WO2006098554A1 - Nouveaux composes, isomere de ceux-ci ou sels pharmaceutiquement acceptables de ceux-ci en tant qu’antagonistes du recepteur vanilloide ; et composition pharmaceutique contenant ceux-ci - Google Patents

Nouveaux composes, isomere de ceux-ci ou sels pharmaceutiquement acceptables de ceux-ci en tant qu’antagonistes du recepteur vanilloide ; et composition pharmaceutique contenant ceux-ci Download PDF

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Publication number
WO2006098554A1
WO2006098554A1 PCT/KR2006/000583 KR2006000583W WO2006098554A1 WO 2006098554 A1 WO2006098554 A1 WO 2006098554A1 KR 2006000583 W KR2006000583 W KR 2006000583W WO 2006098554 A1 WO2006098554 A1 WO 2006098554A1
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Prior art keywords
phenyl
butyl
alkyl
methanesulfonylamino
benzyl
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PCT/KR2006/000583
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English (en)
Inventor
Young-Ger Suh
Hee-Doo Kim
Uh Taek Oh
Hyeung-Geun Park
Ho Sun Seung
Seol Rin Park
Joo Hyun Kim
Youn Hee Nam
Young-Ho Park
Song Seok Shin
Sun-Young Kim
Jin Kwan Kim
Yeon Su Jeong
Yung Hyup Joo
Ki-Wha Lee
Jin Kyu Choi
Kyung Min Lim
Hyun Ju Koh
Joo Hyun Moh
Byoung Young Woo
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Amorepacific Corporation
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Publication of WO2006098554A1 publication Critical patent/WO2006098554A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C327/44—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and a pharmaceutical composition containing the same
  • neurotic/allergic/inflammatory skin disease such as psoriasis, pruritus and prurigo(Southall et al., 2003, J. Pharmacol. Exp. Ther:, 304, pp217-222); 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, ppl65-70); cardiac disease such as myocardial ischemia etc.(Scotland et al., 2004, Circ. Res. 95, ppl027-1034; Pan et al., 2004, Circulation, 110, ppl 826-1831) can be enumerated.
  • neurotic/allergic/inflammatory skin disease such as psoriasis, pruritus and prurigo(Southall et al., 2003, J. Pharmacol. Exp
  • the vanilloid receptor (VRl) is the receptor for capsaicin (8-methyl-N-vanillyl- 6-nonenamide), a pungent ingredient in hot peppers. The molecular cloning thereof was also reported in 1997 (Caterina et al., 1997, Nature 389, ⁇ p816-824). This receptor is a non-selective cation channel composed of 6 transmembrane domains and belongs to the TRP channel family. Recently, it was named TRPVl.
  • the vanilloid receptor is highly expressed in primary afferent sensory neurons. It is also reportedly expressed in various organs and tissues such as the bladder, kidney, lung, intestine and skin, and in the central nervous system (CNS) including the brain and non-neuronal tissues (Mezey et al, 2000, PNAS, 97, pp3655-3660; Stander et al., 2004, Exp. Dermatol.
  • TRPVl receptor knock-out mice exhibit a normal response to harmful physical stimuli, but show a reduced response to painful heat and vanilloids, and exhibit little hyperalgesia to thermal stimuli even in an inflammatory state (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).
  • vanilloid receptor knock-out mice exhibited reduced responses to thermal or noxious stimuli, thus raising the possibility that vanilloid receptor antagonists may be utilized for prevention or treatment of various pain conditions.
  • vanilloid receptor antagonist capsazepine also decreases hyperalgesia caused by physical stimuli in models of inflammatory and neuropathic pain (Walker et al., 2003, JPET, 304, pp56-62; Garcia-Martinez et al., 2002, Proc. Natl. Acad. Sci. 99, 2374-2379).
  • Vanilloid receptors are distributed in human epidermal keratinocytes as well as in primary afferent sensory nerves(Denda et al., 2001, Biochem. Biophys. Res. Commun., 285, pp 1250- 1252; Inoue et al., 2002, Biochem. Biophys. Res.
  • R 14 and R 15 are independently hydrogen, C1-C5 alkyl, halogen, or phenyl;
  • R 1 and R 2 represent independently hydrogen, -SO 2 R 16 , -SOR 16 , C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl, C1-C5 alkoxycarbonyl, C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein, each phenyl may be unsubstituted or substituted with one or more substituent selected from carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkylcarbonyl, C1-C5 alkylthio, C1-C5 alkylsulfonyl, and C1-C5 alkoxycarbonyl, and R 16 represents hydrogen, amino, C1-C5 alkyl, C2-
  • One preferred aspect of the present invention is a compound of the formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • X represents CHR 13 wherein R 13 represents hydrogen, halogen, or C1-C5 alkyl
  • R 4 , R 5 , R 6 , and R 7 independently represent hydrogen, carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkoxy, halo (C1-C5) alkyl, Cl-
  • X represents CHR 13 wherein R 13 represents hydrogen, halogen, or C1-C5 alkyl
  • R 1 and R 2 represent independently hydrogen, -SO 2 R 16 , -SOR 16 , C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl, phenyl, phenyl (C1-C3) alkyl, or Cl- C3 alkoxyphenyl, wherein R 16 represents hydrogen, C1-C5 alkyl, C2-C5 alkenyl, trifluoromethyl, phenyl, or benzyl;
  • R 10 is C3-C5 alkyl or CF 3 and even more preferred in which R 10 is isopropyl or ter-butyl, and most preferred tert-butyl.
  • Y represents CH 2 -CH 2 ;
  • R 1 represents hydrogen;
  • R 2 represents -SO 2 R 16 wherein R 16 represents hydrogen, C1-C5 alkyl, C2-C5 alkenyl, or trifluoromethyl;
  • R 5 represents carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkylcarbonyl, C1-C5 alkylcarbonylamino, C1-C5 alkylsulfonylamino, phenylsulfonylamino, or C1-C5 alkoxycarbonyl; and
  • R 10 represents isopropyl or tert-butyl.
  • Another aspect of the present invention is a compound of the above formula (I), an isomer, or a pharmaceutically acceptable salt thereof;
  • R 1 represents methanesulfonyl or trifluoromethanesulfonyl
  • R 2 and R 3 represent hydrogen
  • R 4 , R 5 , R 6 , and R 7 independently represent hydrogen, methyl, ethyl, ethenyl, fluoro, chloro, bromo, nitro, carboxy, methylcarbonyl, methoxycarbonyl, methoxy, or CF 3 ;
  • R 8 , R 9 , Rn, and R 12 independently represent hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, t-butyl, sec-butyl, methoxy, bromo, chloro, trifluoromethyl, or methoxycarbonyl; and
  • R 10 represents isopropyl or t-butyl.
  • Another aspect of the present invention is a compound of the above formula (I) 5 an isomer, or a pharmaceutically acceptable salt thereof;
  • X represents CHR 13 wherein R 13 represents hydrogen or C1-C5 alkyl
  • Y represents CHR 14 , CHR 14 -CHR 15 , , wherein R 14 and R 15 are independently hydrogen, C1-C5 alkyl, halogen, or phenyl;
  • R 1 and R 2 represent independently hydrogen, -SO 2 R 16, wherein R 16 represents C1-C5 alkyl;
  • R 3 represents hydrogen
  • R 4 , R 5 , R 6 and R 7 independently represent hydrogen, carboxy, C1-C5 alkyl, halogen, nitro, cyano, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, halo (C1-C5) alkyl, halo (C 1 -C5) alkoxy, C 1 -C5 alkylcarbonyl, or C 1 -C5 alkoxycarbonyl; R 8 ,
  • R 9 , and R 11 independently represent hydrogen, C1-C5 alkyl, C1-C5 alkoxy, halo (Cl- C5) alkyl, or halogen;
  • R 1O is C3-C5 alkyl or CF 3 and even more preferably isopropyl or ter-butyl, and most preferably tert-butyl; and _R 12 represents hydrogen or fluoro, and particularly preferred hydrogen.
  • X represents CHR 13 wherein R 13 represents hydrogen or methyl ;
  • Y represents CHRi 4 -CHR 15 , wherein Ri 4 and R 15 are independently hydrogen or methyl;
  • R 4 , R 5 , and R 6 independently represent hydrogen, C1-C3 alkyl, halogen, nitro, cyano, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, halo (C1-C3) alkyl, halo (Cl- C3) alkoxy ;
  • R 8 , R 9 , and R 11 independently represent hydrogen, C1-C3 alkyl, C1-C3 alkoxy, halo (C1-C3) alkyl, or halogen;
  • Rio is C3-C5 alkyl or CF 3 and preferably isopropyl or tert-butyl;
  • Ri 2 represents hydrogen or fluoro, and particularly preferred hydrogen.
  • X represents CH 2 ;
  • Y represents CH 2 CH 2 ;
  • R 2 represents methanesulfonyl
  • Ri, R 3 , R 4 , and R 7 represent hydrogen
  • R 8 , R 9 , Rn and Ri 2 independently represent hydrogen or fluoro;
  • R 5 and R 6 independently represent hydrogen, C1-C3 alkyl, halogen, nitro, cyano, ethenyl, or ethynyl;
  • Preferred examples of compounds according to the invention are selected from the group consisting of,
  • Particularly preferred compounds according to the present invention are 3 - [4-(t-butyl)phenyl]-N- [3 -fluoro-4-(methanesulfonylamino) benzyljthiopropionamide,
  • the above Scheme 1 shows a proposed process for synthesizing thioamide compounds.
  • the substituted benzylamines is reacted with substituted phenyl propionic acids to synthesize the N-benzyl-phenylpropionamide compounds.
  • the N- benzyl-phenylpropionamide compound is treated with lawesson's reagent or P 4 S 1O to yield obtain thioamide derivatives.
  • step 3 shows the five-step reaction to prepare various thioamide derivatives.
  • step 1 under argon atmosphere, ortho-substituted 4-iodoaniline, methanesulfonyl chloride and pyridine are stirred in dichloromethane and mesylated to yield compound with mesyl group (4).
  • step 2 nitrile group is introduced to the compound (4) by refluxing with cuprous cyanide at 13O 0 C or stirring it together with zinc cyanide and tetrakis(triphenyl)palladium(O) catalyst in DMF at 80 0 C for 2 hours.
  • step 3 hydro genation for the compound (5) is carried out by using c-HCI to yield the amine compound (6) (J Am.
  • step 4 the compound (6) is reacted with 3-[4-(t-butyl)phenyl] propionic acid (3) to synthesize amide derivatives (7).
  • step 5 the amide compound (7) is treated with lawesson's reagent to yield thioamide derivatives (8).
  • the above Scheme 5 shows the four-step reaction to prepare the compound (14) in which one ortho position of methanesulfonylamino group is substituted with nitro group.
  • the reactant, 4-amino-3-nitrobenzonitrile compound (10) is mesylated by using strong base such as KH to yield the intermediate compound (11).
  • Nitril group of compound (11) is reduced by using BH 3 as a mild condition to obtain the amine compound (12), and the amine compound (12) is reacted with 3-[4-(t- butyl)phenyl]propionic acid compound (3) to yield the amide compound (13).
  • the compound (13) is treated with lawesson's reagent to afford thioamide derivatives (14) according to the same procedure as described in Example 2.
  • the above Scheme 7 shows a proposed process to synthesize the conjugated thioamide derivatives (21).
  • the acid compound (3) is reacted with the amine compound (6a) to yield the amide compound according to the same procedure as described in step 4 of the Scheme 3.
  • the amide compound is treated with lawesson's reagent to yield the thioamide derivatives (21) according to the same procedure as described in 5 step of the Scheme 3.
  • the amino group of the compound (22) is treated with di-t-butyl dicarbonate to afford the compound (23).
  • the nitro group of the compound (23) is reduced to give the compound (24).
  • the amino group of the compound (24) is reacted with methanesulfonic anhydride to yield compound (25).
  • the protecting group, BOC is removed by using CF 3 COOH to obtain the compound (26), and the compound (26) is subjected to condensation reaction with the compound (27) to yield the unsaturated amide compound (28).
  • the unsaturated amide compound (28) is treated with lawesson's reagent to obtain the unsaturated thioamide derivatives (29).
  • DMTMM 4-(4,6-dimethoxy- l,3,5-triazin-2-yl)-4-methylmorpholinium chloride
  • the Scheme 13 shows a process for synthesizing the (R) -iV-[4-(l-ammoethyi)- 2-fluoro-6-vinylphenyl]methanesulfonamie (43).
  • Butylvinylether is coupled to the iodoaniline (34) to yield the compound (35).
  • Iodination of the compound (35) can be achieved by using NIS.
  • the compound (36) is reacted with (R)-(+)- 2-methyl-2- propane-2-sulfmamide (37) to yield 2-methylpropane-2-sulfinc acid [l-(4-amino-3- fluoro-5-iodophenyl)ethyl]amide (38).
  • the compound (38) is reduced with IN HCl solution to yield the compound (39).
  • the compound (39) was synthesized according to similar procedure in the Scheme 3 to yield the compound (43).
  • the Scheme 14 shows a process for synthesizing the streospecific thiopropionamide (44) with vinyl moiety.
  • the Scheme 15 shows a process for synthesizing the thioamide compound with substitution on alpha and beta carbon of carbonyl carbon.
  • the unsaturated ester compound (46) was achieved via Wadsworth-Horner-Emmons Reaction.
  • the ester compound (46) is hydrolysed with lithium hydroxide monohydrate to yield the acidic compound (47).
  • the acidic compound (47) is reacted with benzylamine to yield the compound (48).
  • the compound (48) is reacted with Lawsson's reagent to yield the thioamide compound (49).
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
  • a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient together with an pharmaceutically acceptable carrier is present in an effective amount for preventing or treating pain, acute pain, neuropathic pain, post-operative pain, migraine, arthralgia, neuropathies, nerve injury, diabetic neuropathy, neurodegeneration, stroke, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, urinary bladder hypersensitiveness, irritable bowel syndrome, fecal urgency, Crohn's disease, respiratory disorder such as asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane, stomach-duodenal ulcer, inflammatory bowel disease or inflammatory diseases.
  • the present invention also provides a pharmaceutical composition for preventing and treating a disease associated with the pathological stimulation and/or aberrant expression of vanilloid receptor, wherein said composition comprises a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof; and pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition for preventing and treating a condition related to vanilloid receptor, where said composition comprises a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.
  • said condition related to vanilloid receptor is 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, or heart disease.
  • said condition related to vanilloid receptor is acute pain, chronic pain, neuropathic pain, post-operative pain, rheumatic arthrodynia, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, neurodegeneration, stroke, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, vitiligo, prurigo, asthma, chronic obstructive pulmonary disease, urinary incontinence, inflammatory bowel disease, hyperacusis, tinnitus, vestibular hypersensitiveness, or inotropic ischemia.
  • inventive compounds can be used in a pharmaceutical composition for treating pain, wherein the pain is -or is associated with- a condition selected from osteoarthritis ("OA”), rheumatoid arthritis. (“RA”), Ankylosing Spondylitis (“AS”), diabetic neuropathic pain, post-operative pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches.
  • OA osteoarthritis
  • RA rheumatoid arthritis.
  • AS Ankylosing Spondylitis
  • diabetic neuropathic pain including fibromyalgia, myofascial pain syndrome and back pain
  • migraine and other types of headaches including fibromyalgia, myofascial pain syndrome and back pain.
  • the compounds of the present invention are said to be useful to treat pain associated with osteoarthritis, it shall not be excluded that this also comprises the treatment of other signs and symptoms of osteoarthritis. Besides reducing the pain associated with osteoarthritis, the pharmacological intervention of osteoarthritis may be aimed at maintaining the mobility and minimizing the disability of the joints.
  • OA osteoarthritis
  • OA osteoarthritis
  • idiopathic (primary) OA the most common form of the disease, no predisposing factor is apparent. Secondary OA is attributable to an underlying cause. Pain and joint dysfunction are the cardinal symptoms of OA.
  • the joint pain of OA is often described as a deep ache and is localized to the involved joint.
  • the pain of OA is aggravated by joint use and relieved by rest, but, as the disease progresses, it may become persistent.
  • Nocturnal pain, interfering with sleep is seen particularly in advance OA of the hip and may be enervating. Stiffness of the involved joint on arising in the morning or after a period of inactivity may be prominent but usually lasts less than 20 minutes.
  • the compounds according to the present invention are said to be of use in treating pain associated with an inflammatory autoimmune disease of the joints, this refers to the administration of the compounds or combinations of the compounds of the present invention to reduce at least one pain symptom experienced by a subject suffering from an inflammatory autoimmune disease of the joints including back pain, joint pain and muscle pain associated with RA or AS.
  • treatment of an inflammatory autoimmune disease of the joints may also include a decrease of the inflammation and/or swelling of the synovium and may help to improve the functionality (i.e. maintaining mobility, and minimizing disability) of the joints, in particular in patients suffering from RA or AS.
  • RA is a chronic inflammatory autoimmune disease that causes the immune system to attack the joints, and particularly the synovium in the joint.
  • the synovium becomes inflamed and causes swelling and pain.
  • Cardinal symptoms of RA are joint pain and stiffness but additional symptoms include muscle aches, anemia and fever.
  • Diagnosis of RA can be confirmed by detecting an antibody in the blood called the "rheumatic (or “rheumatoid”) factor" and/or by a blood sedimentation test. Other useful and common tests are the detection of the "antinuclear antibody" or the "C-reactive protein".
  • AS Ankylosing Spondylitis, which is a chronic, progressive autoimmune disease characterized by arthritis, inflammation and eventual immobility of the joints, particularly the spinal joints. It causes pain and stiffness in the back (often in the morning hours) as a result of ongoing swelling and irritation of the spinal joints (vertebrae). Inflammation of the tendons and ligaments that connect and provide support to the vertebrae can lead to pain and tenderness in the ribs, shoulder blades, hips, thighs, shins, heels and along the bony points of the spines.
  • non-inflammatory musculoskeletal pain refers to the administration of the compounds or combinations of the compounds of the present invention to reduce the pain experienced by a subject suffering from non-inflammatory musculoskeletal pain including back pain, fibromyalgia, and myofascial pain syndrome.
  • One outcome of treatment may be reducing the pain experienced by the subject relative to the pain experienced by the subject immediately before the administration of the compounds or combinations of the present invention.
  • Another outcome of treatment may be preventing reoccurence of pain which has previously been reduced as a result of pharmacotherapy.
  • Another outcome of treatment may be decreasing the occurrence of and/or the severity of manifestations related to non-inflammatory musculoskeletal pain including back pain, fibromyalgia, and myofascial pain syndrome.
  • the treatment may suitably result in a reduction of increased muscle sensitivity characterized by pain evoked by a normally non-nociceptive stimulus (allodynia) or increased pain intensity evoked by nociceptive stimuli (hyperalgesia).
  • allodynia normally non-nociceptive stimulus
  • nociceptive stimuli hyperalgesia
  • the treatment of noninflammatory musculoskeletal pain can also improve the associated symptoms of back pain, fibromyalgia, and myofascial pain syndrome.
  • fibromyalgia or "FMS” relates to a syndrome that causes widespread pain and stiffness throughout the tissue that supports and moves bones and joints. Fibromyalgia can be diagnosed by the presence of excessive tenderness on applying pressure to at least 11 of 18 specific muscle-tendon sites.
  • Myofascial pain syndrome is a chronic non-degenerative, non-inflammatory musculoskeletal pain condition. Distinct areas within muscles or their delicate connective tissue coverings (fascia) become abnormally thickened or tight. When the myofascial tissues tighten and lose their elasticity, neurotransmitter ability to send and receive messages between the brain and body is damaged. Symptoms include muscle stiffness and aching and sharp shooting pains or tingling and numbness in areas distant from the trigger point. Most commonly trigger points are in the neck, back or buttocks.
  • Back pain is a common non-inflammatory musculoskeletal pain condition that may be either acute or chronic. It may be caused by a variety of diseases and disorders that affect the lumbar spine. Low back pain is often accompanied by sciatica, which is pain that involves the sciatic nerve and is felt in the lower back, the buttocks, and the backs of the thighs.
  • the compounds of the present invention are also useful for treating signs and symptoms of an overactive bladder such as urinary incontinence, more specific urinary urge incontinence, urinary stress incontinence, urinary urgency, nocturia and/or urinary frequency.
  • an overactive bladder such as urinary incontinence, more specific urinary urge incontinence, urinary stress incontinence, urinary urgency, nocturia and/or urinary frequency.
  • compositions according to the present invention are preferably adapted for oral administration.
  • pharmaceutical composition containing the inventive compounds may be also formulated for topical or transcutaneous use.
  • the present invention 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 a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method for preventing or treating a disease selected from pain, migraine, arthralgia, 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, which comprises administering to a mammar including a person in need thereof a therapeutically effective amount of a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the disease is also selected from acute pain, chronic pain, neuropathic pain, post-operative pain, diabetic neuropathy, neurodegeneration, stroke, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, asthma, chronic obstructive pulmonary disease, urinary incontinence or inflammatory bowel disease.
  • the above method is treating pain that is or that is associated with a condition selected from osteoarthritis ("OA"), rheumatoid arthritis ("RA"), Ankylosing Spondylitis (“AS”), diabetic neuropathic pain, non- inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), post-operative pain, migraine and.other types of headache.
  • OA osteoarthritis
  • RA rheumatoid arthritis
  • AS Ankylosing Spondylitis
  • diabetic neuropathic pain non- inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain)
  • post-operative pain migraine and.other types of headache.
  • the present invention relates to the use of a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof as an antagonist of vanilloid receptor.
  • the present invention relates to the use of a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof for prevention or treatment of a condition related to vanilloid receptor, which is more specifically associated with the aberrant expression and/or aberrant activation of a vanilloid receptor.
  • the present invention relates to the use of a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, in preparation of a medicament for prevention or treatment of a condition related to vanilloid receptor.
  • the present invention relates to the use of a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or the treatment of a condition that is selected from pain, inflammatory autoimmune disease of the joints, urinary bladder hypersensitivity including urinary incontinence, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) 5 neurotic/allergic/inflammatory skin disease, psoriasis, asthma, COPD, pruritus or prurigo.
  • IBS irritable bowel syndrome
  • IBD inflammatory bowel disease
  • the present invention relates to the use of a compound for treating pain as described above, wherein the pain is or is associated with a condition that is selected from osteoarthritis ("OA"), rheumatoid arthritis ("RA"), Ankylosing Spondylitis (“AS”), diabetic neuropathic pain, post-operative pain, noninflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches.
  • OA osteoarthritis
  • RA rheumatoid arthritis
  • AS Ankylosing Spondylitis
  • diabetic neuropathic pain post-operative pain
  • noninflammatory musculoskeletal pain including fibromyalgia, myofascial pain syndrome and back pain
  • migraine and other types of headaches include migraine and other types of headaches.
  • a compound of formula (I) , an isomer thereof or a pharmaceutically acceptable salt thereof according to the present invention can be prepared as a pharmaceutical composition containing pharmaceutically acceptable carriers, adjuvants, diluents and the like.
  • the compounds of the present invention can be dissolved in oils, propylene glycol or other solvents which are commonly used to produce an injection. Suitable examples of the carriers include physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc., but are not limited to them.
  • the compounds of the present invention can be formulated in the form of ointment or cream.
  • the compound according to the present invention 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 invention 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 invention 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 invention 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 invention 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 invention are used in a pharmaceutical composition in an amount of 0.0001 ⁇ 10% by weight, and preferably
  • the pharmaceutical composition of the present invention 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 intracerebro ventricular injections.
  • Alkyl includes monovalent saturated aliphatic hydrocarbyl groups.
  • the hydrocarbon chain may be either straight-chained or branched. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, and the like.
  • Alkylcarbonyl includes a carbonyl group linked to a alkyl group defined above and specifically includes, for example, methylcarbonyl (acetyl), ethylcarbonyl, n- propylcarbonyl, isopropylcarbonyl, and the like.
  • Alkoxy includes the group-OR where R is alkyl. Particular alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert- butoxy, sec-butoxy, n-pentoxy, 1,2-dimethylbutoxy, and the like.
  • Alkoxycarbonyl includes the monovalent radical ROC(O)-, wherein R is alkyl as described above. Particular alkoxycarbonyl groups include, by way of example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, and the like.
  • alkenyl is ethenyl (vinyl).
  • Alkynyl includes acetylenically unsaturated hydrocarbyl groups being straight-chained or branched and having at least 1 triple bond.
  • a preferred alkynyl group is ethynyl (acetylene).
  • Alkylamino includes the group -NR 1 R", wherein R' is alkyl and R" is selected from hydrogen or alkyl
  • Alkylsulfonyl includes a radical-S(O) 2 R where R is an alkyl group as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like.
  • Alkylthio includes a radical-S-R where R is an alkyl group as defined herein that may be optionally substituted as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.
  • Cycloalkyl refers to a nonaromatic monovalent hydrocarbon radical having preferably from three to eight carbon atoms. Typical cycloalkyl groups include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Ethynyl 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 which may be different
  • Haloalkoxy includes an “alkoxy” group as defined above which is substituted with one or more halogens which may be the same or different, for example, 2-fluoroethoxy, 2, 2, 2,-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3,- pentafluoropropoxy and the like.
  • halogens which may be the same or different, for example, 2-fluoroethoxy, 2, 2, 2,-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3,- pentafluoropropoxy and the like.
  • Hydrochlor refers to the radical-OH.
  • Niro refers to the radical-NO 2 .
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable 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 .
  • “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. "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.
  • the terms “human”, “patient” and “subject” are used interchangeably herein.
  • “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.
  • Step 1 Synthesis of (E)-3-[4-(t-butyl)phenyl]-2-acrylic acid
  • Step 2 Synthesis of 3-[4-(t-butyl)phenyl] propionic acid (compound 3)
  • Step 3 (4-methanesulfonylaminobenzyl)carbamic acid t-butyl ester 4-(N-BOC) aminometylaniline (Ig, 4.50mmol) in 10ml of methylenechloride was put into the 100 ml of one-neck round bottom flask filled in 30ml methylene chloride. To the solution was added methanesulfonyl chloride (1.5eq, 0.53ml) slowly and pyridine (ImI) stirred for 18 hours. After confirming the completion of the reaction with TLC, the reaction solution was extracted with methylene, washed with water and brine, dried over MgSO 4 , filtered and concentrated under reduced pressure.
  • N-BOC aminometylaniline
  • Step 4 4-methanesulfonylaminobenzylamine hydrochloride 4-methanesulfonylaniinobenzylcarbamic acid t-butyl ester (1.2 g, 4.0 mmol) was put into the 50 ml of one-neck round bottom flask and was poured with 30ml 1,4- dioxane. To the solution was added c-HCl (2 ml) and stirred for 4 hours. After confirming the completion of the reaction with TLC, the reaction solution was concentrated under reduced pressure. The obtained solid was washed with ethylacetate and filtered with glass filter. The obtained solid was dried in a air to yield a solid (0.947 g, 100%).
  • Step 6 3- [4-t-butylphenyl] -N- [4-methanesulfonylbenyl] thiopropionamide 3-[4-t-Butylphenyl]-N-[4-methanesulfonylbenzyl]propionamide (0.31 g,
  • Step 2 Synthesis of 4-cyano-2-fluoromethanesulfonylaminobenzene
  • 2-fluoro-4-iodo-l-methanesulfonylaminobenzen (1.8 Ig, ⁇ .Ommol) prepared in step 1 in DMF (1OmL) was added Zn(CN) 2 (845 mg, 7.2 mmol) and Pd(PPh 3 ) 4 (187 mg, 0.16 mmol) and followed by stirring for 1.5 hours at 8O 0 C ⁇ 9O 0 C.
  • Step 3 Synthesis of 3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride
  • the 4-cyano-2-fluoromethanesulfonylaminobenzen (1.03g) prepared in step 2 was dissolved in methanol (20 ml) and added a catalytic amount of 10 % platinum/carbon and concentrated hydrochloric acid(HCl, 3mL) to carry out hydro genation.
  • the resulting mixture was stirred for 1 hour at room temperature, diluted with ether, filtered through celite, and concectrated under reduced pressure. The residue was washed with ethyl acetate to yield the titled compound (1.13g, 92%).
  • the thioamide compound (91%) was obtained according to the same procedure as described in Example 2.
  • the thioamide compound (75%) was obtained according to the same procedure as described in Example 2.
  • Example 5 The compound of Example 5 (70 mg, 0.16 mmol) and LiOH H 2 O (26 mg, 0.63 mmol) were dissolved in THF/H 2 O (1:1, 4 mL), and stii ⁇ ed for one day at room temperature. The resulting solution was acidified with IN HCl, and then diluted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous MgS O 4j and concentrated under reduced pressure to yield the acidic compound (61 mg, 50%).
  • Step 1 Synthesis ofN-(2-nitro-4-cyanophenyl)methanesulfonamide KH (700 mg, 6.1 mmol) was dissolved in THF (15 mL) at -78 ° C . To the solution was added dropwise the solution of 4-aniino-3-nitro-benzenitrile(compound 10, 500 mg, 3.1 mmol) in THF (10 niL) and followed by stirring for 30 minute and adding dropwise methanesulfonyl chloride (0.35 mL, 4.6 mmol). The reaction solution was stirred for 3 hours and the reaction was quenched with water.
  • Step 2 Synthesis of N-[2-nitiO-4-(aminomethyl)phenyl]methanesulfonamide
  • N-(2-nitro-4-cyanophenyl)methanesulfonamide 120 mg, 0.50 mmol was dissolved in THF (5.0 mL), and to the solution was added dropwise the solution of IM BH 3 in THF (1.5 mL). The reaction solution was stirred for 2 hours, followed by adding 2N HCl (1.0 mL) and stirring for 1 hour. The resulting solution was concentrated under reduced pressure to yield the crude compound (48mg, 39%).
  • N-[2-nitro-4- (aminomethyl)phenyl]methanesulfonamide was used for step 3 without purification process.
  • Step 3 Synthesis of 3-[4-(t-butyl)phenyl]-N-[3-nitro-4-(methanesulfonylamino) benzyl]propionamide
  • N-[2-nitro-4-(aminomethyl)phenyl]methanesulfonamide was reacted with 3-[4- (t-butyl)plienyl]propionic acid to synthesize the title compound (38%) according to the same procedure as described in step 4 of Example 2.
  • Step 4 Synthesis of 3-[4-(t-butyl)phenyl]-N-[3-nitro-4-(methanesulfonylamino) benzyl]thiopropionamide
  • the thioamide compound (58%) was obtained according to the same procedure as described in step 5 of Example 2.
  • Step 1 Synthesis of ethyl (E)-3-[4-(t-butyl)phenyl]-2-propenoate t-butyl benzaldehyde(l g, 6.2 mmol), triethyl phosphonoacetate(1.45 niL, 7.4 mmol), diisopropyl ethylamine(1.6 mL, 9.2 mmol) and LiCl (520 mg, 12 mmol) were dissolved in CH 3 CN (15 mL), the solution was stirred for one day. After confirming the completion of the reaction, the resulting solution was concentrated under reduced pressure.
  • Step 5 Synthesis of 2-[4-(t-butyl)phenyl]-N-[3-fluoro-4-(methanesulfonyl) aminobenzyljcyclopropanecarboxamide
  • the 3-fluoiO-4-methanesulfonylaminobenzylamine hydrochloride was reacted with the 2-[4-(t-butyl)phenyl]cyclopropanecarboxylic acid to synthesize the amide compound (54%) according to the same procedure as described in step 4 of Example 2.
  • Step 6 Synthesis of 2-[4-(t-butyl)phenyl]-N-[3-fluoro-4-(methanesulfonyl amino)benzyl]cyclopiOpanthiocarboxamide
  • Step 1 Synthesis of 3-[4-(trifluoromethyl)phenyl]-N-[3-fluoro-4-(methane sulfonylamino)benzyl]propionamide Under the same condition as Scheme 10, 3-fluoro-4-
  • step 1 The compound prepared in step 1 was stirred with P 4 S 10 (HOmg) to obtain the title compound (54.8mg).
  • Step 1 Synthesis of (E)-3-[4-(t-butyl)phenyl]-N-[3-fluoro-4-(methane sulfonylamino)benzyl]- acrylamide
  • the thioamide compound (10%) was obtained according to the same procedure as described in step 5 of Example 2.
  • Step 1 Synthesis of (i?)-[l-(4-Nitrophenyl)ethyl]carbamic acid t-butyl ester
  • Step 2 Synthesis of (i?)-[l-(Aminophenyl)ethyl]carbamic acid t-butyl ester
  • S [l-(4-nitrophenyl)ethyl]carbamic acid t-butyl ester (25mg, 0.09mmol) was put into 25ml of round-bottom flask, dissolved in methanol.
  • Pd 7.6mg, 30% of substrate
  • Pd/C was filtered off and the filtrate was concentrated under reduced pressure to remove methanol, thereby to yield a transparent yellow liquid (21.7mg, 91.93%).
  • Step 3 Synthesis of (i?)-[l-(4-methanesulfonylaminophenyl)ethyl]carbamic acid t-butyl ester
  • the reacting mixture was diluted with methylene chloride, washed with water and brine, dried over Na 2 SO 4 and concentrated under reduced pressure.
  • the obtained solid was recrystallized with ethyl acetate and hexane to yield a pale yellow crystal (40 mg, 59.7%).
  • Step 4 Synthesis of (i?)-N- [(4-aminoethyl)phenyl]methanesulfonamide (i?)-[l-(4-methanesulfonylaminophenyl)ethyl]carbamic acid t-butyl ester (493.5mg, 1.51 mmol, ⁇ eq.) was put into 100ml of round bottom flask, and dissolved in methylene chloride. Trifluoroacetic acid (362.8 ⁇ Jt, 4.71 mmol, 3 eq.) was added to the solution and stirred over night.
  • Step 5 Synthesis of (i?)-3-(4-t-butylphenyl)-N-[l-(4-methanesulfonylamino phenyl)ethyl] acrylamide
  • reaction solution extracted with methylene chloride, washed with water and brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 1 Synthesis of (R)-3-(4-t-butylphenyl)-N-[l-(4-methanesulfonyl aminophenyl)ethyl]propionamide
  • Step 2 Synthesis of 3-(4-t-butylphenyl)-N-[l-(4-methanesulfonyl aminophenyl)ethyl] thiopropionamide
  • Step 1 Synthesis of 3-[3,4-dimethoxyphenyl]-N-[3-fluoro-4-(methanesulfonyl amino) benzyl] thiopropionamide
  • Step 2 Synthesis of 3-[3,4-dimethoxyphenyl]-N-[3-fluoro-4- (methanesulfonylamino) benzyl] thiopropionamide 3 - [3 ,4-dimethoxyphenyl] -N-[3 -fluoro-4-(methanesulfonylamino)benzyl] propionamide (53 mg) prepared in step 1 was stirred with P 4 S 10 (112mg) to obtain the above compound (37.3 mg , 68%).
  • Step 1 Synthesis of 3-[3,4-dimethylphenyl]-N-[3-fluoro-4-(methanesulfonyl ammo)benzyl]propionamide
  • Step 2 Synthesis of 3 -[3,4-dimethylphenyl] -N- [3 -fluoro-4-(methanesulfonyl amino)benzyl]thiopropionamide
  • Step 1 Synthesis of 3-[4-chlorophenyl]-N-[3-fluoro-4-(methanesulfonyl amino)benzyl] -acrylamide
  • Step 1 Synthesis of 2-[4-chlorophenyl]-N-[3-fluoro-4-(methanesulfonylamino) benzyl] acetamide
  • Step 2 Synthesis of 2-[4- chlorophenyl]-N-[3-fluoro-4-(methanesulfonylamino) benzyl] thioacetamide
  • the above thioamide compound (18 mg, 50%) was obtained by using amide(35 mg, 0.94 mmol) according to the similar procedure as described in step 2 of Example 17.
  • Step 1 Synthesis of 2-[4-isopropylphenyl]-N-[3-fluoro-4-(methanesulfonyl amino)benzyl] acetamide
  • Step 2 Synthesis of 2-[4-isopropylphenyl]-N-[3-fluoro-4-(methanesulfonyl amino)benzyl] thioacetamide
  • the above thioamide compound (28 mg) was obtained by using amide according to the similar procedure as described in step 2 of Example 20.
  • IR (KBr 5 Cm- 1 ): 3260, 2960, 1590, 1512, 1445, 1335, 1158.
  • reaction mixture was purified according to similar procedure of Example 2 to obtain 3-[4-(t-& ⁇ />'/)phenyl]- ⁇ '- ⁇ 3-iodo-4-[(methanesulfonyl)methyl- benzyl ⁇ -thiopropionamide (35 mg, 71%) as a white solid.
  • reaction mixture was purified according to similar procedure to Example 2 to obtain 3-[4-(t-butyl)phenyl]-iV- ⁇ 3-(trifluoromethyl)-4-[(methanesulfonyl)methyl- benzyl ⁇ -thiopropionamide (43 mg, 63%) as a white solid.
  • reaction mixture was purified according to similar procedure of Example 2 to yield 3 - [4-(t-butyl)phenyl] -TV- ⁇ 3 -ethyl-4- [(methanesulfbnyl)methyl-benzyl ⁇ - thiopropionamide (58 mg, 74%) as a white solid.
  • reaction mixture was purified according to similar procedure of Example 2 to obtain 3-[4-(t-butyl)phenyl]-iV- ⁇ 3-(trifluoromethyl)- 4-[(methanesulfonyl)methyl-benzyl]-thiopropionamide (11.4mg, 47%) as a white solid.
  • reaction mixture was purified according to similar procedure of Example 2 to obtain 3-[4-(t-butyl)phenyl]-N- ⁇ 3-(trifluoromethyl)-4-[(methanesulfonyl)methyl- benzylj-thiopropionamide (18.1mg, 70%) as a white solid.
  • Step 3 N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt
  • Step 4 3-(4-t-butyl-phenyl)-N-(3,5-difluoro-4-methanesulfonylamino-benzyl)- propionamide
  • Step 5 3-(4-t-butyl-phenyl)-N-[3,5-difluoro-4-(methanesulfonylamino)- benzyl]-thiopropionamide 3-(4-t-butyl-phenyl)-N-(3,5-difluoro-4-methanesulfonylamino-benzyl)- propionamide (130mg, 0.31mmol) was reacted with P 4 S 10 according to the general procedure to give 3-(4-t-butyl-phenyl)-N-(3,5-difluoro-4-methanesulfonylamino- benzyl)-thiopropionamide (35mg, 26%).
  • the reaction mixture was purified according to similar procedure of Example 2 to obtain 3-[4-(t- ⁇ w ⁇ /)phenyl]-iV-[3-fluoro-4-(methanesulfonylamino) -5-vinylbenzyl]thiopropionamide (41 mg, 83%) as a white solid.
  • reaction mixture was purified according to similar procedure of Example 2 to obtain 3 - [4-(/-butyl)phenyl] -N- [3 -ethynyl-5-fluoro-4-(methanesulfonylmethyl)- benzyljthiopropionamide (20.5 mg, 41%) as a white solid.
  • reaction mixture was purified according to similar procedure of Example 1 to yield 3 - [4-(t-butyl)phenyl] -N- [3 -chloro-5-methyl-4-(methanesulfonyl-amino)benzyl] thiopropionamide (6.9 mg, 56%) as a white solid.
  • Step 1 2-(4-t-butyl-benzyl)-2-methyl-malonic acid dimethyl ester
  • Step 2 3-(4-t-butyl-phenyl)-2-methyl-propionic acid 2-(4-t-butyl-benzyl)-2-methyl-malonic acid dimethyl ester (Ig, 2.99mmol) was diluted with Methanol (10ml) and KOH (252mg, 4.5mmol) dissolved in Methanol (20ml) was added thereto and refluxed for 10 minutes. After completion of reaction, the mixture was concentrated in vacuo and dissolved in water (30ml) and acidified with 3N aqueous HCl to pH4, and extracted with ethyl acetate (20ml* 5).
  • Step 3 3-(4-t-butyl-phenyl)-N-(4-methanesulfonylamino-benzyl)-2-methyl- propionamide
  • N-(4-Aminomethyl-phenyl)-methanesulfonamide (lOOmg, 0.5mmol)
  • EDC (96mg, 0.5mmol)
  • 4-DMAP (6mg, 0.05mmol)
  • 3-(4-t-butyl-phenyl)-2-methyl- propionic acid (HOmg, 0.5mmol) was dissolved in CH 2 Cl 2 (3ml), and TEA (70/ ⁇ 6, 0.5mmol) was added and stirred for 10 mins.
  • reaction mixture was concentrated in vacuo and diluted with Ethyl acetate (50ml), and washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous MgSO 4 and filtered, concentrated in vacuo, and the residue was purified by column chromatography (n- Hexane:Ethyl acetate ⁇ lil) to yield title compound (50 mg, 25%) as a white solid.
  • Step 4 3 -(4-t-butyl-phenyl)-N-(4-methanesulfonylamino-benzyl)-2-methyl- thiopropionamide
  • Step 1 3-(4-t-butyl-phenyl)-2-methyl-propionic acid
  • Step 3 2-(4-t-butyl-benzyl)-N-[4-(methanesulfonylamino)-benzyl]- thiobutyramide
  • Step 1 3-(4-t-butyl-phenyl)-N-[3-fluoro-4-(methanesulfonylamino)-benzyl]-2- methyl-propionamide
  • Step 2 3 -(4-t-butyl-phenyl)-N- [3 -fluoro-4-(methanesulfonylamino)-benzyl]-2- methyl-thiopropionamide
  • Step 1 3-(4-t-butyl-phenyl)-N-[3-fluoro-4-(methanesulfonylamino)-benzyl]-2- ethyl-propionamide
  • Step 2 3 -(4-t-butyl-pheny I)-N- [3 -fluoro-4-(methanesulfonylamino)-benzyl] -2- methyl-thiopropionamide
  • Example 38 3-(4-t-butyI-phenyl)-N-(4-methanesuIfonylamino-3-trifluoromethoxy- benzyl)-thioacrylamide
  • Step 1 N-(4-Cyano-2-trifluoromethoxy-phenyl)-methanesulfonamide
  • pyridine 0.OmL
  • methanesulfonyl chloride 0.57mL
  • the reaction was quenched with water, and the reaction solution was extracted with methylenechloride, washed with water and brine, dried over anhyd. MgSO 4, filtered and concentrated under reduced pressure.
  • Step 2 3 -(4-t-butyl-phenyl)-N-(4-methanesulfonylamino-3 -trifluoromethoxy- benzyl)-acrylamide
  • N-(4-Cyano-2-trifluoromethoxy-phenyl)-methanesulfonamide 500 mg, 1.78 mmol
  • Pd/C 30 mg
  • the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to yield a white solid (340mg, 60%).
  • the solid (150mg, 0.47mmol) was suspended in methylene chloride, and treated with triethylamine followed by 3-(4-t-butyl-phenyl)-acrylic acid (116mg) and DMTMM (154mg). The resulting mixture was stirred for 2days at ambient temperature and concentrated under reduced pressure.
  • Step 3 3-(4-t-butyl-phenyl)-N-(4-methanesulfonylamino-3-trifluoromethoxy- benzyl)-thioacrylamide 3 -(4-t-butyl-phenyl)-N-(4-methanesulfonylamino-3 -trifluoromethoxy-benzyl)- acrylamide (61 mg, 0.13mmol) was reacted with P4S10 according to the general procedure to give 3-(4-t-butyl-phenyl)-N-(4-methanesulfonylamino-3-trifluoromethoxy- benzyl)-thioacrylamide (26 mg, 41%).
  • Step 1 Ethyl (z)-3-[4-(t-butyl)phenyl]-2-fluoro-2-butenoste Triethyl-2-fluoro-2-phosphnoacetate (492 mg, 2.03 mmol) and NaH 60% (72 mg, 1.80 mmol) were added in the THF at O 0 C. The reaction mixture was stirred for 30. t-butyl acetophenone (211 mg, 1.20 mmol) was added into the reaction mixture and then the mixture was stirred for 4hr. After confirming the completion of the reaction, the reaction solvent was removed in vacuo. The residue was extracted with Ether.
  • Step 3 (z)-3 - [4-(t-butyl)phenyl] -2-fluoro-N- ⁇ 3 -fluoro-4- [(methanesulfonyl) aminojbenzyl ⁇ -2-butenamide
  • Step 4 (z)-3-[4-(t-butyl)phenyl]-2-fluoro-N- ⁇ 3-fluoro-4-
  • 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, pp3208-3220) 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 min in 200 U/ml collagenase and 2.5mg/ml trypsin, separately.
  • the ganglia was 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 5 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.
  • 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 25 g) 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.
  • the compound according to the present invention is useful to preventing and treating of pain, migraine, arthralgia, neuralgia, neuropathies, nerve injury, skin disease, urinary bladder hypersensitiveness, irritable bowel syndrome, fecal urgency, Crohn's disease, a respiratory disease, irritation of skin, eye or mucous membrane, stomach-duodenal ulcer, inflammatory diseases, ear disease, and heart disease etc.
  • the compound according to the present invention is useful to preventing and treating of acute pain, chronic pain, neuropathic pain, post-operative pain, rheumatic arthritic pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, HIV -related neuropathy, neurodegeneration, stroke, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, vitiligo, prurigo, asthma, chronic obstructive pulmonary disease, urinary incontinence, inflammatory bowel disease, hyperacusis, tinnitus, vestibular hypersensitiveness, and myocardial ischemia.

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Abstract

La présent invention concerne de nouveaux composés, un isomère de ceux-ci ou des sels pharmaceutiquement acceptables en tant qu’antagonistes du récepteur vanilloïde (récepteur vanilloïde 1; VR1; TRPV1); ainsi qu’une composition pharmaceutique contenant ceux-ci. Cette invention décrit une composition pharmaceutique destinée à la prévention ou au traitement de maladies telles que la douleur, la migraine, l’arthralgie, la névralgie, les neuropathies, les lésions nerveuses, les maladies cutanées, l’hypersensibilité vésicale, le syndrome du côlon irritable, la défécation impérieuse, la maladie de Crohn, les maladies respiratoires, l’irritation de la membrane cutanée oculaire ou muqueuse, l’ulcère gastrique/duodénal, les maladies inflammatoires ainsi que les maladies auriculaires et cardiaques.
PCT/KR2006/000583 2005-03-16 2006-02-21 Nouveaux composes, isomere de ceux-ci ou sels pharmaceutiquement acceptables de ceux-ci en tant qu’antagonistes du recepteur vanilloide ; et composition pharmaceutique contenant ceux-ci WO2006098554A1 (fr)

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WO2005003084A1 (fr) * 2003-07-02 2005-01-13 Grunenthal Gmbh Analogues de 4-(methyl sulfonyl amino)phenyle utilises en tant qu'antagonistes du recepteur vanilloide ayant une excellente activite analgesique, et compositions pharmaceutique les comprenant
WO2005040106A1 (fr) * 2003-10-23 2005-05-06 Amorepacific Corporation Composition pharmaceutique contenant un derive de thiouree et presentant une solubilite et une biodisponibilite ameliorees

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US7622589B2 (en) 2005-03-17 2009-11-24 Pfizer Inc. Substituted sulfonylaminoarylmethyl cyclopropanecarboxamide as VR1 receptor antagonists
US7915448B2 (en) 2005-03-17 2011-03-29 Pfizer Inc. Substituted sulfonylaminoarylmethyl cyclopropanecarboxamide as VR1 receptor antagonists
US7858621B2 (en) 2006-07-27 2010-12-28 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
WO2009096701A3 (fr) * 2008-01-28 2009-09-24 Amorepacific Corporation Nouveaux composés, isomère ou sels pharmaceutiquement acceptables de ces derniers, utilisés comme antagonistes du récepteur vanilloïde, et compositions pharmaceutiques les contenant
JP2011510924A (ja) * 2008-01-28 2011-04-07 アモーレパシフィック コーポレイション バニロイド受容体としての新規化合物、その異性体または薬剤学的に許容し得る塩、及びこれを含有する医薬組成物
US8557872B2 (en) 2008-01-28 2013-10-15 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
US8691855B2 (en) 2008-07-02 2014-04-08 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist and pharmaceutical compositions containing the same
WO2015008206A1 (fr) * 2013-07-14 2015-01-22 Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. Inhibiteurs de la voie de signalisation du récepteur de la somatomédine c convenant au traitement de maladies neurodégénératives
US9770454B2 (en) 2013-07-14 2017-09-26 Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. IGF-1R signaling pathway inhibitors useful in the treatment of neurodegenerative diseases
US10188659B2 (en) 2013-07-14 2019-01-29 Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. IGF-1R signaling pathway inhibitors useful in the treatment of neurodegenerative diseases

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