WO2009096701A2 - Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same - Google Patents

Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same Download PDF

Info

Publication number
WO2009096701A2
WO2009096701A2 PCT/KR2009/000407 KR2009000407W WO2009096701A2 WO 2009096701 A2 WO2009096701 A2 WO 2009096701A2 KR 2009000407 W KR2009000407 W KR 2009000407W WO 2009096701 A2 WO2009096701 A2 WO 2009096701A2
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
trifluoromethyl
acrylamide
methanesulfonylamino
difluoro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2009/000407
Other languages
French (fr)
Other versions
WO2009096701A3 (en
Inventor
Song Seok Shin
Jin Kwan Kim
Sun-Young Kim
Ki-Wha Lee
Byoung Young Woo
Joo-Hyun Moh
Yeon Su Jeong
Kyung Min Lim
Jin Kyu Choi
Hyun-Ju Koh
Young-Ho Park
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amorepacific Corp
Original Assignee
Amorepacific Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amorepacific Corp filed Critical Amorepacific Corp
Priority to JP2010544237A priority Critical patent/JP5643112B2/en
Priority to US12/865,082 priority patent/US8557872B2/en
Priority to EP09706694.8A priority patent/EP2238105B1/en
Priority to CN200980103367.3A priority patent/CN101925575B/en
Publication of WO2009096701A2 publication Critical patent/WO2009096701A2/en
Publication of WO2009096701A3 publication Critical patent/WO2009096701A3/en
Anticipated expiration legal-status Critical
Priority to US14/022,789 priority patent/US20140011881A1/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • 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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present disclosure relates to novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as TRPVl antagonist; and a i pharmaceutical composition containing the same. j i 1
  • the vanilloid receptor- 1 (VRl, or transient receptor potential vanilloid-1,
  • TRPVl is the receptor for capsaicin (8-methyl-N-vaniHyl-6-nonenamide
  • capsaicin 8-methyl-N-vaniHyl-6-nonenamide
  • the molecular cloning of TRPVl was reported in 1997 (Caterina et al, 1997, Nature, 389, ⁇ 816-824), which belongs to the TRP j channel family of non-selective cation channel. TRPVl is activated or sensitized
  • TRPVl is highly expressed in primary afferent sensory neurons, and also reportedly expressed in varjious organs and tissues such as bladder, kidney, lung, intestine, skin, central nervous i system (CNS), and non-neuronal tissues (Mezey et al., 2000, PNAS, 91, pp3655-
  • TRPVl knock-out mice show normal responses in a wide range of behavioural tests including noxious mechanical and acute thermal stimuli, but exhibit little thermal hypersensitivity in inflammation states.
  • TRPVl knock-out mice exhibit reduced responses to thermal or noxious stimuli, which has been supported by the effects of TRPVl antagonists in various animal models of pain (Immke et al., 2006, Semin. Cell. Dev. Biol, 17(5), pp582-91; Ma et al., 2007, Expert Opin. Ther. Targets, 11(3), pp307-20).
  • TRPVl antagonist capsazepine
  • the well-known TRPVl antagonist, capsazepine decreases hyperalgesia caused by physical stimuli in several models of inflammatory and neuropathic pain (Walker et al., 2003, JPET, 304, pp56-62; Garcia-Martinez et al, 2002, PNAS, 99, 2374-2379).
  • TRPVl agonist In addition, treatment of the primary culture of afferent sensory neurons with the TRPVl agonist, capsaicin etc., results in damage to nerve functions and furthermore death of nerve cells.
  • the TRPVl antagonist exerts defense actions against such damage to nerve functions and nerve cell death (Holzer P., 1991, Pharmacological Reviews, 43, ppl43-201; Mezey et al., 2000, PNAS, 97, 3655-3660).
  • the TRPVl is expressed on sensory neurons distributed in all regions of the gastrointestinal tract and is highly expressed in inflammatory disorders such as irritable bowel syndrome and inflammatory bowel disease (Chan et al., 2003, Lancet, 361, pp385-391; Yiangou et al, 2001, Lancet, 357, ⁇ pl338-1339).
  • activation of the TRPVl stimulates sensory nerves, which in turn causes release of neuropeptides which are known to play a critical role in pathogenesis of gastrointestinal disorders such as gastroesophageal reflux disease (GERD) and stomach duodenal ulcer (Holzer P., 2004, Eur. J. Pharmacol. 500, p ⁇ 231-241; Geppetti et al, 2004, Br. J. Pharmacol, 141, ppl313-1320).
  • GDD gastroesophageal reflux disease
  • the TRPVl -expressing afferent nerves are abundantly distributed in airway mucosa, and bronchial hypersensitivity is very similar mechanism to hyperalgesia.
  • Protons and lipoxygenase products known as endogenous ligands for the TRPVl, are well known as crucial factors responsible for development of asthma and chronic obstructive pulmonary diseases (Hwang et al, 2002, Curr. Opin. Pharmacol. pp235-242; Spina et ah, 2002, Curr. Opin. Pharmacol. pp264- 272).
  • TRPVl knock-out mice are anatomically normal but have higher frequency of low-amplitude, non-voiding bladder contractions and reduced reflex voiding during bladder filling as compared to wild type mice, which is thus indicating that the TRPVl affects functions of the bladder (Birder et ah, 2002, Nat. Neuroscience, 5, pp856-860).
  • the TRPVl is distributed in human epidermal keratinocytes as well as in primary afferent sensory nerves (Denda et ah, 2001, Biochem. Biophys. Res. Commun., 285, ppl250-1252; Inoue et ah, 2002, Biochem. Biophys. Res.
  • TRPVl antagonist capsazepine inhibits inflammatory mediators in human skin cells (Southall et ah, 2003, J. Pharmacol. Exp. Ther., 304, pp217-222). Over recent years, evidence has been accumulation on other roles of TRPVl.
  • TRPVl might be involved in the blood flow/pressure regulation via sensory vasoactive neuropeptide release and in the regulation of plasma glucose levels or in the pathogenesis of type 1 diabetes (Inoue et ah, Cir. Res., 2006, 99, pp 119-31; Razavi et ah, 2006, Cell, 127, p ⁇ ll23-35; Gram et ah, 2007, Eur. J. Neuroscl, 25, ⁇ p213-23). Further, it is reported that TRPVl knock-out mice show less anxiety-related behavior than their wild type littermates with no differences in locomotion (Marsch et ah, 2007, J. Neurosci., 27(4), pp832-9).
  • Compounds of the present disclosure are useful for prophylaxis and treatment of diseases associated with the activity of TRPVl (Nagy et al., 2004, Eur. J. Pharmacol. 500, 351-369) including but not limited to, pain such as acute pain, chronic pain, neuropathic pain, post-operative pain, rheumatic arthritic pain, osteoarthritic pain, postherpetic neuralgia, neuralgia, headache, dental pain, pelvic pain, migraine, bone cancer pain, mastalgia and visceral pain (Petersen et ah, 2000, Pain 88, p ⁇ l25-133; Walker et al., 2003, J. Pharmacol. Exp.
  • pain such as acute pain, chronic pain, neuropathic pain, post-operative pain, rheumatic arthritic pain, osteoarthritic pain, postherpetic neuralgia, neuralgia, headache, dental pain, pelvic pain, migraine, bone cancer pain, mastalgia and vis
  • cardiac diseases such as myocardial ischemia (Scotland et al., 2004, Circ. Res. 95, ppl027-1034; Pan et al., 2004, Circulation 110, ppl826-1831); haemorrhagic shock (Akabori et al., 2007, Ann. Surg., 245(6), pp964-70); hair growth-related disorders such as hirsutism, effluvium, alopecia (Bod ⁇ et al., 2005, Am. J. Patho. 166, pp985-998; Bir ⁇ et al, 2006, J. Invest.
  • cardiac diseases such as myocardial ischemia (Scotland et al., 2004, Circ. Res. 95, ppl027-1034; Pan et al., 2004, Circulation 110, ppl826-1831); haemorrhagic shock (Akabori et al., 2007, Ann. Surg., 245
  • WO 06/101321 and WO 06/101318 relate to VRl modulators with a biphenyl partial structure.
  • the present inventors have consequently synthesized novel compounds having VRl antagonistic activity.
  • Said new compounds have biphenylic structures, wherein one phenyl ring is substituted in para position to its attachment position to the rest of the molecule with a trifluoromethyl group or a fluoro, and has at least one additional substituent in ortho position (relative to said attachment position).
  • the present compounds show remarkable improvement of their physicochemical characteristics, such as metabolic stability or pharmacokinetic profiles. Therefore, it is an object of the present disclosure to provide novel compounds useful as a potent antagonist for a TRPVl, isomer thereof and pharmaceutically acceptable salts thereof; and a pharmaceutical composition comprising the same.
  • the present disclosure provides a novel compound of the following formula (Ia), an isomer, or a pharmaceutically acceptable salt thereof:
  • a iS -C C- Or -CH-CH-;
  • Ri is hydrogen, or C1-C3 alkyl
  • R 2 and R 3 are independently hydrogen, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, halo(Cl-C3)alkyl, (C2-C5)alkenyl, or (C2-C5)alkynyl;
  • R 4 is halo(Cl-C3)alkyl or halogen;
  • R 5 is C2-C10 alkyl, C2-C10 alkoxy, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkylamino, C2-C10 alkylamino, di(Cl-C5 alkyl)amino, C3-C6 cycloalkylamino, C3-C6 cycloalkoxy, or (C3-C6)cycloalkyl(Cl-C3)alkyloxy; and R 6 is hydrogen, Cl-ClO alkyl, Cl-ClO alkoxy, or Cl-ClO alkylamino.
  • the present disclosure also provides a novel compound of the following formula (I), an isomer, or a pharmaceutically acceptable salt thereof:
  • R 1 is hydrogen, methyl, or ethyl
  • R 2 and R 3 are independently hydrogen, halogen, cyano, methyl, ethyl, methoxy, trifluoromethyl, vinyl, or acetylenyl; R 4 is trifluoromethyl or fluoro;
  • R 5 is C2-C5 alkyl, C2-C5 alkoxy, C1-C2 alkoxy (C1-C3) alkoxy, C1-C2 alkoxy
  • R 6 is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, or C1-C5 alkylamino.
  • Another aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; as described above wherein If R 5 is ethoxy, butoxy, pentoxy, (C3-C6)cycloalkoxy, or (C3-C6)cycloalkyl(Cl-C3)alkyloxy, then R 1 is methyl. In another embodiment in the compounds of formula (Ia) or (I) as disclosed further above, if R 5 is ethoxy, butoxy, or pentoxy, and R4 is simultaneously fluoro, then Ri is methyl.
  • R 4 is trifluoromethyl.
  • Ri is preferably methyl.
  • Another aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, Ri is hydrogen; R 2 is halogen; and R 5 is C2-C4 alkyl or C2-C4 alkylamino.
  • One aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable . salt thereof; wherein, Ri is hydrogen; R 2 is fluoro; R 3 is hydrogen, fluoro, cyano, methyl, vinyl, or acetylenyl; R 4 is trifluoromethyl; R 5 is C2-C4 alkyl or C2-C4 alkylamino; and
  • R 6 is hydrogen
  • Another aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, R 1 is hydrogen, methyl, ethyl, or preferably methyl.
  • One aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, Ri is methyl; R 2 is halogen; and R 5 is C2-C4 alkyl, C2-C4 alkyloxy, or C2-C4 alkylamino.
  • Another aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein,
  • Ri is methyl
  • R 2 is fluoro
  • R 3 is hydrogen, fluoro, vinyl, methyl, or acetylenyl
  • R 5 is C2-C4 alkyl, C2-C4 alkyloxy, or C2-C4 alkylamino; and R 6 is hydrogen or C1-C3 alkyl.
  • One aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, R 2 and R 3 are independently hydrogen, fluoro, cyano, methyl, ethyl, methoxy, trifluoromethyl, vinyl, acetylenyl, or preferably hydrogen, fluoro, cyano, methyl, vinyl, or acetylenyl.
  • One aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, R 2 and R 3 are both fluoro.
  • One aspect of the present disclosure is a compound according to the above formula (Ia) or (I) 5 an isomer, or a pharmaceutically acceptable salt thereof; wherein, R 4 is fluoro, or preferably trifluoromethyl.
  • One aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, R 5 and R 6 are both C1-C3 alkyl; or preferably methyl, ethyl, or propyl; or more preferably propyl.
  • One aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, R 6 is hydrogen.
  • One aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, R 5 is ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, or cyclohexylmethoxy, provided that if R 5 is ethoxy, butoxy, pentoxy, or cyclohexylmethoxy, then R 1 is methyl.
  • Another aspect of the present disclosure is a compound of the formula (Ia) or (I) as further described herein, an isomer, or a pharmaceutically acceptable salt thereof, wherein, if Ri is methyl or ethyl, then the compound may be a pure enantiomer or may be a mixture of the (R) and (S)-enantiomer; and then, the C- atom to which Ri is attached is preferably in the (Reconfiguration.
  • Another aspect of the present disclosure is compounds of the formula (Ia) or (I) as further described herein, an isomer, or a pharmaceutically acceptable salt thereof wherein,
  • R 5 is C2-C5 alkyl, (C2 ⁇ C5)alkyloxy, C1-C4 alkylamino, or (C3-
  • R 5 is C2-C4 alkyl, (C2-C4)alkyloxy, or C2-C4 alkylamino; wherein particularly preferably,
  • R 5 is C2-C4 alkyl, or C1-C3 alkylamino; wherein particularly preferably,
  • R 5 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, or cyclohexylmethoxy, wherein particularly preferably,
  • R 5 is C2-C4 alkyl, propoxy, isopropoxy, or C2-C4 alkylamino; wherein even more preferably,
  • R 5 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, propoxy, isopropoxy, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, or sec-butylamino, wherein even more preferably,
  • R 5 is n-propyl, n-butyl, isobutyl, isopropoxy, sec-butoxy, ethylamino, n- propylamino, isopropylamino, n-butylamino, wherein more preferably,
  • R 5 is n-propyl, n-butyl, isobutyl, n-propoxy, ethylamino, propylamine, isopropylamino, n-butylamino, wherein even more preferably,
  • R 5 is propyl, butyl, isobutyl, ethylamino, propylamino, or isopropylamino, wherein even more preferably,
  • R 5 is propyl, butyl, ethylamino, propylamino, or isopropylamino.
  • Preferred examples of compounds according to the disclosure are selected from the group consisting of:
  • the Scheme 1 shows a proposed process for synthesizing acrylamide compound with various substituents.
  • Substituted benzylamine (1) is reacted with phenylacrylic acid (2) to yield benzyl phenylacrylamide (3) using DMTMM ⁇ 4- (4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride ⁇ (Tetrahedron Lett., 1999, 40, 5327).
  • the Scheme 2 shows a proposed process for synthesizing acrylamide compound (11) with various substituents.
  • 4-Substituted 2-aminobenzoic acid (5) which is prepared by hydrogenation of 4-substituted 2-nitrobenzoic acid (4), is converted to the corresponding alkylamino benzoic acid (6) via reductive animation.
  • the substituted benzoic acid (6) is converted to the corresponding Weinreb amide (7), which is reduced by lithium aluminum hydride to yield substituted benzaldehyde (8).
  • the benzaldehyde (8) is converted to methyl phenyl acrylic ester (9) by Wittig reaction.
  • methyl phenyl acrylic ester (9) is hydrolyzed with lithium hydroxide to yield phenyl acrylic acid (10).
  • the phenyl acrylic acid (10) is reacted with substituted benzylamine (1) as shown in scheme 1 to yield benzyl phenylacrylamide (11).
  • the Scheme 3 shows a more efficient process for synthesizing alkylamino benzoic acid (6) which is an intermediate to benzyl phenylacrylamide (11).
  • One pot hydrogenation reaction of 4-substituted 2-nitrobenzoic acid (4) in the presence of an aldehyde and acetic acid replaces the two-step process including hydrogenation of 4 and reductive amination of the corresponding 2-aminobenzoic acid 5.
  • the Scheme 5 shows a proposed process for synthesizing acrylamide compound (20) with various substituents.
  • 4-Substituted 2-hydroxybenzoic acid (13) is reacted with an alkyl halide and potassium carbonate to yield corresponding alkoxy benzoate (14), which is hydrolyzed with lithium hydroxide to give alkoxy benzoic acid (15).
  • the substituted benzoic acid (15) is converted to benzyl phenylacrylamide (20) by similar processes used for benzyl phenylacrylamide (11) shown in Scheme 2.
  • the Scheme 6 shows an alternative process for synthesizing methyl phenyl acrylic ester (18) which is an intermediate to benzyl phenylacrylamide
  • the Scheme 7 shows a proposed process for synthesizing acrylamide compound (25) with various substituents.
  • 4-Triflurometfiyl iodobenzene is converted to substituted phenyl acrylic acid methyl ester (23) by palladium catalyzed coupling reaction.
  • the phenyl acrylic acid methyl ester (23) is hydrolyzed with lithium hydroxide to yield phenyl acrylic acid (24).
  • the phenyl acrylic acid (24) is reacted with substituted benzylamine (1) as described in Scheme 1 to yield benzyl phenylacrylamide (25).
  • the Scheme 8 shows a proposed process for synthesizing acrylamide compound (32) with various substituents.
  • Substituted benzoyl chloride (26) is reacted with 2-amino-2-methyl-l-propanol in the present of a base, and the resulting adduct is treated with thionyl chloride followed by sodium hydroxide to afford dihydro-oxazole compound (27).
  • the compound 27 is reacted with an alkyl halide to give disubstituted dihydro-oxazole (28).
  • the compound 28 is hydrolyzed with conc-HCl to the corresponding benzoic acid, which is converted to the Weinreb amide (29).
  • the Scheme 9 shows a proposed process for synthesizing amide compound (33) with various substituents.
  • Substituted acrylamide (3) is reduced with PdVC under hydrogen pressure to yield amide compound (33).
  • the present disclosure also provides to a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the present disclosure also provides a pharmaceutical composition comprising a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  • the present disclosure also provides a composition comprising a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof; and pharmaceutically acceptable carrier for preventing or treating a condition associated with the pathological stimulation and/or aberrant expression of vanilloid receptor.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, for treating a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV- related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium,
  • the present disclosure relates to the pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof for treating pain as described above, wherein the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non- inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), visceral pain, migraine, and other types of headaches.
  • the present disclosure also provides a pharmaceutical composition comprising a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, which is characterized in that it is adapted for oral administration.
  • the present disclosure relates to the use of a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof for the preparation of a medicament
  • the present disclosure relates to the use of a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a condition that is associated with the aberrant expression and/or aberrant activation of a vanilloid receptor.
  • the present disclosure relates to the use of a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, in preparation of a medicament for the prevention or treatment of a condition that is selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth
  • a condition
  • the present disclosure relates to the use of the compound of formula (Ia) or (I), an isomer thereof, for preparing a medicament for preventing or treating pain as described above, wherein the condition is pain, which is or which is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), visceral pain, migraine, and other types of headaches.
  • a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), visceral pain, migraine, and other types of headaches.
  • the present disclosure relates to a method for inhibiting vanilloid ligand from binding to vanilloid receptor in a patient, comprising contacting cells expressing vanilloid receptor in the patient with the compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a method for preventing or treating a condition associated with the pathological stimulation and/or aberrant expression of vanilloid receptors.
  • the present disclosure also provides a method for preventing or treating a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis, and pancreatitis, which comprises administering to a mammal including
  • the present disclosure relates to the method of treating pain by administering a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof as described above, wherein the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), visceral pain, migraine, and other types of headaches
  • a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), visceral pain, migraine, and other types of headaches
  • a compound of formula (Ia) or (I), an isomer thereof or a pharmaceutically acceptable salt thereof according to the present disclosure can be prepared as a pharmaceutical composition containing pharmaceutically acceptable carriers, adjuvants, diluents and the like.
  • the compounds of the present disclosure can be dissolved in oils, propylene glycol or other solvents which are commonly used to produce an injection.
  • Suitable examples of the carriers include, but not limited to, physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc.
  • the compounds of the present disclosure can be formulated in the form of ointment or cream.
  • the compound according to the present disclosure may also be used in the forms of pharmaceutically acceptable salts thereof, and may be used either alone or in combination or in admixture with other pharmaceutically active compounds.
  • the compounds of the present disclosure may be formulated into injections by dissolving, suspending or emulsifying in water-soluble solvent such as saline and 5% dextrose, or in water-insoluble solvents such as vegetable oils, synthetic fatty acid glyceride, higher fatty acid esters and propylene glycol.
  • the formulations of the disclosure may include any of conventional additives such as dissolving agents, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.
  • the preferable dose level of the compounds according to the present disclosure depends upon a variety of factors including the condition and body weight of the patient, severity of the particular disease, dosage form, and route and period of administration, but may appropriately be chosen by those skilled in the art.
  • the compounds of the present disclosure are preferably administered in an amount ranging from 0.001 to 100 mg/kg of body weight per day, and more preferably from 0.01 to 30 mg/kg of body weight per day. Doses may be administered once a day, or several times a day with each divided portions.
  • the compounds of the present disclosure are used in a pharmaceutical composition in an amount of 0.0001 — 10% by weight, and preferably 0.001 — 1% by weight, based on the total amount of the composition.
  • the pharmaceutical composition of the present disclosure can be administered to a mammalian subject such as rat, mouse, domestic animals, human being and the like via various routes.
  • the methods of administration which may easily be expected include oral and rectal administration; intravenous, intramuscular, subcutaneous, intrauterine, duramatral and intracerebroventricular injections.
  • Alkenyl includes monovalent olefmically unsaturated hydrocarbyl groups being straight-chained or branched and having at least 1 double bond.
  • alkenyl has preferably 2-5 carbon atoms ("C1-C5 alkenyl”), 2-4 carbon atoms (“C2-C4 alkenyl”), or only 2-3 carbon atoms (“C2-C3 alkenyl”).
  • a preferred "alkenyl” group is ethenyl (vinyl).
  • Alkoxy includes the group -OR wherein R is "alkyl” as defined further above. Particular alkoxy groups include, by way of example, methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, tert-butoxy, iso-butoxy, sec-butoxy, n-pentoxy, 1,2-dimethyIbutoxy, and the like.
  • Alkoxyalkoxy refers to the group -OROR', wherein R and R' are the same or different "alkyl” groups as defined further above.
  • Alkoxyalkylamino refers to the group -NH(ROR'), wherein R and R' are the same or different “alkyl” groups as defined further above.
  • Alkyl includes monovalent saturated aliphatic hydrocarbyl groups. The hydrocarbon chain may be either straight-chained or branched.
  • Alkyl has 1-6 carbon atoms ("C1-C6 alkyl”), and in some instances preferably 1-5 carbon atoms (“C1-C5 alkyl”), 1-4 carbon atoms (“C1-C4 alkyl”), or only 1-3 carbon atoms (“C1-C3 alkyl”).
  • This term is exemplified by groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, t-amyl, and the like.
  • Alkynyl includes acetylenically unsaturated hydrocarbyl groups being straight-chained or branched and having at least 1 triple bond.
  • Alkynyl has preferably 2-6 carbon atoms ("C2-C6 alkynyl”), and in some instances even more preferably 2-5 carbon atoms (“C1-C5 alkynyl”), 2-4 carbon atoms ("C2-C4 alkynyl”), or only 2-3 carbon atoms (“C2-C3 alkynyl”).
  • a preferred alkynyl group is ethynyl (acetylenyl).
  • Alkylamino includes the group -NHR 1 , wherein R 1 is alkyl group as defined herein.
  • Dialkylamino includes the group -NR'R", wherein R' and R" are alkyl group as defined herein.
  • Cycloalkyl refers to cyclic saturated aliphatic hydrocarbyl groups.
  • the numbers of C-atoms referenced in connection with a given cycloalkyl group corresponds to the number of ring forming carbon atoms, e.g. "C3-C6 cycloalkyl” refers to a cycloalkyl with between three and six ring-forming C atoms.
  • Examples of “cycloalkyl” are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc. If indicated, a "cycloalkyl” group may be unsubstituted or substituted with one or more alkyl groups, e.g.
  • C1-C6 alkyl groups preferably with C1-C3 alkyl groups, particularly preferably with methyl groups. If a "cycloalkyl" carries more than one alkyl substituent these substituents may be attached to the same or to different ring-forming carbon atoms.
  • Cycloalkoxy refers to the group -OR, wherein R is “cycloalkyl” group as defined further above.
  • Cycloalkylamino refers to the group -NHR, wherein R is “cycloalkyl” group as defined further above.
  • Cycloalkylalkoxy refers to the group -OR-R', wherein R is “alkyl” group and R' is “cycloalkyl” group as defined further above.
  • Examples of “cycloalkylalkoxy” are cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cyclopropylethoxy, etc.
  • Halo or halogen refers to fluoro, chloro, bromo, and iodo. Preferred halo groups are either fluoro or chloro.
  • Haloalkyl includes an “alkyl” group as defined further above which is substituted with one or more halogens which may be the same, e.g. in trifluoromethyl or pentafluoroethyl, or which may be different.
  • isomers refers to especially optical isomers (for example essentially pure enantiomers, essentially pure diastereomers, and mixtures thereof) as well as conformation isomers (i.e. isomers that differ only in their angles of at least one chemical bond), position isomers (particularly tautomers), and geometric isomers
  • Essentially pure e.g. in connection with enantiomers or diastereomers means at least about 90%, preferably at least about 95%, more preferably at least about 97 or at least about 98%, even more preferably at least about 99%, and particularly preferably at least about 99.5% (w/w) of a specified compound, e.g. a particular enantiomer or diastereomer.
  • “Pharmaceutically acceptable” means being devoid of substantial toxic effects when used in doses usually employed in a medicinal dosage, and thereby being approvable or preferably being approved by a regulatory agency of the Federal or a state government or being listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is “pharmaceutically acceptable” as further defined herein, and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2naphthalenesulfonic acid, 4-toluenesulfonic acid,
  • Preventing refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • Subject includes humans and non-human mammals.
  • patient is used interchangeably with “subject” herein and shall include humans and non- human mammals unless specified otherwise.
  • “Therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • Treating or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • treating refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • treating refers to modulating the disease or disorder, either physically, (e. g., stabilization of a discernible symptom),, physiologically,
  • treating refers to delaying the onset of the disease or disorder.
  • treating or “treatment” refers to reducing, modifying or removing one or more discernible symptom of a disease or disorder without modulating the cause of the underlying disease.
  • Example 1 (3f)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3- (2-propylamino-4-trifluoromethyl-phenyl)-acrylamide
  • Step 3 Synthesis of N-methoxy-N-methyl-2-propylamino-4-trifluoromethyl- benzamide
  • Step 4 Synthesis of 3-(2-propylamino-4-trifluoromethyl-phenvD-acrylic acid methyl ester
  • N-Methoxy-N-methyl-2- ⁇ ropylamino-4-trifluoromethyl-benzamide (98.3 mg, 0.339 mmol) was reacted with IM lithium aluminum hydride (0.6 ml) in THF (20ml) at -40 0 C for 1 hr.
  • the reaction mixture was quenched by adding saturated potassium hydrogen sulfate solution. The mixture was stirred for 30min.
  • the reactions solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was extracted with CH 2 Cl 2 (30 ml x 3). The combined organic layer was dried over MgSO 4 and concentrated in vacuo to yield 2-propylamino-4- trifluoromethyl-benzaldehyde (78 mg).
  • N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (84 mg, 0.308 mmol) was reacted with 3-(2- ⁇ ropylamino-4-trifluoromethyl- ⁇ henyl)-acrylic acid (67 mg, 0.245 mmol), NMM (0.4 ml) and DMTMM (121 mg) to give the title compound (62 mg, 52%).
  • Step 3 Synthesis of N-methoxy-N-methyl-2- ⁇ ropoxy-4-trifluoromethyl- benzamide
  • N-Methoxy-N-methyl-2-propoxy-4-trifluoromethyl-benzamide (277 mg) in THF was reacted with 1 M LAH (1 ml) on -50 0 C for 1 hr.
  • the reaction mixture was quenched by adding aqueous potassium hydrogen sulfate (5 ml). The mixture was stirred for 30 min.
  • the reaction solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was was was extracted with ethyl acetate (30 ml x 3). The combined organic layer was washed with brine (30 ml) and dried over MgSO 4 and concentrated in vacuo to yield title compound (232 mg, 100%).
  • Step 5 Synthesis of 3-f2-propoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester
  • Step 7 Synthesis of N-(3,5-difluoro-4-methanesulfonylamino-benzyl)-3-(2- propoxy-4-trifluoromethyl-phenyl)-acrylamide
  • Step 1 Synthesis of 3-(2,6-dipropyl-4-trifluoromethyl- ⁇ henyl)-acrylic acid methyl ester
  • Step 3 Synthesis of (R)-N-ri ⁇ (3,5-difluoro-4-methanesulfonylamino-phenylV ethyl]-3-(2,6-dipropyl-4-trifluoromethyl-phenyl)-acrylamide
  • N-Methoxy-N-methyl-2-ethoxy-4-trifluoromethyl-benzamide (1.04 g) was reacted with 1 M LAH (1 ml) at -40 0 C for 2 hrs as described above to yield title compound (729 mg, 65%)
  • Step 6 Synthesis of ffi)-N-ri-(3,5-difluoro-4-methanesulfonylamino-phenyl)- ethyl]-3-(2-ethoxy-4-trifluoromethyl-pheny ⁇ -acrylamide
  • N-Memoxy-N-methyl-2-nitro-44rifluoromethyl-benzamide (2.54 g, 9.12 mmol) was reacted with Pd/C (441 mg) under hydrogen atmosphere as described above to yield title compound.
  • Step 3 Synthesis of 2-ethylamino-N-methoxy-N-methyl-4-trifluoromethyl- benzamide
  • N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt 25 mg was reacted with 3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylic acid (24 mg, 0.086 mmol), NMM (0.1 ml) and DMTMM (27 mg) at room temperature overnight to yield the title compound (21 mg, 50%).
  • N-(4-Aminomethyl-2-fluoro-6-vinyl-phenyl)-methanesulfonamide, HCl salt (36 mg, 0.15 mmol) was reacted with 3-(2-propylammo-4 ⁇ trifluoromethyl- ⁇ henyl)-acrylic acid (28 mg, 0.10 mmol), NMM (0.1 ml) and DMTMM (35 mg) at room temperature overnight to yield the title compound (17 mg, 34%) after column chromatography.
  • N-(4-Aminomethyl-2-fluoro-6-cyano-phenyl)-methanesulfonamide, HCl salt (26 mg, 0.092 mmol) was reacted with 3-(2-propylammo-4-trifIuoromethyl- phenyl)-acrylic acid (20 mg, 0.073 mmol), NMM (0.1 ml) and DMTMM (28 mg) at room temperature overnight to yield the title compound (8 mg, 22%) after column chromatography.
  • Step 1 Synthesis of 4.4-dimethyl-2-r4-trifluoromethyl- ⁇ henyl)-4,5-dihvdro- oxazole
  • Step 2 Synthesis of N-methoxy-N-methyl-2-propyl-4-trifiuoromethyl-benzamide.
  • Step 3 Synthesis of 3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid methyl ester.
  • Step 4 Synthesis of 3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid.
  • Step 5 Synthesis of fRVN-ri-(3.5-difluoro-4-methanesulfonylamino-phenyl)- ethyl] -3 -C2-propyl-4-trifluoromethyl-phenyl)-acrylamide
  • Step 1 Synthesis of 2-isopropoxy-4-trifluoromethyl-benzoic acid isopropyl ester
  • Step 2 Synthesis of 2-iso ⁇ ropoxy-N-methoxy-N-methyl-4-trifluoromethyl- benzamide.
  • Step 3 Synthesis of 3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester.
  • Step 4 Synthesis of N-ri-(3 n 5-difluoro-4-methanesulfonylamino-phenyl)-ethyll- 3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylamide.
  • Step 1 Synthesis of 3-(4-fluoro-2-hydroxy-phenyl)-acrylic acid methyl ester.
  • Step 2 Synthesis of 3-f4-flu.oiO-2-pro ⁇ oxy-phenyl)-acrylic acid methyl ester
  • Step 4 Synthesis of ⁇ gj-N-[l-(3,5-Difluoro-4-methanesulfoiiylamino-phenyl)- emyl]-3-f4-fluoro-2-propo ⁇ y-phenyl)-acrvlaniide
  • Example 29 fK)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)ethyI]- 3-(4-fluoro-2- propylaminophenyl)-acrylamide
  • Step 1 Synthesis of 2-butoxy-4-trifluoromethyl-benzoic acid butyl ester
  • Step 7 Synthesis of (RJ-3-(2-butoxy-4-trifluoromethyl-phenylVN-ri-(3,5- difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide
  • Step 1 Synthesis of 3-(2-butoxy-4-fluoro-phenyl)-acrylic acid methyl ester
  • Step 3 Synthesis of ⁇ )-3-f2-buto ⁇ y-4-fluoro- ⁇ henyl)-N-[l-f3,5-difluoro-4- methanesulfonylamino-phenvD-ethvll-acrylamide
  • N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (14mg, 0.050mmol) was reacted with 3-(2-propyl-4-trifluoromethyl- ⁇ henyl)- acrylic acid (8mg, 0.031mmol) to give the title compound (12mg, 80%) after purification by column chromatography (gradient 12% to 100% EtOAc in Hex).
  • Step 1 Synthesis of 2-sec-butoxy-N-metho ⁇ y-N-methvl-44rifluoromethyl- benzamide
  • Step 2 Synthesis of 3-r2-sec-butoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester
  • Step 3 Synthesis of 3-(2-sec-butoxy-4-trifluoromethyl-phenyl)-N-ri-(3,5- difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide
  • Step 1 Synthesis of 3-(2-sec-butoxy-4-fluoro-phenyl)-acrylic acid methyl ester
  • Step 3 Synthesis of rRJ-3-(2-sec-butoxy-4-fluoro-phenvD-N-ri-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide
  • Example 42 fK)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]- 3-(2-ethylamino-4-fluoro-phenyl)-acrylamide
  • Step 3 Synthesis of CR)-N-Tl -(3, 5-Difluoro-4-methanesulfonylaminophenyl) ethyl]-3-(4-fluoro-2-ethylaminophenyl)acrylamide
  • Step 1 Synthesis ofN-memoxy-N-methyl-4-fluoro-2-n-buthylammo-benzamide
  • Step 2 Synthesis of 3-(4-fluoro-2-butylamino-phenyl)-acrylic acid methyl ester
  • Step 3 Synthesis of ⁇ ffi)-N-fl-(3,5-Difluoro-4-methanesulfonylaminophenyl) ethyl]-3 -(4-fluoro-2-n-butylaminophenyl) acrylamide
  • Step 2 Synthesis of fi?)-N-[l-( ' 3.,5 ⁇ difluoro-4-methanesulfonylamino-phenv ⁇ - ethyl]-2-methyl-3-(2-propyl-4-trifluoromethyl- ⁇ henyl)-acrylamide
  • Example 49 (/?)-N-[l-(3-Fluoro-4-methanesuIfonyIamino-phenyl)-etliyl]-2- methyI ⁇ 3-(2-propyl-4-trifluoromethyI-phenyl)-acrylamide
  • Example 50 (i?)-3-(2-CyclohexyImethoxy-4-trifluoromethyI-phenyl)-N-[l- (3,5 ⁇ difluoro-4-methanesuIfonyIamino-phenyI)-ethyl]-acrylamide
  • Step 1 Synthesis of 2-cvclohexylmethoxy-4-trifluoromethyl-benzoic acid cyclohexylmethyl ester
  • Step 3 Synthesis of 3-(2-cvclohexylmethoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester
  • Step 4 Synthesis of 3-(2-cvclohexylmethoxy-4-trifluoromethyl-phenyl)-N-[ " l- (3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyll-acrylamide
  • N-(4-Aminomethyl-2,5-difluoro-phenyl)-methanesulfonamide, HCl salt 43mg, 0.154mmol
  • 3-(2-isopropylamino-4-trifluoro-phenyl)- acrylic acid 42mg, 0.154mmol
  • N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-propylamino-4- trifluoromethyl-phenyl)-acrylamide (20 mg, 0.041 mmol) was reduced with Pd/C under hydrogen atmosphere to yield title compound (12 mg 5 59%).
  • Neonatal (2-3 day old or younger than 2-3 day old) SD rats were put in ice for 5 minutes to anesthetize and disinfected with 70% ethanol.
  • DRG of all part of spinal cord were dissected (Wood et al, 1988, J. Neurosci. 8, ⁇ 3208-3220) and collected in DME/F12 medium to which 1.2g/l sodium bicarbonate and 50mg/l gentamycin were added. The DRG were incubated sequentially at 37 0 C for 30 mins in 200 U/ml collagenase and 2.5mg/ml trypsin, separately.
  • the ganglia were washed twice with DME/F12 medium supplemented with 10% horse serum, triturated through a fire-polished Pasteur pipette, filtered through Nitex 80 membrane to obtain single cell suspension and the suspension was washed once more. This was subjected to centrifugation, then resuspended in cell culture medium at certain level of cell density.
  • DME/F12 medium supplemented with 10% horse serum was diluted with identical medium conditioned by C6 glioma cells 2 days on a confluent monolayer (1 :1), and NGF (Nerve Growth Factor) was added to adjust 200ng/ml as final concentration.
  • cytosine arabinoside Ara-C, 100 ⁇ M
  • medium was changed to one without Ara-C.
  • the resuspended cells were plated at a density of 1500-2000 neurons/well onto Terasaki plates previously coated with 10 ⁇ g/ml poly-D-ornithine.
  • DRG nerve cells from the primary culture of 2 days were equilibrated by washing 4 times with HEPES (1OmM, pH 7.4)-buffered Ca 2+ , Mg 2+ -free HBSS (H-HBSS).
  • H-HBSS HEPES (1OmM, pH 7.4)-buffered Ca 2+ , Mg 2+ -free HBSS
  • the solution in each well was removed from the individual well.
  • Medium containing the test compound plus capsaicin (final concentration 0.5 ⁇ M) and 45 Ca (final concentration 10 ⁇ Ci/ml) in H-HBSS was added to each well and incubated at room temperature for 10 mins. Terasaki plates were washed five times with H-HBSS and dried at room temperature. To each well, 0.3% SDS (10 ⁇ l) was added to elute 45 Ca.
  • Analgesic activity test Mouse writhing test by inducing with phenyl-p- quinone
  • mice Male ICR mice (mean body weight 25g) were maintained in a controlled lighting environment (12 h on/ 12 h off) for experiment. Animals received an intraperitoneal injection of 0.3ml of the chemical irritant phenyl-p-quinone (dissolved in saline containing 5% ethanol to be a dose of 4.5mg/kg) and 6 mins later, the number of abdominal constrictions was counted in the subsequent 6 mins period. Animals (10 animals/group) received 0.2ml of test compounds solution in vehicle of ethanol/Tween 80/saline (10/10/80) intraperitoneally 30 min before the injection of phenyl-p-quinone.
  • test compounds solution in vehicle of ethanol/Tween 80/saline (5/5/90) were administered 54 min prior to the 0.2ml of 0.02% phenyl-p-quinone injection.
  • a reduction in the number of writhes responding to the test drug compound relative to the number responding in saline control group was considered to be indicative of an analgesic effect.
  • Analgesic effect was calculated by % inhibition equation (% inhibition ⁇ C-TyC x 100), wherein C and T represent the number of writhes in control and compound-treated group, respectively.
  • Most examples of the present disclosure having good in vitro activities, were tested at various doses (ranging from 0.3 to 3 mg/kg) and all compounds tested in vivo showed analgesic effects from 8 to 59% inhibition at each dose, respectively.
  • the PK properties of the compounds of formula (I) of the present disclosure surprisingly have superior PK characteristics compared to compounds with a tert-butyl phenyl partial structure, with or without other substituents on the phenyl group, which were at least in part disclosed in the art, e.g. in WO 06/101318 or WO 06/101321 (also refer Table 3).
  • Substantial increases in absorption and apparent half-life were observed by the replacement of tert-butyl phenyl by F-phenyl or CF 3 - phenyl (see Table 2 vs 3).
  • Example number in WO 06/101318 b could not be determined due to low plasma concentration (detection limit : 0.100mcg/ml).
  • the compounds of formula (I) of the present disclosure have superior IC 50 values and in some cases also improved PK characteristics compared to compounds with a CF 3 -phenyl partial structure but without additional substituents on the phenyl group, which were at least in part disclosed in the art, e.g. in WO 06/101318 or WO 06/101321.
  • the introduction of an additional substituent in ortho position of the phenyl's attachment position to the cinnamoyl backbone confers improved VRl activity to the compounds.
  • comparative compound “G” has an IC50 value of more than 10 ⁇ M
  • the compounds 1, 3,5-7,10,16-18, 21, 24, 26, 31, 39, 47, 50, and 52 of the present disclosure which all differ from “G” only by additional substituent(s) on phenyl group, all have IC50 values in a range between 0.019 and 0.34 ⁇ M.
  • compound “G” shows only poor PK-properties, while all tested compounds of the present disclosure showed improved PK properties (in terms of T max and AUC).
  • Example number in WO 06/101318 b could not be determined due to low plasma concentration (detection limit : O.lOOmcg/ml).
  • the compound according to the present disclosure is useful to prevent or to treat pain, inflammatory disease of the joints, neuropathies, HlV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis, and pancreatitis.
  • cardiac diseases such as myocardial ischemia, hair growth-related disorders such as
  • the compound according to the present disclosure is useful to preventing and treating of pain, which is or which is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrom and back pain), migraine, and other types of headaches.
  • a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrom and back pain), migraine, and other types of headaches.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Pulmonology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Virology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Otolaryngology (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Cardiology (AREA)
  • Hematology (AREA)
  • Psychiatry (AREA)
  • Ophthalmology & Optometry (AREA)
  • AIDS & HIV (AREA)
  • Molecular Biology (AREA)
  • Obesity (AREA)
  • Communicable Diseases (AREA)
  • Tropical Medicine & Parasitology (AREA)

Abstract

This present disclosure relates to novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor (Vanilloid Receptor 1; VR1; TRPV1) antagonist; and a pharmaceutical composition containing the same. The present disclosure also provides a pharmaceutical composition for preventing or treating a disease such as pain, migraine, arthralgia, neuralgia, neuropathies, nerve injury, skin disorder, urinary bladder hypersensitiveness, irritable bowel syndrome, fecal urgency, a respiratory disorder, irritation of skin, eye or mucous membrane, stomach-duodenal ulcer, inflammatory diseases, ear disease, heart disease and so on.

Description

NOVEL COMPOUNDS, ISOMER THEREOF, OR
PHARMACEUTICALLYACCEPTABLE SALTS THEREOFAS
VANILLOID RECEPTOR ANTAGONIST; AND PHARMACEUTICAL
COMPOSITIONS CONTAINING THE SAME
TECHNICAL FIELD ;
The present disclosure relates to novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as TRPVl antagonist; and a i pharmaceutical composition containing the same. j i 1
BACKGROUND ART I
The vanilloid receptor- 1 (VRl, or transient receptor potential vanilloid-1,
TRPVl) is the receptor for capsaicin (8-methyl-N-vaniHyl-6-nonenamide|), a pungent ingredient in hot peppers. The molecular cloning of TRPVl was reported in 1997 (Caterina et al, 1997, Nature, 389, ρρ816-824), which belongs to the TRP j channel family of non-selective cation channel. TRPVl is activated or sensitized
I by stimuli such as capsaicin, resiniferatoxin, heat, acid, anandamide, lipid metabolites or the like; thus it plays a crucial role as a molecular integrator of noxious stimuli in mammals (Tominaga et al, 1998, Neuron, 21 pp531-J543; Hwang et al, 2000, PNAS, 97, pρ6155-6160). The TRPVl is highly expressed in primary afferent sensory neurons, and also reportedly expressed in varjious organs and tissues such as bladder, kidney, lung, intestine, skin, central nervous i system (CNS), and non-neuronal tissues (Mezey et al., 2000, PNAS, 91, pp3655-
3660; Stander et al, 2004, Exp. Dermatol 13, ρpl29-139; Cortright et al, 2Q01, BBRC, 281, ppll83-1189), and besides TRPVl protein is upregulated in painful disease conditions. Activation of the TRPVl by endogenous/exogenous stimuli leads to not only transmission of noxious stimuli, but also liberation of neuropeptides such as substance P, CGRP (Calcitonin Gene-Related Peptide) in the neurons, thereby causing neurogenic inflammation. TRPVl knock-out mice show normal responses in a wide range of behavioural tests including noxious mechanical and acute thermal stimuli, but exhibit little thermal hypersensitivity in inflammation states. (Caterina et al, 2000, Science, 288, pp306-313; Davis et al, 2000, Nature, 405, ppl83-187; Karai et al, 2004, J. Clin. Invest., 113, ppl344- 1352).
As mentioned above, the TRPVl knock-out mice exhibit reduced responses to thermal or noxious stimuli, which has been supported by the effects of TRPVl antagonists in various animal models of pain (Immke et al., 2006, Semin. Cell. Dev. Biol, 17(5), pp582-91; Ma et al., 2007, Expert Opin. Ther. Targets, 11(3), pp307-20). The well-known TRPVl antagonist, capsazepine, decreases hyperalgesia caused by physical stimuli in several models of inflammatory and neuropathic pain (Walker et al., 2003, JPET, 304, pp56-62; Garcia-Martinez et al, 2002, PNAS, 99, 2374-2379). In addition, treatment of the primary culture of afferent sensory neurons with the TRPVl agonist, capsaicin etc., results in damage to nerve functions and furthermore death of nerve cells. The TRPVl antagonist exerts defense actions against such damage to nerve functions and nerve cell death (Holzer P., 1991, Pharmacological Reviews, 43, ppl43-201; Mezey et al., 2000, PNAS, 97, 3655-3660). The TRPVl is expressed on sensory neurons distributed in all regions of the gastrointestinal tract and is highly expressed in inflammatory disorders such as irritable bowel syndrome and inflammatory bowel disease (Chan et al., 2003, Lancet, 361, pp385-391; Yiangou et al, 2001, Lancet, 357, ρpl338-1339). In addition, activation of the TRPVl stimulates sensory nerves, which in turn causes release of neuropeptides which are known to play a critical role in pathogenesis of gastrointestinal disorders such as gastroesophageal reflux disease (GERD) and stomach duodenal ulcer (Holzer P., 2004, Eur. J. Pharmacol. 500, pρ231-241; Geppetti et al, 2004, Br. J. Pharmacol, 141, ppl313-1320).
The TRPVl -expressing afferent nerves are abundantly distributed in airway mucosa, and bronchial hypersensitivity is very similar mechanism to hyperalgesia. Protons and lipoxygenase products, known as endogenous ligands for the TRPVl, are well known as crucial factors responsible for development of asthma and chronic obstructive pulmonary diseases (Hwang et al, 2002, Curr. Opin. Pharmacol. pp235-242; Spina et ah, 2002, Curr. Opin. Pharmacol. pp264- 272). Moreover, it has been reported that air-polluting substances which are a kind of asthma-causing substances, i.e., particulate matter specifically acts on the TRPVl and such action is inhibited by capsazepine (Veronesi et ah, 2001, NeuroToxicology, 22, pp795-810). Urinary bladder hypersensitiveness and urinary incontinence are caused by various central/peripheral nerve disorders or injury, and TRPVl expressed in afferent nerves and urothelial cells play an important role in bladder inflammation. (Birder et ah, 2001, PNAS, 98, ρpl3396-13401). Further, TRPVl knock-out mice are anatomically normal but have higher frequency of low-amplitude, non-voiding bladder contractions and reduced reflex voiding during bladder filling as compared to wild type mice, which is thus indicating that the TRPVl affects functions of the bladder (Birder et ah, 2002, Nat. Neuroscience, 5, pp856-860). The TRPVl is distributed in human epidermal keratinocytes as well as in primary afferent sensory nerves (Denda et ah, 2001, Biochem. Biophys. Res. Commun., 285, ppl250-1252; Inoue et ah, 2002, Biochem. Biophys. Res. Commun., 291, ppl24-129), and it is then involved in transmission of various noxious stimuli and pains such as skin irritation and pruritus, thereby having close correlation with etiology of dermatological diseases and disorders, such as skin inflammation, due to neurogenic/non-neurogenic factors. This is supported by the report that the TRPVl antagonist, capsazepine inhibits inflammatory mediators in human skin cells (Southall et ah, 2003, J. Pharmacol. Exp. Ther., 304, pp217-222). Over recent years, evidence has been accumulation on other roles of TRPVl. TRPVl might be involved in the blood flow/pressure regulation via sensory vasoactive neuropeptide release and in the regulation of plasma glucose levels or in the pathogenesis of type 1 diabetes (Inoue et ah, Cir. Res., 2006, 99, pp 119-31; Razavi et ah, 2006, Cell, 127, pρll23-35; Gram et ah, 2007, Eur. J. Neuroscl, 25, ρp213-23). Further, it is reported that TRPVl knock-out mice show less anxiety-related behavior than their wild type littermates with no differences in locomotion (Marsch et ah, 2007, J. Neurosci., 27(4), pp832-9).
Based on the above-mentioned information, development of various TRPVl antagonists is under way, and some patents and patent applications relating to TRPVl antagonists under development were published. (Szallasi et al, 2007, Nat. Rev. Drug Discov., 6, ρp357-72; Appendino et al, 2006, Progress in Medicinal Chemistry, 44, ppl45-180; Rami et al, 2004, Drug Discovery Today: Therapeutic Strategies, I5 pp97-104; Correll et al, 2006, Expert Opin. Ther. Patents, 16, pp783-795; Kyle et al, 2006, Expert Opin. Ther. Patents, 16, pp977- 996)
Compounds of the present disclosure, are useful for prophylaxis and treatment of diseases associated with the activity of TRPVl (Nagy et al., 2004, Eur. J. Pharmacol. 500, 351-369) including but not limited to, pain such as acute pain, chronic pain, neuropathic pain, post-operative pain, rheumatic arthritic pain, osteoarthritic pain, postherpetic neuralgia, neuralgia, headache, dental pain, pelvic pain, migraine, bone cancer pain, mastalgia and visceral pain (Petersen et ah, 2000, Pain 88, pρl25-133; Walker et al., 2003, J. Pharmacol. Exp. Ther., 304, pp56-62; Morgan et al, 2005, J. Orofac. Pain, 19, pp248-60 ; Dinis et al, 2005, Eur. Urol., 48, ppl62-7; Akerman et al, 2004, Br. J. Pharmcol, 142, ppl354- 1360; Ghilardi et al, 2005, J. Neuroscl, 25, 3126-31; Gopinath et al, 2005, BMC Womens Health, 5, 2-9) ; nerve-related diseases such as neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, and stroke (Park et al, 1999, Arch. Pharm. Res. 22, pρ432-434; Kim et al, 2005, J. Neuroscl 25(3), ρp662-671); diabetic neuropathy (Kamei et al, 2001, Eur. J. Pharmacol 422, pp83-86); fecal urgency; irritable bowel syndrome (Chan et al, 2003, Lancet, 361, pp385-391); inflammatory bowel disease (Yiangou et al, 2001, Lancet 357, ppl338-1339); gastrointestinal disorders such as gastro-esophageal reflux disease (GERD), stomach duodenal ulcer and Crohn's disease (Holzer P, 2004, Eur. J. Pharm., 500, pp231-241; Geppetti et al, 2004, Br. J. Pharmacol, 141, ppl313-1320); respiratory diseases such as asthma, chronic obstructive pulmonary disease, cough (Hwang et al, 2002, Curr. Opin. Pharmacol. ρp235-242; Spina et al, 2002, Curr. Opin. Pharmacol. pp264-272; Geppetti et al, 2006, Eur. J. Pharmacol, 533, pp207-214 ; McLeod et al, 2006, Cough, 2, 10); urinary incontinence (Birder et al, 2002, Nat. Neuroscience 5, pp856-860); urinary bladder hypersensitiveness (Birder et al, 2001, PNAS, 98, ρpl3396-13401); neurotic/allergic/inflammatory skin diseases such as psoriasis, pruritus, prurigo and dermatitis (Southall et al, 2003, J. Pharmacol. Exp. Ther,, 304, pρ217-222); irritation of skin, eye or mucous membrane (Tominaga et al, 1998, Neuron 21 pp531-543); hyperacusis; tinnitus; vestibular hypersensitiveness (Balaban et al, 2003, Hear Res. 175, pp 165-70); cardiac diseases such as myocardial ischemia (Scotland et al., 2004, Circ. Res. 95, ppl027-1034; Pan et al., 2004, Circulation 110, ppl826-1831); haemorrhagic shock (Akabori et al., 2007, Ann. Surg., 245(6), pp964-70); hair growth-related disorders such as hirsutism, effluvium, alopecia (Bodό et al., 2005, Am. J. Patho. 166, pp985-998; Birό et al, 2006, J. Invest. Dermatol, ppl-4); rhinitis (Seki et al., 2006, Rhinoϊogy, 44? pp 128-34); pancreatitis (Hutter et al, 2005, Pancreas, 30, pp260-5); cystitis (Dinis et al, 2004, J. Neurosci., 24, pp 11253-63; Sculptoreanu et al, 2005, Neurosci. Lett. 381, pp42-6); vulvodynia (Tympanidis et al.,, 2004, Eur. J. Pain, 8, ppl2-33); psychiatric disorders such as anxiety or fear (Marsch et al, 2007, J. Neurosci., 21 (A), pp832-9).
Compounds that are related to VRl activities are discussed e.g. in WO 02/61317, WO 02/090326, WO 02/16318, WO 02/16319, WO 03/053945, WO 03/099284, WO 03/049702, WO 03/049702, WO 03/029199, WO 03/70247, WO 04/07495, WO 04/72068, WO 04/035549, WO 04/014871, WO 04/024154, WO 04/024710, WO 04/029031, WO 04/089877, WO 04/089881, WO 04/072069, WO 04/111009, WO 05/03084, WO 05/073193, WO 05/05139O5 WO 05/049613, WO 05/049601, WO 05/047280, WO 05/047279, WO 05/044802, WO 05/044786, WO 06/097817, WO 06/098554, WO 06/100520, WO 06/101321, WO 06/102645, WO 06/103503, WO 06/111346, WO 06/101321, WO 06/101318, WO 06/1113769, WO 06/116563, WO 06/120481, WO 06/122250, WO 06/122799, WO 06/129164, WO 06/51378, WO 06/95263, WO 07/42906, WO 07/45462, WO 07/50732, WO 07/54474, WO 07/54480, WO 07/63925. WO 07/65663, WO 07/65888, WO 07/67619, WO 07/67710, WO 07/67711, WO 07/67756, WO 07/67757, WO07/63925, WO07/65662, WO07/65663, WO07/65888, WO07/69773, US20070149517, or US20070149513.
More specificically, WO 06/101321 and WO 06/101318 relate to VRl modulators with a biphenyl partial structure. As a result of extensive and intensive studies, the present inventors have consequently synthesized novel compounds having VRl antagonistic activity. Said new compounds have biphenylic structures, wherein one phenyl ring is substituted in para position to its attachment position to the rest of the molecule with a trifluoromethyl group or a fluoro, and has at least one additional substituent in ortho position (relative to said attachment position). Compared to the specific compounds disclosed in WO 06/101321 or WO 06/101318, which do not show this particular combination of features, the present compounds show remarkable improvement of their physicochemical characteristics, such as metabolic stability or pharmacokinetic profiles. Therefore, it is an object of the present disclosure to provide novel compounds useful as a potent antagonist for a TRPVl, isomer thereof and pharmaceutically acceptable salts thereof; and a pharmaceutical composition comprising the same.
DETAILED DESCRIPTION OFTHE DISCLOSURE
The present disclosure provides a novel compound of the following formula (Ia), an isomer, or a pharmaceutically acceptable salt thereof:
Figure imgf000007_0001
formula (Ia) wherein,
A iS -C=C- Or -CH-CH-;
Ri is hydrogen, or C1-C3 alkyl;
R2 and R3 are independently hydrogen, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, halo(Cl-C3)alkyl, (C2-C5)alkenyl, or (C2-C5)alkynyl; R4 is halo(Cl-C3)alkyl or halogen;
R5 is C2-C10 alkyl, C2-C10 alkoxy, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5 alkoxy (C1-C5) alkylamino, C2-C10 alkylamino, di(Cl-C5 alkyl)amino, C3-C6 cycloalkylamino, C3-C6 cycloalkoxy, or (C3-C6)cycloalkyl(Cl-C3)alkyloxy; and R6 is hydrogen, Cl-ClO alkyl, Cl-ClO alkoxy, or Cl-ClO alkylamino.
The present disclosure also provides a novel compound of the following formula (I), an isomer, or a pharmaceutically acceptable salt thereof:
formula (I) wherein,
R1 is hydrogen, methyl, or ethyl;
R2 and R3 are independently hydrogen, halogen, cyano, methyl, ethyl, methoxy, trifluoromethyl, vinyl, or acetylenyl; R4 is trifluoromethyl or fluoro;
R5 is C2-C5 alkyl, C2-C5 alkoxy, C1-C2 alkoxy (C1-C3) alkoxy, C1-C2 alkoxy
(C1-C3) alkylamino, C2-C5 alkylamino, di(Cl-C3 alkyl)amino, C3-C6 cycloalkylamino, C3-C6 cycloalkoxy, or (C3-C6)cycloalkyl(Cl-C3)alkyloxy; and
R6 is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, or C1-C5 alkylamino.
Another aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; as described above wherein If R5 is ethoxy, butoxy, pentoxy, (C3-C6)cycloalkoxy, or (C3-C6)cycloalkyl(Cl-C3)alkyloxy, then R1 is methyl. In another embodiment in the compounds of formula (Ia) or (I) as disclosed further above, if R5 is ethoxy, butoxy, or pentoxy, and R4 is simultaneously fluoro, then Ri is methyl.
In another embodiment in the compounds of formula (Ia) or (I) as disclosed further above, if R5 is ethoxy, butoxy, or pentoxy, then R4 is trifluoromethyl. In this specific embodiment, Ri is preferably methyl.
Another aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, Ri is hydrogen; R2 is halogen; and R5 is C2-C4 alkyl or C2-C4 alkylamino.
One aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable . salt thereof; wherein, Ri is hydrogen; R2 is fluoro; R3 is hydrogen, fluoro, cyano, methyl, vinyl, or acetylenyl; R4 is trifluoromethyl; R5 is C2-C4 alkyl or C2-C4 alkylamino; and
R6 is hydrogen.
Another aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, R1 is hydrogen, methyl, ethyl, or preferably methyl.
One aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, Ri is methyl; R2 is halogen; and R5 is C2-C4 alkyl, C2-C4 alkyloxy, or C2-C4 alkylamino.
Another aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein,
Ri is methyl;
R2 is fluoro;
R3 is hydrogen, fluoro, vinyl, methyl, or acetylenyl;
R5 is C2-C4 alkyl, C2-C4 alkyloxy, or C2-C4 alkylamino; and R6 is hydrogen or C1-C3 alkyl.
One aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, R2 and R3 are independently hydrogen, fluoro, cyano, methyl, ethyl, methoxy, trifluoromethyl, vinyl, acetylenyl, or preferably hydrogen, fluoro, cyano, methyl, vinyl, or acetylenyl. One aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, R2 and R3 are both fluoro.
One aspect of the present disclosure is a compound according to the above formula (Ia) or (I)5 an isomer, or a pharmaceutically acceptable salt thereof; wherein, R4 is fluoro, or preferably trifluoromethyl.
One aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, R5 and R6 are both C1-C3 alkyl; or preferably methyl, ethyl, or propyl; or more preferably propyl.
One aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, R6 is hydrogen.
One aspect of the present disclosure is a compound according to the above formula (Ia) or (I), an isomer, or a pharmaceutically acceptable salt thereof; wherein, R5 is ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, or cyclohexylmethoxy, provided that if R5 is ethoxy, butoxy, pentoxy, or cyclohexylmethoxy, then R1 is methyl.
Another aspect of the present disclosure is a compound of the formula (Ia) or (I) as further described herein, an isomer, or a pharmaceutically acceptable salt thereof, wherein, if Ri is methyl or ethyl, then the compound may be a pure enantiomer or may be a mixture of the (R) and (S)-enantiomer; and then, the C- atom to which Ri is attached is preferably in the (Reconfiguration.
Another aspect of the present disclosure is compounds of the formula (Ia) or (I) as further described herein, an isomer, or a pharmaceutically acceptable salt thereof wherein,
R5 is C2-C5 alkyl, (C2~C5)alkyloxy, C1-C4 alkylamino, or (C3-
C6)cycloalkylalkoxyoxy, wherein preferably, R5 is C2-C4 alkyl, (C2-C4)alkyloxy, or C2-C4 alkylamino; wherein particularly preferably,
R5 is C2-C4 alkyl, or C1-C3 alkylamino; wherein particularly preferably,
R5 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, or cyclohexylmethoxy, wherein particularly preferably,
R5 is C2-C4 alkyl, propoxy, isopropoxy, or C2-C4 alkylamino; wherein even more preferably,
R5 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, propoxy, isopropoxy, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, or sec-butylamino, wherein even more preferably,
R5 is n-propyl, n-butyl, isobutyl, isopropoxy, sec-butoxy, ethylamino, n- propylamino, isopropylamino, n-butylamino, wherein more preferably,
R5 is n-propyl, n-butyl, isobutyl, n-propoxy, ethylamino, propylamine, isopropylamino, n-butylamino, wherein even more preferably,
R5 is propyl, butyl, isobutyl, ethylamino, propylamino, or isopropylamino, wherein even more preferably,
R5 is propyl, butyl, ethylamino, propylamino, or isopropylamino.
Preferred examples of compounds according to the disclosure are selected from the group consisting of:
N- [ 1 -(3 , 5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3 -(2-ρropylamino-4- trifluoromethyl-phenyl)-acrylamide,
N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-propylamino-4- trifluoromethyl-phenyl)-acrylamide,
(i?)-3-(2-Butylamino-4-trifluoromethyl-ρhenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide, (R)-N- [ 1 -(3 ,5 -Difluoro-4-methanesulfonylamino-ρhenyl)-ethyl] -3 -(2-propoxy-4- trifluoromethyl-phenyl)-acrylamide,
(R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2,6-dipropyl-
4-trifluoromethyl-phenyl)-acrylamide, (R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethoxy-4- trifluoromethyl-phenyl)-acrylamide, (R)-N-[ 1 -(3 ,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3 -(2- ethylamino-4-trifluoromethyl-phenyl)-acrylamide,
N-(3-Fluoro-4-methanesulfonylamino-5-methyl-benzyl)-3-(2-propylamino-4- trifluoromethyl-phenyl)-acrylamide,
N-(3-Fluoro-4-methanesulfonylamino-5-vinyl-benzyl)-3-(2-propylamino-4- trifluoromethyl-phenyl)-acrylamide,
N-(3 -Cyano-5 -fluoro-4-methanesulfonylamino-benzyl)-3 -(2-propylamino-4- trifluoromethyl-phenyl)-acrylamide, N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-propoxy-4- trifluoromethyl-phenyl)-acrylamide,
(R)-3-(2,6-Dibutyl-4-trifluoromethyl-phenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-3-(2,6-Diethyl-4-trifluoromethyl-ρhenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-ethylamino-4- trifluoromethyl-phenyl)-acrylamide,
3 -(2-Ethylamino-4-trifluoromethyl-phenyl)-N-(3 -fluoro-4- methanesulfonylamino-5-methyl-benzyl)-acrylamide, N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-isopropoxy-4- trifluoromethyl-phenyl)-acrylamide,
(R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-4- trifluoromethyl-phenyl)-acrylamide,
N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-propyl-4-trifluoromethyl- phenyl)-acrylamide,
N-(3-Fluoro-4-methanesulfonylamino-5-methyl-benzyl)-3-(2-propyl-4- trifluoromethyl-phenyl)-acrylamide, (R)-3-(2-Butyl-4-trifluoromethyl-ρhenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide5
(R)-N-[ 1 -(3,5 -Difluoro-4-methanesulfonylamino-ρhenyl)-propyl] -3 -(2-propyl-4- trifluoromethyl-phenyl)-acrylamide, (i?)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-ρhenyl)-ethyl]-3-(2-isoρropoxy-
4-trifluoromethyl-phenyl)-acrylamide,
(R)-N-[l-(3,5-DifluoiO-4-metlianesulfonylamino-phenyl)-ethyl]-3-(4-fluoro-2- propoxy-phenyl)-acrylamide,
(R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(4-fluoro-2- propylamino-phenyl)-acrylamide,
(R)-3-(2-Butoxy-4-trifluoromethyl-ρhenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-3 -(2-Butoxy-4-fluoro-pheny I)-N- [ 1 -(3 , 5-difluoro-4-methanesulfonylamino- phenyl)-ethyl] -acrylamide, N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-propyl-4- trifluoromethyl-phenyl)-acrylamide,
(R)-3 -(2-Butyl-4-trifluoromethyl-ρhenyl)-N- [ 1 -(3 -fluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-3-(2-sec-Butoxy-4-trifluoromethyl-phenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-3-(2-sec-Butoxy-4-fluoro-phenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide, (R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-ρhenyl)-ethyl]-3-(2- ethylamino-4-fluoro-phenyl)-acrylamide, N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-ethylammo-4-fluoro- phenyl)-acrylamide,
(R)-N-(2-Fluoro-4-{ l-[3-(2-propyl-4-trifluoromethyl-phenyl)-allylaπiino]-ethyl}- phenyl)-methanesulfonamide5
(R)-3-(2-Butylamino-4-fluoro-phenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
3-(2-Butylamino-4-fluoro-phenyl)-N-(3,5-difluoro-4-methanesulfonylamino- benzyl)-acrylamide, (i?)~N-[l-(3,5-Difluoro-4-methanesulfonylamino-ρhenyl)-ethyl]-3-(2-isobutyI-4- trifluoromethyl-phenyl)-acrylamide3
(R)-3-(2-Cyclohexylmethoxy-4-trifluoromethyl-phenyl)-N-[l-(3,5-difluoro- 4methanesulfonylamino-phenyl)-ethyl]-acrylamide, (i?)-N-[l-(3,5-Difluoro-4-methanesulfonylammo-phenyl)-ethyl]-3-(4-fIuoro-2- ρropyl-phenyl)-acrylamide,
N-(3-Fluoro-4-methanesulfonylamino-5-vinyl-benzyl)-3-(2-isopropylamino-4- trifluoromethyl-phenyl)-acrylamide5 and
(R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethylJ-3-(2- propylamino-4-trifluoromethyl-phenyl)-propionamide.
Particularly preferred examples of compounds according to the disclosure are selected from the group consisting of:
N-[ 1 -(3 , 5-Difluoro-4-methanesulfonylamiiio-phenyl)-ethyl] -3 -(2-propylamino-4- trifluoromethyl-phenyl)-acrylamide,
(R)-3-(2-Butylamino-4-trifluoromethyl-phenyl)-N-[l-(3,5-difluoro-4-methane sulfonylamino-phenyl)-ethyl]-acrylamide,
(i?)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propoxy-4- trifluoromethyl-ρhenyl)-acrylamide, (i?)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2,6-dipropyl-
4-trifluoromethyl-ρhenyl)-acrylamide,
(R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethoxy-4- trifluoromethyl-phenyl)-acrylamide,
(R)-N- [ 1 -(3 , 5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3 -(2-ethylamino- 4-trifIuoromethyl-phenyl)-acrylarnide,
N-(3-Fluoro-4-methanesulfonylamino-5-methyl-benzyl)-3-(2-propylamino-4- trifluoromethyl-phenyl)-acrylamide,
N-(3-Fluoro-4-methanesulfonylamino-5-vinyl-benzyl)-3-(2-propylamino-4- trifluoromethyl-phenyl)-acrylamide, N-(3-Cyano-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-proρylamino-4- trifluoromethyl-phenyl)-acrylamide5
(R)-3 -(2, 6-Diethyl-4-trifluoromethyl-ρhenyl)-N-[ 1 -(3 ,5-difluoro-4-methane sulfonylamino-phenyl)-ethyl]-acrylamide,
N-(3 , 5 -Difluoro-4-methanesulfonylamino-benzy l)-3 -(2-ethylamino-4-trifluoro methyl-phenyl)-acrylamide5
N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-isopropoxy-4-trifluoro methyl-phenyl)-acrylamide,
(i?)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-4- trifluoromethyl-phenyl)-acrylamide,
(R)-3-(2-Butyl-4-trifluoromethyl-phenyl)-N-[l-(3,5-difluoro-4-methanesulfonyl amino-pheny l)-ethy 1] - aery lamide, (R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-isoρroρoxy-
4-trifluoromethyl-phenyl)-acrylamide,
(R)-3 -(2-Butoxy-4-trifluoromethyl-phenyl)-N- [l-(3.5 -difluoro-4-methanesulfonyl amino-phenyl)-ethyl]-acrylamide,
(i?)-3-(2-Butoxy-4-fluoro-phenyl)-N-[l-(3,5-difluoro-4-methanesulfonylamino- phenyl)-ethyl]-acrylamide,
N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-propyl-4- trifluoromethyl-phenyl)-acrylamide,
(i?)-3-(2-Butyl-4-trifluoromethyl-ρhenyl)-N-[l-(3-fluoro-4-methanesulfonyl amino-phenyl)-ethyl]-acrylamide, (R)-3 -(2-sec-Butoxy-4-trifluoromethyl-pheny I)-N- [ 1 -(3 , 5-difluoro-4-methane sulfonylamino-phenyl)-ethyl]-acrylamide,
(i?)-3 -(2-sec-Butoxy-4-fluoro-pheny I)-N- [ 1 -(3 , 5 -difluoro-4-methanesulfonyl amino-phenyl)-ethyl] -acrylamide,
(i?)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-etliyl]-3-(2-ethylamino- 4-fluoro-phenyl)-acrylamide,
(R)-N-(2-Fluoro-4- { 1 - [3 -(2-propyl-4-trifluoromethyl-phenyl)-allylamino]-ethyl } - phenyl)-methanesulfonamide,
(R)-3-(2-Butylamino-4-fluoro-phenyl)-N-[l-(3,5-difluoro-4-methanesulfonyl amino-phenyl)-ethyl]-acrylamide, (i?)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-isobutyl-4- trifluoromethyl-phenyl)-acrylamide, and
N-(3 -Fluoro-4-methanesulfonylamino-5 -vinyl-benzyl)-3 -(2-isoproρylamino-4- trifluoiOmethyl-phenyl)-acrylamide.
The compounds of the formula (Ia) or (I) of the present disclosure can chemically be synthesized by the following reaction schemes. However, these are given only for illustration of the disclosure and not intended to limit to them.
[Scheme 1]
Figure imgf000016_0001
1
The Scheme 1 shows a proposed process for synthesizing acrylamide compound with various substituents. Substituted benzylamine (1) is reacted with phenylacrylic acid (2) to yield benzyl phenylacrylamide (3) using DMTMM {4- (4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride} (Tetrahedron Lett., 1999, 40, 5327).
[Scheme 2]
Figure imgf000016_0002
The Scheme 2 shows a proposed process for synthesizing acrylamide compound (11) with various substituents. 4-Substituted 2-aminobenzoic acid (5), which is prepared by hydrogenation of 4-substituted 2-nitrobenzoic acid (4), is converted to the corresponding alkylamino benzoic acid (6) via reductive animation. The substituted benzoic acid (6) is converted to the corresponding Weinreb amide (7), which is reduced by lithium aluminum hydride to yield substituted benzaldehyde (8). The benzaldehyde (8) is converted to methyl phenyl acrylic ester (9) by Wittig reaction. The methyl phenyl acrylic ester (9) is hydrolyzed with lithium hydroxide to yield phenyl acrylic acid (10). The phenyl acrylic acid (10) is reacted with substituted benzylamine (1) as shown in scheme 1 to yield benzyl phenylacrylamide (11).
[Scheme 3]
Figure imgf000017_0001
The Scheme 3 shows a more efficient process for synthesizing alkylamino benzoic acid (6) which is an intermediate to benzyl phenylacrylamide (11). One pot hydrogenation reaction of 4-substituted 2-nitrobenzoic acid (4) in the presence of an aldehyde and acetic acid replaces the two-step process including hydrogenation of 4 and reductive amination of the corresponding 2-aminobenzoic acid 5.
[Scheme 4]
Figure imgf000017_0002
The Scheme 4 shows an alternative process for synthesizing Weinreb amide (7) which is an intermediate to benzyl phenylacrylamide (11). 4-Substituted
2-nitrobenzoic acid (4) is converted to the corresponding Weinreb amide (12).
Hydrogenation of the weinreb amide (12) followed by reductive amination with an aldehyde yields Weinreb amide (7).
Figure imgf000018_0001
The Scheme 5 shows a proposed process for synthesizing acrylamide compound (20) with various substituents. 4-Substituted 2-hydroxybenzoic acid (13) is reacted with an alkyl halide and potassium carbonate to yield corresponding alkoxy benzoate (14), which is hydrolyzed with lithium hydroxide to give alkoxy benzoic acid (15). The substituted benzoic acid (15) is converted to benzyl phenylacrylamide (20) by similar processes used for benzyl phenylacrylamide (11) shown in Scheme 2.
[Scheme 6]
Figure imgf000018_0002
The Scheme 6 shows an alternative process for synthesizing methyl phenyl acrylic ester (18) which is an intermediate to benzyl phenylacrylamide
(20). 4-Substituted 2-hydroxybenzaldehyde (21) is converted to corresponding methyl phenyl acrylic ester (22) by Wittig reaction, which is reacted with an alkyl halide and potassium carbonate to yield methyl phenyl acrylic ester (18).
[Scheme 7]
Figure imgf000019_0001
The Scheme 7 shows a proposed process for synthesizing acrylamide compound (25) with various substituents. 4-Triflurometfiyl iodobenzene is converted to substituted phenyl acrylic acid methyl ester (23) by palladium catalyzed coupling reaction. The phenyl acrylic acid methyl ester (23) is hydrolyzed with lithium hydroxide to yield phenyl acrylic acid (24). The phenyl acrylic acid (24) is reacted with substituted benzylamine (1) as described in Scheme 1 to yield benzyl phenylacrylamide (25).
[Scheme 8]
Figure imgf000019_0002
The Scheme 8 shows a proposed process for synthesizing acrylamide compound (32) with various substituents. Substituted benzoyl chloride (26) is reacted with 2-amino-2-methyl-l-propanol in the present of a base, and the resulting adduct is treated with thionyl chloride followed by sodium hydroxide to afford dihydro-oxazole compound (27). After treated with n-butyl lithium at low temperature, the compound 27 is reacted with an alkyl halide to give disubstituted dihydro-oxazole (28). The compound 28 is hydrolyzed with conc-HCl to the corresponding benzoic acid, which is converted to the Weinreb amide (29). After reducing compound 29 with lithium aluminum hydride, the resulting aldehyde is converted to the phenyl acrylic ester (30) under suitable Wittig reaction conditions. The acrylic ester (30) is hydrolyzed with lithium hydroxide to yield the corresponding acrylic acid (31). Substituted benzylamine (1) is reacted with acrylic acid (31) as described in Scheme 1 to yield benzyl phenylacrylamide (32).
[Scheme 9]
Figure imgf000020_0001
The Scheme 9 shows a proposed process for synthesizing amide compound (33) with various substituents. Substituted acrylamide (3) is reduced with PdVC under hydrogen pressure to yield amide compound (33).
The present disclosure also provides to a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof for use as a medicament.
In one embodiment, the present disclosure also provides a pharmaceutical composition comprising a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier. In another embodiment, the present disclosure also provides a composition comprising a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof; and pharmaceutically acceptable carrier for preventing or treating a condition associated with the pathological stimulation and/or aberrant expression of vanilloid receptor.
In one preferred aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, for treating a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV- related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis, and pancreatitis.
In a particularly preferred aspect, the present disclosure relates to the pharmaceutical composition comprising a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof for treating pain as described above, wherein the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non- inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), visceral pain, migraine, and other types of headaches. The present disclosure also provides a pharmaceutical composition comprising a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, which is characterized in that it is adapted for oral administration.
In one aspect, the present disclosure relates to the use of a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof for the preparation of a medicament
In another aspect, the present disclosure relates to the use of a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a condition that is associated with the aberrant expression and/or aberrant activation of a vanilloid receptor.
In a preferred aspect, the present disclosure relates to the use of a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, in preparation of a medicament for the prevention or treatment of a condition that is selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis and pancreatitis.
In a particularly preferred aspect, the present disclosure relates to the use of the compound of formula (Ia) or (I), an isomer thereof, for preparing a medicament for preventing or treating pain as described above, wherein the condition is pain, which is or which is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), visceral pain, migraine, and other types of headaches.
In another aspect, the present disclosure relates to a method for inhibiting vanilloid ligand from binding to vanilloid receptor in a patient, comprising contacting cells expressing vanilloid receptor in the patient with the compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.
In another aspect, the present disclosure relates to a method for preventing or treating a condition associated with the pathological stimulation and/or aberrant expression of vanilloid receptors.
In another aspect, the present disclosure also provides a method for preventing or treating a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis, and pancreatitis, which comprises administering to a mammal including a person in need thereof a therapeutically effective amount of the compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.
In a particularly preferred aspect, the present disclosure relates to the method of treating pain by administering a compound of formula (Ia) or (I), an isomer thereof, or a pharmaceutically acceptable salt thereof as described above, wherein the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), visceral pain, migraine, and other types of headaches
Hereinafter, the formulating methods and kinds of excipients will be described, but the present disclosure is not limited to them. A compound of formula (Ia) or (I), an isomer thereof or a pharmaceutically acceptable salt thereof according to the present disclosure can be prepared as a pharmaceutical composition containing pharmaceutically acceptable carriers, adjuvants, diluents and the like. For instance, the compounds of the present disclosure can be dissolved in oils, propylene glycol or other solvents which are commonly used to produce an injection. Suitable examples of the carriers include, but not limited to, physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc. For topical administration, the compounds of the present disclosure can be formulated in the form of ointment or cream.
The compound according to the present disclosure may also be used in the forms of pharmaceutically acceptable salts thereof, and may be used either alone or in combination or in admixture with other pharmaceutically active compounds. The compounds of the present disclosure may be formulated into injections by dissolving, suspending or emulsifying in water-soluble solvent such as saline and 5% dextrose, or in water-insoluble solvents such as vegetable oils, synthetic fatty acid glyceride, higher fatty acid esters and propylene glycol. The formulations of the disclosure may include any of conventional additives such as dissolving agents, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.
The preferable dose level of the compounds according to the present disclosure depends upon a variety of factors including the condition and body weight of the patient, severity of the particular disease, dosage form, and route and period of administration, but may appropriately be chosen by those skilled in the art. The compounds of the present disclosure are preferably administered in an amount ranging from 0.001 to 100 mg/kg of body weight per day, and more preferably from 0.01 to 30 mg/kg of body weight per day. Doses may be administered once a day, or several times a day with each divided portions. The compounds of the present disclosure are used in a pharmaceutical composition in an amount of 0.0001 — 10% by weight, and preferably 0.001 — 1% by weight, based on the total amount of the composition.
The pharmaceutical composition of the present disclosure can be administered to a mammalian subject such as rat, mouse, domestic animals, human being and the like via various routes. The methods of administration which may easily be expected include oral and rectal administration; intravenous, intramuscular, subcutaneous, intrauterine, duramatral and intracerebroventricular injections.
DETAILED DESCRIPTION QF THE DEFINITIONS
When describing the compounds, pharmaceutical compositions containing such compounds, methods of using such compounds and compositions, and use of such compounds and compositions, all terms used in the present application shall have the meaning usually employed by a relevant person skilled in the art, e.g. by a medicinal chemists, pharmacist or physician. By the way of example some definitions of specific groups are given below: "Alkenyl" includes monovalent olefmically unsaturated hydrocarbyl groups being straight-chained or branched and having at least 1 double bond. "Alkenyl" has preferably 2-5 carbon atoms ("C1-C5 alkenyl"), 2-4 carbon atoms ("C2-C4 alkenyl"), or only 2-3 carbon atoms ("C2-C3 alkenyl"). Particular alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CHaCH=CH2), isopropenyl (C (CH3) =CH2), and the like. A preferred "alkenyl" group is ethenyl (vinyl).
"Alkoxy" includes the group -OR wherein R is "alkyl" as defined further above. Particular alkoxy groups include, by way of example, methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, tert-butoxy, iso-butoxy, sec-butoxy, n-pentoxy, 1,2-dimethyIbutoxy, and the like.
"Alkoxyalkoxy" refers to the group -OROR', wherein R and R' are the same or different "alkyl" groups as defined further above.
"Alkoxyalkylamino" refers to the group -NH(ROR'), wherein R and R' are the same or different "alkyl" groups as defined further above. "Alkyl" includes monovalent saturated aliphatic hydrocarbyl groups. The hydrocarbon chain may be either straight-chained or branched. "Alkyl" has 1-6 carbon atoms ("C1-C6 alkyl"), and in some instances preferably 1-5 carbon atoms ("C1-C5 alkyl"), 1-4 carbon atoms ("C1-C4 alkyl"), or only 1-3 carbon atoms ("C1-C3 alkyl"). This term is exemplified by groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, t-amyl, and the like.
"Alkynyl" includes acetylenically unsaturated hydrocarbyl groups being straight-chained or branched and having at least 1 triple bond. "Alkynyl" has preferably 2-6 carbon atoms ("C2-C6 alkynyl"), and in some instances even more preferably 2-5 carbon atoms ("C1-C5 alkynyl"), 2-4 carbon atoms ("C2-C4 alkynyl"), or only 2-3 carbon atoms ("C2-C3 alkynyl"). A preferred alkynyl group is ethynyl (acetylenyl). "Alkylamino" includes the group -NHR1, wherein R1 is alkyl group as defined herein.
"Dialkylamino" includes the group -NR'R", wherein R' and R" are alkyl group as defined herein.
"Cycloalkyl" refers to cyclic saturated aliphatic hydrocarbyl groups. The numbers of C-atoms referenced in connection with a given cycloalkyl group corresponds to the number of ring forming carbon atoms, e.g. "C3-C6 cycloalkyl" refers to a cycloalkyl with between three and six ring-forming C atoms. Examples of "cycloalkyl" are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc. If indicated, a "cycloalkyl" group may be unsubstituted or substituted with one or more alkyl groups, e.g. with C1-C6 alkyl groups, preferably with C1-C3 alkyl groups, particularly preferably with methyl groups. If a "cycloalkyl" carries more than one alkyl substituent these substituents may be attached to the same or to different ring-forming carbon atoms.
"Cycloalkoxy" refers to the group -OR, wherein R is "cycloalkyl" group as defined further above.
"Cycloalkylamino" refers to the group -NHR, wherein R is "cycloalkyl" group as defined further above.
"Cycloalkylalkoxy" refers to the group -OR-R', wherein R is "alkyl" group and R' is "cycloalkyl" group as defined further above. Examples of "cycloalkylalkoxy" are cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cyclopropylethoxy, etc.
"Cyano" refers to the radical -C≡N "Ethenyl" or "vinyl" refers to -CH=CH2 which is also designated "vinyl" in the present application.
"Ethynyl" or "acetylenyl" refers to -C≡CH.
"Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. Preferred halo groups are either fluoro or chloro.
"Haloalkyl" includes an "alkyl" group as defined further above which is substituted with one or more halogens which may be the same, e.g. in trifluoromethyl or pentafluoroethyl, or which may be different.
"Isomer" refers to especially optical isomers (for example essentially pure enantiomers, essentially pure diastereomers, and mixtures thereof) as well as conformation isomers (i.e. isomers that differ only in their angles of at least one chemical bond), position isomers (particularly tautomers), and geometric isomers
(e.g. cis-trans isomers).
"Essentially pure", e.g. in connection with enantiomers or diastereomers means at least about 90%, preferably at least about 95%, more preferably at least about 97 or at least about 98%, even more preferably at least about 99%, and particularly preferably at least about 99.5% (w/w) of a specified compound, e.g. a particular enantiomer or diastereomer.
"Pharmaceutically acceptable" means being devoid of substantial toxic effects when used in doses usually employed in a medicinal dosage, and thereby being approvable or preferably being approved by a regulatory agency of the Federal or a state government or being listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. "Pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure that is "pharmaceutically acceptable" as further defined herein, and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4methylbicyclo [2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid,3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced. "Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or carrier with which a compound of the disclosure is administered and which is "pharmaceutically acceptable" as further defined herein.
"Preventing" or "prevention" refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
"Subject" includes humans and non-human mammals. The term "patient" is used interchangeably with "subject" herein and shall include humans and non- human mammals unless specified otherwise. "Therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. "Treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e. g., stabilization of a discernible symptom),, physiologically,
(e. g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder. In yet another embodiment, "treating" or "treatment" refers to reducing, modifying or removing one or more discernible symptom of a disease or disorder without modulating the cause of the underlying disease.
MODE FOR CARRYING OUT THE DISCLOSURE
The present disclosure is more specifically explained by following examples and experimental examples. However, it should be understood that the extent of the present disclosure is not limited to the following examples and experimental examples
Example 1 : (3f)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3- (2-propylamino-4-trifluoromethyl-phenyl)-acrylamide
Figure imgf000029_0001
Step 1: Synthesis of 2-amino-4-(trifluoromethyl)-benzoic acid
2-Nitro-4-trifluoromethyl-benzoic acid (3.07 g, 13.0 mmol) was stirred with Pd/C under hydrogen atmosphere for 2 hrs. The reaction mixture was filtered with celite to remove Pd/C. The filterate was concentrated in vacuo. The residue was extracted with CH2Cl2 (30 ml x 3) and H2O (30 ml). The combined organic layer was dried over MgSO4 and then concentrated to yield title compound (2.66 & 99%). 1H NMR (300MHz, DMSO-d6): δ 7.82 (d, IH)5 7.02 (s, IH), 7.05(m, IH), 2.41(br, IH)
Step 2: Synthesis of 2-propylamino-4-ftrifluoromethyl)-benzoic acid
2-Amino-4-(trifluoromethyl)benzoic acid (714 mg, 3.48 mmol), propionylaldehyde (0.27 ml, 3.74 mmol), acetic acid (3.49 mmol) and sodium triacetoxyborohydiϊde (1.12g, 5.25 mmol) were added in THF(40 ml). The reaction mixture was stirred overnight. The reaction mixture was quenched by adding sat. NaHCO3 (50 ml). The aqueous mixture was extracted with CH2Cl2 (30ml x 3). A combined organic layer was dried over MgSO4, concentrated in vacuo, and purified with column chromatography to yield title compound (155mg, 18%).
1H NMR (300MHz, CDCl3): δ 8.04 (d, IH, J= 8.4 Hz), 6.89 (s, IH), 6.79 (d, IH, J= 8.1 Hz), 3.21 (t, 2H, J= 7.2 Hz), 1.75 (m, 2H), 1.02 (t, 3H, J= 7.8Hz).
Step 3: Synthesis of N-methoxy-N-methyl-2-propylamino-4-trifluoromethyl- benzamide
2-Propylamino-4-(trifluoromethyl)benzoic acid (147 mg, 0.594 mmol) in CH2Cl2 WaS reacted with N,O-dimethylhydroxy amine (82 mg), NMM (0.2 ml) and DMTMM (222 mg) at room temperature overnight. The reaction mixture was quenched by adding H2O(3 ml). The reaction solvent was removed under reduced pressure. Water (30 ml) was added to the resulting residue, which was extracted with ethylacetate (30 ml x 3). The combined organic layer was washed with sat. NaHCO3 solution (30 ml), IN HCl aqueous solution (30 ml) and brine (30 ml), and then dried over MgSO4. The filterate was concentrated in vacuo. The residue was purified with column chromatography to yield the title compound (98mg,
57%).
1H NMR (300MHz, CDCl3): δ 7.43 (d, IH, J= 7.8 Hz) 6,85 (s, IH), 6.82 (d, IH), 3.56(s, 3H), 3.34 (s, 3H), 3.10 (t, 2H, J = 6.9 Hz), 1.71 (m, 2H), 1.01 (t, 3H, J =6.9 Hz).
Step 4: Synthesis of 3-(2-propylamino-4-trifluoromethyl-phenvD-acrylic acid methyl ester
N-Methoxy-N-methyl-2-ρropylamino-4-trifluoromethyl-benzamide (98.3 mg, 0.339 mmol) was reacted with IM lithium aluminum hydride (0.6 ml) in THF (20ml) at -40 0C for 1 hr. The reaction mixture was quenched by adding saturated potassium hydrogen sulfate solution. The mixture was stirred for 30min. The reactions solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was extracted with CH2Cl2 (30 ml x 3). The combined organic layer was dried over MgSO4 and concentrated in vacuo to yield 2-propylamino-4- trifluoromethyl-benzaldehyde (78 mg). 2-Proρylamino-4-trifluoromethyl- benzaldehyde in toluene was reacted with methyl (triphenylphosphoranylidene) acetate (137 mg) at 100 0C overnight. The reaction solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was extracted with ethyl acetate (30 ml x 3). The combined organic layer was dried over MgSO4 and filtered. The filterate was concentrated in vacuo and purified with column chromatography to yield title compound (67 mg, 69%).
1H NMR (300MHz, CDCl3): δ 7.76 (d, IH, J = 15.9 Hz), 7.41 (d, IH, J = 8.1 Hz), 6.92 (d, IH, J = 8.7 Hz), 6.84 (s, IH), 6.38 (d, IH, J = 15.6 Hz), 3.82 (s, 3H), 3.17 (m, 2H), 1.70 (m, 2H), 1.04 (t, 3H5 J = 7.8 Hz).
Step 5: Synthesis of 3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylic acid
3-(2-Propylamino-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (67.3 mg, 0.234 mmol) was reacted with aqueous IN LiOH solution (5 ml) in
THF/CH3OH (10ml/5ml) for 1 hr. The reaction solvent removed in vacuo. Water
(30 ml) was added to the resulting residue, which was neutralized with IN HCl solution, an then extracted with ethyl acetate (30ml x 3). The combined organic layer was dried over MgSO4 and concentrated in vacuo to yield title compound (55 mg, 0.201 mmol, 86%).
1H NMR (300MHz, CDCl3): δ 7.80 (d, IH, J = 15.6 Hz), 7.48 (d, IH, J = 7.5 Hz), 6.82 (s, IH), 6.79 (s, IH), 6.36 (d, IH, J = 15.6 Hz), 3.10 (t, 2H, J = 6.9 Hz), 1.75 (m, 2H), 0.97 (t, 3H, J - 7.5 Hz) Step 6: Synthesis of ^)-N-[I -(3.5-difluoro-4-methanesulfonylamino-phenyl)- ethvl]r3-f2-propylamino-4-trifluoromethyl-phenylVacrylamide
(R)-N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (70 mg, 0.24 mmol) in THF was reacted with 3-(2-propylamino-4~ trifluoromethyl-ρhenyl)-aerylic acid (55mg, 0.20 mmol), NMM (0.2 ml) and DMTMM (86 mg, 0.34 mmol) at room temperature overnight. The reaction mixture was quenched by adding H2O. The reaction solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was extracted with ethyl acetate (30 ml x 3). The combined organic layer was dried over MgSO4. The filterate was concentrate under reduced pressure and purified with column chromatography to yield the title compound (35 mg, 59%). 1H NMR (300MHz, CDCl3): δ 7.79 (d, IH, J = 15 Hz), 7.37 (d, IH, J - 7.8 Hz), 6.96 (d, IH5 J = 8.4 Hz), 6.86 (d, IH, J = 8.1 Hz), 6.82 (s, IH), 6.48 (br, IH), 6.33 (d, IH, J = 15.3 Hz), 5.93 (d, IH, J = 7.2 Hz)5 5.15 (t, IH, J = 7.2 Hz), 3.19 (s, 3H)5 3.14 (t, 2H5 J = 7.2 Hz), 1.70 (m5 2H)5 0.97 (t, 3H, J - 7.5 Hz) ESI [M-H]": 504
Example 2: N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2- propyIamino-4-trifluoromethyI-phenyI)-acryIamide
Figure imgf000032_0001
N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (84 mg, 0.308 mmol) was reacted with 3-(2-ρropylamino-4-trifluoromethyl- ρhenyl)-acrylic acid (67 mg, 0.245 mmol), NMM (0.4 ml) and DMTMM (121 mg) to give the title compound (62 mg, 52%).
1H NMR (300MHz, CDCl3): δ 7.75 (d, IH, J = 15.6 Hz), 7.33 (d, IH, J = 7.8 Hz), 6.95 (d, IH5 J = 8.4 Hz), 6.84 (d, IH, J = 8.1 Hz), 6.79 (s, IH), 6.30 (d, IH, J = 15.6 Hz), 6.03 (br, IH), 4.59 (br, IH, J = 6.9 Hz), 4.50 (d, 2H, J = 6.0 Hz), 3.16 (s, 3H), 3.12 (t, 2H5 J = 7.2 Hz), 1.64 (m, 2H), 0.96 (t, 3H, J = 7.5 Hz)
Example 3 : (iJ)-3-(2-Butylamino-4-trifluoromethyl-phenyl)-N-[l-(3,5- difluoro-4-methanesulfonylamino-phenyl)~ethyl]-acrylamide
Figure imgf000033_0001
(R)-N-[4-(l-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HCl salt (25mg, 0.09mmol) was reacted with 3-(2-butylamino-4-trifluoromethyl- phenyl)-acrylic acid (25mg, 0.09mmol) to give the title compound (15mg, 32%) after purification by crystallization from Hex/EtOAc.
1R NMR(300MHz, CDCl3): δ 7.75(d, IH, J =15.3Hz), 7.37(d, IH, J =8.4Hz), 7.00(m, 2H), 6.90(d, IH, J=8.4Hz), 6.83(s, IH), 6.33(d, IH, J =15.3Hz), 6.12(s, IH), 5.83(d, IH, J=7.8Hz), 5.18(m, IH), 4.18(bs, IH), 3.21(s, 3H), 3.17(m, 2H), 1.48(m, 5H)3 0.97(t, 3H, J=7.5Hz). ESI [M-H]-; 518
Example 4: N-(3,5-Difluoro-4-methanesulfonylamino-benzyI)-3-(2-propoxy- 4-trifluoromethyI-phenyl)-acrylamide
Figure imgf000033_0002
Step 1: Synthesis of 2-propoxy-4-trifluoromethyl-benzoic acid propyl ester
2-Hydroxy-4-trifluoromethyl-benzoic acid (673 mg, 3.26 mmol) was reacted with propylbromide (0.85 ml) and K2CO3 (1.42 g) in DMF (15 ml) at 65 0C overnight. The reaction mixture was quenched by adding 10 ml Of H2O. The mixture was extracted with ethylacetate (30 ml x 3). A combined organic layer was washed with H2O (50 ml x 6) and brine (50 ml), and dried over MgSO4. The filterate was concentrated in vacuo to yield title compound (908 mg, 99%).
1H NMR (300MHz, CDCl3): δ 7.83 (d, IH, J = 8.1 Hz), 7.21 (d, IH, J = S.I Hz),
7.15 (s, IH), 4.28 (t, 2H, J = 6.9 Hz), 4.03 (t, 2H, J = 63 Hz), 1.88 (m, 2H), 1.82 (m, 2H), 1.07 (m, 6H)
Step 2: Synthesis of 2-propoxy-4-trifluoromethyl-benzoic acid
2-Propoxy-4-trifluoromethyl-benzoic acid propyl ester (957 mg, 3.44 mmol) was reacted with IN LiOH (10 ml) at room temperature for 4 hrs. The reaction solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which wasneutralized with 1 N aqueous HCl solution. The aqueous mixture was extracted with ethylacetate (30 ml x 3). A combined organic layer was dried over MgSO4, and concentrated in vacuo to yield quantitatively title compound.
1H NMR (300MHz, CDCl3): δ 8.32 (d, IH, J - 7.8 Hz), 7.40 (d, IH, J = 8.1 Hz),
7.16 (s, IH), 4.28 (t, 2H, J = 6.6 Hz), 1.98 (m, 2H), 1.26 (m, 3H)
Step 3: Synthesis of N-methoxy-N-methyl-2-ρropoxy-4-trifluoromethyl- benzamide
2-Propoxy~4-(trifluoromethyl)benzoic acid (457 mg, 1.93 mmol) in THF was reacted with N,O-dimethylhydroxy amine (378 mg), NMM (0.65 ml) and DMTMM (947mg) at room temperature overnight. The reaction solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which wasextracted with ethyl acetate (30 ml x 3). The combined organic layer was washed with 1 M NaHCO3 (30 ml), IN HCl (30 ml) and brine (30 ml) and dried over MgSO4. The filterate was purified with column chromatography (Hex/EtOAc = 4/1) to yield the title compound (277 mg, 49%). 1H NMR (300MHz, CDCl3): δ 7.36 (d, IH3 J = 7.8 Hz)5 7.25 (d, IH, J = 8.1 Hz), 7.12 (s, IH), 4.01 (t, 2H, J = 6.3 Hz), 3.46 (s, 3H), 3.35 (br, 3H), 1.83 (m, 2H), 1.03 (t, 3H, J = 6.9 Hz) Step 4: Synthesis of 2-propoxy-4-trifluoromethyl-benzaldehyde
N-Methoxy-N-methyl-2-propoxy-4-trifluoromethyl-benzamide (277 mg) in THF was reacted with 1 M LAH (1 ml) on -50 0C for 1 hr. The reaction mixture was quenched by adding aqueous potassium hydrogen sulfate (5 ml). The mixture was stirred for 30 min. The reaction solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was was extracted with ethyl acetate (30 ml x 3). The combined organic layer was washed with brine (30 ml) and dried over MgSO4 and concentrated in vacuo to yield title compound (232 mg, 100%). 1H NMR (300MHz, CDCl3): δ 10.54 (s, IH), 7.93 (d, IH, J - 8.1 Hz), 7.27 (d, IH, J = 8.1 Hz), 7.21 (s, IH), 4.10 (t, 2H, J = 6.6 Hz), 1.91 (m, 2H), 1.10 (t, 3H, J = 7.2 Hz)
Step 5: Synthesis of 3-f2-propoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester
2-Propoxy-4-trifluoromethyl-benzaldehyde (232 mg, 1 mmol) in toluene was reacted with methyl (triphenylphosphoranylidene)acetate (382 mg, 1.14 mmol) at 110 0C overnight. The reaction solvent was removed under reduced pressure. Water (30 ml) was added to the resulting residue, which was extracted with ethyl acetate (30 ml x3). The combined organic layer was washed with brine (30 ml) and dried over MgSO4. The filterate was purified with column chromatography to yield title compound (198 mg, 69%). 1H NMR (300MHz, CDCl3): δ 7.98 (d, IH, J = 16.2 Hz), 7.58 (d, IH, J = 8.1 Hz), 7.21 (m, IH), 7.11 (s, IH), 6.60 (d, IH, J = 16.2 Hz), 4.04 (t, 2H, J = 6.0 Hz), 3.81 (s, 3H), 1.91 (m, 2H), 1.09 (t, 3H, J = 7.5 Hz).
Step 6: Synthesis of 3-(2-propoxy-4-trifluoromethyl-phenylVacrylic acid
3-(2-Propoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (198 mg) was reacted with IN LiOH (5 ml) in THF (10 ml) and CH3OH (5 ml) for 1 hr. The reaction mixture was concentrated in vacuo. Water (30 ml) was added to the resulting residue, which was neutralized with IN HCl solution. The mixture was extracted with ethyl acetate (30 ml x 3). The combined organic layer was dried over MgSO4. The filterate was concentrated in vacuo to yield title compound (136 mg, 72%).
1H NMR (300MHz, CDCl3): δ 7.93 (d, IH5 J = 16.2 Hz), 7.71 (d, IH, J = 8.4 Hz), 7.21 (m, IH), 7.12 (s, IH), 6.59 (d, IH, J = 16.2 Hz), 4.04 (t, 2H, J = 6.0 Hz), 1.78 (m, 2H), 1.06 (t, 3H, J = 7.5 Hz)
Step 7: Synthesis of N-(3,5-difluoro-4-methanesulfonylamino-benzyl)-3-(2- propoxy-4-trifluoromethyl-phenyl)-acrylamide
N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt
(78 mg, 0.286 mmol) in THF was reacted with 3-(2-propoxy-4-trifluoromethyl- phenyl)-acrylic acid (67 mg, 0.246 mmol), NMM (0.2 ml) and DMTMM (86 mg) to give the title compound (92 mg, 76%) after column chromatography ( Hex/EtOAc = 1/1).
1R NMR (300MHz5 CDCl3): δ 7.90 (d, IH, J = 15.9 Hz), 7.52 (d, IH5 J = 8.4 Hz),
7.21 (m, IH), 7.06 (s, IH)5 6.93 (d, IH5 J = 7.8 Hz), 6.55 (d, IH, J = 16.2 Hz), 5.96 (br, IH)5 4.51 (d, 2H5 J - 6.0 Hz), 4.00 (t, 2H, J = 6.0 Hz), 3.16 (s, 3H), 1.87
(m, 2H), 1.04 (t, 3H, J = 7.5 Hz)
ESI [M-H]-: 505
Example 5: (jRj-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyI)-ethyϊ]-3- (2-propoxy-4-trifluoromethyI-phenyl)-acryIamide
Figure imgf000036_0001
(R)-N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt
(81 mg, 0.28 mmol) was reacted with 3-(2-propoxy-4-trifluoromethyl-phenyl)- acrylic acid (68 mg, 0.25 mmol), NMM (0.2 ml) and DMTMM (86 mg) at room temperature overnight to yield the title compound (89 mg, 72%) after column chromatography^ Hex/EtOAc = 1/1).
1H NMR (300MHz, CDCl3): δ 7.92 (d, IH5 J = 15.6 Hz), 7.55 (d, IH, J = 7.8 Hz), 7.19 (d, IH, J = 10.8 Hz), 7.10 (s, IH), 6.99 (d, IH5 J = 8.7 Hz)5 6.55 (d, IH5 J = 15.9 Hz)5 5.99 (br, IH)5 5.78 (br, IH)5 5.19 (m, IH), 4.03 (t5 2H, J = 6.6 Hz), 3.20 (s, 3H), 1.90 (m, 2H), 1.08 (t, 3H5 J = 7.5 Hz)
Example 6: (i?)-N-[l-(3?5-Difluoro-4-methaiiesuIfonyIamino-phenyl)-ethyl]-3- (2,6-dipropyl-4-trifluoromethyI-phenyl)-acryIamide
Figure imgf000037_0001
Step 1: Synthesis of 3-(2,6-dipropyl-4-trifluoromethyl-ρhenyl)-acrylic acid methyl ester
In a 100ml flask, 4-iodobenzotrifluoride (Ig, 3.68mmol) was dissolved in 10ml DMF, and Pd(OAc)2 (165mg, 0.2eq), K2CO3 (2.54g, 5.0eq), KOAc (1.8g, 5.0eq)5 norbonylene (692mg, l.Oeq), methyl acrylate (0.33ml, l.Oeq), and iodopropane (3.75g, 6.0eq) were added stepwisely at room temperature. The resulting reaction mixture was stirred for 3 days. After the completion of the reaction, the Na2S2O3 solution was poured into the reaction mixture, which was stirred for 30 minutes, extracted with EtOAc 50ml (3 times), and dried with anh.MgSO4. The organic layer was filtered, concentrated in vacuo, and purified with column chromatography (Hexane : EtOAc = 8 : 1) to give the title compound (0.343g, 30%).
1H NMR(SOOMHZ, CDCl3): δ 7.83(d, IH, J= 16.2Hz ), 7.31(s, 2H)5 6.01 (d, IH, J = 16.2Hz), 3.84(s, 3H), 2.62(m, 4H), 1.58(m, 4H), 0.94(m, 6H).
Step 2: Synthesis of 3-(2,6-dipropyl-4-trifluoromethyl-phenyl)-acrylic acid
3-(2,6-Dipropyl-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (343 mg) was reacted with IN LiOH (5 ml) in THF (10 ml) and CH3OH (5 ml) for 1 hr. The reaction mixture was concentrated in vacuo. Water (30 ml) was added to the resulting residue, which wasneutralized with IN HCl solution. The mixture was extracted with ethyl acetate (30 ml x 3). The combined organic layer was dried over MgSO4. The filterate was concentrated in vacuo to yield title compound (250 mg, 82%).
Step 3: Synthesis of (R)-N-ri~(3,5-difluoro-4-methanesulfonylamino-phenylV ethyl]-3-(2,6-dipropyl-4-trifluoromethyl-phenyl)-acrylamide
(R)-N-[4-(l-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HCl salt (250mg, 0.87mmol) was reacted with 3-(2,6-dipropyl-4-trifluoromethyl- phenyl)-acrylic acid (261mg, 0.87mmol) to give the title compound (181mg,
39%) after purification by crystallization from Hex/EtOAc. 1H NMR(300MHz, DMSO-d6): δ 9.49(s, IH), 8.70(t, IH5 J= 7.5Hz), 7.56(d, IH,
J -15.9Hz), 7.42(s, 2H), 7.15(m, 2H), 6.23(d, IH, J =16.2Hz), 5.05(m, IH),
3.05(s, 3H), 2.61(m, 4H), 1.51(m, 4H), 1.41(d, 3H, J=7.2Hz), 0.88(m, 6H).
ESI [M-H]": 531
Example 7: fi?)-N-[l-(3,5-Difluoro-4-methanesulfonylammo-phenyl)-ethyl]-3- (2-ethoxy-4-trifluoromethyl-phenyl)-acryIamide
Figure imgf000038_0001
Step 1 : Synthesis of 2-ethoxy-4-trifluoromethyl-benzoic acid
2-Hydroxy-4-trifluoromethyl-benzoic acid (1.20 g, 5.82 mmol) was reacted with ethyliodide (2.2 eq) and K2CO3 (1.69 g) in DMF solution. The reaction mixture was quenched by adding H2O. The mixture was extracted with ethyl acetate (40 ml x 3). A combined organic layer was washed sat NaHCO3 solution (30 ml), H2O (40 ml x 5), and brine, and then dried over MgSO4. The filterate was concentrated in vacuo to yield 2-ethoxy-4-trifluoromethyl benzoic acid ethyl ester. The ester obtained above was reacted with 1 N LiOH (15 ml) in THF and CH3OH cosolvent for 2 hrs as described above to yield title compound
(1.2O g, 88%).
1H NMR (300MHz, CDCl3): δ 8.32 (d, IH, J = 8.1 Hz), 7.40 (d, IH, J = 8.1 Hz), 7.26 (s, IH), 4.40 (q, 2H, J = 6.9 Hz), 1.62 (t, 3H, J = 6.9 Hz)
Step 2: Synthesis of N-methoxy-N-methyl-2-ethoxy-4-trifluoromethyl-benzamide
2-Ethoxy-4-trifluoromethyl-benzoic acid (1.20 g, 5.12 mmol) was reacted with N,O-dimethylhydroxy amine (609 mg), NMM (0.95 ml) and DMTMM (1.47 mg) as described above to give the title compound (1.04 g, 73%) after column chromatography (Hex/EtOAc = 5/ 1 ) .
1H NMR (300MHz, CDCl3): δ 7.40 (br, IH), 7.23 (br, IH), 7.10 (s, IH), 4.13 (t, 2H, J = 6.3 Hz)5 3.49 (s, 3H), 3.37 (br, 3H), 1.42 (t, 3H, J = 6.9 Hz)
Step 3: Synthesis of 2-ethoxy-4-trifluoromethyl-benzaldehyde
N-Methoxy-N-methyl-2-ethoxy-4-trifluoromethyl-benzamide (1.04 g) was reacted with 1 M LAH (1 ml) at -40 0C for 2 hrs as described above to yield title compound (729 mg, 65%)
1H NMR (300MHz, CDCl3): δ 10.52 (s, IH), 7.93 (d, IH, J = 8.1 Hz), 7.27 (d, IH, J = 8.1 Hz), 7.20 (s, IH), 4.21 (q, 2H, J = 6.6 Hz), 1.52 (t, 3H, J = 6.9 Hz) Step 4: Synthesis of 3-r2-ethoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester
2-Ethoxy-4-trifluoromethyl-benzaldehyde (729 mg, 3.34 mmol) was reacted with methyl (triphenylphosphoranylidene)acetate (1.45 g, 4.34 rnmol) at 110 0C overnight as described above to yield title compound (476.5 mg, 52%). 1H NMR (300MHz5 CDCl3): δ 7.97 (d, IH, J = 16.5 Hz), 7.58 (d, IH, J = 16.2 Hz), 7.58 (d, IH, J = 7.8 Hz), 7.21 (m, IH)5 7.11 (s, IH), 6.60 (d, IH, J = 15.9 Hz), 4.14 (q, 2H, J = 6.9 Hz), 3.82 (s, 3H), 1.58 (t, 3H, J = 7.5 Hz)
Step 5: Synthesis of 3-(2-ethoxy-4-trifluoromethyl-phenylVacrylic acid
3-(2-Ethoxy-4-trifluoromethyl-ρhenyl)-acrylic acid methyl ester (477 mg, 1.74 mmol) was reacted with IN LiOH (7.5 ml) in THF and CH3OH for 1.5 hrs as described above to yield title compound (440 mg, 97%)
1H NMR (300MHz, CDCl3): δ 8.07 (d, IH, J = 16.2 Hz), 7.62 (d, IH, J = 8.1 Hz), 7.26 (m, IH), 7.12 (s, IH), 6.62 (d, IH, J = 16.2 Hz), 4.16 (q, 2H, J = 6.9 Hz), 1.52 (t, 3H, J = 6.9 Hz)
Step 6: Synthesis of ffi)-N-ri-(3,5-difluoro-4-methanesulfonylamino-phenyl)- ethyl]-3-(2-ethoxy-4-trifluoromethyl-phenyπ-acrylamide
(R)-N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt
(70 mg, 0.24 mmol) was reacted with 3-(2-ethoxy-4-trifluoromethyl-phenyl)- acrylic acid (59 mg, 0.22 mmol), NMM (0.2 ml) and DMTMM (73 mg, 0.26 mmol) to give the title compound (77 mg, 69%) after column chromatography
(Hex/EtOAc = 1/1).
1H NMR (300MHz, CDCl3): δ 7.94 (d, IH, J = 15.9 Hz), 7.56 (d, IH, J = 8.1 Hz),
7.19 (d, IH, J = 8.1 Hz), 7.09 (s, IH), 6.75 (d, IH, J = 8.1 Hz), 6.57 (d, IH, J = 15.9 Hz), 6.08 (br, IH), 5.87 (d, IH, J = 7.8 Hz), 5.20 (t, IH) 4.13 (q, 2H, J = 6.9
Hz), 3.20 (s, 3H), 1.52 (t, 3H, J = 7.5 Hz)
ESI [M-H]": 491 Example 8: N-(3,5-Difluoro-4-methanesulfonyIamino-benzyϊ)-3-(2-ethoxy-4- trifluoromethyl-phenyl)-acrylamide
Figure imgf000041_0001
N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt
(60 mg, 0.22 mmol) was reacted with 3-(2-emoxy-4-trifluoromethyl-phenyl)- acrylic acid (52 mg, 0.20 mmol), NMM (0.2 ml) and DMTMM (73 mg, 0.25 mmol) at room temperature to yield the title compound (50 mg, 52%) after column chromatography (Hex/EtOAc = 1/1). 1H NMR (300MHz, CDCl3): δ 7.94 (d, IH, J = 15.6 Hz), 7.56 (d, IH, J = 7.8 Hz), 7.21 (d, IH5 J = 7.8 Hz), 7.11 (s, IH), 7.00 (m, 2H), 6.77 (d, IH, J = 8.4 Hz), 6.62 (d, IH, J = 15.9 Hz), 6.03 (br, IH), 4.56 (d, 2H, J = 6.0 Hz), 4.15 (q, 2H, J = 7.2 Hz), 3.21 (s, 3H), 1.48 (t, 3H, J = 7.2 Hz)
Example 9: f2?>N-[l-(3-Fluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2- ethoxy-4-trifluoromethyl-phenyl)-acrylamide
Figure imgf000041_0002
(R)-N-(4-Aminoethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (60 mg, 0.22 mmol) was reacted with 3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylic acid (51 mg, 0.19 mmol), NMM (0.2 ml) and DMTMM (72 mg) at room temperature overnight to yield the title compound (62 mg, 0.13 mmol, 68%) after column chromatography (Hex/EtOAc = 1/1).
1H NMR (300MHz, CDCl3): δ 7.91 (d, IH, J = 15.6 Hz), 7.55 (m, IH), 7.44 (m, IH), 7.15 (d, IH, J = 9.0 Hz), 7.08 (s, IH), 6.93 (m, IH), 6.55 (d, IH, J = 15.0
Hz), 5.95 (br, IH), 5.87 (d, IH, J = 7.8 Hz), 5.21 (t, IH) 4.14 (q, 2H3 J = 6.9 Hz),
3.02 (s, 3H), 1.53 (t, 3H, J = 7.5 Hz) Example 10: (3?j-N-[l-(3,5-Difluoro-4-methanesu]fonyIamino-phenyI)-ethyI]- 3-(2-ethyIamino-4-trifluoromethyl-phenyl)-acryIamide
Figure imgf000042_0001
Step 1: Synthesis ofN-methoxy-N-methyl-2-nitro-4-trifluoromethyl-benzamide
2-Nitro-4-trifluoromethyl-benzoic acid (2.753 mg, 11.7 mmol) in THF was reacted with N,O-dimethylhydroxy amine (1.277 g, 13.1 mmol), NMM (3 ml) and DMTMM (3.34 g) at room temperature overnight. The reaction mixture was quenched by adding H2O. The mixture was extracted with ethyl acetate (50 ml x 3). The combined organic layer was washed IM NaHCO3 (50 ml x 2), 3% HCl (50 ml x 2) and brine (50 ml), and then dried over MgSO4. The fϊlterate was concentrated in vacuo to yield the title compound (2.84 g, 87%). 1H NMR (300MHz, CDCl3): δ 8.43 (s, IH), 7.99 (d, IH, J = 8.1 Hz), 7.69 (d, IH, J = 7.8 Hz), 3.39 (s, 6H)
Step 2: Synthesis of 2-amino-N-methoxy-N-methyl-4-trifluoromethyl-benzamide
N-Memoxy-N-methyl-2-nitro-44rifluoromethyl-benzamide (2.54 g, 9.12 mmol) was reacted with Pd/C (441 mg) under hydrogen atmosphere as described above to yield title compound.
1H NMR (300MHz, CDCl3): δ 7.47(d, IH, J = 7.8 Hz), 6.93 (s, IH), 6.91 (d, IH, J
= 7.8 Hz), 3.56 (s, 3H), 3.36 (s, 3H).
Step 3: Synthesis of 2-ethylamino-N-methoxy-N-methyl-4-trifluoromethyl- benzamide
2-Amino-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (482 mg, 1.94 mmol) was reacted with acetaldehyde (0.12 ml, 2.14 mmol) and sodium acetoxyborohydride (892 mg, 4.20 mmol) in CH2Cl2 at room temperature as described above to yield title compound (95 mg, 17%).
1H NMR (300MHz, CDCl3): δ 7.44 (d, IH, J = 8.1 Hz), 6.86 (s, IH), 6.84 (d, IH, J = 7.8 Hz), 3.57 (s, 3H), 3.35 (s, 3H), 3.18 (q, 2H5 J =6.9 Hz), 1.28 (t, 3H, J = 7.2 Hz).
Step 4: Synthesis of 2-ethylammo-4-trifluoromethyl-benzaldehyde
2-Ethylamino-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (95 mg,
0.343 mmol) was reacted with LAH in THF at -40 0C for 1.5 hrs as described above to yield title compound (22 mg, 29%) after column chromatography (hexane/ethylacetate = 20/1). 1H NMR (300MHz, CDCl3): δ 9.88 (s, IH), 8.35 (br, IH), 7.57 (d, IH, J = 7.8 Hz), 6.88 (s, IH), 6.87 (d, IH5 J = 7.8 Hz), 3.30 (q, 2H, J =6.9 Hz), 1.35 (t, 3H, J = 7.2 Hz).
Step 5: Synthesis of 3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylic acid
2-Ethylamino-4-trifluoromethyl-benzaldehyde (22 mg) was reacted with methyl (triphenylphosphoranylidene)acetate (49 mg, 0.14 mmol) at 110 0C overnight as described above to yield 3-(2-ethylamino-4-trifluoromethyl-phenyl)- acrylic acid methyl ester. 3-(2-Ethylamino-4-trifiuoromethyl-phenyl)-acrylic acid methyl ester was reacted with IN LiOH (5 ml) as described above to yield the title compound (20.2 mg)
1U NMR (300MHz, CDCl3): δ 7.87 (d, IH, J = 15.6 Hz), 7.45 (d, IH, J = 8.1 Hz), 6.94 (d, IH, J = 7.8 Hz), 6.86 (s, IH), 6.39 (d, IH, J = 15.6 Hz)5 3.27 (q, 2H, J = 7.2 Hz), 1.35 (t, 3H, J = 7.2 Hz). Step 6: Synthesis of ^J-N-ri-β^-difluoro^-methanesulfonylamino-phenyl)- ethvn-3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylamide
(R)-N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (31 mg, 0.108 mmol) was reacted with 3-(2-ethylamino-4-trifluoromethyl- phenyl)-acrylic acid (20mg, 0.078 mmol), NMM (0.1 ml) and DMTMM (27 mg) to give the title compound (11 mg, 29%).
1H NMR (300MHz, CDCl3): δ 7.79 (d, IH, J - 15 Hz)5 7.37 (d, IH, J = 7.8 Hz), 6.96 (d, IH, J = 8.1 Hz), 6.62 (s, IH), 6.48 (br, IH), 6.33 (d, IH, J = 15.3 Hz), 5.52 (d, IH), 5.18 (t, IH), 3.16 (s, 3H), 3.14 (t, 2H, J = 7.2 Hz), 1.70 (m, 3H), 1.35 (t, 3H, J = 7.5 Hz) ESI [M-H]": 490
Example 11 : N-(3-Fluoro-4-methanesulfonylamino-5-methyl-benzyl)-3-(2- propylamino-4-trifluoromethyl-phenyl)-acrylamide
Figure imgf000044_0001
N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt (25 mg) was reacted with 3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylic acid (24 mg, 0.086 mmol), NMM (0.1 ml) and DMTMM (27 mg) at room temperature overnight to yield the title compound (21 mg, 50%). 1H NMR (300MHz, CDCl3): δ 7.80 (d, IH, J = 15.3 Hz), 7.36 (d, IH, J = 8.1 Hz), 7.14 (m, IH), 7.11 (m, IH), 6.88 (m, IH), 6.80 (d, IH, J = 15.3 Hz), 6.15 (t, IH), 4.56 (d, 2H, J = 6.0 Hz), 3.13 (t, 2H, J = 7.2 Hz), 3.02 (s, 3H), 2.24 (s, 3H), 1.70 (m, 2H), 0.96 (t, 3H, J = 7.5 Hz) ESI [M-H]-.- 486 Example 12: N-(3-Fluoro-4-methanesulfonylamino-5-vinyI-benzyl)-3-(2- propylamino-4-trifluoromethyl-phenyI)-acrylamide
Figure imgf000045_0001
N-(4-Aminomethyl-2-fluoro-6-vinyl-phenyl)-methanesulfonamide, HCl salt (36 mg, 0.15 mmol) was reacted with 3-(2-propylammo-4~trifluoromethyl- ρhenyl)-acrylic acid (28 mg, 0.10 mmol), NMM (0.1 ml) and DMTMM (35 mg) at room temperature overnight to yield the title compound (17 mg, 34%) after column chromatography. 1H NMR (300MHz, CDCl3): δ 7.80 (d, IH, J = 15.3 Hz), 7.38 (m, IH), 7.22 (m, IH), 7.15 (m, IH), 7.11 (m, IH), 6.90 (d, IH, J = 7.2 Hz), 6.83 (s, IH), 6.34 (d, IH, J = 15.0 Hz), 5.95 (br, 2H)5 5.81 (d, IH, J = 17.4 Hz), 5.46 (d, IH5 J = 10.8 Hz), 4.58 (d, 2H, J = 6.0 Hz), 3.16 (t, 2H9 J = 6.0 Hz), 3.08 (s, 3H), 1.69 (m, 2H), 1.03 (t, 3H5 J = 7.5 Hz) ESI [M-H]": 498
Example 13: N-(3-Cyano-5-fluoro-4-methanesulfonylamino-ben2yl)-3-(2- propylamino-4-trifluoromethyl-phenyl)-acrylamide
Figure imgf000045_0002
N-(4-Aminomethyl-2-fluoro-6-cyano-phenyl)-methanesulfonamide, HCl salt (26 mg, 0.092 mmol) was reacted with 3-(2-propylammo-4-trifIuoromethyl- phenyl)-acrylic acid (20 mg, 0.073 mmol), NMM (0.1 ml) and DMTMM (28 mg) at room temperature overnight to yield the title compound (8 mg, 22%) after column chromatography.
1H NMR (300MHz, CDCl3): δ 7.82 (d, IH, J = 4.7 Hz), 7.45 (m, IH), 7.40 (m, IH), 7.37 (m, IH), 7.21 (s, IH), 7.11 (m, IH)5 6.90 (d, IH, J = 7.8 Hz), 6.84 (s, IH), 6.36 (d, IH, J = 15.0 Hz), 6.10 (br, IH), 4.58 (d, 2H, J = 6.3 Hz), 3.32 (s, 3H)5 3.16 (t, 2H, J = 6.0 Hz)5 1.69 (m, 2H)5 1.03 (t, 3H, J = 7.5 Hz) ESI [M-H]-: 497
Example 14: N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2- propoxy-4-trifluoromethyl-phenyl)-acrylamide
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide5 HCl salt (53 mg, 0.19 mmol) was reacted with 3-(2-ρroρoxy-4-trifluoromethyl- ρhenyl)-acrylic acid (49 mg, 0.18 mmol), NMM (0.1 ml) and DMTMM (60 mg) at room temperature overnight to yield the title compound (63 mg, 70%) after column chromatography (Hex/EtOAc = 1/1). 1H NMR (300MHz, CDCl3): δ 7.96 (d, IH, J = 15.6 Hz), 7.56 (d, IH, J = 7.8 Hz), 7.30 (s, IH), 7.20 (m IH), 7.11 (d, IH, J = 7.5 Hz), 6.97 (s, IH)5 6.61 (d, IH, J = 15.9 Hz), 6.41 (br, IH), 6.03 (br, IH), 4.54 (d, IH, J = 6.3 Hz)5 4.03 (t, 2H, J = 6.6 Hz), 3.48 (s, IH)5 3.26 (s, 3H), 1.85 (m, 2H)5 1.06 (t, 3H, J = 7.5 Hz)
Example 15: 3-(2-Ethoxy-4-trifluoromethyI-phenyl)-N-(3-fluoro-4- methanesulfonyIamino-5-trifluoromethyl-benzyl)-acrylamide
Figure imgf000046_0002
N-(4-Aminomethyl-2-fluoro-6-trifluoromethyl-phenyl)- methanesulfonamide, HCl salt (61 mg, 0.19 mmol) was reacted with 3-(2-ethoxy- 4-trifluoromethyl-phenyl)-acrylic acid (45 mg, 0.17 mmol), NMM (0.1 ml) and DMTMM (64 mg, 0.22 mmol) at room temperature to yield the title compound (63 mg, 0.12 mmol, 69%) after column chromatography (Hex/EtOAc = 1/1). 1H NMR (300MHz5 CDCl3): δ 7.95 (d, IH5 J = 15.6 Hz), 7.56 (d, IH, J = 7.5 Hz), 7.40 (m, IH), 7.19 (d, IH5 J = 8.1 Hz), 7.10 (s, IH), 6.63 (d, IH, J = 15.6 Hz), 6.22 (br, IH), 4.60 (d, 2H, J = 6.0 Hz), 4.12 (q, 2H, J = 7.2 Hz), 3.28 (s, 3H), 1.50 (t, 3H, J = 7.2 Hz).
Example 16: (i?)-3-(2,6-Dibutyl-4-trifluoromethyl-phenyl)-N-[l-(3,5-difluoro- 4-methanesuIfonylamino-phenyl)-ethyl]- acrylamide
Figure imgf000047_0001
(R)-N-[4-(l-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HCl salt (43mg, 0.15mmol) was reacted with 3-(2,6-dibutyl-4-trifluoromethyl-ρhenyl)- acrylic acid (50mg, 0.15mmol) to give the title compound (30mg, 35%) after purification by crystallization from Hex/EtOAc.
1H NMR(300MHz, CDCl3): δ 7.80(d, IH, J = 15.9Hz)5 7.29(s, IH), 7.26(s, 2H), 7.05(10, 2H), 6.02(s, IH), 5.95(d, IH5 J =15.9Hz), 5.74(s, IH), 5.34(s, IH), 5.21(m, IH)5 3.22(s, 3H), 2.63(m, 4H)5 1.32(m, HH), 0.91(m, 6H). ESI [M+H]+:
Example 17: (Λ)-3-(2,6-Diethyl-4-trifluoromethyl-phenyl)-N-[l-(3,5-difluoro- 4-methanesuIfonylamino-phenyl)-ethyl]- acrylamide)
Figure imgf000047_0002
(R)-N-[4-(l -Amino-ethyl)-256-difluoro-phenyl]-methanesulfonamide, HCl salt (38mg, 0.13mmol) was reacted with 3-(2,6-diethyl-4-trifluoromethyl-phenyl)- acrylic acid (36mg, 0.13mmol) to give the title compound (20mg, 30%) after purification by crystallization from Hex/EtOAc. 1H NMR(SOOMHZ, CDCl3): δ 7.84(d, IH, J= 16.5Hz), 7.29(s, IH), 7.30(s, 2H), 7.01(m, 2H)5 6.06(s, IH), 6.02(d, IH, J" =16.2Hz), 5.72(s, IH), 5.30(m, IH), 5.24(m, IH), 3.19(s, 3H), 2.69(m, 4H), 1.24(m, 9H). ESI [M-H]": 503
Example 18: N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2- ethylamino-4-trifluoromethyl-phenyl)-acrylamide
Figure imgf000048_0001
N-(4-Aminomethyl-355-difluoro-phenyl)-methanesulfonamide, HCl salt
(42mg, 0.154mmol) was reacted with 3-(2-ethylamino-4-trifluoromethyl-phenyl)- acrylic acid (40mg, 0.154mmol) to give the title compound (36mg, 49%) after purification by crystallization from Hex/EtOAc. 1H NMR(300MHz, CDCl3): δ 7.80(d, IH, J = 15Hz), 7.38(m, 2H), 6.95(m, 2H), 6.84(s, IH), 6.35(d, IH, J -15.6Hz), 5.99(s, IH), 4.55(d, 2H, J =6Hz), 3.26(m, 2H), 3.22(s, 3H), 1.33(m, 3H). ESI [M-H]": 476
Example 19: 3-(2-Ethylamino-4-trifluoromethyl-phenyl)-N-(3-fluoro-4- methanesuIfonylamino-5-methyI-benzyl)-acrylamide
Figure imgf000048_0002
N-(4-aminomethyl-3-fluoro-5-methyl-phenyl)-methanesulfonamide, HCl salt (28mg, 0.104mmol) was reacted with 3-(2-ethylamino-4-trifluoromethyl- ρhenyl)-acrylic acid (27mg, 0.104mmol) to give the title compound (29mg, 59%) after purification by crystallization from Hex/EtOAc.
1H NMR(SOOMHZ, DMSO-d6): δ 8.59(bs, IH), 7.67(d, IH, /= 15.6Hz), 7.47(m, 2H), 6.88(m, IH), 6.57(d, IH, J =15.6Hz), 6.04(s, IH), 4.40(d, 2H, J =5.4Hz), 3.15(m5 2H), 2.96(s, 3H), 2.20(s, 3H), 1.18(m, 3H). ESI [M+H]+:
Example 20: N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2- isopropoxy-4-trifluoromethyl-phenyl)-acrylamide
Figure imgf000049_0001
N-(4-Aminomethyl-3,5-difluoro-phenyl)-methanesulfonamide, HCl salt (14mg, 0.051mmol) was reacted with 3-(2~isopropoxy-4-trifluoromethyl-phenyl)- acrylic acid (14mg, 0.051mmol) to give the title compound (llmg, 40%) after purification by crystallization from Hex/EtOAc.
1H NMR(300MHz, DMSO-d6): δ 9.50(s, IH), 8.70(d, IH, J = 7.8Hz), 7.69(m, 2H), 7.24(m, 4H), 6.78(d, IH, J =15.9Hz), 4.85(m, IH), 4.52(d, 2H, J =6.0Hz), 3.02(S5 3H), 1.31(m, 6H). ESI [M-H]-; 491
Example 21: N-[l-(3,5-DiJfluoro-4-methanesuIfonylamino-phenyl)-ethyl]-3-(2- propyl-4-trifluoromethyI-phenyI)-acrylamide
Figure imgf000049_0002
Step 1: Synthesis of 4.4-dimethyl-2-r4-trifluoromethyl-ρhenyl)-4,5-dihvdro- oxazole
To an ice-cold solution of 2-amino-2-methyl-l-propanol (21.4g, 240mmol) and triethylamine (16.8mL, 120mmol) in THF was added dropwise 4- trifluoromethyl benzyl chloride (25.Og, 120mmol). After the addition, the reaction mixture was stirred at O0C for 30 mins and then stirred at ambient temperature for 8hrs. The precipitate was removed by filtration and the filtrate was concentrated by evaporating the solvent under reduced pressure. The resulting residue was treated dropwise with thionyl chloride with vigorous stirring at O0C. After complete addition, the reaction mixture was further stirred at ambient temperature for lhr. Ether was poured into the reaction mixture and the precipitate was collected by filtration. The precipitate was dissolved in water and the aqueous solution was hydrolyzed with 10% (w/v) NaOH. The aqueous phase was extracted three times with ether, and the combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex/EtOAc = 5/1) to yield the title compound (25.4g, 87%). 1H NMR(300MHz, CDCl3): δ 8.05(d, 2H, J =7.8Hz), 7.66(6, 2H, J =7.8Hz), 4.14(s, 2H), 1.39(s, 6H).
Step 2: Synthesis of N-methoxy-N-methyl-2-propyl-4-trifiuoromethyl-benzamide.
A solution of 4,4-dimethyl-2-(4-trifluoromethyl-phenyl)-4,5-dihydro- oxazole (2.43g, lO.Ommol) in THF was cooled to -780C under argon, and n-BuLi
(2.5M in hexane, 4.OmL, lO.Ommol) was added dropwise to the solution. The resulting dark brown solution was stirred for 2hrs at -6O0C and then cooled again to -780C, to which was added propyl iodide (1.88mL, 19.0mmol). The reaction mixture was allowed to warm up to room temperature, and then stirred overnight. The reaction was quenched by adding water and the aqueous phase was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give dark brown residue.
A mixture of the crude residue obtained above and 6N HCl (5.OmL) was heated at reflux for 8hrs. After cooling to ambient temperature, water was added to the reaction mixture and the aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The resulting residue dissolved in THF was treated with IN LiOH, and the resulting mixture was stirred 18hrs at ambient temperature and then 18hrs at 7O0C. After cooling, the reaction mixture was acidified with 2N HCl and then extracted three times with chloroform. The combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give crude benzoic acid product.
The resulting crude acid was dissolved in dichloromethane, to which were added successively N,O-dimethylhydroxylamine, HCl (630mg, 6.46mmol), NMM (0.7ImL, 6.46mmol), and EDC (990mg, 7.75mmol). The resulting mixture was stirred overnight at ambient temperature and then quenched by adding water. The aqueous layer was extracted three times with EtOAc, and the combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex/EtOAc = 2/1) to yield the title compound (230 mg, 8%). 1H NMR(300MHz, CDCl3): δ 7.50(s, IH), 7.48(d, IH, J =7.8Hz), 7.36(d, IH, J =7.8Hz), 3.43(bs, 3H), 3.36(bs, 3H)5 2.65(t, 2H5 J =7.8Hz)5 1.67(m, 2H)5 0.97(t, 3H, J=7.2Hz).
Step 3: Synthesis of 3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid methyl ester.
To a solution of N-methoxy-N-methyl-2-piOpyl-4-trifluoromethyl- benzamide (230mg5 0.84mmol) in THF (15mL) was added dropwise 1.0M LiAlH4 (0.42mL, 0.42mmol) at -780C. The mixture was warmed up to -2O0C and stirred for 30mins. An aqueous solution of sodium potassium tartrate (10% w/v) was added to the reaction mixture and the resulting mixture was vigorously stirred for 30 mins, to which was added Et2O. After separation of two phases, the aqueous layer was extracted three times with ether and the combined organic layer was washed with brine, dried over anhydrous MgSO4; filtered and concentrated under reduced pressure. The product was vacuum dried to yield the 2-propyl-4-tritluoromethyl-benzaldehyde.
To a solution of the aldehyde obtained above in toluene was added methyl (triphenylphosphoranylidene)acetate (285mg, 0.85mmol), and the resulting mixture was heated at 8O0C for 3hrs. The reaction mixture was diluted with EtOAc, and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc = 4/1) to give the title compound (220mg, 96%).
1R NMR(300MHz, CDCl3): δ 7.98(d, IH, J =15.9Hz), 7.63(d, IH, J =8.4Hz), 7.46(d, IH, J =8.4Hz), 7.45(s, IH), 6.42(d, IH, J =15.9Hz), 3.83(s, 3H), 2.77(t, 2H, J =7.5Hz), 1.63(m, 2H), 0.98(t, 3H, J=7.5Hz).
Step 4: Synthesis of 3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid.
To a suspension of 3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (220mg, 0.8 lmmol) in THF (3mL) was added a solution of IN-LiOH
(6 ml), and the mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with H2O, which was washed three times with EtOAc, acidified with IN HCl to pH 1~2. The resulting solution was extracted three times with methylene chloride and then dried over anhydrous MgSO4 and concentrated in vacuo to give the title compound (155mg, 74%).
1B. NMR(300MHz, CDCl3): δ 8.09(d, IH, J =15.9Hz), 7.67(d, IH, J =7.8Hz), 7.49(d, IH, J=7.8Hz), 7.47(s, IH), 6.44(d, IH, 7=15.9Hz), 2.79(t, 2H, /=7.5Hz), 1.64(m, 2H), 0.99(t, 3H, /=7.5Hz). Step 5: Synthesis of fRVN-ri-(3.5-difluoro-4-methanesulfonylamino-phenyl)- ethyl] -3 -C2-propyl-4-trifluoromethyl-phenyl)-acrylamide
To a suspension of (i?)-N-[4-(l-amino-ethyl)-2,6-difluoro-phenyl]- methanesulfonamide, HCl salt (67mg, 0.23mmol) in THF (5mL) was added N- methylmorpholine (51 1, 0.46mmol). The mixture was stirred for 5 minutes, to which were added 3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid (60mg, 0.23mmol) and 4-(4,6-dimemoxy[l,3,5]triazin-2-yl)-4-memylmorpholinium chloride hydrate (DMTMM, 76mg, 0.28mmol). The mixture was stirred overnight at room temperature and was concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with saturated sodium bicarbonate, IN HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by recrystallization from n-Hex/EtOAc to give title compound (83mg, 74%). 1H NMR(300MHz, CD3OD): δ 7.99 (d, IH, J= 15.6 Hz), 7.86 (d, IH, J= 8.7 Hz), 7.60 (bs, 2H), 7.18 (d, 2H, J= 8.7 Hz), 6.75 (d, IH, J= 15.6 Hz), 5.20 (m, IH), 3.17 (s, 3H), 2.90 (t, 2H, J= 7.8 Hz), 1.70 (m, 2 H), 1.61 (d, 3H, J= 7.2 Hz), 1.06 (t, 3H, J= 7.2 Hz). ESI [M-H]-: 489
Example 22 : N-(3,5-Difluoro-4-methanesuIfonyIamino-benzyI)-3-(2-propyI-4- trifluoromethyl-phenyl)-acrylamide
Figure imgf000053_0001
N-(4-Aminomethyl-2,5-difluoro-phenyl)-methanesulfonamide, HCl salt
(33mg, 0.12mmol) was reacted with 3-(2-propyl-4-trifluoromethyl-phenyl)- acrylic acid (25mg, 0.097mmol) to give the title compound (30mg, 65%) after purification by column chromatography (gradient 12% to 100% EtOAc in Hex). 1R NMR(300MHz, CD3OD): δ 8.05 (d, IH, /= 15.6 Hz), 7.87 (d, IH, J= 8.7 Hz), 7.62 (bs, 2H), 7.16 (d, 2H, J = 8.7 Hz), 6.76 (d, IH, J = 15.6 Hz), 4.61 (s, 2H), 3.18 (S5 3H), 2.93 (t, 2H5 J= 7.8 Hz)5 1.71 (m, 2 H), 1.09 (t, 3H5 J= 7.5 Hz). ESI [M+H]+:
Example 23: N-(3-Fluoro-4-methanesulfonylamino-5-methyl-benzyl)-3-(2- propyl-4-trifluoromethyl-phenyI)-acrylamide
Figure imgf000054_0001
N-(4-Ammomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt (32mg, 0.12mmol) was reacted with 3-(2-propyl-4-trifluoromethyl-phenyl)- acrylic acid (25mg, 0.097mmol) to give the title compound (30mg, 63%) after purification by column chromatography (gradient 12% to 100% EtOAc in Hex). 1H NMR(300MHz, CD3OD): δ 8.05 (d, IH, J= 15.6 Hz)5 7.85 (d, IH, J= 8.1 Hz), 7.60 (m, 2H), 7.30 (m, 2H)5 6.74 (d, IH5 J= 15.6 Hz), 4.64 (s, 2H), 3.08 (s, 3H), 2.92 (t, 2H, J= 7.5 Hz), 2.38 (d, 3H, J= 2.1 Hz)5 1.72 (m, 2 H)5 1.08 (t, 3H5 J = 7.5 Hz).
ESI [M+H]+:
Example 24: (i?)~3-(2-Butyϊ-4-trifluoromethyl-phenyl)-N- [l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide
Figure imgf000054_0002
3-(2-Butyl-4-trifluoromethyl-phenyl)-acrylic acid was obtained by the procedure in example 21.
(R)-N-[4-(l-Amino-ethyl)-256-difluoro-phenyl]-methanesulfonamide, HCl salt (38mg, 0.13mmol) was reacted with 3-(2-butyl-4-trifluoromethyl-phenyl)- acrylic acid (30mg, O.llmmol) to give the title compound (29mg, 43%) after purification by column chromatography (gradient 12% to 100% EtOAc in Hex). 1H NMR(300MHz, CD3OD): δ 7. 90 (d, IH, J = 15.6 Hz)3 7.76 (d, IH, J = 8.7 Hz), 7.51 (bs, 2H)5 7.08 (d, 2H, J = 8.7 Hz), 6.65 (d, IH, J = 15.6 Hz), 5.10 (m, IH), 3.07 (s, 3H), 2.82 (t, 2H, J= 7.8 Hz), 1.55 (m, 2 H), 1.51 (d, 3H, J= 7.2 Hz), 1.40 (m, 2 H), 0.94 (t, 3H, J= 7.2 Hz). ESI [M-HP: 503
Example 25: (i?)-N-[l-(3,5-Difluoro-4-methanesuIfonylamino-phenyl)- propyI]-3-(2-propyl-4-trifl«ororaethyI-phenyI)-acryIamide
Figure imgf000055_0001
(R)-N-[4-(l-Amino-propyl)-2,6-difluoro-phenyl]-methanesulfonamide, HCl salt (15mg, 0.050mmol) was reacted with 3-(2-propyl-4-trifluoromethyl- phenyl)-acrylic acid (8mg, 0.031mmol) to give the title compound (15mg, 97%) after purification by column chromatography (gradient 12% to 100% EtOAc in Hex).
1H NMR(300MHz, DMSO-d6): δ 8.65 (d, IH, J- 8.1 Hz), 7.69 (m, 4H), 7.11 (d, 2H, J= 8.4 Hz), 6.75 (d, IH, J= 15.6 Hz), 4.82 (m, IH), 2.98 (s, 3H)5 2.75 (t, 2H, J= 7.8 Hz), 1.71 (m, 2 H), 1.52 (m, 2 H), 1.23 (m, 2 H), 0.89 (m, 6H). ESI [M+H]+:
Example 26: (R)-N- [l-(3,5-Difluoro-4-methanesuIfonylamino-phenyl)-ethyl]- 3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylamide
Figure imgf000055_0002
Figure imgf000056_0001
Step 1 : Synthesis of 2-isopropoxy-4-trifluoromethyl-benzoic acid isopropyl ester
A mixture of 2-hydroxy-4-trifluoromethyl-benzoic acid (500 mg, 2.42 mmol) in DMF (5 mL) was added potassium carbonate (837 mg, 6.06 mmol) and 2-bromopropane (906 mg, 5.33 mmol). The resulting mixture was stirred for 48 hours at 110 °C . The reaction mixture was diluted with EtOAc, which was washed with IN HCl, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography^ex/EtOAc^S/l) to give the title compound (200 mg, 28 %). 1H NMR(300MHz, CDCl3): δ 7.73 (d, IH, J = 8.1 Hz), 7.19 (d, IH, J = 8.4 Hz), 7.15 (s, IH), 5.31 - 5.29 (m, IH), 4.68 - 4.60 (m, IH), 1.40 (d, 6H, J= 6.9 Hz), 1.36 (d, 6H, J = 6.6 Hz).
Step 2: Synthesis of 2-isoρropoxy-N-methoxy-N-methyl-4-trifluoromethyl- benzamide.
To a suspension of 2-isopropoxy-4-trifluoromethyl-benzoic acid isopropyl ester (35 mg, 0.12 mmol) in THF (1 ml) was added a solution of 0.5 N-LiOH (2 eq), and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was acidified with IN HCl, and hthen extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was vacuum dried to yield the 2-isopropoxy-4-trifluoromethyl- benzoic acid. To an ice-cold suspension of 2-isopropoxy-4-trifluoromethyl- benzoic acid and N, (9-dimethylhydroxylamine hydrochloride (13 mg, 0.132 mmol) in CH2Cl2 (1 mL) was added Ν-methylmorpholine (0.015 ml, 0.132 mmol), and the resulting mixture was stirred for 5 minutes, to which were added N-(3- dimethylammopropyl)~N -ethyl carbodiimide hydrochloride (26 mg, 0.132 mmol). The resulting mixture was stirred for 2 hours at room temperature, and then diluted with EtOAc. The organic layer was washed with IN HCl5 water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatographyCHex/EtOAc^S/l) to give the title compound (28 mg, 80 %).
1H ΝMR(300MHz, CDCl3): δ 7.26 - 7.18 (m, 2H), 7.11 (s, IH), 4.66 - 4.60 (m, IH), 3.46 (s, 3H), 3.35 (s, 3H), 1.34 (d, 6H, J= 6.0 Hz).
Step 3: Synthesis of 3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester.
To a suspension of 2-isopropoxy-N~methoxy-N-methyl-4-trifluoromethyl~ benzamide (28 mg, 0.096 mmol) in THF (1.5 mL) was added dropwise 1.0M LiAlH4 (0.048 ml, 0.5 eq) at -6O0C. The mixture was slowly warmed up to -2O0C until the reaction was completed. The reaction was slowly quenched with sat'd KHSO4 (1 mL) and then diluted with water (1 mL). The reaction mixture was extracted with ether and the combined organic layer was dried over anhydrous MgSO4; filtered and concentrated under reduced pressure. The resulting compound was vacuum dried to yield the 2-isopropoxy-4-trifluoromethyl- benzaldehyde. To the aldehyde prepared above was added toluene (1 mL) followed by portionwise addition of methyl (triρhenylphosphoranylidene)acetate (32 mg, 0.105 mmol) (exothermic). Toluene (1 mL) was added to the reaction mixture, and the resulting mixture was heated at 8O0C for 3 hours. The reaction mixture was cooled to room temperature, and then was directly loaded to a short silica-gel column and eluted with the solvent (Hex/EtOAc = 20/1) to give the title compound (20 mg, 72 %). 1H NMR(SOOMHZ, CDCl3): δ 7.96 (d, IH, J= 16.2 Hz), 7.58 (d, IH, J- 8.1 Hz), 7.17 (d, IH, J= 7.8 Hz), 7.11 (s, IH), 6.57 (d, IH, J= 16.2 Hz), 4.71 - 4.63 (m, IH)3 3.81 (s, 3H), 1.41 (d, 6H, J= 6.3 Hz).
Step 4: Synthesis of N-ri-(3n5-difluoro-4-methanesulfonylamino-phenyl)-ethyll- 3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylamide.
Figure imgf000058_0001
To a suspension of 3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (15 mg, 0.052 mmol) in THF (1 ml) was added a solution of 0.5 N- LiOH (0.2 ml), and the resulting mixture was stirred for 3 hours at room temperature. The reaction mixture was acidified with IN HCl to pH 1~2. The mixture solution was extracted three times with methylene chloride, and the combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give 3-(2-isopiOpoxy-4-trifluoromethyl-phenyl)-acrylic acid (14 mg, 98 %). To a suspension of 3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylic acid (14 mg, 0.051 mmol) and N-[4-(l-amino-ethyl)-2,6-difiuoro-phenyl]- methanesulfonamide, HCl salt (17.2 mg, 0.060 mmol) in DMF (2 mL) was added N-methylmorpholine (0.007 ml, 0.060 mmol). The mixture was stirred for 5 minutes, to which were added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (26 mg, 0.132 mmol). The mixture was stirred for 12 hours at room temperature, and then diluted with EtOAc (4 mL). The organic layer was washed with IN HCl, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography (Hex/EtOAc = 1/1) to give the title compound (24 mg, 79 %). 1H ΝMR(300MHz, CDCl3): δ 7.93 (d, IH, J= 15.6 Hz), 7.56 (d, IH, J= 7.8 Hz), 7.16 (d, IH, J= 8.1 Hz), 7.10 (s, IH), 7.01 (d, IH, J= 8.4 Hz), 6.54 (d, IH, J = 15.6 Hz), 5.82 (d. IH5 J= 6.9 Hz), 5.19 (t, IH, J= 6.9 Hz), 4.67 - 4.63 (m, IH), 3.20 (s, 3H), 1.56 (d, 6H, J= 6.3 Hz). 1.40 (d, 3H, J= 5.4 Hz). ESI [M-H]-; 505
Example 27: (KJ-N-[l-(3,5-Difluoro-4-methanesuIfonyIamino-phenyl)-ethyl]- 3-(4-fluoro-2-propoxy-ρhenyI)-acryIamide
Figure imgf000059_0001
Step 1: Synthesis of 3-(4-fluoro-2-hydroxy-phenyl)-acrylic acid methyl ester.
2-Hydroxy-4-fluoro-benzaldehyde (306 mg, 1.99 mmol) was reacted with methyl (triρhenylphosphoranylidene)acetate (681 g, 2.044 mmol) at 110 0C overnight as described above to yield title compound (334 mg, 85%).
1H NMR (300MHz, CDCl3): δ 7.93 (d, IH, J = 15.9 Hz), 7.45 (m, IH)5 6.65 (m,
IH), 6.59 (m, IH), 6.56 (s, IH), 6.53 (d, IH, J = 16.2 Hz), 5.27 (br, IH), 3.82 (s,
3H).
Step 2: Synthesis of 3-f4-flu.oiO-2-proρoxy-phenyl)-acrylic acid methyl ester
3-(4-Fluoro-2-hydroxy-phenyl)-acrylic acid methyl ester (110.5 mg) was reacted with K2CO3 (111 mg) and propane iodide (0.1 ml) at 80 0C overnight as described above to yield title compound (134HIg, 100%)
1U NMR (300MHz, CDCl3): δ 7.90 (d, IH, J = 15.9 Hz), 7.45 (t, IH, J = 7.5 Hz), 6.65 (m, IH), 6.59 (m, IH), 6.49 (d, IH, J = 15.9 Hz)5 3.96 (t, 2H, J = 6.6 Hz), 3.78 (s, 3H), 1.89 (m, 2H), 1.07 (t, 3H, J = 7.5 Hz).
Step 3: Synthesis of 3-(4-fluoro-2-propoxy-phenyl)-acrylic acid
3-(4-Fluoro-2-propoxy-ρhenyl)-acrylic acid methyl ester (134 mg, 0.563 mmol) was reacted with aqueous IN LiOH (5 ml) as described above to yield title compound (117 mg, 92%). 1H NMR (300MHz5 CDCl3): δ 8.00 (d, IH, J = 16.5 Hz), 7.49 (t, IH, J = 8.4 Hz), 6.67 (m, 2H) 6.50 (d, IH5 J = 15.9 Hz), 3.98 (t, 2H, J = 6.6 Hz)5 1.91 (m, 2H)5 1.09 (t, 3H, J = 7.2 Hz).
Step 4: Synthesis of ^gj-N-[l-(3,5-Difluoro-4-methanesulfoiiylamino-phenyl)- emyl]-3-f4-fluoro-2-propoχy-phenyl)-acrvlaniide
(R)-N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (85 mg, 0.29 mmol) was reacted with 3-(4-fluoro-2-propoxy-phenyl)-acrylic acid (65 mg, 0.29 mmol), NMM (0.15 ml) and DMTMM (98 mg) at room temperature overnight to yield the title compound (77 mg, 58%) after column chromatography( Hex/EtOAc = 1/1).
1R NMR (300MHz5 CDCl3): δ 7.84 (d, IH, J = 15.6 Hz)5 7.43 (t, IH5 J = 6.9 Hz)5 6.98 (d, IH, J = 8.7 Hz), 6.63 (m, 2H), 6.47 (d, IH5 J = 15.6 Hz)5 5.87 (br, IH), 5.18 (m, IH), 4.11 (t, 2H5 J = 6.9 Hz)5 3.19 (s, 3H)5 1.87 (m, 2H), 1.09 (t, 3H5 J = 7.5 Hz)
Example 28: N-(3,5-Difluoro-4-methanesulfonyIamino-benzyI)-3-(4-fluoro-2- propoxy-phenyl)~acrylamide
Figure imgf000060_0001
N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide5 HCl salt
(66 mg, 0.24 mmol) was reacted with 3-(4-fϊuoro-2-propoxy-ρhenyl)-acrylic acid
(51 mg, 0.23 mmol), NMM (0.15 ml) and DMTMM (78 mg) at room temperature overnight to yield the title compound (52 mg, 0.12 mmol, 53%) after column chromatography( Hex/EtOAc = 1/1).
1U NMR (300MHz5 CDCl3): δ 7.90 (d, IH5 J = 15.9 Hz)5 7.44 (t, IH, J = 6.6 Hz)5 6.99 (d, IH5 J = 8.1 Hz), 6.65 (m, 2H), 6.52 (d, IH, J = 15.6 Hz)5 5.89 (br, IH)5
4.55 (d, 2H5 J = 6.0 Hz), 3.98 (t, 2H, J = 6.6 Hz), 3.21 (s, 3H)5 1.90 (m, 2H), 1.08 (t, 3H5 J = 7.5 Hz).
Example 29: fK)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)ethyI]- 3-(4-fluoro-2- propylaminophenyl)-acrylamide
Figure imgf000061_0001
Step 1. Synthesis of N-methoxy-N-methyl-4-fluoro-2-nitro-benzamide
To a solution of 4-fluoro-2-nitrobenzoic acid (1 g, 5.4 mmol), N3O- dimethylhydroxylamine hydrochloride (0.58 g, 5.95 mmol) and N- methylmorpholine (0.65 mL, 5.91 mmol) in dichloromethane (20 mL) was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.14 g, 5.95 mmol). The mixture was stirred for 80 minutes at room temperature. The mixture was concentrated under reduced pressure and then diluted with EtOAc and water. The organic layer was washed with 3 N HCl, saturated aqueous NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give N-methoxy-N-methyl-4-fluoro-2-nitro-benzamide
(1.15 g, 95%).
1H NMR(300MHz, CDCl3): δ 7.89 ~ 7.85 (m, 1 H), 7.58 ~ 7.54 (m, 1 H), 7.47 ~ 7.41 (m, 1 H), 3.37 (s, 3 H), 3.36 (s, 3 H).
Step 2. Synthesis of N-methoxy-N-methyl-2-amino-4-fluoro-benzamide
A mixture of N-methoxy-N-methyl-4-fluoro-2-nitro-benzamide (1.15 g, 5.04 mmol) and 5% palladium charcoal (190 mg) in EtOH (30 mL) was shaken overnight under hydrogen atmosphere (3 atm). The mixture was filtered and concentrated under reduced pressure to give N-methoxy-N-methyl-2-amino-4- fluoro-benzamide (0.9 g, 90%). 1H NMR(SOOMHZ, CDCl3): δ 7.44 ~ 7.39 (m, 1 H), 6.40 ~ 6.30 (m, 2 H), 4.90 (bs, 2 H), 3.57 (s, 3 H), 3.34 (s, 3 H).
Step 3. Synthesis of N-methoxy-N-methyl-4-fluoro-2-propylamino-benzamide
To a solution of N-methoxy-N-methyl-2-amino-4-fluoro-benzamide (0.27 g, 1.36 mmol), propionaldehyde (0.15 mL, 2.08 mmol), and AcOH (0.12 mL, 2.1 mmol) in dichloromethane (20 mL) was added sodium triacetoxyborohydride (576 mg, 2.72 mmol) at 50C. The mixture was stirred for 90 minutes at the same temperature and then 40 minutes at room temperature. The reaction was quenched by adding water. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give N-methoxy-N-methyl-4-fiuoro-2- propylamino-benzamide quantitatively. 1H NMR(300MHz, CDCl3): δ 7.40 (t, 1 H, J= 7.2 Hz), 6.34 ~ 6.25 (m, 2 H), 3.58 (s, 3 H), 3.33 (s, 3 H), 3.03 (t, 2 H, J= 6.9 Hz), 1.72 ~ 1.59 (m, 2 H), 1.00 (t, 3 H, J= 7.2 Hz).
Step 4. Synthesis of 3-(4-fluoro-2-propylamino-phenyl)-acrylic acid methyl ester
To a solution of N-methoxy-N-methyl-4-fluoro-2-propylamino-benzamide
(0.33 g, 1.37 mmol) in THF (4 mL) was added dropwise LiAlH4 (1 M in THF, 0.7 mL) at -450C. The mixture was stirred for 40 minutes at -350C and then quenched by adding saturated aqueous KHSO4 solution. The mixture was diluted with EtOAc, washed with 3 N HCl, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was reacted with methyl (triphenylphosphoranylidene)acetate (0.5 g, 1.5 mmol) in toluene (4 mL) overnight at 1000C. The mixture was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.23 g, 69%) after purification by column chromatography (EtOAc : hexane = 1 : 10).
1H NMR(300MHz, CDCl3): δ 7.72 (d, 1 H, J = 15.6 Hz), 7.34 ~ 7.29 (m, 1 H),
6.41 ~ 6.29 (m, 2 H), 6.27 (d, 1 H, J= 15.6 Hz), 4.16 (bs, 1 H), 3.80 (s, 3 H), 3.12 ~ 3.07 (m, 2 H), 1.76 ~ 1.63 (m, 2 H), 1.02 (t, 3 H, J= 7.2 Hz).
Step 5. Synthesis of (R)-N-[I -(3, 5-difluoro-4-methanesulfonylaminophenyl) ethyll-3-(4-fluoro-2-propylamino-phenyl)-acrylamide
To a solution of 3-(4-fluoro-2-propylamino-phenyl)-acrylic acid methyl ester (0.23 g, 0.95 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 N LiOH (4 mL). The mixture was stirred for 2 hours at room temperature, concentrated under reduced pressure, and then acidified with 3 N HCl. The mixture was diluted with EtOAc, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-(4-fluoro-2-propylamino- phenyl)-acrylic acid (0.17 g, 79%) after purification by crystallization form EtOAc and hexane. To a mixture of 3-(4-fluoro-2-propylamino-phenyl)-acrylic acid (50 mg, 0.22 mmol), (R)-[l-(3,5-difluoro-4-methanesulfonylamino phenyl)ethylamine hydrochloride (64 mg, 0.22 mmol) and N-methylmorpholine (36 μLs 0.33 mmol) in THF (5 mL) was added 4-(4,6-dimethoxy[l,3,5]triazin-2- yl)-4-methylmorpholirium chloride hydrate (DMTMM, 68 mg, 0.25 mmol). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc and water, and the aqueous layer was washed with 2 N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (35 mg, 34%) after purification by crystallization form EtOAc and hexane, 1H NMR(300MHz, CDCl3): δ 7.78 (d, 1 H, J= 15 Hz), 7.32 ~ 7.26 (m, 1 H), 6.93 (d, 2 H5 J= 8.4 Hz), 6.78 (s, 1 H), 6.37 ~ 6.29 (m, 2 H), 6.22 (d, 1 H, J= 15 Hz), 5.87 (d, 1 H, J= 6.9 Hz), 5.13 (t, 1 H, J= 6.9 Hz), 4.48 (bs, 1 H), 3.18 (s, 3 H), 3.08 (t, 2 H, J= 6.9 Hz), 1.71 ~ 1.58 (m, 2 H), 1.49 (d, 3 H, J= 6.9 Hz), 0.99 (t, 3 H, J= 7.2 Hz). Example 30: N-[l-(3,5-Difluoro-4-methanesuIfonyIaminobenzyl]-3-(4- fluoro-2-«-propylamino-phenyl)-acrylamide
Figure imgf000064_0001
To a mixture of 3-(4-fluoro-2-propylamino-phenyl)-acrylic acid (50 mg,
0.22 mmol), (3,5-difluoro-4-methanesulfonylamino)benzylamine hydrochloride (61 mg, 0.22 mmol) and N-methylmorpholine (36 μL, 0.33 mmol) in THF (5 mL) was added 4-(4,6-dimethoxy[l,3,5]triazin-2-yl)-4-methylmorpholirium chloride hydrate (DMTMM, 68 mg, 0.25 mmol). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc and water, and the aqueous layer was washed with 2 N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (9 mg, 9%) after purification by column chromatography (EtOAc : hexane = 1 : 1). 1H NMR(300MHz, CDCl3): δ 7.60 (d, 1 H5 J= 15 Hz), 7.32 ~ 7.26 (m, 1 H), 6.96 (d, 2 H, J = 8.1 Hz), 6.93 ~ 6.32 (m, 2 H), 6.14 (d, 1 H, J= 15 Hz), 6.13 (br, 1 H), 5.95 (br, 1 H), 4.53 (d, 2 H, J = 5.7 Hz), 4.25 (br, 1 H), 3.21 (s, 3 H), 3.09 (m, 2 H), 1.72 ~ 1.65 (m, 2 H), 1.01 (t, 3 H, J= 7.2 Hz).
Example 31: fi2>3-(2-Butoxy-4-trifluoromethyl-phenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide
Figure imgf000064_0002
Step 1 : Synthesis of 2-butoxy-4-trifluoromethyl-benzoic acid butyl ester
2-Hydroxy-4-trifluoromethyl-benzoic acid (755 mg) was reacted with butylbromide (0.96 ml) and K2CO3 (1.15 g) in DMF solution as described above to yield title compound.
1H NMR (300MHz, CDCl3): δ 8.01 (s, IH), 7.801 (d, IH, J = 7.8 Hz), 7.19 (m, 2H), 4.32 (t, 2H, J = 6.6 Hz), 4.06 (t, 2H, J = 6.3 Hz), 1.82 (m, 2H), 1.75 (m, 2H), 0.98 (m, 6H)
Step 2: Synthesis of 2-butoxy-4-trifluoromethyl-benzoic acid
2-Butoxy-4-trifluoromethyl-benzoic acid butyl ester was reacted with IN LiOH (10 ml) as described above to yield title compound (687 mg).
1H NMR (300MHz, CDCl3): δ 8.29 (d, IH, J = 8.4 Hz), 7.38 (d, IH, J = 8.1 Hz), 4.31 (t, 2H, J = 6.3 Hz), 1.94 (m, 2H), 1.53 (m, 2H), 1.02 (t, 3H, J = 7.5 Hz)
Step 3: Synthesis of 2-butoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide
2-Butoxy-4-trifluoromethyl-benzoic acid (687 mg) was reacted with N5O- dimethylhydroxy amine (331 mg), NMM (0.65 ml) and DMTMM (911 mg) as described above to yield the title compound (825 mg) after column chromatography (Hex/EtOAc = 7.5/1). 1H NMR (300MHz, CDCl3): δ 7.36 (br, IH), 7.22 (d, IH, J = 8.1 Hz), 7.11 (s, IH),
4.04 (t, 2H, J = 6.3 Hz), 3.45 (s, 3H), 3.35 (s, 3H), 1.77 (m, 2H), 1.46 (m, 2H),
0.99 (t, 3H, J = 7.5 Hz)
Step 4: Synthesis of 2-butoxy-4-trifluoromethyl-benzaldehvde
2-Butoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (825 mg) was reacted with 1 M LAH (31 ml) at -50 0C for 1 hour as described above to yield title compound (423 mg) after column chromatography (Hex/EtOAc = 20/1).
1H NMR (300MHz, CDCl3): δ 10.53 (s, IH), 7.92 (d, IH, J = 7.8 Hz), 7.27 (d, IH, J = 8.7 Hz), 7.21 (s, IH), 4.10 (t, 2H, J = 6.3 Hz), 1.89 (m, 2H)5 1.57 (m, 2H),
1.01 (t, 3H, J = 7.2 Hz) Step 5: Synthesis of 3-r2-butoxy-4-trifluoromethyl-phenylVacrylic acid methyl ester
2-Butoxy-4-trifluoromethyl-benzaldehyde (420 mg) was reacted with methyl (triphenylphosphoranylidene)acetate (679 mg) at 110 0C overnight as described above to yield title compound (464 mg) after column chromatography (Hex/EtOAc = 20/1).
1H NMR (300MHz, CDCl3): δ 7.91 (d, IH5 J = 16.5 Hz), 7.53 (d, IH, J = 7.8 Hz), 7.13 (m, IH), 7.06 (s, IH), 6.54 (d, IH, J = 16.2 Hz), 4.03 (t, 2H, J = 6.6 Hz), 3.77 (s, 3H), 1.82 (m, 2H), 1.48 (m, 2H), 0.96 (t, 3H, J = 7.5 Hz)
Step 6: Synthesis of 3-(2-butoxy-4-trifluoromethyl-phenyl)-acrylic acid
3-(2-Butoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (464 mg) was reacted with IN LiOH (10 ml) in THF and CH3OH for 1 hr as described above to yield title compound
1H NMR (300MHz, CDCl3): δ 8.05 (d, IH, J = 16.2 Hz), 7.60 (d, IH, J = 8.1 Hz), 7.20 (m, IH), 7.12 (s, IH), 6.62 (d, IH, J = 16.2 Hz), 4.09 (t, 2H, J = 6.0 Hz), 1.85 (m, 2H), 1.56 (m, 2H), 1.04 (t, 3H, J = 7.5 Hz)
Step 7: Synthesis of (RJ-3-(2-butoxy-4-trifluoromethyl-phenylVN-ri-(3,5- difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide
(R)-N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (75 mg, 0.26 mmol) was reacted with 3-(2-butoxy-4-trifluoromethyl-phenyl)- acrylic acid (63 mg, 0.230 mmol), NMM (0.15 ml) and DMTMM (75 mg) at room temperature overnight to yield the title compound (52 mg, 0.10 mmol, 43%) after column chromatography^ Hex/EtOAc = 1/1).
1H NMR (300MHz, CDCl3): δ 7.93 (d, IH, J = 15.6 Hz), 7.55 (d, IH, J = 7.8 Hz), 7.18 (d, IH5 J = 8.1 Hz), 6.99 (d, IH, J = 6.6 Hz), 6.75 (d, IH5 J = 8.4 Hz)5 6.52 (d,
IH, J = 15.6 Hz)5 5.89 (br, IH), 5.18 (t, IH), 4.10 (d, 2H, J = 6.0 Hz), 3.19 (s, 3H)5
1.87 (m, 2H)5 1.52 (m, 2H), 0.99 (t, 3H5 J = 7.2 Hz). ESI [M-H]--. 519
Example 32: 3-(2-Butoxy-4-trifluoromethyl-phenyl)-N-(3,5-difluoro-4- methanesulfonylamino-benzyl)-acrylamide
Figure imgf000067_0001
N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (65 mg, 0.24 mmol) was reacted with 3-(2-butoxy-4-trifluoromethyl-phenyl)- acrylic acid (57 mg, 0.20 mmol), NMM (0.2 ml) and DMTMM (66 mg) to give the title compound (62 mg, 012 mmol, 62%) after column chromatography ( Hex/EtOAc = 1/1).
1H NMR (300MHz, CDCl3): δ 7.96 (d, IH, J = 15.6 Hz), 7.56 (d, IH, J = 8.1 Hz), 7.20 (d, IH, J = 7.2 Hz), 7.11 (s, IH), 6.99 (d, IH5 J = 8.1 Hz), 6.75 (d, IH, J = 8.1 Hz), 6.52 (d, IH, J = 15.6 Hz), 6.05 (br, IH), 4.55 (d, 2H, J = 6.3 Hz), 4.10 (d, 2H, J = 6.9 Hz), 3.20 (s, 3H), 1.88 (m, 2H), 1.57 (m, 2H), 0.98 (t, 3H, J = 7.2 Hz).
Example 33 : (#>3-(2-Butoxy-4-fluoro-phenyl)-N-[l-(3,5-diflιioro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide
Figure imgf000067_0002
Step 1: Synthesis of 3-(2-butoxy-4-fluoro-phenyl)-acrylic acid methyl ester
3-(4-Fluoro-2-hydroxy-phenyl)-acrylic acid methyl ester (106 mg) was reacted with K2CO3 (125 mg) and butyl iodide (0.1 ml) at 80 0C for 3 hrs as described above to yield title compound (121 mg).
1H NMR (300MHz, CDCl3): δ 7.90 (d, IH, J = 16.2 Hz), 7.45 (m, IH), 6.64 (m, 2H), 6.47 (d, IH, J = 15.9 Hz), 4.00 (t, 2H5 J = 6.6 Hz), 3.79 (s, 3H), 1.84 (m, 2H)5 1.53 (m, 2H)5 0.99 (t, 3H, J = 7.2 Hz)
Step 2: Synthesis of 3-f2-butoxy-4-fruoro-phenyl)-acrylic acid
3-(2-Butoxy-4-fluoro-phenyl)-acrylic acid methyl ester (121 mg) was reacted with IN LiOH (5ml) in THF and CH3OH for 2 hrs as described above to yield title compound (116 mg).
1H NMR (300MHz, CDCl3): δ 7.99 (d, IH, J - 16.2 Hz), 7.48 (m, IH), 6.65 (m, 2H), 6.49 (d, IH5 J = 16.2 Hz), 4.02 (t, 2H, J = 6.3 Hz)5 1.86 (m, 2H), 1.54 (m, 2H), 1.00 (t, 3H5 J = 7.2 Hz).
Step 3: Synthesis of ^)-3-f2-butoχy-4-fluoro-ρhenyl)-N-[l-f3,5-difluoro-4- methanesulfonylamino-phenvD-ethvll-acrylamide
(R)-N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (75 mg, 0.26 mmol) was reacted with 3-(2-butoxy-4-fluoro-phenyl)-acryIic acid (60 mg, 0.25 mmol), NMM (0.15 ml) and DMTMM (82 mg) at room temperature overnight to yield the title compound (87 mg5 0.19 mmol, 74%) after column chromatography (Hex/EtOAc = 1/1).
1H NMR (300MHz, CDCl3): δ 7.85 (d, IH, J = 15.9 Hz), 7.42 (m, IH)5 6.94 (d, 2H, J - 8.4 Hz), 6.62 (m, 2H), 6.47 (d, IH, J = 15.6 Hz), 6.23 (d, IH5 J = 7.2 Hz), 5.13 (t, IH), 4.11 (t, 2H, J = 6.3 Hz)5 3.17 (s, 3H)5 1.81 (m, 2H), 1.54 (m, 2H)5 1.46 (d, 3H, J = 6,6 Hz)5 0.90 (t, 3H5 J = 7.2 Hz). ESI [M-H]": 469
Example 34: 3-(2-Butoxy-4-fluoro-phenyl)-N-(3,5-difluoro-4- methanesulfonylamino-benzyty-acrylamide
Figure imgf000068_0001
N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt
(73 mg, 0.26 mmol) was reacted with 3-(4-fluoro-2-propoxy-phenyl)-acrylic acid
(55 mg, 0.23 mmol), NMM (0.15 ml) and DMTMM (73 mg) at room temperature overnight to yield the title compound (85 mg, 0.19 mmol, 81%) after column chromatography^ Hex/EtOAc = 1/1).
1H NMR (300MHz5 CDCl3): δ 7.89 (d, IH, J = 15.6 Hz), 7.45 (m, IH), 6.94 (d, 2H, J = 8.4 Hz), 6.98 (m, IH), 6.64 (m, IH), 6.50 (d, IH, J = 15.6 Hz)3 6.07 (br, IH), 4.55 (d, 2H, J = 6.0 Hz), 4.13 (t, 2H, J = 6.3 Hz), 3.20 (s, 3H)5 1.83 (m, 2H), 1.52 (m, 2H), 0.88 (t, 3H, J = 7.2 Hz).
Example 35: N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2- propyl-4-trifluoromethyl-phenyl)-acrylamide
Figure imgf000069_0001
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt (14mg, 0.050mmol) was reacted with 3-(2-propyl-4-trifluoromethyl-ρhenyl)- acrylic acid (8mg, 0.031mmol) to give the title compound (12mg, 80%) after purification by column chromatography (gradient 12% to 100% EtOAc in Hex). 1H NMR(300MHz, DMSO-d6): δ 8.79 (t, IH), 7.69 (m, 4H), 7.74 (m, 2H), 7.60 (m, 2H), 7.26 (m, 2H), 6.72 (d, IH, J= 15.6 Hz), 4.45 (s, IH), 4.38 (d, IH, J= 5.4 Hz), 3.01 (s, 3H), 2.70 (t, 2H, J = 7.5 Hz), 1.54 (m, 2 H), 1.23 (m, 2 H), 0.91 (m, 3H). ESI [M+H]+: Example 36: (i?)-3-(2-ButyI-4-trifluoromethyI-phenyI)-N-[l-(3-fluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide
Figure imgf000070_0001
(R)-N-[4-(l-Amino-ethyl)-2-fluoro-phenyl]-methanesulfonamide, HCl salt
(20mg, 0.074mmol) was reacted with 3-(2-butyl-4-trifluoromethyl-phenyl)- acrylic acid (8mg, 0.031mmol) to give the title compound (5mg, 35%) after purification by column chromatography (gradient 12% to 100% EtOAc in Hex). 1H NMR(300MHz, DMSO-d6): δ 8.66 (d, IH, J= 8.1 Hz), 7.66 (m, 3H)5 7.51 (bs, 2H), 7.31 (t, IH, J= 8.4 Hz), 7.17 (d, IH, J= 11.4 Hz), 7.09 (d, IH, J= 8.1 Hz), 6.70 (d, IH, J = 15.6 Hz), 5.00 (m, IH), 2.91 (s, 3H), 2.78 (t, 2H, J = 7.8 Hz), 1.47 (m, 2 H), 1.40 (d, 3H, J= 12 Hz), 1.32 (m, 2 H), 0.89 (t, 3H, J= 7.2 Hz). ESI [M-H]-; 485
Example 37: N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-propyl]-3- (2-ethoxy-4-trifluoromethyl-phenyl)-acrylamide
Figure imgf000070_0002
To a suspension of 3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylic acid (39 mg, 0.151 mmol) and N-[4-(l-amino-propyl)-2,6-difluoro-phenyl]- methanesulfonamide, HCl salt (50 mg, 0.166 mmol) in DMF (2 mL) was added
N-methylmorpholine (0.02 ml, 0.018 mmol). The mixture was stirred for 5 minutes, to which were added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (33 mg, 0.166 mmol). The mixture was stirred for 12 hours at room temperature, and then diluted with EtOAc (4 mL). The organic layer was washed with IN HCl, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography (Hex/EtOAc = 1/1) to give the title compound. (43 mg, 51 %). 1H NMR(300MHz, DMSO-d6): δ 9.50 (bs, IH), 8.65 (d, IH, J= 7.8 Hz)5 7.74 (d, IH5 J= 7.8 Hz)5 7.67 (d5 IH5 J= 15.9 Hz), 7.33 (d, IH5 J= 8.1 Hz)5 7.31 (s, IH), 7.15 (d, IH5 J= 8.7 Hz), 6.82 (d, IH, J= 15.9 Hz)5 4.87 - 4.80 (m, IH), 4.19 (q, 2H5 J= 6.9 Hz), 3.04 (s, 3H), 1.75 - 1.70 (m, 2H), 1.39 (t, 3H, J= 6.9 Hz). 0.88 (t, 3H, J= 6.9 Hz).
Example 38: 3-(2-Butoxy-4-trifluororaethyl-phenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-propyl]~acrylamide
Figure imgf000071_0001
N-[4-( 1 -Amino-propyl)-2,6-difluoro-phenyl]-methanesulfonamide5 HCl salt (50 mg, 0.166 mmol) was reacted with 3-(2-butoxy-4-trifluoromethyl- phenyl)-acrylic acid (43.5 mg, 0.151 mmol) to give the title compound (43 mg, 54 %) after purification by column chromatography.
1H NMR(300MHz, DMSO-d6): δ 9.47 (bs, IH)5 8.65 (d, 2H, J= 8.1 Hz)5 7.73 (d, IH, J= 8.4 Hz), 7.68 (d, IH5 J= 16.2 Hz), 7.33 (s, IH), 7.15 (d, 2H, J= 8.7 Hz), 6.80 (d, IH5 J= 16.2 Hz)5 4.82 (q, IH, J= 7.2 Hz), 4.12 (d, 2H, J= 6.3 Hz), 3.04 (s, 3H), 1.83 - 1.67 (m, 4H), 1.51 - 1.41 (m, 2H)5 0.96 - 0.86 (m, 6H).
Example 39: (Λ)-3-(2-sec-Butoxy-4-trifluoromethyl-phenyl)>N-[l-(3,5- difluoro-4-methanesuIfonyIamino-phenyl)-ethyl]-acrylamide
Figure imgf000071_0002
. „ 2009/096701
Step 1: Synthesis of 2-sec-butoxy-N-methoχy-N-methvl-44rifluoromethyl- benzamide
A mixture of 2-hydroxy-4-trifluoromethyl-benzoic acid (300 mg, 1.45 mmol) in DMF was added potassium carbonate (442 mg, 3.20 mmol) followed by 2-iodobutane (589 mg, 3.2 mmol). The mixture was stirred for 48 hours at 110 0C and then diluted with EtOAc. The organic layer was washed with IN HCl, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was dissolved in THF (2 ml) and then added a solution of 0.5 N-LiOH (2 eq). The mixture was stirred for 2 hours at room temperature and then diluted with EtOAc. The organic layer was washed with IN HCl, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue and N,O- dimethylhydroxylamine hydrochloride (316 mg, 0.16 mmol) in CH2Cl2 (5 mL) was added N-methylmorpholine (0.176 ml, 0.160 mmol). The mixture was stirred for 5 minutes, to which were added N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (316 mg, 0.160 mmol). The mixture was stirred for 2 hours at room temperature and then diluted with EtOAc. The organic layer was washed with IN HCl, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography to give the title compound. (374 mg, 84 %). 1H NMR(300MHz5 CDCl3): δ 7.23 - 7.19 (m, 2H), 7.09 (s, IH), 4.40 - 4.37 (m, IH), 3.42 (s, 3H), 3.34 (s, 3H), 1.77 - 1.67 (m, 2H), 1.30 (d, 3H, J= 3.0 Hz), 0.97 (t, 3H, J= 7.2 Hz).
Step 2: Synthesis of 3-r2-sec-butoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester
2-sec-Butoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (130 mg, 0.425 mmol) was processed with reduction and wittig reaction as described above to give the title compound (100 mg, 61 %) after purification by column chromatography. 1H NMR(300MHz, CDCl3): 7.97 (d, IH, J = 16.2 Hz), 7.58 (d, IH5 J = 7.8 Hz), 7.17 (d5 IH, J= 7.8 Hz)5 7.09 (s, IH)5 6.57 (d, IH, J= 16.2 Hz), 4.48 - 4.42 (m, IH), 3.81 (s, 3H), 1.86 - 1.69 (m, 2H)5 1.35 (d, 3H5 J= 6.0 Hz), 1.01 (t, 3H5 J = 7.2 Hz).
Step 3: Synthesis of 3-(2-sec-butoxy-4-trifluoromethyl-phenyl)-N-ri-(3,5- difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide
N- [4-( 1 - Amino-ethy l)-2,6-difluoro-phenyl]-methanesulfonamide, HCl salt (17.7 mg, 0.062 mmol) was reacted with 3-(2-sec-butoxy-4-trifluoiOmethyl- phenyl)-acrylic acid (16.2 mg, 0.056 mmol) to give the title compound (15 mg,
52 %) after purification by column chromatography.
1B. NMR(300MHz, CDCl3): δ 7.93 (d, IH5 J= 15.9 Hz)5 7.56 (d, IH5 J= 8.1 Hz)5
7.11 (d5 IH, J = 8.1 Hz), 7.09 (s, IH), 6.99 (d, 2H, J = 8.1 Hz), 6.53 (d, IH, J = 15.9 Hz)5 5.96 (d, IH, J= 7.2 Hz), 5.23 - 5.14 (m, IH), 4.43 (q, IH5 J= 6.0 Hz),
3.19 (s, 3H)5 1.86 - 1.77 (m, IH)5 1.73 - 1.62 (m, IH)5 1.52 (d, 3H, J = 6.9 Hz),
1.33 (d, 3H5 J= 6.0 Hz)5 0.99 (t, 3H5 J= 7.2 Hz).
ESI [M-H]": 519
Example 40: (i?)-3-(2-sec-Butoxy-4-fluoro-phenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide
Figure imgf000073_0001
Step 1 : Synthesis of 3-(2-sec-butoxy-4-fluoro-phenyl)-acrylic acid methyl ester
3-(4-Fluoro-2-hydroxy-phenyl)-acrylic acid methyl ester (120 mg) was reacted with K2CO3 (165 mg) and 2-iodobutan (0.12 ml) at 100 0C for 3 hrs as described above to yield title compound (105 mg)
1H NMR (300MHz, CDCl3): δ 7.90 (d, IH, J = 15.9 Hz)5 7.45 (m5 IH)5 6.63 (m, 2H), 6.45 (d, IH5 J = 15.9 Hz)5 4.33 (m, IH5 J = 6.0 Hz)5 3.79 (s, 3H)5 1.82 (m, IH)5 1.71 (m, IH)5 1.33 (d, 2H5 J = 6.0 Hz)5 0.99 (t, 3H5 J = 7.2 Hz)
Step 2: Synthesis of 3-f2-sec-butoxy-4-fluoro-phenyl)-acrylic acid
3-(2-sec-Butoxy-4-fluoro-ρhenyl)-acrylic acid methyl ester (105 mg) was reacted with IN LiOH (5 ml) in THF and CH3OH for 2 hrs as described above to yield title compound (82 mg)
1H NMR (300MHz5 CDCl3): δ 7.97 (d, IH5 J = 16.2 Hz)5 7.50 (m, IH)5 6.62 (m5 2H), 6.47 (d, IH9 J = 16.2 Hz), 4.02 (m, IH, J = 6.0 Hz)5 1.86 (m, IH), 1.73 (m, IH)5 1.34(d, 3H)5 1.00 (t, 3H, J = 7.2 Hz).
Step 3: Synthesis of rRJ-3-(2-sec-butoxy-4-fluoro-phenvD-N-ri-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide
(R)-N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (69 mg, 0.24 mmol) was reacted with 3-(2-sec-butoxy-4-fluoro-phenyl)-acrylic acid (55 mg, 0.23 mmol), NMM (0.15 ml) and DMTMM (75 mg) at room temperature overnight to yield the title compound (15 mg, 14%) after column chromatography (Hex/EtOAc = 1/1).
1H NMR (300MHz5 CDCl3): δ 7.87 (d, IH5 J = 15.6 Hz)5 7.43 (m, IH), 6.99 (d, IH5 J = 8.7 Hz)5 6.64 (m, 2H), 6.41 (d, IH, J = 15.6 Hz)5 6.11 (s, IH)5 5.80 (d, IH5 J= 7.5 Hz)5 5.17 (t, IH)5 4.33 (m, IH, J = 6.0 Hz)5 3.19 (s, 3H)5 1.78 (m, IH), 1.67 (m, IH), 1.49 (d, 3H, J = 7.2 Hz), 1.32 (d, 3H, J = 6.0 Hz), 0.98 (t, 3H, J = 7.2 Hz). ESI [M-H]': 469
Example 41: 3-(2-sec-Butoxy-4-fluoro-phenyI)-N-(3,5-difluoro-4- methanesulfonylamino-benzyl)-acrylamide
Figure imgf000074_0001
N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt
(42 mg, 0.15 lnmol) was reacted with 3-(4-fluoro-2-propoxy-phenyl)-acrylic acid
(34 mg, 0.14 mmol), NMM (0.15 ml) and DMTMM (43 mg) at room temperature overnight to yield the title compound (15 mg, 23%) after column chromatography^ Hex/EtOAc = 1/1).
1H NMR (300MHz, CDCl3): δ 7.89 (d, IH5 J = 15.9 Hz), 7.44 (m, IH), 6.97 (d, IH, J = 8.4 Hz), 6.65 (s, IH), 6.60 (d, IH, J = 9.3 Hz), 6.47 (d, IH, J = 15.6 Hz), 6.08 (s, IH), 6.00 (s, IH, J= 7.5 Hz), 4.53 (d, 2H, J = 6.0 Hz), 4.34 (m, IH, J = 6.0 Hz), 3.20 (s, 3H), 1.78 (m, IH), 1.67 (m, IH), 1.49 (d, 3H, J = 7.2 Hz), 1.34 (d, 3H5 J = 6.0 Hz), 0.99 (t, 3H, J = 7.2 Hz).
Example 42: fK)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]- 3-(2-ethylamino-4-fluoro-phenyl)-acrylamide
Figure imgf000075_0001
Step 1: Synthesis ofN-methoxy-N-methyl-4-fluoro-2-ethylamino-benzamide
To a solution of N-methoxy-N-methyl-2-amino-4-fluoro-benzamide (0.20 g, 1.01 mmol), acetaldehyde (86 μL, 1.53 mmol), and AcOH (87 μL, 2.1 mmol) in dichloromethane (20 mL) was added sodium triacetoxyborohydride (430 mg, 2.03 mmol) at 50C. The mixture was stirred for 90 minutes at the same temperature and then 40 minutes at room temperature. The reaction was quenched by adding water. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give N-methoxy-N-methyl-4-fluoro-2-ethylamino-benzamide quantitatively.
1H NMR(300MHz, CDCl3): δ 7.43 ~ 7.38 (m, 1 H)5 6.35 ~ 6.25 (m, 2 H), 3.58 (s, 3 H), 3.33 (s, 3 H), 3.16 - 3.07 (m, 2 H), 1.27 (t, 3 H, J= 6.9 Hz). Step 2: Synthesis of 3-(4-fluoro-2-ethylamino-phenylVacrylic acid methyl ester
To a solution of N-methoxy-N-methyl-4-fluoro-2-ethylamino-benzamide (0.23 g, 1.02 mmol) in THF (4 mL) was added dropwise LiAlH4 (1 M in THF, 0.51 mL) at -450C. The mixture was stirred for 40 minutes at -350C and then quenched by adding saturated aqueous KHSO4 solution. The mixture was diluted with EtOAc, washed with 3 N HCl, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was reacted with methyl (triphenylphosphoranylidene)acetate (375 mg, 1.12 mmol) in toluene (4 mL) overnight at 1000C. The mixture was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.13 g, 57%) after purification by column chromatography (EtOAc : hexane = 1 : 10). 1H NMR(300MHz, CDCl3): δ 7.73 (d, 1 H, J= 15.6 Hz), 7.32 (t, 1 H3 J= 7.2 Hz), 6.42 ~ 6.32 (m, 2 H), 6.27 (d, 1 H, J= 15.6 Hz), 4.09 (br, 1 H), 3.80 (s, 3 H), 3.19 ~ 3.15 (m, 2 H), 1.31 (t, 3 H5 J= 7.2 Hz).
Step 3: Synthesis of CR)-N-Tl -(3, 5-Difluoro-4-methanesulfonylaminophenyl) ethyl]-3-(4-fluoro-2-ethylaminophenyl)acrylamide
To a solution of 3-(4-fluoro-2-ethylamino-phenyl)-acrylic acid methyl ester (128 mg, 0.57 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 N LiOH (4 mL). The mixture was stirred for 2 hours at room temperature, concentrated under reduced pressure, and then acidified with 3 N HCl. The mixture was diluted with EtOAc, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-(4- fluoro-2-ethylamino-phenyl)-acrylic acid (88 mg, 73%) after purification by crystallization form EtOAc and hexane. To a mixture of 3-(4-fluoro-2- ethylamino-phenyl)-acrylic acid (40 mg, 0.19 mmol), (R)-[l-(3,5-difluoro-4- methanesulfonylaminophenyl)-ethylamine hydrochloride (55 mg, 0.19 mmol) and N-methylmorpholine (31 μL, 0.28 mmol) in THF (4 mL) was added 4-(4,6- dimethoxy[l,3,5]triazin-2-yl)-4-methylmorpholirium chloride hydrate (DMTMM, 58 mg, 0.21 mmol). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc and water, washed with 2 N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (4.9 mg, 6%) after purification by column chromatography (EtOAc : hexane = 1 : 10 to 2:1).
1H NMR(300MHz, CDCl3 + DMSO-d6): δ 9.05 (br, 1 H), 8.00 (d, 1 H, J = 7.8 Hz), 7.62 (d, 1 H, J = 15.3 Hz), 7.29 (t, 1 H, J= 7.8 Hz), 7.01 (d, 2 H, J= 8.4 Hz), 6.40 (d, 1 H, J= 15.3 Hz), 6.37 ~ 6.28 (m, 2 H)5 5.13 (t, 1 H, J= 6.9 Hz), 4.50 (bs, 1 H), 3.20 ~ 3.10 (m, 2 H), 3.08 (s, 3 H), 1.48 (d, 3 H, J= 6.9 Hz), 1.28 (t, 3 H, J = 7.2 Hz). ESI [M-H]-; 440
Example 43 : N-(3,5-Difluoro-4-methanesulfonylaminobenzyl)-3-(4-fluoro- 2-ethylaminophenyl)acrylamide
Figure imgf000077_0001
To a mixture of 4-fluoro-2-ethylaminocinnamic acid (40 mg, 0.19 mmol), (3,5-difluoro-4-methanesulfonylamino)benzylamine hydrochloride (52 mg, 0.19 mmol) and N-methylmorpholine (31 μL, 0.28 mmol) in THF (4 mL) was added 4- (4,6-dimethoxy[l,3,5]triazin-2-yl)-4-methylmorpholirium chloride hydrate (DMTMM, 58 mg, 0.21 mmol). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc and water, and the organic layer was washed with 2 N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (17 mg, 21%) after trituration with ethyl ether.
1H NMR(SOOMHZ, CDCl3 + DMSO-d6): δ 9.07 (bs, 1 H), 8.14 (br, 1 H), 7.66 (d, 1 H, J= 15.6 Hz), 7.31 (t, 1 H, J= 7.2 Hz), 6.98 (d, 2 H, J= 8.1 Hz), 6.40 (d, 1 H, J= 15.3 Hz), 6.37 ~ 6.29(m, 2 H), 4.55 (br, 1 H), 4.47 (d, 2 H, J= 5.7 Hz), 3.18 ~ 3.12 (m, 2 H), 3.09 (s, 3 H), 1.29 (t, 3 H, /= 7.2 Hz).
Example 44: (ϋJ)-N-(2-Fluoro-4-{l-[3-(2-propyl-4-trifluoromethyl-phenyl)- allylamino]-ethyl}-phenyl)-methanesulfonamide
Figure imgf000078_0001
(R)-N- [4-( 1 -Amino-ethyl)-2-fluoro-phenyl]-methanesulfonamide, HCl salt (31mg, 0.12mmol) was reacted with 3-(2-ρropyl-4-trifluoromethyl-phenyl)- acrylic acid (25mg, 0.097mmol) to give the title compound (32mg, 70%) after purification by recrystallization from Hex/EtOAc.
1H NMR(300MHz, DMSO-d6): δ 8.70 (d, IH, J= 7.5 Hz), 7.66 (m, 3H), 7.33 (t, IH, J= 8.1 Hz), 7.23 (d, IH, J= 11.7 Hz), 7.15 (d, IH, J= 8.4 Hz), 6.70 (d, IH, J = 15.6 Hz), 5.02 (m, IH), 2.98 (s, 3H), 2.75 (t, 2H, J = 6.9 Hz), 1.50 (m, 2 H), 1.40 (d, 3H, J= 6.9 Hz), 1.32 (m, 2 H), 0.89 (t, 3H, J= 7.5 Hz).
Example 45: (K>3-(2-Butylamino-4-fluoro-phenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]- acrylamide
Figure imgf000078_0002
Step 1 : Synthesis ofN-memoxy-N-methyl-4-fluoro-2-n-buthylammo-benzamide
To a solution of N-methoxy-N-methyl-2-ammo-4-fluorobezoic acid amide
(0.35 g, 1.75 mmol), butyrylaldehyde (0.23 mL, 2.62 mmol), and AcOH (0.15 mL,
2.62 mmol) in dichloromethane (20 mL) was added sodium triacetoxyborohydride (0.74 g, 3.49 mmol) at 50C. The mixture was stirred for 5 hours at the same temperature and overnight at room temperature. The reaction was quenched by adding water. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound quantitatively.
1H NMR(300MHz, CDCl3): δ 7.43 ~ 7.38 (m, 1 H), 6.35 ~ 6.24 (m, 2 H), 3.58 (s, 3 H), 3.33 (s, 3 H), 3.10 ~ 3.02 (m, 2 H), 1.67 ~ 1.35 (m, 4 H), 0.95 (t, 3 H, J - 7.2 Hz).
Step 2: Synthesis of 3-(4-fluoro-2-butylamino-phenyl)-acrylic acid methyl ester
To a solution of N-memoxy~N-methyl-4-fluoro-2-n-butylamino- benzamide (0.5 g, 1.97 mmol) in THF (8 mL) was added dropwise LiAlH4 (1 M in THF, 1.0 mL) at -450C. The mixture was stirred for 40 minutes at -350C and then quenched by adding saturated aqueous KHSO4 solution. The mixture was diluted with EtOAc, washed with 3 N HCl, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was reacted with methyl (triρhenylphosphoranylidene)acetate (725 mg, 2.17 mmol) in toluene (4 mL) overnight at 1000C. The mixture was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.15 g, 30%) after purification by column chromatography (EtOAc : hexane = 1 : 10).
1H NMRPOOMHZ5 CDCl3): δ 7.71 (d, 1 H, J= 15.9 Hz)5 7.31 (t, 1 H, J= 8.4 Hz), 6.42 ~ 6.31 (m, 2 H), 6.26 (d, 1 H, J = 15.9 Hz), 4.13 (br5 1 H)5 3.15 ~ 3.09 (m, 2 H), 1.71 ~ 1.61 (m, 2 H), 1.49 ~ 1.41 (m, 2 H), 0.98 (t, 3 H, J= 7.2 Hz).
Step 3: Synthesis of ιffi)-N-fl-(3,5-Difluoro-4-methanesulfonylaminophenyl) ethyl]-3 -(4-fluoro-2-n-butylaminophenyl) acrylamide
To a solution of 3-(4-fluoro-2-butylamino-phenyl)-acrylic acid methyl ester (145 mg, 0.58 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 N LiOH (4 mL). The mixture was stirred for 2 hours at room temperature, concentrated under reduced pressure, and then acidified with 3 N HCl. The mixture was diluted with EtOAc, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-(4- fluoro-2-butylamino-ρhenyi)-acrylic acid (120 mg, 88%) after purification by crystallization form EtOAc and hexane. To a mixture of 3-(4-fluoro~2- butylamino-phenyl)-acrylic acid (52 mg, 0.22 mmoϊ), (R)-[I -(3, 5-difluoro-4- methanesulfonylaminophenyl)ethylamine hydrochloride (64 mg, 0.22 mmol) and N-methylmorpholine (36 μL, 0.33 mmol) in THF (5 mL) was added 4-(4,6- dimethoxy[l,3,5]triazin-2-yl)-4-methylmorpholirium chloride hydrate (DMTMM, 68 mg, 0.25 mmol). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc and water, washed with 2 N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (4.5 mg, 4%) after trituration with ethyl ether. 2:1). 1H NMR(300MHz, CDCl3): δ 7.78 (d, 1 H, J= 14.7 Hz), 7.30 (t, 1 H, J= 6.9 Hz)5 6.95 ~ 6.90 (m, 3 H)5 6.36 ~ 6.30 (m, 2 H), 6.23 (d, 1 H, J= 14.7 Hz), 5.95 (d, 1 H, J= 6.6 Hz), 5.11 (t, 1 H, J= 6.9 Hz), 4.50 (bs, 1 H), 3.18 (s, 3 H), 3.10 (t, 2 H, J= 6.9 Hz), 1.68 ~ 1.58 (m, 2 H), 1.48 (d, 3 H, J- 6.9 Hz), 1.43 ~ 1.38 (m, 2 H), 0.95 (t, 3 H, J= 7.2 Hz). ESI [M-H]": 468
Example 46: 3-(2-Butylamino-4-fluoro-phenyl)-N-(3,5-difluoro-4- methanesulfonylamino-benzyl)- acrylamide
Figure imgf000080_0001
To a mixture of 3-(4-fluoro-2-butylammo-phenyl)-acrylic acid (52 mg, 0.22 mmol), (3,5-difluoro~4-methanesulfonylamino)benzylamine hydrochloride
(61 mg, 0.22 mmol) and N-methylmorpholine (36 μL, 0.33 mmol) in THF (5 mL) was added 4-(4,6-dimethoxy[l,3,5]triazin-2-yl)-4-methylmorpholirium chloride hydrate (DMTMM, 68 mg, 0.25mmol). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was . „ . Λ „ 2009/096701
diluted with EtOAc and water, washed with 2 N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (45 mg, 45%) after trituration with ethyl ether. 1R NMR(300MHz, CDCl3 + DMSO-d6): δ 8.71 (bs, 1 H), 7.73 (br, 1 H), 7.68 (d, 1 H, J= 15.6 Hz), 7.30 (t, 1 H, J= 7.5 Hz), 6.97 (d, 2 H, J= 8.4 Hz), 6.40 ~ 6.30 (m, 3 H), 4.49 (d, 2 H, J- 6 Hz), 3.14 - 3.09 (m, 5 H), 1.69 ~ 1.59 (m, 2 H), 1.50 ~ 1.38 (m, 2 H), 0.96 (t, 3 H, J= 1.5 Hz).
Example 47: (Λ)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyI]- 3-(2-isobutyl-4-trifluoromethyI-phenyl)-acrylamide
Figure imgf000081_0001
3-(2-Isopropyl-4-trifluoromethyl-phenyl)-acrylic acid was obtained by the procedure in example 21. (R)-N-[4-(l-Ammo-ethyl)-2,6-difluoro-ρhenyl]-methanesulfonamide, HCl salt (55mg, 0.20mmol) was reacted with 3-(2-isobutyl-4-trifluoromethyl-phenyl)- acrylic acid (40mg, 0.15mmol) to give the title compound (18mg, 24%) after purification by recrystallization from ether.
1H NMR(300MHz, DMSO-d6): δ 8.74 (d, IH, J= 7.8 Hz), 7.67 (m, 4H), 7.17 (d, 2H, J= 8.7 Hz), 6.70 (d, IH, J= 15.6 Hz), 5.03 (m, IH), 3.04 (s, 3H), 2.78 (t, 2H),
2.67 (m, IH), 1.47 (m, 2 H), 1.41 (d, 3H, J= 6.9 Hz), 1.31 (m, 2 H), 0.87 (m, 9H).
Example 48: (J¥)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyI)-ethyl]> 2-methyl-3-(2-propyI-4-trifluoromethyl-phenyI)-acrylamide
Figure imgf000081_0002
Figure imgf000082_0001
Step 1: Synthesis of 2-methyl-3-f2-propyl-4-trifluoromethyl-phenylVacrylic acid
To a suspension of N-methoxy-N-methyl-2-propyl~4-trifluoromethyl- benzamide (150mg, 0.58mmol) in THF (1OmL) was added dropwise 1.0M LiAlH4 (0.3OmL, 0.30mmol) at -780C. The mixture was warmed up to -2O0C and stirred for 30 mins. An aqueous solution of sodium potassium tartarate (10% w/v) was added to the reaction mixture and the resulting mixture was vigorously stirred for 30mins, to which was added Et2O. After separation of two phases, the aqueous layer was extracted three times with ether and the combined organic layer was washed with brine, dried over anhyd. MgSO4> filtered and concentrated under reduced pressure. The product was vacuum dried to yield the 2-propyl-4- trifluoromethyl-benzaldehyde. To an ice-cold suspension of NaH (60% in mineral oil, 45mg, 1.13mmol) in THF (2mL) was added triethyl-2-phosphonopropionate (O.lόmL, 0.75mmol), and the resulting mixture was stirred for lOmins at ambient temperature. A solution of aldehyde obtained above in THF was added to the reaction mixture and the resulting mixture was stirred for 3 hrs at ambient temperature. The reaction mixture was diluted with water and EtOAc5 and the aqueous layer was extracted three times with EtOAc. The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (gradient 12% to 100% EtOAc in Hex) to give 2-methyl-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid ethyl ester (68mg5 39%).
To a suspension of 2-methyl-3-(2-propyl-4-trifluoromethyl-phenyl)- acrylic acid ethyl ester (68mg, 0.23mmol) in THF (ImL) was added a solution of IN-LiOH (10 ml), and the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H2O and then washed three times with EtOAc, acidified with IN HCl to pH 1-2. The solution was extracted three times with methylene chloride and then dried over anhydrous MgSO4 and concentrated in vacuo to give the title compound (60mg, 96%).
1H NMR(300MHz5 CDCl3): δ 7.91(s, IH)5 7.48(bs, 2H), 7.30(d, IH, J =8.7Hz), 2.63(t, 2H, J=8.1Hz), 1.96(s, 3H), 1.61(m, 2H), 0.95(t, 3H, J=7.2Hz).
Step 2: Synthesis of fi?)-N-[l-('3.,5~difluoro-4-methanesulfonylamino-phenvπ- ethyl]-2-methyl-3-(2-propyl-4-trifluoromethyl-ρhenyl)-acrylamide
To a suspension of (iζ)-N-[4-(l-amino-ethyl)~2,6-difluoro-phenyl]- methanesulfonamide, HCl salt (30mg, O.llmmol) in THF (2mL) was added N- methylmorpholine (23 1, 0.21mmol). The mixture was stirred for 5 minutes, to which were added 2-methyl-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid
(22mg, 0.081mmol) and 4-(4,6-dimethoxy[l,3,5]triazin-2-yl)-4- methylmorpholinium chloride hydrate (DMTMM5 27mg, 0.098mmol). The mixture was stirred overnight at room temperature and was concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with saturated sodium bicarbonate, IN HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in Hex) to give title compound (18mg, 44%).
1H NMR(SOOMHZ, DMSO-d6): δ 8.41 (d, IH5 J= 7.8 Hz), 7.58 (m, 2H)5 7.41 (m, 2H), 7.13 (d, 2H, J = 8.4 Hz), 5.04 (m, IH), 2.97 (s, 3H)5 2.62 (t, 2H), 1.86 (s, 3H), 1.52 (m, 2 H), 1.43 (d, 3H, J= 6.9 Hz)5 0.87 (t, 3H5 J= 7.2 Hz).
Example 49: (/?)-N-[l-(3-Fluoro-4-methanesuIfonyIamino-phenyl)-etliyl]-2- methyI~3-(2-propyl-4-trifluoromethyI-phenyl)-acrylamide
Figure imgf000083_0001
(R)-N-[4-(l-Amino-ethyl)-2-fluoro-phenyl]-methanesulfonamide, HCl salt (52mg, 0.19mmol) was reacted with 2-methyl-3-(2-propyl-4-trifluoromethyl- phenyl)-acrylic acid (40mg, 0.15mmol) to give the title compound (68mg, 93%) after purification by column chromatography (gradient 12% to 100% EtOAc in
Hex).
1H NMR(SOOMHZ5 DMSO-d6): δ 9.51 (bs, IH), 8.41 (d, IH5 J= 7.8 Hz)5 7.58 (m,
2H), 7.29 (m, 5H)5 5.06 (m, IH), 3.00 (s, 3H), 2.60 (t, 2H), 1.86 (s, 3H), 1.50 (m,
2 H), 1.44 (d, 3H9 J= 7.2 Hz), 0.87 (t, 3H, J= 7.5 Hz).
Example 50: (i?)-3-(2-CyclohexyImethoxy-4-trifluoromethyI-phenyl)-N-[l- (3,5~difluoro-4-methanesuIfonyIamino-phenyI)-ethyl]-acrylamide
Figure imgf000084_0001
1.LAH1THF
Step3 2.Wittig,tolueπe
Figure imgf000084_0002
Step 1: Synthesis of 2-cvclohexylmethoxy-4-trifluoromethyl-benzoic acid cyclohexylmethyl ester
2-Hydroxy-4-trifluoromethyl-benzoic acid (246 mg, 1.19 mmol) was reacted with toluene-4- sulfonic acid cyclohexylmethyl ester (640 mg, 2.34 mmol) as described above to give the title compound (470 mg, 99 %) after purification by column chromatography. 1H NMR(300MHz, CDCl3): δ 7.83 (d, IH, J= 7.8 Hz), 7.20 (d, IH, 7= 7.8 Hz), 7.13 (s, IH), 4.13 (d, 2H, J-= 6.6 Hz), 3.84 (d, 2H, J= 5.7 Hz), 2.04 - 1.74 (m, 12H), 1.33 - 1.02 (m, 10H). Step 2: Synthesis of 2-cvclohexylmethoxy-N-methoxy-N-methyl-4-trifluoro methyl-benzamide
2-Cyclohexylmethoxy-4-trifluoromethyl-benzoic acid cyclohexylmethyl ester (528 mg, 1.33 mmol) was reacted with IN LiOH (2.65 mg, 2.65 mmol) as described above to give 2-cyclohexylmethoxy-4-trifhioromethyl-benzoic acid (361 mg, 90 %) after drying by vacuum.
2-Cyclohexylmethoxy-4-trifluoromethyl-benzoic acid (361 mg, 1.19 mmol) was reacted with N,O-dimethylhydroxyamine, HCl salt (128 mg, 1.31 mmol) as described above to give the title compound (363 mg, 88 %) after purification by vacuum dry.
1H NMR(SOOMHZ, CDCl3): δ 7.36 (s, IH), 7.23 (d, IH, J= 7.5 Hz), 7.10 (s, IH), 3.83 (d, 2H, J = 5.7 Hz), 3.42 (s, 3H), 3.37 (s, 3H), 1.84 - 1.73 (m, 6H), 1.49 - 1.05 (m, 5H).
Step 3: Synthesis of 3-(2-cvclohexylmethoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester
2-Cyclohexylmethoxy-N-methoxy-N-methyl-4-trifluoromethyl- benzamide (363 mg, 1.05 mmol) was processed by LAH reduction and wittig reaction as described above to give the title compound (250 mg, 69 %) after purification by column chromatography(n-Hex/EtOAc=20/l). 1H NMR(300MHz, CDCl3): δ 7.97 (d, IH, J= 16.2 Hz), 7.58 (d, IH, J= 7.8 Hz), 7.19 (d, IH, J= 7.8 Hz), 7.09 (s, IH), 6.60 (d, IH, J= 16.2 Hz), 3.86 (d, 2H, J = 5.7 Hz), 3.82 (s, 3H)5 1.91 - 1.77 (m, 6H), 1.43 - 1.05 (m, 5H).
Step 4: Synthesis of 3-(2-cvclohexylmethoxy-4-trifluoromethyl-phenyl)-N-["l- (3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyll-acrylamide
Figure imgf000085_0001
N-[4-(l-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HCl salt (28.8 mg, 0.101 mmol) was reacted with 3-(2-cyclohexylmethoxy-4- trifluoromethyl-phenyl)-acrylic acid (30 mg, 0.091 mmol) to give the title compound (33 mg, 65 %) after purification by column chromatography. 1H NMR(300MHz, CDCl3): δ 7.88 (d, IH, J= 15.6 Hz), 7.50 (d, IH, J= 8.1 Hz), 7.12 (d, IH, J- 8.1 Hz), 7.03 (s, IH)5 6.94 (d, 2H, J= 8.4 Hz), 6.51 (d, IH, J = 15.9 Hz), 6.04 (s, IH), 5.82 (d, IH, J= 7.2 Hz), 5.17 - 5.10 (m, IH), 3.80 (d, IH, J- 5.7 Hz), 3.15 (s, 3H), 1.86 - 1.65 (m, 6H), 1.47 (d, 3H, J= 6.9 Hz), 1.28 - 1.02 (m, 5H).
Example 51: N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-piperidm -l-yI-4-trifluoromethyl-phenyl)~acrylaimde
Figure imgf000086_0001
N-(4-Aminomethyl-3,5-difluoro-phenyl)-methanesulfonamide, HCl salt
(59mg, 0.217mmol) was reacted with 3-(2-piperid-l-yl-4-trifluoromethyl- phenyl)-acrylic acid (65mg, 0.217mmol) to give the title compound (25mg, 22%) after purification by crystallization from Hex/EtOAc. 1H NMR(300MHz, CDCl3): δ 7.98(d, IH, J= 15.6Hz), 7.60(m, 2H), 6.99(m, 2H), 6.79(d, IH, J=8.4Hz), 6.46(d, IH, J=15.6Hz), 6.00(s, IH), 4.37(d, 2H, J=6.3Hz), 3 ,21(s, 3H), 2.92(m, 4H), 1.77(m, H), 1.61(m, 4H)
Example 52: (Λ)-N-[l-(3,5-Difluoro-4-methanesuIfonyIamino-phenyl)-3-(2- piperidm~l-yl~4-trifluoromethyl-phenyϊ)~acrylamide
Figure imgf000086_0002
(R)-N-[4-(l-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HCl salt (129mg, 0.451mmol) was reacted with 3-(2-piperid-l-yl-4-trifluoromethyl- phenyl)-acrylic acid (135mg, 0.451mmol) to give the title compound (65mg, 27%) after purification by crystallization from Hex/EtOAc. 1H NMR(300MHz, CDCl3): δ 7.94(d, IH5 J = 15.9Hz)5 7.55(d5 IH5 J =8.4Hz), 7.23(m, 2H)5 7.01(m, 2H)5 6.43(d, IH5 J =15.6Hz), 5.99(s, IH)5 5.83(s5 IH)5 5.20(m, IH)5 3.21(s5 3H)5 2.92(m5 4H)5 1.76(m, 4H)5 1.59(m, 2H)5 1.53(d, 3H5 J =6.6Hz).
Example 53: (2?)-N-[l-(3,5-Difluoro-4-methanesuIfonyIamino-phenyI)-ethyl]- 3-(4-fluoro-2-propyI-phenyl)-acrylamide
Figure imgf000087_0001
3-(4-Fluoro-2-propyl-phenyl)-acrylic acid was prepared as described above. (R)-N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide5 HCl salt (28 mg, 0.097 mmol) was reacted with 3-(4-fluoro-2-propyl-phenyl)-acrylic acid (15 mg5 0.072 mmol), NMM (0.20 ml) and DMTMM (36 mg) at room temperature overnight to yield the title compound (12 mg, 38%) after column chromatography (Hex/EtOAc = 3/2). 1H NMR (300MHz5 CDCl3): δ 7.91 (d, IH5 J = 15.3 Hz), 7.00 (d, IH5 J = 8.4 Hz), 7.48 (m, IH)5 6.92 (m, 2H), 6.25 (d, IH, J = 15.3 Hz)5 6.05 (br5 IH)5 5,82 (d, IH, J = 6.9 Hz), 5.17 (t, IH5 J- 7.1 Hz)5 3.20 (s, IH)5 2.72 (t, 2H, J = 7.5 Hz), 1.60 (m, 2H), 0.95 (t, 3H, J = 7.2 Hz) Example 54: N-(3-Fluoro-4-methanesulfonylamino-5-vinyl-benzyl)-3-(2- isopropylamino-4-trifluoromethyl-phenyl)-acrylamide
Figure imgf000088_0001
N-(4-Aminomethyl-2,5-difluoro-phenyl)-methanesulfonamide, HCl salt (43mg, 0.154mmol) was reacted with 3-(2-isopropylamino-4-trifluoro-phenyl)- acrylic acid (42mg, 0.154mmol) to give the title compound (34mg, 42%) after purification by crystallization from Hex/EtOAc.
1H NMR(SOOMHZ, DMSO-d6): δ 8.71(s, IH), 7.70(d, IH, J =15.3Hz), 7.50(m, 2H), 7.10(m, 3H), 6.83(s, IH), 6.57(d, lHs J=15.3Hz), 5.85(m, IH), 5.70(m, IH), 5.42(m, IH)5 4.42(d, 2H, J =5.4Hz)5 3.58(m, IH), 2.98(s, 3H)5 1.18(d, 6H5 J =6.0Hz). ESI [M-H]": 498
Example 55: (2?J-N-[l-(3,5-Difluoro-4-methanesulfonyIamino-phenyl)-ethyl]- 3-(2-propylamino-4-trifluoromethyl-phenyl)-propionamide
Figure imgf000088_0002
(R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2- propylamino-4-trifluoromethyl-phenyl)-acrylamide (12 mg) was reduced with Pd/C (15 mg) under hydrogen atmosphere to yield title compound (7 mg, 60%). 1H NMR (300MHz5 CDCl3): δ 7.02 (d, IH5 J = 7.5 Hz), 6.95 (d, IH5 J = 8.7 Hz)5 6.87-6.71 (m, 3H)5 6.17 (br, IH), 5.62 (d, IH, J = 7.8 Hz), 4.96 (t, IH5 J = 7.2 Hz), 3.15 (s, 3H), 3.00 (m, 2H), 2.83 (m, 2H), 2.47 (m, 2H), 1.32 (d, 3H5 J = 6.6 Hz), 0.96 (t, 3H, J = 7.5 Hz). Example 56: N-(3,5-Difluoro-4-methanesuIfonyIamino-benzyl)-3-(2- propylamino-4-trifluoromethyl-phenyl)-propionamide
Figure imgf000089_0001
N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-propylamino-4- trifluoromethyl-phenyl)-acrylamide (20 mg, 0.041 mmol) was reduced with Pd/C under hydrogen atmosphere to yield title compound (12 mg5 59%). 1H NMR (300MHz, CDCl3): δ 7.08 (d, IH, J = 7.5 Hz)5 6.95 (d, IH, J = 8.4 Hz), 36.87 (d, IH, J = 7.8 Hz), 6.78 (s, IH), 6.76 (m, IH), 6.29 (s, IH), 5.93 (t, IH), 4.36 (d, 2H, J = 6.3 Hz), 3.19 (s, 3H), 3.09 (m, 2H), 2.91 (m, 2H), 2.55 (m, 2H), 1.70 (m, 2H), 1.02 (t, 3H, J = 7.5 Hz)
Experimental example: Biological potency test
1. 45 Ca influx test
1) Separation of spinal dorsal root ganglia (DRG) in newborn rats and primary culture thereof
Neonatal (2-3 day old or younger than 2-3 day old) SD rats were put in ice for 5 minutes to anesthetize and disinfected with 70% ethanol. DRG of all part of spinal cord were dissected (Wood et al, 1988, J. Neurosci. 8, ρρ3208-3220) and collected in DME/F12 medium to which 1.2g/l sodium bicarbonate and 50mg/l gentamycin were added. The DRG were incubated sequentially at 370C for 30 mins in 200 U/ml collagenase and 2.5mg/ml trypsin, separately. The ganglia were washed twice with DME/F12 medium supplemented with 10% horse serum, triturated through a fire-polished Pasteur pipette, filtered through Nitex 80 membrane to obtain single cell suspension and the suspension was washed once more. This was subjected to centrifugation, then resuspended in cell culture medium at certain level of cell density. As the cell culture medium, DME/F12 medium supplemented with 10% horse serum was diluted with identical medium conditioned by C6 glioma cells 2 days on a confluent monolayer (1 :1), and NGF (Nerve Growth Factor) was added to adjust 200ng/ml as final concentration. After the cells were grown 2 days in medium where cytosine arabinoside (Ara-C, 100 μM) was added to kill dividing nonneuronal cells, medium was changed to one without Ara-C. The resuspended cells were plated at a density of 1500-2000 neurons/well onto Terasaki plates previously coated with 10 μg/ml poly-D-ornithine.
2) 45 Ca influx experiments
DRG nerve cells from the primary culture of 2 days were equilibrated by washing 4 times with HEPES (1OmM, pH 7.4)-buffered Ca 2+, Mg2+-free HBSS (H-HBSS). The solution in each well was removed from the individual well. Medium containing the test compound plus capsaicin (final concentration 0.5 μM) and 45Ca (final concentration 10 μCi/ml) in H-HBSS was added to each well and incubated at room temperature for 10 mins. Terasaki plates were washed five times with H-HBSS and dried at room temperature. To each well, 0.3% SDS (10 μl) was added to elute 45Ca. After the addition of scintillation cocktail of into each well, the amount of 45Ca influx into neuron was measured by counting radioactivity. Antagonistic activities of test compounds against vanilloid receptor were calculated as percent of the inhibition of maximal response of capsaicin at a concentration of 0.5 μM. The results are displayed in Table 1 below.
[Table 1 J Results of Calcium Influx Test
Figure imgf000091_0001
Figure imgf000092_0001
2. Analgesic activity test: Mouse writhing test by inducing with phenyl-p- quinone
Male ICR mice (mean body weight 25g) were maintained in a controlled lighting environment (12 h on/ 12 h off) for experiment. Animals received an intraperitoneal injection of 0.3ml of the chemical irritant phenyl-p-quinone (dissolved in saline containing 5% ethanol to be a dose of 4.5mg/kg) and 6 mins later, the number of abdominal constrictions was counted in the subsequent 6 mins period. Animals (10 animals/group) received 0.2ml of test compounds solution in vehicle of ethanol/Tween 80/saline (10/10/80) intraperitoneally 30 min before the injection of phenyl-p-quinone. In the case of oral administration, 0.2ml of test compounds solution in vehicle of ethanol/Tween 80/saline (5/5/90) were administered 54 min prior to the 0.2ml of 0.02% phenyl-p-quinone injection. A reduction in the number of writhes responding to the test drug compound relative to the number responding in saline control group was considered to be indicative of an analgesic effect. Analgesic effect was calculated by % inhibition equation (% inhibition^C-TyC x 100), wherein C and T represent the number of writhes in control and compound-treated group, respectively. Most examples of the present disclosure having good in vitro activities, were tested at various doses (ranging from 0.3 to 3 mg/kg) and all compounds tested in vivo showed analgesic effects from 8 to 59% inhibition at each dose, respectively.
3. PK study
Pharmacokinetics of compounds in rats were analyzed using the following experiment. Rats were fasted overnight prior to administration and until approximately 4 hrs after administration. Rats were given a single oral administration of compound at same dose. Administration volume was 10ml/kg. Blood samples were collected from the retro-orbital sinus at various times over the following 7 hrs. Immediately after each collection, plasmas were separated from blood cells by centrifugation and stored at -20 °C until the analysis was performed. The plasma samples were analyzed using a reverse phase high- performance chromatography (HPLC) method. The results are displayed in table 2 below.
[ Table 2 ] PK results for the compound having CF3 -phenyl with meta substituent
Figure imgf000093_0001
Figure imgf000094_0001
4. Comparative examples
As shown in Tables 2 and 3, the PK properties of the compounds of formula (I) of the present disclosure surprisingly have superior PK characteristics compared to compounds with a tert-butyl phenyl partial structure, with or without other substituents on the phenyl group, which were at least in part disclosed in the art, e.g. in WO 06/101318 or WO 06/101321 (also refer Table 3). Substantial increases in absorption and apparent half-life were observed by the replacement of tert-butyl phenyl by F-phenyl or CF3- phenyl (see Table 2 vs 3).
[Table 3] PK results for the compound having tert-butyl-phenyl
Figure imgf000094_0002
Figure imgf000095_0001
a Example number in WO 06/101318 b could not be determined due to low plasma concentration (detection limit : 0.100mcg/ml). c Example number in WO 06/101321
As shown in Tables 2 and 4, the compounds of formula (I) of the present disclosure have superior IC50 values and in some cases also improved PK characteristics compared to compounds with a CF3-phenyl partial structure but without additional substituents on the phenyl group, which were at least in part disclosed in the art, e.g. in WO 06/101318 or WO 06/101321. Surprisingly, the introduction of an additional substituent in ortho position of the phenyl's attachment position to the cinnamoyl backbone confers improved VRl activity to the compounds. For example, whilst comparative compound "G" has an IC50 value of more than 10 μM, the compounds 1, 3,5-7,10,16-18, 21, 24, 26, 31, 39, 47, 50, and 52 of the present disclosure which all differ from "G" only by additional substituent(s) on phenyl group, all have IC50 values in a range between 0.019 and 0.34 μM. In addition, compound "G" shows only poor PK-properties, while all tested compounds of the present disclosure showed improved PK properties (in terms of T max and AUC). Likewise, while comparative compound "F" has a moderate IC50 value of 0.57 μM, the IC50 values of the corresponding examples of the present disclosure Ex 12 (0.15 μM) and 54 (0.027 μM) are significantly improved. [Table 4] PK results for the compound having CF3-phenyl
Figure imgf000096_0001
a Example number in WO 06/101318 b could not be determined due to low plasma concentration (detection limit : O.lOOmcg/ml).
In summary, the presently disclosed compounds of formula (I) show a significantly improved "balance" between VRl activity and PK properties compared to the compounds disclosed in the art.
INDUSTRIAL APPLICABILITY
As explained above, the compound according to the present disclosure is useful to prevent or to treat pain, inflammatory disease of the joints, neuropathies, HlV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis, and pancreatitis.
More specifically, the compound according to the present disclosure is useful to preventing and treating of pain, which is or which is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrom and back pain), migraine, and other types of headaches.
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

WHAT IS CLAIMED IS
1. A compound of an isomer, or a pharmaceutically acceptable salt thereof;
Figure imgf000098_0001
formula (I) wherein,
Ri is hydrogen, methyl, or ethyl;
R2 and R3 are independently hydrogen, halogen, cyano, methyl, ethyl, methoxy, trifluoromethyl, vinyl, or acetylenyl; R4 is trifluoromethyl or fluoro;
R5 is C2-C5 alkyl, C2-C5 alkoxy, C1-C2 alkoxy (C1-C3) alkoxy, C1-C2 alkoxy (C1-C3) alkylamino, C2-C5 alkylamino, di(Cl-C3 alkyl)amino, C3-C6 cycloalkylamino, C3-C6 cycloalkoxy, or (C3-C6)cycloalkyl(Cl-C3)alkyloxy; and R6 is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, or C1-C5 alkylamino.
2. The compound according to claim 1, an isomer, or a pharmaceutically acceptable salt thereof; wherein, provided that if R5 is ethoxy, butoxy, pentoxy, (C3-C6)cycloalkoxy, or (C3-C6)cycloalkyl(Cl-C3)alkyloxy, then R1 is methyl.
3. The compound according to claim 1, an isomer, or a pharmaceutically acceptable salt thereof; wherein, R1 is hydrogen; R2 is halogen; and R5 is C2-C4 alkyl or C2-C4 alkylamino.
4. The compound according to claim 1, an isomer, or a pharmaceutically acceptable salt thereof; wherein, R1 is hydrogen; R2 is fluoro; R3 is hydrogen, fluoro, cyano, methyl, vinyl, or acetylenyl; R4 is trifluoromethyl; R5 is C2-C4 alkyl or C2-C4 alkylamino; and R6 is hydrogen.
5. The compound according to claim 1, an isomer, or a pharmaceutically acceptable salt thereof; wherein R1 is methyl.
6. The compound according to claim 1, an isomer, or a pharmaceutically acceptable salt thereof; wherein, Ri is methyl; R2 is halogen; and R5 is C2-C4 alkyl, C2-C4 alkyloxy, or C2-C4 alkylamino.
7. The compound according to claim 1, an isomer, or a pharmaceutically acceptable salt thereof; wherein,
R1 is methyl;
R2 is fluoro;
R3 is hydrogen, fluoro, vinyl, methyl, or acetylenyl;
R5 is C2-C4 alkyl, C2-C4 alkyloxy, or C2-C4 alkylamino; and
R6 is hydrogen or C1-C3 alkyl.
8. The compound according to claims any one of 1 to 7, an isomer, or a pharmaceutically acceptable salt thereof; wherein R2 and R3 are both fluoro.
9. The compound according to claims any one of 1 to 8, an isomer, or a pharmaceutically acceptable salt thereof; wherein R6 is hydrogen.
10. The compound according to claims any one of 1 to 9, an isomer, or a pharmaceutically acceptable salt thereof, wherein R5 is ethyl, propyl, isopropyl, n- butyl, isobutyl, sec-butyl, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, or cyclohexylmethoxy, provided that if R5 is ethoxy, butoxy, pentoxy, or cyclohexylmethoxy, then Ri is methyl.
11. The compound according to claims any one of 1 to 10, an isomer, or a pharmaceutically acceptable salt thereof, wherein R5 is propyl, butyl, isobutyl, ethylamino, propylamino, or isopropylamino
12. The compound according to anyone of claims 1, 2, and 5 to 11, wherein if Ri is methyl or ethyl, then the atom to which Ri is attached is in (R)- configuration.
13. The compound according to claim 1, an isomer, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of;
(i?)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2- propylamino-4-trifluoromethyl-phenyl)-acrylamide, N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-propylamino-4- trifluoromethyl-phenyl)-acrylamide,
(i?)-3-(2-Butylamino-4-trifluoromethyl-ρhenyl)-N-[l-(3,5-difiuoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(i?)-N-[l-(3,5-Difiuoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propoxy-4- trifluoromethyl-phenyl)-acrylamide,
(i?)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2,6-dipropyl- 4-trifluoromethyl-phenyl)-acrylamide,
(R)-N- [ 1 -(3 , 5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3 -(2-ethoxy-4- trifluoromethyl-phenyl)-acrylamide,
(R)-N- [1 -(3 ,5-Difiuoro-4-methanesulfonylammo-phenyl)~ethyl]-3 -(2- ethylamino-4-trifiuoromethyl-phenyl)-acrylamide,
N-(3-Fluoro-4-methanesulfonylamino-5-methyl-benzyl)-3-(2-propylamino-4- trifluoromethyl-phenyl)-acrylamide,
N-(3-Fluoro-4-methanesulfonylammo-5-vinyl-benzyl)-3-(2-propylamino-4- trifluoromethyl-phenyl)-acrylamide5
N-(3-Cyano-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-proρylamino-4- trifluoromethyl-ρhenyl)-acrylamide,
N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-ρropoxy-4- trifluoromethyl-phenyl)-acrylamide,
(R)-3-(2,6-Dibutyl-4-trifluoromethyl-ρhenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-3-(2,6-Diethyl-4-trifluoromethyl-ρhenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
N-(3 , 5-Difluoro-4-methanesulfonylamino-benzyl)-3 -(2-ethylamino-4- trifluorometliyl-phenyl)-acrylamide,
3-(2-Ethylamino-4-trifluoromethyl-phenyl)-N-(3-fluoro-4- methanesulfonylamino-5-methyl-benzyl)-acrylamide,
N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-isopropoxy-4- trifluoromethyl-phenyl)-acrylamide,
(i?)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-4- trifluoromethyl-phenyl)-acrylamide,
N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-propyl-4-trifluoromethyl- phenyl)-acrylamide,
N-(3-Fluoro-4-methanesulfonylamino-5-methyl-benzyl)-3-(2-propyl-4- trifluoromethyl-phenyl)-acrylamide,
(R)-3-(2-Butyl-4-trifluoromethyl-phenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-propyl]-3-(2-propyl-4- trifluoromethyl-phenyl)-acrylamide,
(i?)-N-[ 1 -(3,5 -Difluoro-4-methanesulfonylamino-phenyl)-ethyl] -3 -(2-isopropoxy-
4-trifluoromethyl-phenyl)-acrylamide,
(R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(4-fluoro-2- propoxy-phenyl)-acrylamide,
(R)-N-[l-(335-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(4-fluoro-2- propylamino-phenyl)-acrylamide,
(i?)-3-(2-Butoxy-4-trifluoromethyl-ρhenyl)-N-[ 1 -(3 ,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-3-(2-Butoxy-4-fluoro-phenyl)-N-[l-(355-difluoro-4-methanesulfonylamino- phenyl)-ethyl]-acrylamide,
N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-propyl-4- trifluoromethyl-phenyl)-acrylamide,
(R)-3-(2-Butyl-4-trifluoromethyI-phenyl)-N-[l-(3-fluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-3-(2-sec-Butoxy-4-trifluorometh.yl-ρhenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-ρhenyl)-ethyl]-acrylamide,
(R)-3-(2-sec-Butoxy-4-fluoro-ρhenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-ρhenyl)-ethyl]-3-(2- ethylamino-4-fluoro-phenyl)-acrylamide,
N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-ethylamino-4-fluoro- ρhenyl)-acrylamide,
(R)-N-(2-Fluoro-4-{l-[3-(2-ρropyl-4-trifluoromethyl-ρhenyl)-allylaminoJ-ethyl}- phenyl)-methanesulfonamide,
(R)-3-(2-Butylamino-4-fluoro-phenyl)-N-[l-(3,5-difIuoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
3-(2-Butylamino-4-fluoro-phenyl)-N-(3,5-difluoro-4-methanesuIfonylammo- benzyl)-acrylamide,
(R)-N-[I-(S, 5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-isobutyl-4- trifluoromethyl-ρhenyl)-acrylamide,
(R)-3-(2-Cyclohexylmethoxy-4-trifluoromethyl-phenyl)-N-[l-(3,5-difluoiO- 4methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-N- [ 1 -(3 , 5-Difluoro-4-methanesulfony lamino-phenyl)-ethyl]-3 -(4-fluoro-2- ρroρyl-phenyl)-acrylamide,
N-(3-Fluoro-4-methanesulfonylamino-5-vinyl-benzyl)-3-(2-isopropylamino-4- trifluoromethyl-phenyl)-acrylamide, and
(R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-ρhenyl)-ethyl]-3-(2- propylamino-4-t[-ifluoromethyl-phenyl)-propionamide.
14. The compound according to claim 1, an isomer, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of;
(R)-N-[l-(3,5-Difluoro-4-methanesulfonylammo-ρhenyl)-ethyl]-3-(2- ρropylamino-4-trifluoromethyl-ρhenyl)-acrylamide,
(i?)-3-(2-Butylamino-4-trifluoromethyl-ρhenyl)-N-[l-(3J5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propoxy-4- trifluoromethyl-phenyl)-acrylamide,
(R)-N-[l-(3,5-DifluoiO-4-methanesulfonylamino-phenyl)-ethyl]-3-(2,6-dipropyl-
4-trifluoromethyl-phenyl)-acrylamide,
(i?)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethoxy-4- trifluoromethyl-phenyl)-acrylamide,
(R)-N- [ 1 -(3 , 5-Difluoro-4-methanesulfonylamino-ρhenyl)-ethyl] -3 -(2-ethylamino-
4-trifluoromethyl-phenyl)-acrylamide,
N-(3-Fluoro-4-methanesulfonylamino-5-methyl-benzyl)-3-(2-propylamino-4- trifluoromethyl-phenyl)-acrylamide,
N-(3-Fluoro-4-methanesulfonylamino-5-vinyl-benzyl)-3-(2-proρylamino-4- trifluoromethyl-phenyl)-acrylamide,
N-(3-Cyano-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-propylamino-4- trifluoromethyl-pheiiyl)-acrylamide,
(R)-3-(2,6-Diethyl-4-trifluoromethyl-phenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-ρhenyl)-ethyl]-acrylamide,
N-(3s5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-ethylamino-4- trifluoromethyl-phenyl)-acrylamide,
N-(335-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-isopropoxy-4- trifl.uoromethyl-phenyl)-acrylamide,
(R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-4- trifluoromethyl-phenyl)-acrylamide,
(R)-3-(2-Butyl-4-trifluoromethyl-ρhenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-N-[l-(3s5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-isopiOpoxy-
4-trifluoromethyl-phenyl)-acrylamide,
(R)-3-(2-Butoxy-4-trifluoromethyl-ρhenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-3-(2-Butoxy-4-fluoro-phenyl)-N-[l-(3,5-difluoro-4-methanesulfonylamino- phenyl)-ethyl]-acrylamide,
N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-propyl-4- trifluoromethyl-phenyl)-acrylamide,
(i?)-3-(2-Butyl-4-trifluoromethyl-ρhenyl)-N-[l-(3-fluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-3-(2-sec-Butoxy-4-trifluoromethyl-phenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-3-(2-sec-Butoxy-4-fluoro-phenyl)-N-[ 1 -(3 ,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(i?)-N-[l-(355-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethylamino-
4-fluoro-phenyl)-acrylamide,
(i?)-N-(2-Fluoro-4-{ l-[3-(2-proρyl-4-trifluoromethyl-ρhenyl)-allylamino]-ethyl}- phenyl)-methanesulfonamide,
(i?)-3-(2-Butylamino-4-fluoro-phenyl)-N-[l-(3,5-difluoro-4- methanesulfonylamino-phenyl)-ethyl]-acrylamide,
(R)-N-[l-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-isobutyl-4- trifluoromethyl-phenyl)-acrylamide, and
N-(3-Fluoro-4-methanesulfonylamino-5-vinyl-benzyl)-3-(2-isopropylamino-4- trifluoromethyl-phenyl)-acrylamide.
15. A compound according to anyone of claims 1 to 14 for use as a medicament.
16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14, an isomer, or a pharmaceutically acceptable salt thereof, as an active ingredient and a pharmaceutically acceptable carrier.
17. The pharmaceutical composition according to claim 16, for preventing or treating a condition associated with the pathological stimulation and/or aberrant expression of vanilloid receptors.
18. The pharmaceutical composition according to claim 16 or 17, for treating a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis, and pancreatitis.
19. The pharmaceutical composition according to claim 18, wherein the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), visceral pain, migraine, and other types of headaches.
20. Use of the compound according to any one of claims 1 to 14, an isomer, or a pharmaceutically acceptable salt thereof for the preparation of a medicament.
21. Use of the compound according to any one of claims 1 to 14, an isomer, or a pharmaceutically acceptable salt thereof, in preparation of a medicament for prevention or treatment of a condition that is associated with the aberrant expression and/or aberrant activation of a vanilloid receptor.
22. Use of the compound according to any one of claims 1 to 14, an isomer, or a pharmaceutically acceptable salt thereof, in preparation of a medicament for prevention or treatment of a condition that is selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV- related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis and pancreatitis.
23. The use of the compound according to claim 22, wherein the condition is pain, which is or which is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), visceral pain, migraine, and other types of headaches.
PCT/KR2009/000407 2008-01-28 2009-01-28 Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same Ceased WO2009096701A2 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2010544237A JP5643112B2 (en) 2008-01-28 2009-01-28 Novel compounds as vanilloid receptors, isomers or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the same
US12/865,082 US8557872B2 (en) 2008-01-28 2009-01-28 Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
EP09706694.8A EP2238105B1 (en) 2008-01-28 2009-01-28 Novel compounds as vanilloid receptor antagonists
CN200980103367.3A CN101925575B (en) 2008-01-28 2009-01-28 Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanillic acid receptor antagonist
US14/022,789 US20140011881A1 (en) 2008-01-28 2013-09-10 Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP08001555 2008-01-28
EP08001555.5 2008-01-28

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US14/022,789 Division US20140011881A1 (en) 2008-01-28 2013-09-10 Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same

Publications (2)

Publication Number Publication Date
WO2009096701A2 true WO2009096701A2 (en) 2009-08-06
WO2009096701A3 WO2009096701A3 (en) 2009-09-24

Family

ID=40913409

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2009/000407 Ceased WO2009096701A2 (en) 2008-01-28 2009-01-28 Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same

Country Status (6)

Country Link
US (2) US8557872B2 (en)
EP (1) EP2238105B1 (en)
JP (1) JP5643112B2 (en)
KR (1) KR101619341B1 (en)
CN (1) CN101925575B (en)
WO (1) WO2009096701A2 (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101697573B1 (en) 2010-11-29 2017-01-19 삼성전자 주식회사 Semiconductor device, fabricating method thereof, and semiconductor package comprising the semiconductor device
HK1214587A1 (en) * 2012-12-28 2016-07-29 Nippon Zoki Pharmaceutical Co., Ltd. Cinnamic acid amide derivative
US9834537B2 (en) 2013-11-27 2017-12-05 Korea Institute Of Science And Technology Compounds as chloride channel blocking agent
EP4317422A3 (en) 2017-04-13 2024-05-01 Senti Biosciences, Inc. Combinatorial cancer immunotherapy
SG11202103317XA (en) 2018-10-17 2021-05-28 Senti Biosciences Inc Combinatorial cancer immunotherapy
US11419898B2 (en) 2018-10-17 2022-08-23 Senti Biosciences, Inc. Combinatorial cancer immunotherapy
KR20200053746A (en) 2018-11-09 2020-05-19 (주)아모레퍼시픽 Sol-gel composition
CN112409281B (en) * 2020-08-20 2022-11-18 上海大学 Synthetic method of (E)-3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylic acid
CN112679446A (en) * 2020-10-26 2021-04-20 都创(上海)医药科技有限公司 Method for synthesizing trans-3- (3-chloro-2-fluoro-6- (1H-tetrazole-1-yl) phenyl) acrylic acid

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006101321A1 (en) 2005-03-19 2006-09-28 Amorepacific Corporation Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same

Family Cites Families (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2001280229B2 (en) 2000-08-21 2006-12-07 Pacific Corporation Novel thiourea derivatives and the pharmaceutical compositions containing the same
ATE328868T1 (en) 2000-08-21 2006-06-15 Pacific Corp NEW (THIO)UREA COMPOUNDS AND MEDICINAL COMPOSITIONS CONTAINING THEM
WO2002061317A2 (en) 2001-01-30 2002-08-08 Parker Hannifin Corporation Thermoplastic reinforced hose construction and method of making the same
GB0110901D0 (en) 2001-05-02 2001-06-27 Smithkline Beecham Plc Novel Compounds
WO2003029199A1 (en) 2001-09-28 2003-04-10 Takeda Chemical Industries, Ltd. Benzene derivatives, process for preparing the same and use thereof
MXPA04005427A (en) 2001-12-10 2005-04-19 Amgen Inc Vanilloid receptor ligands and their use in treatments.
ATE420644T1 (en) 2002-02-20 2009-01-15 Abbott Lab CONDENSED AZABICYCLIC COMPOUNDS AS INHIBITORS OF THE VANILLOID RECEPTOR 1 (VR1)
WO2003099284A1 (en) 2002-05-22 2003-12-04 Amgen Inc. Amino-pyridine, -pyridine and pyridazine derivatives for use as vanilloid receptor ligands for the treatment of pain
EP1535922A4 (en) 2002-07-11 2006-10-04 Takeda Pharmaceutical PYRROLOPYRIDINE DERIVATIVE AND USE THEREOF
BR0313255A (en) 2002-08-08 2005-07-12 Amgen Inc Compound, pharmaceutical composition, use of a compound and methods of making a medicament and preparing a compound
GB0221157D0 (en) 2002-09-12 2002-10-23 Glaxo Group Ltd Novel treatment
WO2004024710A1 (en) 2002-09-13 2004-03-25 Glaxo Group Limited Urea compounds active as vanilloid receptor antagonists for the treatment of pain
US7157462B2 (en) 2002-09-24 2007-01-02 Euro-Celtique S.A. Therapeutic agents useful for treating pain
EP1551811A1 (en) 2002-10-17 2005-07-13 Amgen Inc. Benzimidazole derivatives and their use as vanilloid receptor ligands
US7265138B2 (en) 2003-02-10 2007-09-04 Amgen Inc. Vanilloid receptor ligands and their use in treatments
ATE450533T1 (en) 2003-02-14 2009-12-15 Glaxo Group Ltd CARBOXAMIDE DERIVATIVES
WO2004089877A1 (en) 2003-04-14 2004-10-21 Astrazeneca Ab New hydroxynaphthyl amides
PT2017265E (en) 2003-06-12 2011-07-29 Abbott Lab Fused compounds that inhibit vanilloid receptor subtype 1 (vr1) receptor
KR100707123B1 (en) * 2003-07-02 2007-04-16 그뤼넨탈 게엠베하 4-methylsulfonylaminophenyl analogues as vanilloid antagonist showing excellent analgesic activity and the pharmaceutical composition containing the same
GB0325287D0 (en) 2003-10-29 2003-12-03 Merck Sharp & Dohme Therapeutic agents
EP1685112B1 (en) 2003-11-08 2011-07-20 Bayer Schering Pharma Aktiengesellschaft Tetrahydro-quinolinylurea derivatives as vr1 antagonists
JP2007511479A (en) 2003-11-08 2007-05-10 バイエル・ヘルスケア・アクチェンゲゼルシャフト Bicyclic amide, carbamate or urea derivative
EP1685124A1 (en) 2003-11-10 2006-08-02 MERCK SHARP & DOHME LTD. Substituted nitrogen-containing six-membered amino-heterocycles as vanilloid-1 receptor antagonists for treating pain
WO2005049613A1 (en) 2003-11-14 2005-06-02 Merck Sharp & Dohme Limited Bicyclic pyrimidin-4-(3h)-ones and analogues and derivatives thereof which modulate the function of the vanilloid-1 receptor (vr1)
GB0326633D0 (en) 2003-11-14 2003-12-17 Merck Sharp & Dohme Therapeutic agents
WO2005073193A1 (en) 2004-01-23 2005-08-11 Amgen Inc. Vanilloid receptor ligands and their use in treatments
CA2587149C (en) 2004-11-10 2010-02-02 Pfizer Inc. Substituted n-sulfonylaminobenzyl-2-phenoxyacetamide compounds
ES2331153T3 (en) 2005-03-10 2009-12-22 Pfizer Inc. N-SULFONYLAMINOFENILETIL-2-PHENOXYACETAMIDE SUBSTITUTED COMPOUNDS.
WO2006098554A1 (en) * 2005-03-16 2006-09-21 Amorepacific Corporation Novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and a pharmaceutical composition containing the same
JP4521463B2 (en) 2005-03-17 2010-08-11 ファイザー株式会社 N- (N-sulfonylaminomethyl) cyclopropanecarboxamide derivatives useful for the treatment of pain
GB0506147D0 (en) 2005-03-24 2005-05-04 Merck Sharp & Dohme Therapeutic agents
US20060223837A1 (en) 2005-03-24 2006-10-05 Ellen Codd Biaryl derived amide modulators of vanilloid VR1 receptor
WO2006103503A1 (en) 2005-03-28 2006-10-05 Pfizer Japan Inc. Substituted aryloxoethyl cyclopropanecarboxamide compounds as vr1 receptor antagonists
US20060235036A1 (en) 2005-04-15 2006-10-19 Doherty Elizabeth M Vanilloid receptor ligands and their use in treatments
DE102005018191A1 (en) 2005-04-19 2006-10-26 Grünenthal GmbH Substituted cyclic urea derivatives and their use for the preparation of medicaments
US20060241296A1 (en) 2005-04-25 2006-10-26 Doherty Elizabeth M Vanilloid receptor ligands and their use in treatments
ATE526320T1 (en) 2005-05-11 2011-10-15 Abbott Lab ANTAGONISTS OF THE SUBTYPE 1 (VR1) VANILLOID RECEPTOR, AND APPLICATIONS THEREOF
GB0509573D0 (en) 2005-05-11 2005-06-15 Merck Sharp & Dohme Therapeutic compounds
DE102005038947A1 (en) 2005-05-18 2006-11-30 Grünenthal GmbH Substituted benzo [d] isoxazol-3-yl-amine compounds and their use in medicaments
CA2610354C (en) 2005-05-31 2011-03-29 Pfizer Inc. Substituted aryloxy-n-bicyclomethyl acetamide compounds as vr1 antagonists
WO2007042906A1 (en) 2005-10-07 2007-04-19 Glenmark Pharmaceuticals S.A. Substituted benzofused derivatives and their use as vanilloid receptor ligands
PE20110285A1 (en) 2005-10-19 2011-06-04 Gruenenthal Chemie SULFONAMIDOPHENYL PROPIONAMIDE DERIVATIVES AS LIGANDS OF THE VANILOID RECEPTOR SUBTYPE 1
TW200819441A (en) 2005-10-28 2008-05-01 Abbott Lab Prodrugs of compounds that inhibit TRPV1 receptor
CN101351463A (en) 2005-11-08 2009-01-21 欧加农股份有限公司 2-(Benzimidazol-1-yl)-N-(4-phenylthiazol-2-yl)acetamide derivatives for use in the treatment of TRPV1-related disorders
WO2007054480A1 (en) 2005-11-08 2007-05-18 N.V. Organon 2-(benzimidazol-1-yl)-acetamide biaryl derivatives and their use as inhibitors of the trpv1 receptor
BRPI0619208A2 (en) 2005-11-30 2011-09-20 Astellas Pharma Inc 2-aminobenzamide derivative c07d 307/14 c07d 307/22 c07d 309/14 c07d 319/12 c07d 401/12 c07d 405/12 c07d 413/12 c07d 417/12
GB0524808D0 (en) 2005-12-05 2006-01-11 Novartis Ag Organic compounds
WO2007067711A2 (en) 2005-12-08 2007-06-14 Amphora Discovery Corporation Certain chemical entities, compositions, and methods for modulating trpv1
GB0525069D0 (en) 2005-12-08 2006-01-18 Novartis Ag Organic compounds
GB0525068D0 (en) 2005-12-08 2006-01-18 Novartis Ag Organic compounds
WO2007067619A2 (en) 2005-12-08 2007-06-14 Amphora Discovery Corporation Certain chemical entities, compositions, and methods for modulating trpv1
WO2007067710A1 (en) 2005-12-08 2007-06-14 Amphora Discovery Corporation Certain chemical entities, compositions, and methods for modulating trpv1
WO2007067756A2 (en) 2005-12-08 2007-06-14 Amphora Discovery Corporation Certain chemical entities, compositions, and methods for modulating trpv1
WO2007067757A2 (en) 2005-12-08 2007-06-14 Amphora Discovery Corporation Certain chemical entities, compositions, and methods for modulating trpv1
WO2007069773A1 (en) 2005-12-15 2007-06-21 Shionogi & Co., Ltd. A pharmaceutical composition comprising an amide derivative
WO2007076104A1 (en) * 2005-12-23 2007-07-05 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7906508B2 (en) * 2005-12-28 2011-03-15 Japan Tobacco Inc. 3,4-dihydrobenzoxazine compounds and inhibitors of vanilloid receptor subtype 1 (VRI) activity
PL2054411T3 (en) * 2006-07-27 2015-02-27 Amorepacific Corp Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006101321A1 (en) 2005-03-19 2006-09-28 Amorepacific Corporation Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
WO2006101318A1 (en) 2005-03-19 2006-09-28 Amorepacific Corporation Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2238105A4

Also Published As

Publication number Publication date
US8557872B2 (en) 2013-10-15
EP2238105A4 (en) 2012-02-22
CN101925575B (en) 2014-06-18
EP2238105A2 (en) 2010-10-13
WO2009096701A3 (en) 2009-09-24
KR20100119757A (en) 2010-11-10
JP5643112B2 (en) 2014-12-17
CN101925575A (en) 2010-12-22
US20110015230A1 (en) 2011-01-20
EP2238105B1 (en) 2014-04-16
KR101619341B1 (en) 2016-05-11
US20140011881A1 (en) 2014-01-09
JP2011510924A (en) 2011-04-07

Similar Documents

Publication Publication Date Title
EP2238105B1 (en) Novel compounds as vanilloid receptor antagonists
CA2658925C (en) Novel sulfonylamino acrylamide derivatives, isomer thereof,or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
CZ20013248A3 (en) Novel compounds and preparations functioning as protease inhibitors
US7960584B2 (en) Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
KR102221928B1 (en) Aminocyclobutane derivatives, method for preparing same and the use thereof as drugs
EP1882687A1 (en) Heterocyclic compounds useful as vanilloid receptor antagonists and pharmaceutical compositions containing the same
EP2307394B1 (en) Sulphonamides as vanilloid receptor antagonist
WO2007120012A1 (en) Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
JP2014530198A (en) Amine-substituted methanesulfonamide derivatives as vanilloid receptor ligands
WO2006098554A1 (en) Novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and a pharmaceutical composition containing the same
RU2448108C2 (en) Novel compounds, isomers thereof or pharmacutically acceptable salts thereof as vanilloid receptor antagonists and pharmaceutical composition containing said compounds
KR101645537B1 (en) Novel Compounds, Isomer Thereof, or Pharmaceutically Acceptable Salts Thereof as Vanulloid Receptor Antagonist and Pharmaceutical Compositions Containing the Same
DK2054411T3 (en) HIS UNKNOWN RELATIONS, ISOMS THEREOF, OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF, AS VANILLOID RECEPTOR ANTAGONIST AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
EP1857440A1 (en) Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200980103367.3

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09706694

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 1556/MUMNP/2010

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2010544237

Country of ref document: JP

Ref document number: 2009706694

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 20107016895

Country of ref document: KR

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 12865082

Country of ref document: US