5mM D-glucose monohydrate, 5μΜ Fluo8-AM, pH=7.4). Compounds diluted in probenecid buffer (Hank's balanced salt solution, 10 mM HEPES, 1.8 mM CaC , 1 mM MgC , 2 mM probenecid, 5mM D-glucose monohydrate, pH=7.4) were added in a volume of 10 μΙ_ and allowed to incubate for 30 min at room temperature. The final assay DMSO concentration was 0.5%. The agonist, Bz-ATP (Tocris), was added in a volume of 10 μΙ_ at a concentration representing the ECso value. The ECso value of Bz-ATP was determined each assay day prior to compound profiling. The fluorescence was measured for an interval of 120 sec at 2 sec intervals. The excitation and emission wavelengths used to monitor fluorescence were 470-495 nm and 515-575 nm, respectively. The data was analyzed based on the increase in peak relative fluorescence units (RFU) compared to the basal fluorescence and the data was normalized to the agonist control. The compounds were tested in triplicates per plate and mean values were plotted in Excel XLFit to determine I C50 values, percentage of maximal inhibition and the Hill coefficients.
Human P2X4 HEK Human P2X4 HEK
Example Number Cells (FLIPR Assay) Cells (FLIPR Assay) avg IC50 [nM] avg Efficacy [%]
1 37 90
2 90 81
3 18 90
4 70 87
5 47 98
6 27 93
7 6 108
8 7 104
9 31 87
10 1543 75
1 1 153 78
12 1359 79
13 2330 91
14 7667 62
15 12 97
16 14 86
17 435 90
18 >25000 25
19 185 87 20 13106 58
21 34 87
22 57 67
23 28 96
24 37 95
25 39 79
26 42 90
27 45 87
28 56 83
29 57 79
30 80 75
31 97 102
32 109 84
33 1 14 90
34 1 18 97
35 186 87
36 194 90
37 189 93
38 201 98
39 224 90
40 276 88
41 306 100
42 452 90
43 492 96
44 1083 90
45 1688 89
46 2599 94
47 5192 81
48 9502 76
49 16832 63
50 379 93
51 54 95
52 4747 82 53 70 102
54 63 85
55 258 76
56 26 101
57 1701 95
58 1 10 94
59 101 81
60 >25000 34
Human P2X4 HEK Cell Elektophysiology Assay Electrophysiology Assay
Cell culture conditions: HEK-293 mito-Photina pcDNA3(neo-)/pPURO N/pcDNA3_P2RX4, clone 2a/4 (HEK-293 mito-Photina/hP2RX4) cells are cultured in EMEM Minimum Essential Medium Eagle with Earl's salts Balanced Salt Solution (BioWhittaker cat. BE12-125F) supplemented with 5 mL of 200 mM Ultraglutaminel (BioWhittaker cat. BE17-605E/U1 ), 5 mL of 100X Penicillin/Streptomycin (BioWhittaker cat. DE17-602E; final concentration 1 %), 4 mL of 50 mg/mL G418 (Sigma cat. G8168- 100mL; final concentration 400 μg mL), 10 μί of 10 mg/mL Puromicin (InvivoGen cat. ant-pr-1 ; final concentration 0,2 μg/mL) and 50 mL of Fetal Bovine Serum (Sigma cat. F7524; final concentration 10%).
Experimental protocol: HEK-293 cell lines are seeded 72 or 96 hours before experiment, at a concentration of 5 or 2.5 million cells, respectively onto a T225 flask. Just before the experiments cells are washed twice with D-PBS w/o Ca2+/Mg2+ (Euroclone cat. ECB4004L) and detached from the flask with trypsin-EDTA (Sigma, cat. T4174 diluted 1/10). Cells are then re-suspended in the suspension solution: 25 mL EX-CELL ACF CHO medium (Sigma, cat. C5467); 0.625 mL HEPES (BioWhittaker, cat. BE17-737E); 0.25 mL of 100x Penicillin/Streptomycin (BioWhittaker, cat. DE17-602E), 0.1 mL of Soybean Trypsin Inhibitor 10 mg/mL (Sigma, cat. T6522) and placed on the QPatch 16X.
Compound preparation and storage: Compound stock solutions (10 mM; 100% DMSO; stored at -20°C) are used. Fresh solutions from stock (1 or 3 mM, 100% DMSO) are prepared just before the experiments (0.1 % final DMSO concentration).
DMSO solution is obtained from SIGMA (cat.# D-5879) and stored at room temperature. Patch clamp analysis with QPatch16X (Figure 1): Standard whole-cell voltage clamp experiments are performed at room temperature using the multihole technology.
For the voltage clamp experiments on hP2X4, data are sampled at 2 KHz. After establishment of the seal and the passage in the whole cell configuration, the cells are held at -90 mV and the hP2X4 current is evoked by the agonist in the absence (vehicle period, i.e. 0.1 % DMSO) or in the presence of the compound under investigation at increasing concentrations; see the application protocol in Figure 1.
Output: the maximum inward current induced by the agonist (ATP 5 microM).
The intracellular solution contains (mM) 135 CsF, 10 NaCI, 1 EGTA, 10 HEPES (pH 7.2 with CsOH) whereas the extracellular solution (mM) 145 NaCI, 4 KCI, 0.5 MgCI2, 1 CaCI2,
10 HEPES, 10 Glucose (pH 7.4 with NaOH).
EX VIVO STUDIES
Human Monocyte P2X4 Assay
The principle of the assay is to measure calcium influx through endogenous P2X4 channels into primary human monocytes, following activation by 2',3'-0-(4-benzoyl- benzoyl)-ATP (Bz-ATP). Intracellular calcium concentration changes are measured with a FliprTM (Molecular Devices) device using a calcium sensitive dye (Fluo-8). In primary monocytes P2X4 is located at the lysosome membrane, therefore exocytosis has to be triggered to expose P2X4 at the cellular membrane.
Human peripheral blood mononuclear cells (PBMCs) from anticoagulated blood (blood cells, BC) are isolated via density gradient centrifugation. Whole blood is diluted 1 :3 with PBS. Samples of 30 mL are layered carefully on top of 15 mL Biocoll (BIOCHROM) in 50 mL centrifuge tubes (Falcon). Tubes are centrifuged at 914 xg for 25 min at RT without brake. The PBMC layer is removed with a 10 mL pipette and transferred into tubes with ice-cold PBS in a total volume of 50 mL. Cells are washed twice by pelleting at 300 xg at 4°C, for 10 min and for 5 min respectively. PBMCs are re-suspended in 10 mL medium (X-vivo, Biozym Scientific) and counted in a Neubauer chamber.
Monocytes are isolated by negative selection using the Monocyte isolation kit II from Miltenyi (#130-091 -153) according to the instructions. Isolation should be done fast and cells and solutions should be kept on ice at any time. PBMCs in batches of 10exp8 cells are pelleted (300 xg, 10 min) and re-suspended with 300 μί MACS buffer in a 50 mL Falcon tube. FcR Blocking reagent (100μΙ) and Biotin-Ab (100μΙ) are added, mixed and incubated on ice for 10 min. MACS buffer (300 μί) and anti-Biotin Micro-beads (100 μί) are added, mixed and incubated on ice for 15 min. Cells are washed by pelleting (300 xg for 10 min) and re-suspended in 500 μΙ_ MACS buffer. For each batch one separation column is placed in the MACS separator and rinsed with 3 mL MACS buffer. The cell suspension is added to the column, followed by 3 x 3 mL MACS buffer for washing, and the eluent containing the monocytes is collected. Cells were pelleted (300 xg for 10 min), re-suspended in X-vivo medium and counted. Monocytes are seeded into fibronectin- coated micro-plates (384-well, black, flat transparent bottom; Corning #3848) at a density of 30,000 cells/well in 50 μΙ_, and cultivated over night (37°C, 5% C02).
Test substances are dissolved in 100% DMSO at a stock concentration of 10 mM and stored at -20°C in aliquots. Serial dilutions (2x) are prepared in DMSO and diluted 500x with assay buffer to generate the antagonist plate. In the Flipr measurement, 10 μΙ_ per well are transferred (4x dilution) and a final top concentrations of 5 μΜ and 0.05% DMSO are obtained in the assay. Agonist BzATP is stored at 10 mM in aliquots and diluted to an intermediate concentration of 15 μΜ to generate the agonist plate. In the Flipr measurement, 10 μΙ_ per well are transferred (5x dilution) so that a final assay concentration of 3 μΜ is obtained.
For the experiment, the medium of the cell plate is discarded manually and 70 L/well loading buffer is added and incubated for 1 h (37°C, 5% CO2). Loading buffer contained HBSS (w/o calcium/magnesium), 10 mM Hepes pH 7.4, 5 μΜ Fluo-8 (AM) (Tebu-bio) and 50 mM methylamine (Sigma) to trigger exocytosis. Loading buffer is discarded manually and 30 ^UweW low-calcium assay buffer (5 mM KCI, 145 mM NaCI, 0.5 mM CaCI2, 13 mM glucose, 10 mM Hepes pH 7.4) is added. The antagonist plate is transferred (10 [\Uwe\\) and after 15 min at RT the agonist plate (10 [\Uwe\\) is transferred.
Agonist addition is recorded for 240 seconds after a 10 second baseline. For analysis, a baseline correction is applied, and the maximum of the curve is extracted. Data are normalized towards 0% inhibition (signal at 3 μΜ BzATP) and 100% inhibition (absence of BzATP stimulation) and fitted with a four-parameter sigmoidal inhibition curve using Prism GraphPad to obtain IC50 values.
Human Whole Blood P2X4 Assay
In this assay, ex vivo, the blood of healthy female volunteers is first sensitized with lipopolysacharide (LPS) and then stimulated with ATP to trigger the release of Interleukin 1 beta (I L-1 β). In this system, the efficacy of P2X4 antagonists on the production of I L-1 β in whole blood is tested. The cells are first treated with 100 ng/ml LPS for 2h and then stimulated with 3mM ATP and treated in triplicates with the test compounds at different concentrations. After 1 h incubation, supernatant is taken and following centrifugation I L-1 β in the supernatant is assayed using standard ELISA kits. The assay is performed with blood from different donors
IN VIVO STUDIES
CFA Inflammation Model in Mice with Pain Behaviour Read Out
Wild type female C57BL/6 mice (Taconic) receive intraplantar injection of complete Freund's adjuvant (CFA) (30 μΙ_, 1 mg/mL, Sigma) into the left hind paw under isoflurane anesthesia. Animals are administered orally on day 2 post-CFA injection. Spontaneous pain-related behavior in freely moving animals is assessed using the automated dynamic weight bearing device (DWB, Bioseb, France) one hour after compound treatment according to published and validated protocols (Robinson et al., 2012; Tetreault et al., 201 1 ; Gruen et al. 2014). For behavioral testing, the animal is placed inside a Plexiglas chamber in which the exerted pressure on the floor is measured. The animals are allowed to move freely within the apparatus for 5 min and subsequently pain behavior is recorded for a test period of another 5 min. The relative weight distribution is calculated by determining the ratio of the weight put on naive (contralateral) vs. that put on the intraplantar CFA treated (ipsilateral) paws.
CFA-lnduced Mechanical Hyperalgesia Model in Rat
Male Sprague Dawley rats are used. Mechanical hyperalgesia is induced by injecting 25 μΙ_ of Complete Freund's Adjuvant (CFA) into the plantar surface of the left hind paw. Mechanical hyperalgesia is measured using the Pressure Application Measurement apparatus (Ugo Basile, Gemonio, Italy). Briefly, a linearly increasing pressure is applied to an area of approximately 50 mm2 of the plantar side of the hind paw, until a behavioural response (paw withdrawal) is observed or until the pressure reaches 1000 gf. The pressure at which the behavioural response occurres is recorded as the Paw Withdrawal Threshold (PWT). Both CFA-injected and contralateral PWTs are determined for each rat, in each treatment group and at each time point of the studies. Rats receive 3 oral doses of test compound at approximately 12 hours interval starting 1 hour prior to CFA injection. Mechanical hyperalgesia testing is performed 2 hours before CFA injection and 2 hours after the last dosing.

Claims

A compound of formula (I)
Figure imgf000120_0001
represents a group selected from
Figure imgf000120_0002
wherein * indicates the point of attachment of said group with the rest of the molecule;
R2 represents phenyl, heteroaryl, 2-oxopyridin-1 (2H)-yl, R9R10N(C=O)- or R120-,
wherein said phenyl or heteroaryl groups are optionally substituted one to three times with R11, being, independently from each other, the same or different, or
substituted with two adjacent substituents R11 which together represent a methylendioxy group to form a 5-membered ring;
R2a represents hydrogen, cyano, nitro, halogen, Ci-C2-alkyl or Ci-C2-haloalkyl; R2b represents hydrogen, halogen, Ci-C2-alkyl or Ci-C2-haloalkyl;
R2c represents hydrogen, halogen, Ci-C2-alkyl or Ci-C2-haloalkyl,
wherein not less than one of R2a, R2b and R2c represents hydrogen;
R3 represents hydrogen or fluoro; R4 represents hydrogen, fluoro, methyl or OH;
R5 represents hydrogen or Ci-C3-alkyl;
R6 represents hydrogen, halogen, cyano, nitro, OH , Ci-C4-alkyl, C1-C4- haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy or F3CS-;
R6a and R6b are the same or different and represent, independently from each
other, respectively
R6a hydrogen, halogen, hydroxy, nitro, cyano, Ci-C4-alkyl, C3-C6-cycloalkyl,
Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, HO-(C2-C4-alkoxy)-,
(Ci-C4-alkoxy)-(C2-C4-alkoxy)-, R9R10N-, R8-C(0)-NH-, R8-C(0)-,
R8-0-C(0)-, R9R10N-C(O)- or (Ci-C4-alkyl)-S02-;
R6b hydrogen, halogen, hydroxy, nitro, cyano, Ci-C4-alkyl, C3-C6-cycloalkyl,
Ci-C4-haloalkyl, Ci-C4-haloalkoxy, HO-(C2-C4-alkoxy)-,
(Ci-C4-alkoxy)-(C2-C4-alkoxy)-, R9R10N-, R8-C(0)-NH-, R8-C(0)-,
R8-0-C(0)-, R9R10N-C(O)- or (Ci-C4-alkyl)-S02-; or
R6a and R6b adjacent to each other together represent a group selected from
-0-CH2-CH2-, -0-CH2-0- or -0-CH2-CH2-0-;
R7a, R7b and R7c are the same or different and represent, independently from each other, hydrogen, hydroxy, halogen, Ci-C4-alkyl or Ci-C4-haloalkyl;
R8 represents, independently from each respective occurence, hydrogen,
Ci-C6-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, C3-C6-cycloalkyl or Ci-C4-haloalkyl; R9 and R10 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-methyl,
C2-C4-haloalkyl or (CH3)2N-Ci-C4-alkyl or together with the nitrogen atom to which they are attached form a
4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C6-alkyl or Ci-C6-haloalkyl group and being optionally substituted, one to three times, independently from each other, with halogen or Ci-C4-alkyl;
R11 represents, independently from each other, halogen, hydroxy, nitro, cyano, Ci-C4-alkyl, C2-C4-alkenyl, Ci-C4-haloalkyl, Ci-C6-hydroxyalkyl,
Ci-C4-alkoxy, Ci-C4-haloalkoxy, (Ci-C4-alkoxy)-(Ci-C4-alkyl)-,
(Ci-C4-haloalkoxy)-(Ci-C4-alkyl)-, R9R10N-(Ci-C4-alkyl)-, R9R10N-,
R8-C(0)-NH-, R8-C(0)-, R8-0-C(0)-, R9R10N-C(O)-, (Ci-C4-alkyl)-S-, (Ci-C4-alkyl)-S02-, C3-C6-cycloalkyl or 4- to 6-membered heterocycloalkyl; R12 represents Ci-C6-alkyl, Ci-C4-haloalkyl, (Ci-C4-alkoxy)-(Ci-C4-alkyl)-, phenyl, heteroaryl, phenyl-Ci-C4-alkyl, heteroaryl-Ci-C4-alkyl, 4- to 6- membered heterocycloalkyl-(Ci-C4-alkyl)-, R9R10N-C(O)-(Ci-C4-alkyl)-; wherein said phenyl or heteroaryl groups are optionally substituted one to three times with R11, being, independently from each other, the same or different, or
substituted with two adjacent substituents R11 which together represent a methylendioxy group to form a 5-membered ring;
or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
2. A compound of formula (I) according to claim 1 , characterized in that
R1 represents a group selected from:
Figure imgf000122_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;
R2 represents phenyl, heteroaryl, 2-oxopyridin-1 (2H)-yl or R120-,
wherein said phenyl or heteroaryl groups are optionally substituted one to three times with R11, being, independently from each other, the same or different, or
substituted with two adjacent substituents R11 which together represent a methylendioxy group to form a 5-membered ring;
R2a represents hydrogen, halogen; R2b; R2c represents hydrogen;
R3; R4; R5 represents hydrogen;
R6 represents hydrogen, halogen, Ci-C4-alkyl, Ci-C4-haloalkyl;
R6a and R6b are the same or different and represent, independently from each other, respectively hydrogen or halogen;
R7a, R7b and R7c represent hydrogen;
R8 represents, independently from each respective occurrence, hydrogen, d-Ce-alkyl; R9 and R10 are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-methyl, or together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NRa in which Ra represents a Ci-C6-alkyl or C2-C6-haloalkyl group and being optionally substituted, one to three times, independently from each other, with halogen or Ci-C4-alkyl;
R11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl,
R8-0-C(0)-, R9R10N-C(O)-, Cs-Ce-cycloalkyl or 4- to 6-membered heterocycloalkyl;
R12 represents Ci-C6-alkyl, Ci-C4-haloalkyl, (Ci-C4-alkoxy)-(Ci-C4-alkyl)-,
phenyl, heteroaryl, phenyl-Ci-C4-alkyl, heteroaryl-Ci-C4-alkyl, 4- to 6- membered heterocycloalkyl-(Ci-C4-alkyl)-, R9R10N-C(O)-(Ci-C4-alkyl)-; wherein said phenyl or heteroaryl groups are optionally substituted one to three times with R11, being, independently from each other, the same or different, or
substituted with two adjacent substituents R11 which together represent a methylendioxy group to form a 5-membered ring;
or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
3. A compound of formula (I) according to claim 1 or 2, characterized in that
R1 represents a group selected from:
Figure imgf000123_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;
represents phenyl, heteroaryl, 2-oxopyridin-1 (2H)-yl or R120-, wherein said phenyl or heteroaryl groups are optionally substituted one to three times with R11, being, independently from each other, the same or different;
R2a represents hydrogen or halogen; R2b; R2c represent hydrogen;
R3; R4; R5 represent hydrogen;
R6 represents hydrogen, halogen, trifluoromethyl;
R6a and R6b are the same or different and represent, independently from each
other, respectively R6a R6b hydrogen, halogen;
R7a and R7b represent hydrogen;
R8 represents hydrogen;
R9 and R10 are the same or different and represent, independently from each other, hydrogen, cyclopropylmethyl or together with the nitrogen atom to which they are attached form a
5-membered nitrogen containing heterocyclic ring, being optionally substituted, one to three times, independently from each other, with halogen;
R11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R8-0-C(0)-, R9R10N-C(O)-cyclopropyl or tetrahydro-2H-pyran-2- yi;
R12 represents Ci-C6-alkyl, Ci-C4-haloalkyl, methoxy-(Ci-C4-alkyl)-, phenyl, phenylmethyl, pyridylmethyl, (1 -methylpiperidin-4-yl)methyl, (CH3)2N-C(0)- CH2-; wherein said phenyl groups are optionally substituted one to two times with halogen, methyl or trifluoromethyl, being, independently from each other, the same or different;
or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
4. A compound of formula (I) according to claim 1 to 3, characterized in that
R1 represents a group selected from:
Figure imgf000125_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;
R2 represents phenyl, pyridyl, pyrazolyl, oxazolyl, 2-oxopyridin-1 (2H)-yl or R120-,
wherein said phenyl, pyridyl, pyrazolyl or isoxazolyl groups are optionally substituted one to two times with R11, being, independently from each other, the same or different;
R2a; R2b; R2c represent hydrogen;
R3; R4; R5 represent hydrogen;
R6 represents hydrogen, fluoro or chloro; R6a represents hydrogen or fluoro; R6b represents hydrogen;
R7a and R7b represent hydrogen;
R8 represents hydrogen;
R9 and R10 are different and represent hydrogen and cyclopropyl-methyl or together with the nitrogen atom to which they are attached form a
5-membered nitrogen containing heterocyclic ring, being optionally substituted, one to two times, with fluoro;
R11 represents, independently from each other, fluoro, chloro, methyl,
difluoromethyl, trifluoromethyl, R8-0-C(0)-, R9R10N-C(O)-, cyclopropyl or tetrahydro-2H-pyran-2-yl;
R12 represents C2-C5-alkyl, C2-C4-haloalkyl, phenyl, phenylmethyl, 2- pyridylmethyl; wherein said phenyl groups are optionally substituted one to two times with fluoro, chloro or methyl, being, independently from each other, the same or different;
or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
5. A compound of formula (I) according to claim 1 to 4, characterized in that
Figure imgf000126_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;and
R6 represents hydrogen or halogen;
R6a represents hydrogen or halogen; R6b hydrogen;
R3; R4, and R5 represents hydrogen.
6. A compound of formula (I) according to claim 1 to 4, characterized in that
R1 represents a group selected from:
Figure imgf000126_0002
wherein * indicates the point of attachment of said group with the rest of the molecule;
R7a and R7b represent hydrogen fluoro, or chloro,
R3; R4, and R5 represents hydrogen.
7. A compound of formula (I) according to claim 1 to 3, characterized in that
R2 represents phenyl, pyridyl, isoxazolyl, pyrazolyl, 2-oxopyridin-1 (2H)-yl or R120-, wherein said phenyl, pyridyl, isoxazolyl or pyrazolyl groups are optionally substituted one to three times with R11, being, independently from each other, the same or different; wherin
R11 represents, independently from each other, halogen, Ci-C4-alkyl, C1-C4- haloalkyl, R8-0-C(0)-, R9R10N-C(O)-, C3-C6-cycloalkyl or 4- to 6-membered heterocycloalkyl; R8 in the occurrence defining R11, represents, hydrogen,
Ci-C6-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, C3-C6-cycloalkyl or Ci-C4-haloalkyl;
R9 and R10 are are different and represent hydrogen and cyclopropyl-methyl or together with the nitrogen atom to which they are attached form a
5-membered nitrogen containing heterocyclic ring, being optionally substituted, one to two times, with fluoro; and wherein
R12 represents C2-C5-alkyl, C2-C4-haloalkyl, phenyl, phenylmethyl, 2- pyridylmethyl; wherein said phenyl groups are optionally substituted one to two times with fluoro, chloro or methyl, being, independently from each other, the same or different.
8. A compound according to claim 1 to 7 selected from the following list:
2-(2-Chlorophenyl)-N-[3-(5-chloropyridin-3-yl)-5-sulfamoylphenyl]acetamide
2-(2-Chlorophenyl)-N-[3-(1 -cyclopropyl-1 H-pyrazol-4-yl)-5- sulfamoylphenyl]acetamide
2-(2-Chlorophenyl)-N-[3-(3,5-dimethyl-1 ,2-oxazol-4-yl)-5- sulfamoylphenyl]acetamide
2-(2-Chlorophenyl)-N-{3-[1 -(difluoromethyl)-1 H-pyrazol-4-yl]-5- sulfamoylphenyljacetamide
3'-{[(2-Chlorophenyl)acetyl]amino}-6-fluoro-5'-sulfamoylbiphenyl-3-carboxylic acid
3'-{[(2-Chlorophenyl)acetyl]amino}-N-(cyclopropylmethyl)-6-fluoro-5'- sulfamoylbiphenyl-3-carboxamide
2-(2-Chlorophenyl)-N-{5'-[(3,3-difluoropyrrolidin-1 -yl)carbonyl]-2'-fluoro-5- sulfamoylbiphenyl-3-yl}acetamide
2-(2-Chlorophenyl)-N-{3-sulfamoyl-5-[1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazol-5- yl]phenyl}acetamide
2-(2-Chlorophenyl)-N-[3-(1 H-pyrazol-5-yl)-5-sulfamoylphenyl]acetamide N-[3-(3-Chlorophenoxy)-5-sulfamoylphenyl]-2-[4-(trifluoromethyl)phenyl]acetamide 2-(2-Chloro-6-fluorophenyl)-N-[3-(3-chlorophenoxy)-5-sulfamoylphenyl]acetamide
2-(4-Bromophenyl)-N-[3-(3-chlorophenoxy)-5-sulfamoylphenyl]acetamide
N-[3-(3-Chlorophenoxy)-5-sulfamoylphenyl]-2-[2-chloro-4- (trifluoromethyl)phenyl]acetamide
N-[4-Bromo-3-(3-chlorophenoxy)-5-sulfamoylphenyl]-2-[4- (trifluoromethyl)phenyl]acetamide
2-Phenyl-N-[3-(pyridin-3-yl)-5-sulfamoylphenyl]acetamide
2-(2-Chlorophenyl)-N-[3-(pyridin-3-yl)-5-sulfamoylphenyl]acetamide
N-[3-(1 -Methyl-1 H-pyrazol-4-yl)-5-sulfamoylphenyl]-2-phenylacetamide
2-(2-Chlorophenyl)-N-[3-(1 -methyl-1 H-pyrazol-4-yl)-5-sulfamoylphenyl]acetamide
2-(2-Chlorophenyl)-N-(3'-chloro-5-sulfamoylbiphenyl-3-yl)acetamide
N-(3'-Chloro-5-sulfamoylbiphenyl-3-yl)-2-phenylacetamide
N-[3-(3-Chlorophenoxy)-5-sulfamoylphenyl]-2-phenylacetamide
N-[3-(3-Chlorophenoxy)-5-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide
N-[3-(2-Fluoro-2-methylpropoxy )-5-sulfamoylphenyl]-2-(2 -fluorophenyl )acetamide
2-(2-Fluorophenyl)-N-[3-(3-methylbutoxy)-5-sulfamoylphenyl]acetamide
N-{3-[(3-Methylbenzyl)oxy]-5-sulfamoylphenyl}-2-(pyridin-3-yl)acetamide
2-(2-Fluorophenyl)-N-[3-(pyridin-2-ylmethoxy)-5-sulfamoylphenyl]acetamide
N-[3-(3-Fluorophenoxy)-5-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide
2-(2-Fluorophenyl)-N-[3-(2-methylpropoxy)-5-sulfamoylphenyl]acetamide
N-{3-[(4-Fluorobenzyl)oxy]-5-sulfamoylphenyl}-2-(2-fluorophenyl)acetamide
N-{3-[(4-Fluorobenzyl)oxy]-5-sulfamoylphenyl}-2-(pyridin-3-yl)acetamide
2-(2-Fluorophenyl)-N-(3-phenoxy-5-sulfamoylphenyl)acetamide N-{3-[(2-Fluoro-4-methylbenzyl)oxy]-5-sulfamoylphenyl}-2-(2- fluorophenyl)acetamide
N-[3-(4-Fluorophenoxy)-5-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide
2-(2-Fluorophenyl)-N-{3-[(3-methylbenzyl)oxy]-5-sulfamoylphenyl}acetamide
N-[3-(4-Fluorophenoxy)-5-sulfamoylphenyl]-2-(pyridin-3-yl)acetamide
2-(2-Fluorophenyl)-N-[3-sulfamoyl-5-(2,2,2-trifluoroethoxy)phenyl]acetamide
N-[3-(2-Fluoro-2-methylpropoxy)-5-sulfamoylphenyl]-2-(pyridin-3-yl)acetamide
N-(3-Ethoxy-5-sulfamoylphenyl)-2-(2-fluorophenyl)acetamide
N-{3-[(2-Fluoro-4-methylbenzyl)oxy]-5-sulfamoylphenyl}-2-(pyridin-3-yl)acetamide
N-[3-(3-Fluorophenoxy)-5-sulfamoylphenyl]-2-(pyridin-3-yl)acetamide
N-[3-(2-Methylpropoxy)-5-sulfamoylphenyl]-2-(pyridin-3-yl)acetamide
N-[3-(3-Methylbutoxy)-5-sulfamoylphenyl]-2-(pyridin-3-yl)acetamide
2-(3-{[(2-fluorophenyl)acetyl]amino}-5-sulfamoylphenoxy)-N,N-dimethylacetamide
N-[3-(2,4-Dichlorophenoxy)-5-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide
N-[3-(2,4-Dichlorophenoxy)-5-sulfamoylphenyl]-2-(pyridin-3-yl)acetamide
N-(3-Phenoxy-5-sulfamoylphenyl)-2-(pyridin-3-yl)acetamide
2-(Pyridin-3-yl)-N-[3-(pyridin-2-ylmethoxy)-5-sulfamoylphenyl]acetamide
2-(pyridin-3-yl)-N-[3-sulfamoyl-5-(2,2,2-trifluoroethoxy)phenyl]acetamide
N-(3-Ethoxy-5-sulfamoylphenyl)-2-(pyridin-3-yl)acetamide
N-[3-(3-Methylphenoxy)-5-sulfamoylphenyl]-2-(pyridin-3-yl)acetamide
2-(2-Fluorophenyl)-N-[3-(3-methylphenoxy)-5-sulfamoylphenyl]acetamide
2-(2-Fluorophenyl)-N-{3-[(1 -methylpiperidin-4-yl)methoxy]-5- sulfamoylphenyl}acetamide N-[3-(2,2-Dimethylpropoxy)-5-sulfamoylphenyl]-2-(pyridin-3-yl)acetamide
2-(Pyridin-3-yl)-N-{3-sulfamoyl-5-[3-(trifluoromethyl)phenoxy]phenyl}acetamide
2-(2-Fluorophenyl)-N-{3-sulfamoyl-5-[3-(trifluoromethyl)phenoxy]phenyl}acetamide
2-(2-Fluorophenyl)-N-[3-(2-methoxy-2-methylpropoxy)-5- sulfamoylphenyl]acetamide
N-[3-(2-Methoxy-2-methylpropoxy)-5-sulfamoylphenyl]-2-(pyridin-3-yl)acetamide 2-(2-Chlorophenyl)-N-[3-(2-oxopyridin-1 (2H)-yl)-5-sulfamoylphenyl]acetamide N-(3'-Chloro-5-sulfamoylbiphenyl-3-yl)-2-(pyridin-2-yl)acetamide N-[3-(1 -Methyl-1 H-pyrazol-4-yl)-5-sulfamoylphenyl]-2-(pyridin-2-yl)acetamide
9. A compound of general formula I, or a stereoisomer, a tautomer, an N oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 8, for use in the treatment or prophylaxis of a disease.
10. Use of a compound of general formula I, or a stereoisomer, a tautomer, an N
oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 8, for the prophylaxis or treatment of a disease.
1 1 . Use of a compound of general formula I, or a stereoisomer, a tautomer, an N
oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 8, for the preparation of a medicament for the prophylaxis or treatment of a disease.
12. Use according to claims 9 to 1 1 , wherein said disease is a genitourinary, gastrointestinal, proliferative or pain-related disease, condition or disorder; cancer; fibrotic diseases including lung fibrosis, heart fibrosis, kidney fibrosis and fibrosis of other organs; gynaecological diseases including dysmenorrhea, dyspareunia, endometriosis and adenomyosis; endometriosis-associated pain; endometriosis- associated symptoms, wherein said symptoms are in particular endometriosis- associated, dysmenorrhea, dyspareunia, dysuria, or dyschezia; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis; idiopathic bladder hypersensitivity; gastrointestinal disorders including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, gastroesophageal reflux, gastrointestinal distension, Crohn's disease and the like; Parkinson's disease; Alzheimer's disease; myocardial infarction; atherosclerosis; lipid disorders; and pain-associated diseases selected from the group consisting of hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome), arthritis (such as osteoarthritis and rheumatoid arthritis), burns, migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer, traumatic nerve-injury, post-traumatic injuries (including fractures and sport injuries), trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgias, HIV and HIV treatment-induced neuropathy, pruritus; impaired wound healing and disease of the skeleton like degeneration of the joints, ankylosing spondylitis.
13. Use according to any one of claims 9 to 1 1 , wherein said disease is a gynaecological disease, preferably dysmenorrhea, dyspareunia or endometriosis, adenomyosis, endometriosis-associated pain, or other endometriosis-associated symptoms, wherein said symptoms are in particular endometriosis-associated, dysmenorrhea, dyspareunia, dysuria, or dyschezia.
14. Use according to any one of claims 9 to 1 1 , wherein said disease is associated with pain syndromes (including acute, chronic, inflammatory and neuropathic pain), preferably inflammatory pain, low back pain, surgical pain, visceral pain, dental pain, premenstrual pain, endometriosis-associated pain, pain associated with fibrotic diseases, central pain, pain due to burning mouth syndrome, pain due to burns, pain due to migraine, cluster headaches, pain due to nerve injury, pain due to neuritis, neuralgias, pain due to poisoning, pain due to ischemic injury, pain due to interstitial cystitis, cancer pain, pain due to viral, parasitic or bacterial infections, pain due to traumatic nerve-injury, pain due to post-traumatic injuries (including fractures and sport injuries), pain due to trigeminal neuralgia, pain associated with small fiber neuropathy, pain associated with diabetic neuropathy, chronic lower back pain, phantom limb pain, pelvic pain syndrome, chronic pelvic pain, neuroma pain, complex regional pain syndrome, pain associated with gastrointestinal distension, chronic arthritic pain and related neuralgias, and pain associated with cancer, pain associated with chemotherapy, HIV and HIV treatment-induced neuropathy; and pain associated with diseases or disorders selected from the group consisting of hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome) and arthritis (such as osteoarthritis and rheumatoid arthritis).
A pharmaceutical composition comprising at least one compound according to any one of the claims 1 to 8, together with at least one pharmaceutically acceptable auxiliary.
An intermediate of formulae 15a 15b, 16a and 16b
Figure imgf000132_0001
15a 15b 16a 16b wherein R2, R2a, R2b and R2c are as defined in any one of the previous claims claims 1 to 7.
17. An intermediate of formula
3-Bromo-/V-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide
3-Amino-5-bromo-/V-(2,4-dimethoxybenzyl)benzenesulfonamide
/V-{3-Bromo-5-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2- chlorophenyl)acetamide
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