WO2006098554A1 - Novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and a pharmaceutical composition containing the same - Google Patents
Novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and a pharmaceutical composition containing the same Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenyl
- butyl
- alkyl
- methanesulfonylamino
- benzyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 158
- 150000003839 salts Chemical class 0.000 title claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 24
- 239000000085 vanilloid receptor antagonist Substances 0.000 title description 12
- 208000002193 Pain Diseases 0.000 claims abstract description 59
- 230000036407 pain Effects 0.000 claims abstract description 49
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- 108010062740 TRPV Cation Channels Proteins 0.000 claims abstract description 41
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 141
- -1 phenylsulfonylamino Chemical group 0.000 claims description 95
- 229910052739 hydrogen Inorganic materials 0.000 claims description 94
- 239000001257 hydrogen Substances 0.000 claims description 94
- 238000000034 method Methods 0.000 claims description 61
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 58
- 150000002431 hydrogen Chemical group 0.000 claims description 56
- 125000005843 halogen group Chemical group 0.000 claims description 50
- 229910052736 halogen Inorganic materials 0.000 claims description 47
- 150000002367 halogens Chemical group 0.000 claims description 45
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- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 38
- WPZSAUFQHYFIPG-UHFFFAOYSA-N propanethioamide Chemical compound CCC(N)=S WPZSAUFQHYFIPG-UHFFFAOYSA-N 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 31
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 28
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 27
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 25
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
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- IHRLABACBKPYLT-UHFFFAOYSA-N prop-2-enethioamide Chemical compound NC(=S)C=C IHRLABACBKPYLT-UHFFFAOYSA-N 0.000 claims description 6
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 5
- YECWGJQVGHUSKC-UHFFFAOYSA-N 3-(4-tert-butylphenyl)-n-[[3-fluoro-4-(methanesulfonamido)phenyl]methyl]-2-methylpropanethioamide Chemical compound C=1C=C(NS(C)(=O)=O)C(F)=CC=1CNC(=S)C(C)CC1=CC=C(C(C)(C)C)C=C1 YECWGJQVGHUSKC-UHFFFAOYSA-N 0.000 claims description 5
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- MYDAHVLZPZRGIL-UHFFFAOYSA-N 3-(4-tert-butylphenyl)-n-[[3-chloro-4-(methanesulfonamido)phenyl]methyl]propanethioamide Chemical compound C1=CC(C(C)(C)C)=CC=C1CCC(=S)NCC1=CC=C(NS(C)(=O)=O)C(Cl)=C1 MYDAHVLZPZRGIL-UHFFFAOYSA-N 0.000 claims description 4
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- LDIOVQVYRVNTDD-UHFFFAOYSA-N 3-(3,4-dimethylphenyl)-n-[[3-fluoro-4-(methanesulfonamido)phenyl]methyl]propanethioamide Chemical compound C1=C(C)C(C)=CC=C1CCC(=S)NCC1=CC=C(NS(C)(=O)=O)C(F)=C1 LDIOVQVYRVNTDD-UHFFFAOYSA-N 0.000 claims description 3
- MNCFTWGHUHAMAO-UHFFFAOYSA-N 3-(4-tert-butylphenyl)-n-[[3-ethenyl-5-fluoro-4-(methanesulfonamido)phenyl]methyl]propanethioamide Chemical compound C1=CC(C(C)(C)C)=CC=C1CCC(=S)NCC1=CC(F)=C(NS(C)(=O)=O)C(C=C)=C1 MNCFTWGHUHAMAO-UHFFFAOYSA-N 0.000 claims description 3
- HYXKMTKGMVEXJG-UHFFFAOYSA-N 3-(4-tert-butylphenyl)-n-[[4-(methanesulfonamido)-3-(trifluoromethoxy)phenyl]methyl]prop-2-enethioamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C=CC(=S)NCC1=CC=C(NS(C)(=O)=O)C(OC(F)(F)F)=C1 HYXKMTKGMVEXJG-UHFFFAOYSA-N 0.000 claims description 3
- WBYKBXVBLMPNGZ-UHFFFAOYSA-N 3-(4-tert-butylphenyl)-n-[[4-(methanesulfonamido)-3-methylphenyl]methyl]propanethioamide Chemical compound C1=C(NS(C)(=O)=O)C(C)=CC(CNC(=S)CCC=2C=CC(=CC=2)C(C)(C)C)=C1 WBYKBXVBLMPNGZ-UHFFFAOYSA-N 0.000 claims description 3
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- HWGVPMPYDKYYCH-UHFFFAOYSA-N 3-(4-tert-butylphenyl)-n-[[2-chloro-4-(methanesulfonamido)phenyl]methyl]propanethioamide Chemical compound C1=CC(C(C)(C)C)=CC=C1CCC(=S)NCC1=CC=C(NS(C)(=O)=O)C=C1Cl HWGVPMPYDKYYCH-UHFFFAOYSA-N 0.000 claims description 2
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- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
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- IPSRAFUHLHIWAR-UHFFFAOYSA-N zinc;ethane Chemical compound [Zn+2].[CH2-]C.[CH2-]C IPSRAFUHLHIWAR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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.
Abstract
This present invention 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 invention provides a pharmaceutical composition for preventing or treating a disease such as 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.
Description
Novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and a pharmaceutical composition containing the same
Technical field
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
Background Art
As diseases associated with the activity of vanilloid receptor (Nagy et al., 2004, Eur. J. Pharmacol. 500, 351-369) pain such as acute pain, chronic pain, neuropathic pain, post-operative pain, rheumatic arthritic pain, osteoarthritic pain, postherpetic neuralgia, neuralgia, headache, and migraine(Petersen et al., 2000, Pain, 88, ppl25-133; Walker et al., 2003, J. Pharmacol. Exp. Ther., 304, pp56-62); nerve-related diseases such as neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, and stroke(Park et al., 1999, Arch. Pharm. Res. 22, pp432-434; Kim et al., 2005, J. Neurosci. 25(3), pp662-671); 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); disease of digestive organ such as 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(Hwang et al., 2002, Curr. Opin. Pharmacol. pp235-242;
Spina et al., 2002, Curr. Opin. Pharmacol. pp264-272); urinary incontinence (Birder et al., 2002, Nat. Neuroscience, 5, pp856-860); urinary bladder hypersensitiveness (Birder et al., 2001, Proc. Natl. Acad. Sci. 98, ppl3396-13401); 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.
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, ρp816-824). 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. On the other hand, it is known that the vanilloid receptor is activated by stimuli such as capsaicin, resiniferatoxin, heat, acids, anandamide, lipid metabolites or the like; thus it plays a crucial role as a molecular integrator of physico-chemically noxious stimuli in mammals (Tominaga et al., 1998, Neuron 21 pp531-543; Hwang et al., 2000, PNAS, 97, pp6155-6160). Activation of the vanilloid receptor 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) and the like, thereby causing neurogenic inflammation. 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. 13, ppl29-139; Cortright et al., 2001, BBRC, 281, ppll83-1189). In particular, 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). Lately, an additional role of the vanilloid receptor is also expected by the report of possibility that the vanilloid receptor may be present in the form of a heteromultimer with TRP V3, another TRP channel (Smith et al., 2002, Nature, 418, ppl86-190).
As mentioned above, the 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. Recently, this possibility is supported by the report that the well-known 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). In addition, treatment of the primary culture of afferent sensory neurons with the vanilloid receptor agonist, capsaicin etc., results in damage to nerve functions and furthermore death of nerve cells. The vanilloid receptor 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 vanilloid receptor is expressed on sensory neurons distributed in myenteric ganglia,
muscle layer, mucosa and epithelial cells in all regions of the gastrointestinal tract. In particular, the vanilloid receptor is highly expressed in inflammatory disorders of the colon and ileum.
In addition, activation of the vanilloid receptor stimulates sensory nerves, which in turn causes release of neuropeptides which are known to play a critical role in pathogenesis of bowel disorders. The role of the vanilloid receptor in development of gastrointestinal disorders is well elucidated and documented in recent scientific papers and journals, for example, Holzer P, 2004, Eur. J. Pharm. 500, pp231-241; Geppetti et al, 2004, Br. J. Pharmacol., 141, ppl313-1320. According to such references, it seems that the vanilloid receptor antagonists will be effective for prevention or treatment of gastrointestinal diseases such as gastro-esophageal reflux disease (GERD) and gastroduodenal ulcer (DU). It has been reported that the number of sensory nerves expressing the vanilloid receptor is increased in patients suffering from irritable bowel syndromes and such increased expression of the vanilloid receptor is known to be involved in the development of the disease (Chan et al., 2003, Lancet, 361, pp385-391). Other investigations showed that expression of the vanilloid receptor is significantly increased in patients suffering from inflammatory bowel disorders. Taken together, it appears that the vanilloid receptor antagonist may also be therapeutically effective for such bowel disorders (Yiangou et al., 2001, Lancet, 357, ppl338-1339). The vanilloid receptor-expressing afferent nerves are abundantly distributed in airway mucosa. Bronchial hypersensitivity is very similar to hyperalgesia, and protons and lipoxygenase products, known as endogenous ligands for the vanilloid receptor, 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
al., 2002, Curr. Opin. Pharmacol. pp264-272). Further, it has been reported that air- polluting substances, which are a kind of asthma-causing substances, i.e., particulate matter specifically acts on the vanilloid receptor and such action is inhibited by capsazepine, thus suggesting the possible applicability of vanilloid receptor antagonists to respiratory diseases (Veronesi et al., 2001, NeuroToxicology, 22, pp795-810). Urinary bladder hypersensitiveness and urinary incontinence are caused by various central/peripheral nerve disorders or injury, and capsaicin-responsive sensory nerves play an important role in bladder function control and inflammation. In addition, immunoreactivity of the vanilloid receptor was reported in urinary bladder epithelium (urothelium) in rats and it was found that bladder overactivity induced by capsaicin was due to stimulation of vanilloid receptors present in nerve fibers, or various transmitters which are released by vanilloid receptors (Birder et al., 2001, Proc. Natl. Acad. Sci. 98, ppl3396-13401). Further, VRl (TRPVl) -/- mice are anatomically normal, but exhibit higher frequency of low-amplitude, non-voiding bladder contractions, as compared to wild type mice, thus indicating that the vanilloid receptor affects functions of the bladder (Birder et al., 2002, Nat. Neuroscience, 5, pp856-860). Some of vanilloid agonists are recently under development as therapeutics for treating bladder diseases. 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. Commun., 291, ppl24- 129), and are 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 vanilloid
receptor antagonist, capsazepine inhibits inflammatory factors in human skin cells (Southall et al, 2003, J. Pharmacol. Exp. Ther., 304, pp217-222).
Based on the above-mentioned information, development of various vanilloid receptor antagonists is under way, and some patents and patent applications relating to vanilloid receptor antagonists under development were recently published, in which the above mentioned information is described well (Rami et al., 2004, Drug Discovery
Today: Therapeutic Strategies, 1, pp97-104).
As a result of extensive and intensive studies based on the theoretical background discussed above, the present inventors have synthesized novel compounds having antagonistic activity by selective action on a vanilloid receptor and thus completed the present invention.
Therefore, it is an object of the present invention to provide novel compounds useful as a potent antagonist for a vanilloid receptor, isomer thereof and pharmaceutically acceptable salts thereof; and a pharmaceutical composition comprising the same.
Disclosure of the invention
The present invention provides a novel compound of the following formula (I), isomer thereof or pharmaceutically acceptable salts thereof; a pharmaceutical composition containing the same
(I)
wherein,
X represents CHR13 wherein R13 represents hydrogen, halogen, or C1-C5 alkyl;
R1 and R2 represent independently hydrogen, -SO2R16, -SOR16, 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 R16 represents hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, trifluoromethyl, phenyl, or phenyl (C1-C3) alkyl ;
R3 represents hydrogen, hydroxy, C1-C5 alkyl, halo (C1-C5) alkyl, COOBu-t,
MePhSO2-, 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;
R4, R5, R6, and R7 independently represent hydrogen, carboxy, C1-C5 alkyl, halogen, nitro, cyano, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkylcarbonyl, C1-C5 alkylcarbonylamino, C1-C5 alkylsulfonylamino, phenylsulfonylamino, C1-C5 alkylthio,
C1-C5 alkylsulfonyl, or C1-C5 alkoxycarbonyl; and
R8, R9, R1O, Rn, and Ri2 independently represent hydrogen, carboxy, C1-C5 alkyl, nitro, C2-C5 alkenyl, C1-C5 alkoxy, C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, or halogen.
One preferred aspect of the present invention is a compound of the formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof,
wherein,
X represents CHR13 wherein R13 represents hydrogen, halogen, or C1-C5 alkyl;
5 wherein Ri4 and Ri5 independently represents hydrogen, C1-C5 alkyl, halogen, or phenyl;
Ri and R2 represent independently hydrogen, -SO2R16, -SORj6, C1-C5 alkyl, Cl- 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 R16 represents hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, trifluoromethyl, phenyl, or phenyl (C1-C3) alkyl ;
R3 represents hydrogen, hydroxy, C1-C5 alkyl, halo (C1-C5) alkyl, COOBu-t, SO2PhCH3, 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;
R4, R5, R6, and R7 independently represent hydrogen, carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkoxy, halo (C1-C5) alkyl, Cl-
C5 alkylcarbonyl, C1-C5 alkylcarbonylamino, C1-C5 alkylsulfonylamino, phenylsulfonylamino, C1-C5 alkylthio, C1-C5 alkylsulfonyl, or C1-C5 alkoxycarbonyl; and
R8, R9, R1O, Rn, and Ri2 independently represent hydrogen, carboxy, C1-C5 alkyl, nitro, C2-C5 alkenyl, C1-C5 alkoxy, C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, or halogen.
Preferably, in the above formula (I)
X represents CHR13 wherein R13 represents hydrogen, halogen, or C1-C5 alkyl;
Y represents CH2-CH2 or CH=CH;
R1 and R2 represent independently hydrogen, -SO2R16, -SOR16, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl, phenyl, phenyl (C1-C3) alkyl, or Cl- C3 alkoxyphenyl, wherein R16 represents hydrogen, C1-C5 alkyl, C2-C5 alkenyl, trifluoromethyl, phenyl, or benzyl;
R3, R7, and R12 represent hydrogen;
R4, R5, and R6 independently represent hydrogen, carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkoxy, halo (C1-C5) alkyl, Cl- C5 alkylcarbonyl, C1-C5 alkylcarbonylamino, C1-C5 alkylsulfonylamino, phenylsulfonylamino, or C1-C5 alkoxycarbonyl; and
R8, R% R1O, and R11 independently represent hydrogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkylsulfonyl, or halogen.
In general, compounds of formula (I) are preferred in which R10 is C3-C5 alkyl or CF3 and even more preferred in which R10 is isopropyl or ter-butyl, and most preferred tert-butyl.
More preferably, in the above formula (I),
Y represents CH2-CH2;
R1 represents hydrogen;
R2 represents -SO2R16 wherein R16 represents hydrogen, C1-C5 alkyl, C2-C5 alkenyl, or trifluoromethyl;
R5 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
R10 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;
wherein,
R1 represents methanesulfonyl or trifluoromethanesulfonyl;
R2 and R3 represent hydrogen;
R4, R5, R6, and R7 independently represent hydrogen, methyl, ethyl, ethenyl, fluoro, chloro, bromo, nitro, carboxy, methylcarbonyl, methoxycarbonyl, methoxy, or CF3;
R8, R9, Rn, and R12 independently represent hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, t-butyl, sec-butyl, methoxy, bromo, chloro, trifluoromethyl, or methoxycarbonyl; and
R10 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;
wherein
X represents CHR13 wherein R13 represents hydrogen or C1-C5 alkyl;
Y represents CHR14, CHR14-CHR15,
, wherein R14 and R15 are independently hydrogen, C1-C5 alkyl, halogen, or phenyl;
R1 and R2 represent independently hydrogen, -SO2R16, wherein R16 represents C1-C5 alkyl;
R3 represents hydrogen;
R4, R5, R6 and R7 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; R8,
R9, and R11 independently represent hydrogen, C1-C5 alkyl, C1-C5 alkoxy, halo (Cl- C5) alkyl, or halogen;
R1O is C3-C5 alkyl or CF3 and even more preferably isopropyl or ter-butyl, and most preferably tert-butyl; and _R12 represents hydrogen or fluoro, and particularly preferred hydrogen.
Preferably, in the above formula (I),
X represents CHR13 wherein R13 represents hydrogen or methyl ;
Y represents CHRi4-CHR15, wherein Ri4 and R15 are independently hydrogen or methyl;
Ri represents hydrogen, and R2 represents -SO2R16; wherein R16 represents Cl- C3 alkyl;
R3 and R7 represent hydrogen;
R4, R5, and R6 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 ;
R8, R9, and R11 independently represent hydrogen, C1-C3 alkyl, C1-C3 alkoxy, halo (C1-C3) alkyl, or halogen;
Rio is C3-C5 alkyl or CF3 and preferably isopropyl or tert-butyl; and
Ri2 represents hydrogen or fluoro, and particularly preferred hydrogen.
More preferably, in the above Formula (I),
X represents CH2;
Y represents CH2CH2;
R2 represents methanesulfonyl;
Ri, R3, R4, and R7 represent hydrogen;
R8, R9, Rn and Ri2 independently represent hydrogen or fluoro;
R5 and R6 independently represent hydrogen, C1-C3 alkyl, halogen, nitro, cyano, ethenyl, or ethynyl; and
Rio represents t-butyl.
Even more preferably, in the above figure (I),
R5 is selected from hydrogen, methyl, fluoro, chloro, nitro, ethenyl, or ethynyl; and R6 is selected from hydrogen, fluoro, chloro, or methyl.
Preferred examples of compounds according to the invention are selected from the group consisting of,
3-[4-(t-butyl)phenyl]-N-[4-(methanesulfonylamino) benzyl]thiopropionamide, 3 - [4-(t-butyl)phenyl] -N- [3 -fluoro-4-(methanesulfonylamino) benzyljthiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -chloro-4-(methanesulfonylamino) benzyljthiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -methyl-4-(methanesulfonylamino) benzyljthiopropionamide,
3 - [4-(t-butyl)phenyl]-N- [3 -methoxycarbonyl-4- (methanesulfonylamino)benzyl]thiopropionamide, 3 - [4-(t-butyl)phenyl] -N- [3 ,5-dimethyl-4-(methanesulfonylamino) benzyljthiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -carboxy-4-(methanesulfonylamino)benzylJ thiopropionamide,
3 - [4-(t-bulyl)phenyl] -N- [3 -iiitro-4-(niethanesulfonylamino) benzyl]thiopropionamide,
2- [4-(t-butyl)phenyl]-N- [3 -fluoro-4-(methane sulfonylamino)benzyl]cyclopropanthiocarboxamide, 2-[4-(trifluoromethyl)phenyl]-N-[3-fluoro-4-(methanesulfonyl amino)benzyl]thiopropionamide,
(E)-3 - [4-(t-butyl)phenyl] -N- [3 -fluoro-4-(methanesulfonylamino)benzyl] -2- thioacrylamide,
(R)-3 - [4-(t-butyl)phenyl] -N- [ 1 -(4-metlianesulfonylaminophenyl) ethyl] thioacrylamide,
(R)-3-[4-(t-butyl)phenyl]-N-[l-(4-methanesulfonylaminophenyl)ethyl] thiopropionamide,
3 - [4-(t-butyl)phenyl] -2-fluoro-N- [4-(methanesulfonylamino)benzyl] thioacrylamide, 3 - [4-(t-butyl)phenyl] -2-fluoro-N- [4-(methanesulfonyamino)benzyl] thiopropionamide,
3-[4-(iso-propyl)phenyl]-N-[3-fluoro-4-(methanesulfonylamino)benzyl] thiopropionamide,
3 - [3 ,4-dimethoxyphenyl] -N- [3 -fluoro-4-(methanesulfonylamino)benzyl] thiopropionamide,
3 - [3 ,4-dimethylphenyl] -N- [3-fluoro-4-(methanesulfonyl amino)benzyl]thiopropionamide,
3 - [4-chlorophenyl] -N- [3 -fluoro-4-(methanesulfonylamino)benzyl] - thioacrylicamide,
2- [4-chlorophenyl] -N- [3 -fluoro-4-(methanesulfonylamino)benzyl] thioacetamide,
2- [4-isopropylphenyl] -N- [3 -fluoro-4-(methanesulfonyl amino)benzyl]thioacetamide, 3 - [4-(t-butyl)phenyl] -N- [2-chloro-4-
(methanesulfonylamino)benzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -iodo-4-(methanesulfonylamino) benzyljthiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [4-(methanesulfonylamino) -3 -vinylbenzyljthiopropionamide,
3-[4-(t-butyl)phenyl]-N-[3-ethyl-4- (methanesulfonylamino)benzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -(trifluoromethyl)-4- (methanesulfonylamino)benzyl]thiopropionamide, 3-[4-(t-butyl)phenyl]-N-[2-(trifluoromethyl)-4-
(methanesulfonylamino)benzyl]thiopropionamide,
3-[4-(t-butyl)phenyl]-N-[3,5-difluoro-4-(methanesulfonylamino)- benzyl] thiopropionamide,
3-[4-(t-butyl)phenyl]-N-[3-fluoro-4-(metlianesulfonylamino)-5-vinyl- benzyljthiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -ethynyl-5-fluoro-4-(methanesulfonylamino)- benzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -cyclopropyl-5 -fluoro-4-(methanesulfonylamino)- benzyljthiopropionamide,
3-[4-(t-butyl)phenyl]-N-[3-chloro-5-methyl-4-(methanesulfonylaniino)- benzyljthiopropionamide,
3 - [4-(t-butyl)phenyl] -N-[3 -cyano-4-(methanesulfonylamino)- benzyl]thiopropionamide, 3-(4-t-butyl-phenyl)-N-(4-methanesulfonylamino-benzyl)-2-metliyl- thiopropionamide,
2-(4-t-butyl-benzyl)-N-(4-methanesulfonylamino-benzyl)-thiobutyramide,
3-(4-t-butyl-phenyl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-2-methyl- thiopropionamide, 3 -(4-t-butyl-phenyl)-N-(3 -fluoro-4-methanesulfonylarnino-benzyl)-2-ethyl- thiopropionamide,
3-(4-t-butyl-phenyl)-N-(4-methanesulfonylamino-3-trifluoromethoxy-benzyl)- thioacrylamide,
3 - [4-(t-butyl)phenyl] -N- [3 -acetyl-4-(methanesulfonylamino)-5 -fluoro- benzyljthiopropionamide, and
(z)-3-[4-(t-butyl)phenyl]-2-fluoro-N-[3-fluoro-4- (methanesulfonylamino)benzyl]-2-butenethioamide.
Particularly preferred compounds according to the present invention are 3 - [4-(t-butyl)phenyl]-N- [3 -fluoro-4-(methanesulfonylamino) benzyljthiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -chloro-4-(methanesulfonylamino) benzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -methyl-4-(methanesulfonylamino)
benzyl]thiopropionamide,
3 - [4-(t-butyl)plienyl] -N- [3 -nitro-4-(methanesulfonylamino) benzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [4-(methanesulfonylamino) -3 -vinylbenzyljthiopropionamide,
3-[4-(t-butyl)phenyl]-N-[3,5-difluoro-4-(methanesulfonylamino)- benzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -fluoro-4-(methanesulfonylamino)-5-vinyl- benzyl]thiopropionamide, 3-[4-(t-butyl)phenyl]-N-[3-ethynyl-5-fluoro-4-(methanesulfonylamino)- benzyljthiopropionamide,
3-[4-(t-butyl)phenyl]-N-[3-chloro-5-methyl-4-(methanesulfonylamino)- benzyl]thiopropionamide, and
3 - [4-(t-butyl)phenyl] -N- [3 -cyano-4-(methanesulfonylamino)- benzyljthiopropionamide.
The compounds of the formula (I) of the present invention can chemically be synthesized by the following reaction schemes. However, these are given only for illustration of the invention and not intended to limit them.
[Scheme 1]
• The above Scheme 1 shows a proposed process for synthesizing thioamide
compounds. At first, 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 P4S1O to yield obtain thioamide derivatives.
[Scheme 2]
The above Scheme 2 shows a proposed process for preparing the acidic compound (3) as an intermediate to synthesize various thioamide derivatives. At first, A- t-butyl-benzaldehyde is subjected to Knoevenagel condensation reaction {Ber. 1898, 31, 2596) to give phenylacrylic acid (2). Hydrogenation for the compound (2) is carried out in the presence of Pd catalyst to yield the acidic compound (3). [Scheme 3]
The above Scheme 3 shows the five-step reaction to prepare various thioamide derivatives. In 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). In step 2, nitrile group is introduced to the compound (4) by refluxing with cuprous cyanide at 13O 0C or stirring it together with zinc cyanide and tetrakis(triphenyl)palladium(O) catalyst in DMF at 800C for 2 hours. In step 3, hydro genation for the compound (5) is carried out by using c-HCI to yield the amine compound (6) (J Am. Chem. Soc. 1994, 116, 1831). In step 4, the compound (6) is reacted with 3-[4-(t-butyl)phenyl] propionic acid (3) to synthesize amide derivatives (7). In step 5, the amide compound (7) is treated with lawesson's reagent to yield thioamide derivatives (8).
[Scheme 4]
Sd g
The above Scheme 4 shows a proposed process to obtain the thioamide compound having carboxyl functional group. Ester group of the compound (8d) is hydrolyzed to yield the compound (9) with carboxyl functional group.
[Scheme 5]
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 BH3 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.
[Scheme 6]
15 16
17 IS 6a
The above Scheme 6 shows six-step reaction to prepare the thioamide compound (20) to which cyclopropane is introduced. In step 1, the compound (15) is obtained by Honer-Emmons reaction (J Am. Chem. Soc. 1966, 88, 5654) from the reactant, 4-t-butyl-benzaldehyde. In step 2, the compound (15) is reduced with Dibal-H to obtain the alcohol compound (16). Double bond of the primary alcohol compound (16) is propanated by the Simmon-Smith reaction to obtain intermediate compound (17). In step 4, the primary alcohol compound (17) is oxidated in the presence of PDC (Tetrahedron Lett. 1979, 20, 399.) to yield the acidic compound (18), and the compound
(18) is reacted with the amine compound (6a) to synthesize the amide compound (19). The amide compound (19) is treated with lawesson's reagent to yield thioamide derivative (20) according to the same procedure as described in 5 step of Example 3.
[Sch erne 7]
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.
[Scheme 8]
As depicted in the above Scheme 8, 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 CF3COOH 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).
[Scheme 9]
As depicted in the above Scheme 9, the compound (28) is reduced to prepare the amide derivatives (30). This compound (30) is treated with lawesson's reagent to obtain the thioamide derivatives (31).
[Scheme 10]
As depicted in the above Scheme 10, a new method using 4-(4,6-dimethoxy- l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (hereinafter referred as DMTMM) is used to synthesize the amide derivatives (Tetrahedron, 2001, 57, 1551). The method makes synthesis of unsaturated amide derivatives easier. The saturated or unsaturated thioamide derivatives is synthesized by using amide with P4S10 reagent.
[Scheme 11]
The above Scheme 11 shows a proposed process to synthesize the thioamide derivatives (8) by one-step reaction from the amine compound and acid compound
(Tetrahedron Lett. 1995, 36, 6745-6746).
The scheme 12 shows a proposed process to synthesize the thioamide compound with acetyl group from ester.
[Scheme 13]
reflux
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).
[Scheme 14]
The Scheme 14 shows a process for synthesizing the streospecific thiopropionamide (44) with vinyl moiety.
[Schemel5]
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 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.
In said pharmaceutical composition, 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.
In the above, 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.
More specifically, 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.
In one preferred aspect, the present invention provides a pharmaceutical composition for treating a condition selected from pain, inflammatory disease of the joints including autoimmune diseases of the joints, urinary bladder hypersensitivity including urinary incontinence, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), neurotic/allergic/inflammatory skin disease, psoriasis, asthma, chronic obstructive pulmonary disease (COPD), pruritus or prurigo
comprising a compound, an isomer thereof or a pharmaceutically acceptable salt thereof according to formula (I) as defined further above.
More specifically, the 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.
If 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.
The term "osteoarthritis (OA)" as used herein typically includes diseases with a failure of a diarthrodial (movable, syno vial-lined) joint. In 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. Typically, 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.
If 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. Besides the pain relief, 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.
One outcome of the administration of the compounds of the present invention to patients suffering from RA and/or AS may thus be reducing the pain experienced by the subject suffering from RA or AS relative to the pain experienced by the subject immediately before the administration of the compounds or combinations of the present invention. Another outcome of said treatment may be preventing the re-occurence of pain which has previously been reduced as a result of pharmaco- or other therapy. Another outcome of treatment may be decreasing the occurrence of and/or the severity of manifestations related to an inflammatory autoimmune disease of the joints, including particularly RA and AS. The treatment may suitably result in an improved functionality of the joints, such as decreased stiffness, improved mobility.
The term "RA" refers to Rheumatoid Arthritis. 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" stands for 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.
Treatment of "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). Finally, the treatment of noninflammatory musculoskeletal pain can also improve the associated symptoms of back pain, fibromyalgia, and myofascial pain syndrome.
The terms "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.
The pharmaceutical compositions according to the present invention are preferably adapted for oral administration. Alternatively, if skin diseases are to be treated the pharmaceutical composition containing the inventive compounds may be also formulated for topical or transcutaneous use.
In another aspect, 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. In another aspect, 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.
In the above method, 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.
In one preferred aspect of the invention, 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.
In another aspect, 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. In another aspect, 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.
In another aspect, 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.
In a preferred aspect, 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.
In a particularly preferred aspect, 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.
Hereinafter, the formulating methods and kinds of excipients will be described, but the present invention is not limited to them.
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. For instance, 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. For topical administration, 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
0.001 ~ 1% by weight, based on the total amount of the composition.
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.
Detailed description of the invention 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:
"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" includes monovalent olefmically unsaturated liydrocarbyl groups being straight-chained or branched and having at least 1 double bond. Particular alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), isopropenyl (-C (CH3) =CH2), and the like. A preferred "alkenyl" group 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 -NR1R", wherein R' is alkyl and R" is selected from hydrogen or alkyl "Alkylsulfonyl" includes a radical-S(O)2R 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.
"Amino" refers to the radical -NH2.
"Carboxy" refers to the radical -C(=O)OH.
"Cyano" refers to the radical -CN,
"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.
"Ethenyl" refers to -CH=CH5 which in the present application is also designated "vinyl"
"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. "Hydroxy" refers to the radical-OH.
"Nitro" refers to the radical-NO2.
"Pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or 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 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. 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, 21iydroxyethanesulfonic 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, hydroxynaplithoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced.
"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.
Mode for carrying out invention
The present invention is more specifically explained by following examples and experimental examples. However, it should be understood that the extent of the present invention is not limited to the following examples and experimental examples.
Example 1: 3-[4-(t-butyI)phenyl]-N-[4-(methanesulfonylamino) benzyljthiopropionamide
Step 1 : Synthesis of (E)-3-[4-(t-butyl)phenyl]-2-acrylic acid
4-(t-Butyl)benzaldehyde (0.5 mL, 3.0 mmol) was dissolved in pyridine(5.0 mL) and followed by adding malonic acid(470 mg, 4.5 mmol) thereto and adding dropwise piperidine (0.090 mL, 0.9 mmol). The reaction mixture was refluxed for 4 hours as confirming CO2 generation. After the completion of the reaction, the resultant mixture was acidified with 2N-HC1 at 00C and pH3 to yield a solid compound. The solid compound was filtered under reduced pressure and washed with H2O to obtain acidic compound (520 mg, 85%).
1H-NMR (300MHz, CDCl3): δ 1.32 (s, 9H)3 6.43 (d, IH5 J = 16 Hz), 7.42 (d, 2H5 J = 8.61 Hz)5 7.50 (d, 2H5 J= 8.4 Hz)5 7.78 (d, IH, J= 16 Hz)
Step 2: Synthesis of 3-[4-(t-butyl)phenyl] propionic acid (compound 3)
3-[4-(t-butyl)phenyl]-2-acrylic acid (530 mg, 1.3 mmol) was dissolved in anhydrous THF (12 niL), and added a catalytic amount of 10 % palladium active carbon to carry out hydrogenation, followed by stirring for 2 hours at room temperature. The resulting mixture was diluted with ether, filtered through celite pad, and then concentrated under reduced pressure to yield acidic compound (compound 3, 480 mg, 95%).
1H-NMR (300MHz5 CDCl3): δ 1.29 (s, 9H), 2.69 (t, 2H, J= 7.9 Hz), 2.95 (t, 2H, J= 7.9 Hz), 7.14 (d, 2H, J= 8.2 Hz)5 7.31 (d, 2H, J= 8.4 Hz)
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 MgSO4, filtered and concentrated under reduced pressure. The obtained solid was column-chromatographed (n-hexane /ethyl acetate = 1/1) to yield compound (1.20 g, 4.0 mmol, 88.9%)
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 5 : 3-[4-t-Butylphenyl]-N-[4-methanesulfonylbenzyl]propionamide 4-Methanesulfonylbenzylamine hydrochloride (0.25g, l.Oόmmol), 3-(4-t- butylphenyl) propionic acid (l.leq, 0.24g), and DMTMM (1.2eq, 0.35Ig) were put into the 50 ml of one-neck round bottom flask. And the solution was added with triethylamine (0.5ml), stirred for 3 days at room temperature. The reaction solution was extracted with EtOAc, washed with water, dried over anh. MgSO4, filtered and concentrated under reduced pressure. The obtained sunstance was column- chromatographed (n-Hexane: EtOAc=I :1) to yield compound (0.305 g, 0.79 mmol, 74.5%).
Step 6: 3- [4-t-butylphenyl] -N- [4-methanesulfonylbenyl] thiopropionamide 3-[4-t-Butylphenyl]-N-[4-methanesulfonylbenzyl]propionamide (0.31 g,
0.79mmol), P2S5 (2.0eq, 0.35g) were put into the 50ml of one-neck round bottom flask and poured 25ml of toluene. And the solution was refluxed during 4 hours. The reaction
mixture was extracted with EtOAc, washed with water, dried over anh.MgSO4, filtered and concentrated under reduced pressure. The obtained sunstance was column- chromatographed (n-Hexane: EtOAc= 2:1) to yield title compound (0.32 g, 0.77 mmol, 70.5%).
1HNMR (300MHz, CDC13): 7.29 (m, 4H) 7.13 (m, 4H) 6.45 (s, IH) 4.71 (d, 2H, J = 5.4 Hz) 3.11 (m, 2H) 3.01 (s, 3H) 2.96(m, 2H) 1.31(s, 9H)
Example 2 : 3- [4-(t-butyl)phenyl] -N- [3-fluoro-4-(methanesulfonylamino) benzyl] thiopropionamide
Step 1: Synthesis of 2-fluoro-4-iodo-l-methanesulfonylaminobenzene
To the solution of 2-fluoro-4-iodoaniline (1.5Og, 6.33 mmol) in CH2Cl2 (4OmL) was added pyridine (1.02ml) and MsCl (700//β, 9.50 mmol). The mixture was stirred for 1 hour at room temperature, and then the reaction was quenched with 1.5N aqueous HCl solution. The resulting mixture was extracted with CH2Cl2, dried over anhydrous
MgSO4, and then the remaining liquid was concentrated under reduced pressure. The residue was purified by column chromatogrphy (ethyl acetate/n-hexane = 1/1) to yield the compound (1.89g, 95%).
1H-NMR (300MHz5 CDCl3): δ 3.01 (s, 3H), 6.51 (s, IH), 7.30 (t, IH5 J= 8.3 Hz), 7.47
(dd, 2H, J= 1.2, 1.7 Hz)
Step 2: Synthesis of 4-cyano-2-fluoromethanesulfonylaminobenzene To the solution of 2-fluoro-4-iodo-l-methanesulfonylaminobenzen (1.8 Ig, ό.Ommol) prepared in step 1 in DMF (1OmL) was added Zn(CN)2 (845 mg, 7.2 mmol) and Pd(PPh3)4 (187 mg, 0.16 mmol) and followed by stirring for 1.5 hours at 8O0C ~ 9O0C. The resulting mixture was diluted with ethyl acetate (2OmL), washed with water and brine, and dried over anhydrous MgSO4. The remaining liquid was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/n-hexane = 1/2) to yield the compound (1.03g, 80%).
1H-NMR (300MHz, CDCl3): δ 3.07 (s, 3H), 6.83 (s, IH), 7.37 (dd, IH, J= 9.5, 1.7 Hz), 7.41 (d, IH, J= 9.8 Hz), 7.65 (t, IH, J= 8.0 Hz)
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%).
1H NMR (300MHz, CD3OD): δ 3.02 (s, 3H), 4.11 (s, 2H), 7.27 (d, IH, J= 8.5 Hz), 7.33 (dd, IH, J= 9.8, 1.8 Hz), 7.57 (t, IH, J= 8.3Hz)
Step 4: Synthesis of 3-[4-(t-butyl)phenyl]-N-[-3-fluoro-4- (methanesulfonylamino)benzyl] propionamide
4-(t-Butyl)phenylpropionic acid (87 mg, 0.42 mmol) was dissolved in methylene chloride (5.0 mL). To the solution was added dropwise DMF (5drops), followed by adding oxalyl chloride (0.073 mL, 0.84 mmol) at O0C and stirring for 2 hours. The residue was obtained by concentrating the resulting solution under reduced pressure. 3-fluoro-4-methanesulfonylaminobenzylamine (84 mg, 0.50 mmol) was dissolved in methylene chloride (5.0 mL) and to the solution was added dropwise Et3N (0.14 mL, 1.0 mmol). To the resulting solution was added the residue obtained from above reaction, followed by stirring for 2 hours. The resulting solution was concentrated under reduced pressure and the residue was column-cliromatographed (ethyl acetate/n- hexane = 1/1) to yield 3-[4-(t-butyl)phenyl]-N-[-3-fluoro-4-
(methanesulfonylamino)benzyl] propionamide (97 mg, 50%).
1H NMR (300MHz, CD3OD): δ 1.29 (s, 9H), 2.52 (t, 2H, J= 7.4 Hz), 2.90 (s, 3H), 2.91 (t, 2H, J= 7.4 Hz), 4.27 (s, 2H), 7.18-7.09 (m, 6H), 7.30 (d, 2H, J= 8.4 Hz); IR (neat, cm"1): 3266, 2960, 1640, 1513, 1465, 1329; Mass (LC): 389.0 [M+H]+
Step 5: Synthesis of 3-[4-(t-butyl)phenyl]-N-[3-fluoro-4-
(methanesulfonylamino) benzyl]thiopropionamide
The 3-[4-(t-butyl)phenyl]-N-[-3-fluoro-4-(methanesulfonylamino)benzyl] propionamide (290 mg, 0.71 mmol) and lawesson's reagent (577 mg, 1.42 mmol) were dissolved in toluene (12 mL), and refluxed for 5 hours. After the completion of the
reaction, the resulting solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and brine, dried over anhydrous MgSO4 ( and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/n-hexane = 1/2) to yield the thioamide compound (240 mg, 80%).
1H-NMR (300MHz, CDCl3) : δ 1.27 (s, 9H), 2.97 (t, 2H, J = 7.1 Hz), 2.99 (s, 3H), 3.11 (t, 2H, J = 7.1 Hz), 4.71 (d, 2H, J = 5.3 Hz), 6.57 (bs, IH), 6.97-6.90 (m, 2H), 7.13 (d, 2H, J= 8.3 Hz), 7.30 (d, 2H, J= 8.2 Hz), 7.48 (t, IH, J= 8.1 Hz); IR (neat, cm"1): 3255, 2961, 1590, 1513, 1445, 1402; Mass (LC) 423.0 [M+H]+
Example 3: 3-[4-(t-butyl)phenyl]-N-[3-chloro-4-(methanesuIfonylamino) benzyljthiopropionamide
The 3-[4-(t-butyl)phenyl]-N-[3-chloro-4-(methanesulfonylamino) benzyl]thiopropionamide (70%) was obtained according to the same procedure as described in Example 2.
1H-NMR (300MHz, CDCl3) : δ 1.27 (s, 9H), 2.98 (t, 2H, J= 6.8 Hz), 2.99 (s, 3H), 3.11 (t, 2H, J = 6.6 Hz), 4.71 (d, 2H, J = 5.3 Hz), 6.75 (bs, IH), 7.06 (dd, IH, J= 8.4, 2.0
Hz), 7.12 (d, 2H, J= 8.3 Hz), 7.30-7.26 (m, 3H), 7.57 (d, IH, J= 8.4 Hz) ;
IR (neat, cm"1): 3307, 2960, 1499, 1390, 1329, 1158; Mass (LC): 439.0 [M+H]+
Example 4 : 3- [4-(t-butyl)phenyl] -N- [3-methyl-4-(methanesulfonylamino) benzyl] thiopropionamide
The 3 -[4-(t-butyl)phenyl] -N- [3 -methyl-4-(methanesulfonylamino) benzyljthiopropionamide (77%) was obtained according to the same procedure as described in Example 2.
1H-NMR (300MHz, CDCl3) : δ 1.28 (s, 9H), 2.27 (s, 3H), 2.95 (t, 2H, J = 7.1 Hz), 3.00 (s, 3H), 3.10 (t, 2H, J= 7.2 Hz), 4.67 (d, 2H, J= 5.1 Hz), 6.23 (bs, IH), 6.99 (dd, IH, J = 8.1, 1.9 Hz), 7.13-7.09 (m, 3H), 7.30 (d, 2H, J = 8.3 Hz), 7.37 (d, IH, J= 8.3 Hz) ; IR (neat, cm"1): 3293, 2960, 1505, 1396, 1322, 1153; Mass (FAB) 419 [M+H]+
Example 5: 3-[4-(t-butyl)phenyl]-N-[3-methoxycarbonyl-4-
(methanesulfonylamino)benzyl]thiopropionamide
The thioamide compound (91%) was obtained according to the same procedure
as described in Example 2.
1H-NMR (300MHz, CDCl3): δ 1.27 (s, 9H), 2.97 (t, 2H, J = 7.5 Hz), 3.03 (s, 3H), 3.10 (t, 2H, J= 7.0 Hz)5 3.92 (s, 3H), 4.73 (d, 2H, J= 5.1 Hz), 7.12 (d, 2H, J= 8.2 Hz), 7.28 (d, 2H, J= 8.2 Hz), 7.33 (dd, IH, J= 8.6, 2.2 Hz), 7.67 (d, IH, J= 8.4 Hz), 7.95 (d, IH, J= 2.0 Hz) ;
IR (neat, cm"1): 3211, 2959, 1689, 1585, 1503, 1398; Mass (LC) 463.2 [M+H]+
Example 6: 3-[4-(t-butyl)phenyl]-N-[3,5-dimethyl-4-(methanesuIfonyI amino) benzyl]thiopropionamide
The thioamide compound (75%) was obtained according to the same procedure as described in Example 2.
1H-NMR (300MHz, CDCl3) : δ 1.27 (s, 9H), 2.38 (s, 6H), 2.95 (t, 2H, J = 7.3 Hz),
3.09 (s, 3H), 3.10 (t, 2H, J= 7.3 Hz), 4.65 (d, 2H, J= 5.1 Hz), 5.75 (bs, IH), 6.96 (s,
2H), 7.13 (d, 2H, J= 8.4 Hz)5 7.29 (d, 2H, J= 8.2 Hz) ;
IR (neat, cm'1): 3182, 2920, 1646, 1517, 1401, 1306 ; Mass (FAB) 433 [M+H]+
Example 7: 3-[4-(t-Butyl)phenyl]-N-[3-carboxy-4-(methanesulfonyl amino)benzyl]
thiopropionamide
The compound of Example 5 (70 mg, 0.16 mmol) and LiOH H2O (26 mg, 0.63 mmol) were dissolved in THF/H2O (1:1, 4 mL), and stiiτed 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 O4j and concentrated under reduced pressure to yield the acidic compound (61 mg, 50%).
1H NMR (300MHz, CD3OD) : δ 1.25 (s, 9H), 2.91 (t, 2H, J = 7.7 Hz), 2.98 (s, 3H), - 3.06 (t, 2H, J= 7.3 Hz), 4.74 (s, 2H), 7.13 (d, 2H, J- 8.2 Hz), 7.27 (d, 2H, J= 8.0 Hz),
7.33 (dd, IH, J= 8.4, 2.2 Hz), 7.58 (d, IH, J= 8.6 Hz), 8.05 (d, IH, J= 1.7 Hz) ;
IR (neat, cm"1): 3229, 2958, 1682, 1502, 1393, 1327;
Mass (LC) 449.2 [M+H]+
Example 8: 3-[4-(t-Butyl)phenyl]-N-[3-nitro-4-(methanesulfonyIamino) benzyl]thiopropionamide
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. The resulting solution was diluted with ethyl acetate, and the combined organic phase was washed with water and brine, dried over anhydrous MgSO4j and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/n-hexane = 1/5) to yield the nitrile compound (120 mg, 16%).
1H-NMR (300MHz, CDCl3): δ 3.24 (s, 3H), 7.90 (dd, IH, J= 8.8, 2.0 Hz), 8.03 (d, IH, J= 8.8 Hz), 8.59 (d, IH, J= 2.0 Hz)
Step 2: Synthesis of N-[2-nitiO-4-(aminomethyl)phenyl]methanesulfonamide The 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 BH3 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.
1H-NMR (300MHz, CDCl3) : δ 1.28 (s, 9H), 2.56 (t, 2H, J= 7.7 Hz)5 2.97 (t, 2H, J = 7.3 Hz), 3.11 (s, 3H), 4.41 (d, 2H, J= 6.0 Hz), 5.76 (bs, IH), 7.12 (d, 2H, J= 8.2 Hz), 7.30 (d, 2H, J= 8.4 Hz), 7.50 (dd, IH, J = 8.6, 2.0 Hz), 7.81 (d, IH, J= 8.8 Hz), 8.10 (d, IH, J= 2.0 Hz), 9.65 (bs, IH)
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.
1H-NMR (300MHz, CDCl3) : δ 1.27 (s, 9H), 2.98 (t, 2H, J = 6.6 Hz), 3.11 (t, 2H, J = 7.1 Hz), 3.12 (s, 3H), 4.80 (d, 2H, J= 5.9 Hz), 7.12 (d, 2H, J= 8.3 Hz), 7.29 (d, 2H, J=
8.4 Hz), 7.47 (dd, IH, J = 8.4, 2.0 Hz), 7.81 (d, IH, J = 8.8 Hz), 8.11 (d, IH, J = 2.0
Hz), 9.69 (bs, IH) ;
IR (neat, cm"1): 3293, 2960, 1623, 1534, 1389, 1344;
Mass (LC) 450.2 [M+H]+
Example 9: 2-[4-(t-butyl)phenyl]-N-[3-fluoro-4-(methane sulfonylamino)benzyl]cyclopropanthiocarboxamide
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 CH3CN (15 mL), the solution was stirred for one day. After confirming the completion of the reaction, the resulting solution was concentrated under reduced pressure. The residue was diluted with EtOAc, washed with water and brine, dried over anhydrous MgSO4, concentrated under reduced pressure. The residue was purified by column chromatograpy (ethyl acetate/n-hexane = 1/20) to yield Synthesis of ethyl (E)S- [4-(t-butyl)phenyl]-2-propenoate (940 mg, 66%).
1H-NMR (300MHz, CDCl3): δ, 1.31 (s, 9H), 1.34 (t, 3H, J= 7.14 Hz), 4.28 (q, 2H, J = 7.14 Hz), 6.41 (d, IH, J = 16 Hz), 7.40 (d, 2H, J = 8.6 Hz), 7.47 (d, 2H, J = 8.4 Hz), 7.68 (d, IH, J= 16 Hz)
Step 2: Synthesis of (£)-3-[4-(t-butyl)phenyl]-2-propen-l-ol
Synthesis of ethyl (E)-3-[4-(t-butyl)phenyl]-2-propenoate (lOOmg, 0.43 mmol) and methyl enechloride (3.0 mL) was dissolved in toluene at -78 °C and to the solution was added dropwise IM diisobutyl aluminium hydride (DIBAL-H, 1.3 mL, 1.3 mmol), and stirred for 3 hours. The reaction was quenched with methanol, and then the organic phase was separated by using Rochelle's solution, diluted with ethyl acetate, followed by extracting and washing with water and brine. The resulting solution was dried over anhydrous MgSO4, concentrated under reduced pressure. The residue was purified by column chromatograpy (ethyl acetate/n-hexane = 1/2) to yield (E)-3-[4-(t-butyl)phenyl]- 2-ρropen-l-ol (72 mg, 88%).
1H NMR (300MHz, CD3OD): δ 1.30 (s, 9H)5 4.21 (dd, 2H, J= 5.7, 1.5 Hz)5 6.35-6.26 (m, IH), 6.59-6.53 (m, IH), 7.38-7.24 (m, 4H)
Step 3: Synthesis of 2-[4-(t-butyl)phenyl]cyclopropylmethanol
(E)-3-[4-(t-butyl)phenyl]-2-propen-l-ol (34 mg, 0.18 mmol) was dissolved in methylene chloiϊde(3.0mL) and to the solution were added dropwise diethyl zinc(1.0M soln in Hexane, 0.54 mL, 0.54 mmol), followed by stirring for a few minutes and adding dropwise diiodomethane (0.070 mL, 0.89 mmol) through 10 minutes. The mixture was stirred for 4 hours at room temperature and the reaction was quenched with NH4Cl saturated aqueous solution. The resulting solution was extracted with methylenechloride, washed with water and brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatograpy (ethyl acetate/n-hexane = 1/2) to yield 2-[4-(t- butyl)phenyl]cyclopropylmethanol (18 mg, 50%).
1H-NMR (300MHz, CDCl3): δ 1.28 (s, 9H), 1.49-1.38 (m,lH), 1.82-1.76 (m, IH), 3.65- 3.53 (m, 2H), 7.02 (d, 2H, J= 8.4 Hz), 7.30 (d, 2H, J= 8.4 Hz)
Step 4: Synthesis of 2-[4-(t-butyl)phenyl]cyclopropanecarboxylic acid
2-[4-(t-butyl)phenyl]cyclopropylmethanol (100 mg, 0.49 mmol) was dissolved in DMF(3.0 mL), followed by adding 4A molecular sieve of PDC (220 mg, 0.59 mmol) and then stirring for one day. After the completion of the reaction, the resulting solution was diluted with ether, filtrated, concentrated under reduced pressure. The residue was
purified by column chromatograpy (ethyl acetate/n-hexane = 1/10) to yield 2-[4-(t- butyl)phenyl]cyclopropanecarboxylic acid (77 nig, 72%).
1H-NMR (300MHz, CDCl3): δ 1.28 (s, 9H), 1.53-1.47 (m, IH), 1.73 (dt, IH, J= 9.2, 5.0 Hz), 2.62-2.56 (m, IH), 7.06 (d, 2H, J= 8.3 Hz), 7.33 (d, 2H, J= 8.4 Hz), 9.30 (d, IH, J = 4.8 Hz)
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.
1H NMR (300MHz, CD3OD): δ 1.28 (s, 9H), 1.51-1.42 (m, IH), 1.89-1.83 (m, IH), 2.40-2.33 (m, IH), 4.36 (d, IH, J= 15 Hz), 4.44 (d, IH, J= 15 Hz), 7.05 (d, 2H, J= 8.3 Hz), 7.14-7.09 (m, 2H), 7.30 (d, 2H, J= 8.4 Hz), 7.46 (t, IH, J= 8.3 Hz) ; IR (neat, cm"1): 2960, 1646, 1514, 1455, 1333, 1157 ; Mass (FAB) 419 [M+H]+
Step 6: Synthesis of 2-[4-(t-butyl)phenyl]-N-[3-fluoro-4-(methanesulfonyl amino)benzyl]cyclopiOpanthiocarboxamide
The thioamide compound (74%) was obtained according to the same procedure as described in step 5 of Example 2.
1H-NMR (300MHz, CDCl3) : «5 1.24 (s, 9H), 1.43 (m, IH), 2.02-1.91 (m, 2H), 2.70 (m, IH), 2.96 (s, 3H), 4.84 (d, IH, J= 5.5 Hz), 7.01 (d, 2H, J= 8.4 Hz), 7.13-7.06 (m, 2H), 7.25 (d, 2H, J= 8.4 Hz), 7.41 (s, IH), 7.49 (t, IH, J= 8.1 Hz)
Example 10: 3-[4-(trifluoromethyl)phenyl]-N-[3-fluoro-4-(methanesulfonyl amino)benzyl]thiopropionamide
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-
(methanesulfonylamino)benzylaminehydrochloride (164 mg), 4-trifluoromethylphenyl propionic acid (418 mg), DMTMM (276 mg) and TEA (0.3 mL) were dissolved in THF(20mL) and the solution was stirred overnight at room temperature. The THF was removed under reduced pressure and the residue was extracted three times with water (30 ml) and MC (30ml). Water was removed from the extracted MC solution, the organic phase was concentrated under reduced pressure. The concentrated organic solution was purified by column chromatography (hexane/ethyl acetate = 1/2, 10OmL) to obtain the purposed compound (213mg, 79%).
1U NMR (300 MHz, CDCl3): 2.50 (t, J = 7.2 Hz, 2H), 2.99 (s, 3H), 3.02 (t, 2H), 4.33 (d, J = 6 Hz, 2H), 5,68 (br, IH, NH), 6,87 (m, 2H), 7.21 (m, 2H), 7.42 - 7.50 (m, 3H) ; IR (KBr, cm"1): 3274 (NH), 1652, 1512, 1325, 1158.
Step 2: Synthesis of 3-[4-(trifluoromethyl)phenyl]-N-[3-fluoro-4-(methane sulfonylamino)benzyl]thiopropionamide
The compound prepared in step 1 was stirred with P4S10 (HOmg) to obtain the title compound (54.8mg).
1H NMR (300 MHz, CDCl3) : 2.96 (t, J = 7.5 Hz, 2H), 3.00 (s, 3H)5 3.22 (t, J = 7.2 Hz, 2H), 3.83 (s, 3H), 3.86 (s, 3H), 4,73 (d, J = 5.4 Hz, 2H), 6.61 (br, NH), 6,90 (m, 2H), 7.34 (m, 2H), 7.43-7.53 (m, 3H) ;
IR (KBr, cm"1): 3265 (NH), 1618, 1591, 1403, 1326, 1159
Example 11: (E)-3-[4-(t-butyl)phenyl]-N-[3-fluoro-4-(methanesuIfonyl amino)benzyl]- thioacrylamide.
Step 1 : Synthesis of (E)-3-[4-(t-butyl)phenyl]-N-[3-fluoro-4-(methane sulfonylamino)benzyl]- acrylamide
4-t-butylphenyl-2-acrylic acid was reacted with 3-fluoro-4- (methanesulfonylamino)benzylamine to synthesize amide compound (32%) according to the same procedure as described in step 4 of Example 2.
1H-NMR (300MHz, CDCl3): δ 1.30 (s, 9H), 3.00 (s, 3H), 4.54 (d, 2H, J = 6.2 Hz), 5.93 (bs, IH), 6.39 (d, IH, J= 16 Hz), 6.48 (bs, IH), 7.15-7.09 (m, 2H), 7.39 (d, 2H, J= 8.4 Hz), 7.45 (d, 2H, J= 8.4 Hz), 7.54 (t, IH, J= 8.3 Hz), 7.66 (d, IH, J= 16 Hz)
Step 2: Synthesis of (E)-3-[4-(t-butyl)phenyl]-N-[3-fluoro-4-(methanesulfonyl amino)benzyl]- thioacrylamide
The thioamide compound (10%) was obtained according to the same procedure as described in step 5 of Example 2.
1H NMR (300MHz, CD3OD) : δ 1.28 (s, 9H), 2.98 (s, 3H), 4.76 (s, 2H), 6.25 (d, IH, J= 12 Hz), 6.41 (d, IH, J= 12 Hz), 7.07 (d, IH, J= 8.4 Hz), 7.15 (dd, IH, J= 11, 1.8 Hz), 7.23 (s, 4H), 7.43 (t IH, J= 8.2 Hz) ; Mass (FAB): 421 [M+H]+
Example 12: (R)-3-[4-(t-butyl)phenyl]-N-[l-(4-methanesulfonylamino phenyl)ethyl] thioacrylamide
(Ri3= Me)
(i?)-methyl-4-nitrobenzylaminehydrochloride (50mg, 0.25mmol) was put into 25ml of flask and dissolved in the saturated solution (NaHCO3 : CH2Cl2 = 1:1). To the solution was added di-t-butyl dicarbonate (135mg, 0.60mmol), followed by stirring for 3 hours. The reacting mixture was diluted with methylene chloride, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The obtained liquid was purified by column chromatography (n-hexane/ethyl acetate = 10/1) to yield
pale yellow liquid (62.0 mg, 94.38%).
[α]D 22: -43.66(C LSS3 CHCl3);
IR (NaCl, neat, cm"1): 3403, 3332, 2977, 2932, 1697, 1522, 1347; 1H NMR (400MHz, CDCl3): 8.20 (d, 2H, J=8.8Hz), 7.47 (d, 2H, J = 8.8 Hz), 4.91 (s, IH), 4.85 (s, IH), 1.46 (d, 3H, J= 6.8 Hz), 1.42 (s, 9H)
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. To the solution was added Pd (7mg, 30% of substrate), substituted by using hydrogen gas and stirred for 2 hours. After confirming the completion of the reaction with thin layer chromatography, 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%).
[α]D 22: -69.75(c 1.02, CHCl3) ;
IR (NaCl neat, cm"1): 3353, 3035, 2974, 2937, 1695, 1623, 1366;
1HNMR (400MHz, CDCl3): 7.10 (d, 2H, J= 8.0 Hz), 6.40 (d, 2H, J = 8.0 Hz), 4.70 (s, 2H), 3.60 (s, 2H), 1.42 (s, 12H)
Step 3: Synthesis of (i?)-[l-(4-methanesulfonylaminophenyl)ethyl]carbamic acid t-butyl ester
After a 25ml of dried two-necked round-bottom flask was filled with argon gas, the solution of (R)-[l-(aminophenyl)ethyl]carbamic acid t-butyl ester (50 mg, 0.21
mmol) and pyridine (511 mg, 0.63 mmol, 3eq) in methylene chloride were added to the flask. Methanesulfonic anhydride (44 mg, 0.25mmol, 1.2eq) was added to the solution at 0 °C and the mixture was stirred for 30 minutes at room temperature. After confirming the completion of the reaction with thin layer chromatography, the reaction was quenched with saturated NaHCO3 aqueous solution. The reacting mixture was diluted with methylene chloride, washed with water and brine, dried over Na2SO4 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%).
mp: 170-172 °C ;
[α]D 20 : +75.76 (c 0.33, CH3OH) ;
IR (KBr pellet, cm'1): 3376, 3266, 3014, 2976, 1683, 1322, 1146 ;
1H NMR (400MHz, CD3OD): 7.25 (d, 2H, J = 8.4 Hz), 7.17 (d, 2H, J = 8.4 Hz), 4.61 (m,
IH), 2.89 (s, 3H), 1.39 (s, 9H), 1.34 (d, 3H, J = 7.2 Hz)
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 μJt, 4.71 mmol, 3 eq.) was added to the solution and stirred over night. After confirming the completion of the reaction with thin layer chromatography, the reaction solution was neutralized with saturated NaHCO3 aqueous solution and extracted with methylene chloride. The extracted compound was washed with saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield yellow syrup (213mg, 63.31%).
1H NMR (400 MHz, CDCl3): 7.16 (d, 2H, J= 8.4 Hz), 7.04 (d, 2H, J= 8.4 Hz), 4.94- 4.66 (m, 2H), 3.33 (s, 3H), 1.40 (s, 9H), 1.31 (d, 3H, J= 6.8 Hz).
Step 5: Synthesis of (i?)-3-(4-t-butylphenyl)-N-[l-(4-methanesulfonylamino phenyl)ethyl] acrylamide
A 25ml of dried two-necked round-bottom flask was filled with argon gas, thereto (i?)-N-[4-(l-Aminoethyl)phenyl]methanesulfonamide (30mg, 0.17 mmol) and 3- (4-t-butylphenyl)acrylic acid (1.2eq., 0.20mmol, 41.45 mg) were diluted with DMF. Triethylamine (2eq., 0/34mmol, 47.39mg) and diethylcyanophosphonate (1.2eq., 0.20 mmol, 30.85μ6) were added to the solution, and stirred for 12 hours. After confirming the completion of the reaction with thin layer chromatography, the reaction solution extracted with methylene chloride, washed with water and brine, dried over Na2SO4 , filtered and concentrated under reduced pressure. The obtained liquid was purified by column chromatography (n-hexane /ethyl acetate = 1/1) to yield a white solid (33.9 mg, 65%).
mp: 125-127 °C ; [α]D 20 -3.02 (CHCl3, c 0.65) ; IR (KBr pellet, cm"1) : 3354, 3057, 2963, 1659 , 1153 ;
1H NMR (400 MHz, CDCl3) : 7.56 (d, IH, J= 15.2 Hz), 7.36 (d, 2H, J= 8.4 Hz), 7.30 (d, 2H, J= 8.4 Hz), 7.25 (d, 2H, J = 8.0 Hz), 7.10 (d, 2H, J = 8.0 Hz), 6.71 (s, IH), 6.30 (d, IH, J= 15.2 Hz)), 5.81 (s, IH), 5.61 (q, IH, J= 3.2 Hz), 2.91 (s, 3H), 1.47 (d, 3H, J= 6.4 Hz)), 1.24 (s, 9H).
Step 6: Synthesis of 3-(4-t-butylphenyl)-N-[l-(4-methanesulfon.ylamino phenyl)ethyl]thioacrylamide
A 25ml of dried two-necked round-bottom flask was filled with argon gas, thereto 3-(4-t-butylphenyl)-N-[l -(4-methanesulfonylaminophenyl)ethyl]acrykmide
(11.5 mg, 0.029 mmol) was diluted with toluene, and followed by adding Lawesson's reagent (0.057mmol, 23.25mg) and refluxing for 1 hour. After confirming the completion of the reaction with thin layer chromatography, the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane /ethyl acetate = 2/1) to yield a yellow solid (10,.4mg,
86.96 %).
mp: 116-118 °C ; [α]D 20 +18.65 (CHCl3, c 0.52); IR (KBr pellet, cm"1): 3267, 2963, 1632, 1323, 1153 ;
1H NMR (400 MHz, CDCl3) : 1.23 (s, 9H), 1.56 (d, 3H, J= 6.8 Hz), 2.92 (s, 3H), 5.83 (quin, IH, J= 6.8 Hz), 6.56 (s, IH), 6.73 (d, IH, J= 15.2 Hz), 7.12 (d, 2H, J= 8.4 Hz), 7.29 (dd, 4H, J=8.4, 2.0Hz), 7.37 (d, 2H, J= 8.4Hz), 7.72 (d, IH, J= 15.2 Hz).
Example 13: (R)-3-[4-(t-butyI)phenyl]-N-[l-(4-methanesulfonylamino phenyl)ethyl] thiopropionamide
3-(4-Ethylphenyl)-N-[l-(4-methanesulfonylaminophenyl)ethyl]acrylamide (39.9 mg, O.lOmmol) was put into a 25ml of dried round bottom flask, and diluted with methanol. To the solution was added a catalytic amount of Palladium (10wt.%) on activated carbon to carry out hydrogenation. The resulting compound was stirred for 2 hours under hydrogen gas atmosphere. After confirming the completion of the reaction with thin layer chromatography, the Pd/C was filtered through celite. The resulting solution was concentrated under reduced pressure, and the residue was column- chromatographed (n-hexane /ethyl acetate = 2/1) to afford a white solid (33.7mg, 84 %).
mp: 130~132°C ; [α]D 20 +14.87 (CHCl3, c.0.2) ; IR (KBr pellet, cm"1): 3378, 3057, 2963, 1644, 1153; 1H NMR (400MHz, CDCl3): 7.23 (d, 2H, J= 7.6Hz), 7.10 (d, 2H, J= 8.8 Hz), 7.08 (d, 2H, J= 7.6 Hz), 7.04 (d, 2H, J= 8.8 Hz), 6.80 (bs, IH), 5.48 (bs, IH), 4.97 (quint, IH, J = 3.2 Hz), 2.90 (s, 3H), 2.86 (t, 2H, J= 7.6Hz), 2.41 (t, 2H, J= 7.6Hz).
Step 2: Synthesis of 3-(4-t-butylphenyl)-N-[l-(4-methanesulfonyl aminophenyl)ethyl] thiopropionamide
A 25ml of dried two-necked round-bottom flask was filled with argon gas, thereto 3 -(4-t-butylphenyl)-N- [ 1 -(4-methanesulfbnylaminophenyl)ethyl]propionamide (19.3mg, 0.05mmol) was diluted with toluene, To the solution was added Lawesson's reagent (O.lOmmol, 38.82mg) and refluxed for 1 hour. After confirming the completion
of the reaction with thin layer chromatography, the resulting solution was concentrated under reduced pressure, and the residue was column-chromatographed (n-hexane /ethyl acetate = 2/1) to yield a white solid (17.1mg, 85.22 %).
mp: 124~126°C ;
[α]D 20 +146.09 (CHCl3, c 0.85) ; IR (KBr pellet, cm"1): 3276, 2962, 1612, 1398, 1153 ;
1H NMR (400MHz, CDCl3): 1.22 (s, 9H), 1.28 (d, 3H, J= 6.8 Hz), 2.88-2.76 (m, 2H), 2.90 (s, 3H), 3.01-2.93 (m, 2H), 5.51 (quint, IH, J= 7.2 Hz), 6.91 (br.lH), 7.06 (d, 2H, J= 8.4Hz), 7.07 (s, 4H), 7.23 (d, IH, J= 8.0 Hz)
Example 14: 3-[4-(t-butyl)phenyl]-2-fluoro-N-[4-(methanesulfonylamino)benzyl] thioacrylamide
A 25ml of dried two-necked round-bottom flask was filled with argon gas, thereto 3-(4-t-butylphenyl)-2-fluoroacrylic acid (200mg, 0.90mmol) and N-(4- aminomethylphenyl)methanesulfonamide (1.08mmol, 216.17mg) were diluted with DF. TEA (2eq., 1.80mmol, 250.88μβ) and diethylcyanophosphonate (1.2eq., 1.08mmol, 163.87/-1) were added to the solution, and stirred for 12 hours. After confirming the completion of the reaction with thin layer chromatography, the resulting solution was extracted with ethyl acetate, washed with water and brine, dried over Na2SO4 , filtered, and concentrated under reduced pressure. The obtained liquid was column-
chromatographed (n-hexane /ethyl acetate = 1/1) to yield a white solid (120.5mg, 33.11%).
mp: 138-140 °C ; IR (KBr pellet, cm"1): 3236, 2925, 1732, 1644, 1147;
1H NMR (400 MHz, CDCl3): 7.53 (d, 2H, J= 8.4 Hz), 7.38 (d, 2H, J= 8.4 Hz), 7.28 (d, 2H, J= 8.4 Hz), 7.18 (d, 2H, J= 8.4 Hz), 6.95 (d, IH, J= 39.6 Hz), 6.92 (s, IH), 6.71 (s, IH), 4.53 (d, 2H, J= 5.6 Hz), 2.93 (s, 3H), 1.29 (s, 9H)
Example 15: 3-[4-(t-butyl)phenyI]-2-fluoro-N-[4-(methanesulfonyamino)benzyI] thiopropionamide
A 25ml of dried two-necked round-bottom flask was filled with argon gas, thereto 3-(4-t-butylphenyl)-2-fluoro-N-(4-methanesulfonylaminobenzyl)propionamide (28mg, 0.066mmol) was diluted with toluene, followed by adding Lawesson's reagent
(0.13mmol, 53.65mg) and refluxing for 1 hour. After confirming the completion of the reaction with thin layer chromatography, the resulting solution was concentrated under reduced pressure, and the residue was column-chromatographed (n-hexane /ethyl acetate = 1/1) to yield a white solid (20.5 mg, 73.21 %).
mp: 60-62 °C ;
IR (KBr pellet, cm'1): 3270, 3026, 2962, 1614, 1330, 1155;
1H NMR (400 MHz, CDCl3): 1.24 (s, 9H), 2.94 (s, 3H), 3.23 (ddd, IH, J= 32.8, 14.8,
6.0Hz), 3.44 (ddd, IH, J = 25.2, 14.8, 3.6 Hz)5 4.62 (ddd, 2H, J = 27.6, 15.2, 5.2Hz), 5.45 (ddd, IH, J= 35.4, 5.6, 3.6Hz), 6.67 (s, IH), 7.02 (d, 2H, J= 8.4 Hz), 7.08 (d, 2H, J= 8.4 Hz), 7.12 (d, 2H, J= 8.4Hz), 7.25 (d, 2H, J= 8.4Hz), 7.74 (s, IH).
Example 16: 3-[4-(iso-propyl)phenyI]-N-[3-fluoro-4-(methanesuIfonyl amino)benzyl] thiopropionamide
Under the same condition as Scheme 11, 3- fluoro -4-(methanesulfonylamino) benzylaminehydrochloride (159 mg, 0.624 mmol), 4-isopropylphenyl propion acid (112.8 mg, 0.633 mmol), dithiophosphoric acid-O, and O-diethylester (2 mL) were dissolved in toluene. The solution was stirred overnight at 1150C, and then cooled. IM NaHCO3 aqueous solution (3OmL) was added to the solution and extracted. The extracted organic phase was concentrated under reduced pressure, and purified by column chromatography (hexane/ethyl acetate = 1/1, 8OmL) to obtain the purposed compound (56mg, 22%).
1U NMR (300 MHz, CDCl3): 1.16 (s, 3H), 1.19 (s, 3H), 2.93 (s, 3H), 2.85 (m, IH), 3.02 (m, 2H), 4.67 (d, J = 5.1 Hz, 2H), 6.85 (m, 2H), 7.05 (m, 4H), 7.38 (m, 2H) ; IR (KBr, cm"1): 3252 (NH), 2960, 1590, 1512, 1332, 1158
Step 1 : Synthesis of 3-[3,4-dimethoxyphenyl]-N-[3-fluoro-4-(methanesulfonyl amino) benzyl] thiopropionamide
Under the same condition as Scheme 10, 3- fluoro -4-(methanesulfonylamino) benzylaminehydrochloride (118 mg, 0.463 mmol), 3,4-dimethoxyphenylpropion acid (102.3 mg, 0.487 mmol), DMTMM (198 mg) and TEA (0.2 mL) were dissolved in THF(20 mL) and then the solution was stirred overnight at room temperature. The THF was removed under reduced pressure and the residue was extracted three times with water(30 ml) and MC(30ml), and water was removed from the extracted MC solution. The organic phase was concentrated under reduced pressure and the concentrated organic solution was purified by column chromatography (hexane/ethyl acetate = 1/2, 10OmL) to obtain the purposed compound (72mg, 38%).
1H NMR (300 MHz, CDCl3): 2.52 (t, J = 7.2 Hz, 2H), 2.93 (t, J = 7.2 Hz, 2H), 3.00 (s, 3H), 3.82 (s, 3H), 3.84 (s, 3H), 4.35 (d, J = 6 Hz, 2H), 5.85 (m, IH, NH), 6.74 (m, 4H), 6.91 (m, 2H), 7.42 (m, IH)
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 P4S10 (112mg) to obtain the above compound (37.3 mg , 68%).
1H NMR (300 MHz, CDCl3): 2.96 (t, J = 6.9 Hz, 2H), 3.07 (s, 3H), 3.09 (t, J = 7.2 Hz, 2H), 3.83 (s, 3H), 3.86 (s, 3H), 4.73 (d, J = 5.1 Hz, 2H), 6.48 (br, IH, NH), 6.76 (m, 3H), 6.88 (m, 2H), 7.26 (br, 2H), 7.45 (m, IH) ; IR (KBr, cm"1): 3298 (NH), 2934, 1514, 1448, 1331, 1156.
Example 18: 3-[3,4-DimethyIphenyI]-N-[3-fluoro-4-(methanesulfonyl amino)benzyl]thiopropionamide
The above compound (76mg, 43%) was obtained by using 3,4-dimethylphenyl propion acid (118 mg, 0.463 mmol) according to the similar procedure as described in step 1 of Example 17.
1H NMR (300 MHz, CDCl3) : 2.23 (s, 3H), 2.24 (s, 3H), 2.53 (t, J = 7.2 Hz, 2H), 2.94 (t,
J = 7.2 Hz, 2H), 3.02 (s, 3H), 4.36 (d, J - 5.7 Hz, 2H), 5.66 (m, NH), 6.46 (br, IH), 6.98
(m, 5H), 7.46 (m, 2H).
Step 2: Synthesis of 3 -[3,4-dimethylphenyl] -N- [3 -fluoro-4-(methanesulfonyl amino)benzyl]thiopropionamide
The above compound (26 mg, 40%) was obtained by using amide (62 mg)
according to the similar procedure as described in step 2 of Example 17.
1H NMR (300 MHz, CDCl3) : 2.21 (s, 3H), 2.24 (s, 3H), 2.98 (t, J = 6.9 Hz, 2H), 3.02 (s, 3H), 3.07 (t, J = 6.9 Hz, 2H), 4.71 (d, J = 5.1 Hz, 2H), 6.48 (br, NH), 6.87 (m, 3H), 7.06 (m, 2H), 7.47 (t, IH) ;
IR (KBr5 Cm"1): 3253 (NH), 2924, 1511, 1446, 1330, 1157.
Example 19: 3-[4-chIorophenyl]-N-[3-fluoro-4-(methanesulfonylamino)benzyl]- thioacrylamide
Step 1: Synthesis of 3-[4-chlorophenyl]-N-[3-fluoro-4-(methanesulfonyl amino)benzyl] -acrylamide
The above compound (48mg, 24%) was obtained by using 3-(4-chlorophenyl)- acrylic acid (107 mg) according to the similar procedure as described in step 1 of Example 17.
1H NMR (300 MHz, CDCl3): 3.02 (s, 3H), 4.64 (d, J = 6.3 Hz, 2H), 5.74 (br, NH), 6.39 (d, J = 16.5 Hz, IH), 7.11 (d, IH), 7.37 (m, 2H), 7.43 (2H), 7.53 (m, IH).
Step 2: Synthesis of 3-[4-chlorophenyl]-N-[3-fluoro-4-
(methanesulfonylamino)benzyl] - thioacrylamide
The above thioamide (25 mg, 50%) was obtained by using amide (48 mg) according to the similar procedure as described in step 2 of Example 17.
1H NMR (300 MHz, CDCl3): 2.93 (s, 3H)5 4.32 (d, J = 5.7 Hz5 2H), 6.62 (d, J = 15.9 Hz5 IH)5 7.06 (m, 3H)5 7.27 (m, 2H)5 7.39 (IH) ; IR (KBr5 cm-1): 1583, 1549, 1325, 1148.
Example 20 : 2- [4-chlorophenyl]-N- [3-fluoro-4-(methanesulfonylamino)benzyl] thioacetamide
Step 1: Synthesis of 2-[4-chlorophenyl]-N-[3-fluoro-4-(methanesulfonylamino) benzyl] acetamide
The above amide compound (51 mg, 27%) was obtained by using 2-(4- chlorophenyl)acetic acid (96 mg, 0.562mmol) according to the similar procedure as described in step 1 of Example 17.
1R NMR (300 MHz, CDCl3): 3.00 (s, 3H), 3.59 (s, 2H)5 4.37 (d, J = 6.0 Hz5 2H), 5.90 (m, IH), 6.71 (br, IH), 6.98 (m, 2H)5 7.21 (m, 2H), 7.32 (m, 2H)5 7.46 (t5 IH).
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.
1H NMR (300 MHz5 CDCl3): 3.03 (s5 3H)5 4.12 (s, 2H), 4.83 (d, J = 5.7 Hz5 2H)5 6.53
(br, IH), 7.02 (m, IH), 7.25 (m, 2H), 7.34 (m, 2H), 7.50 (t, IH) ; IR(KBr, cm-1): 1512, 1491, 1406, 1332.
Example 21 : 2-[4-isopropylphenyI]-N-[3-fluoro-4-(methanesuIfonyl amino)benzyl]thioacetamide
Step 1 : Synthesis of 2-[4-isopropylphenyl]-N-[3-fluoro-4-(methanesulfonyl amino)benzyl] acetamide
The above amide compound (163mg, 49%) was obtained by using 2-(4- isopropylphenyl)acetic acid (224 mg, 0.879 mmol) according to the similar procedure as described in step 1 of Example 20.
1H NMR (300 MHz, CDCl3) : 1.18 (s, 3H), 1.21 (s, 3H), 2.85 (m, IH), 2.90 (s, 3H), 3.56 (s, 2H), 4.32 (d, J = 6.0 Hz, 2H), 5.77 (m, IH), 6.52 (br, IH), 6.90 (m, 2H), 7.17 (m, 4H), 7.42 (t, IH) ;
IR(KBr5Cm"1): 3261, 1652, 1508, 1338, 1157.
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.
1H NMR (300 MHz, CDCl3) : 1.23 (s, 3H)3 1.25 (s, 3H), 2.85 (m, IH), 3.01 (s, 3H),
4.16 (s, 2H), 4.83 (d, J = 6.0 Hz, 2H), 6.53 (br, IH), 6.97 (m, 2H)5 7.23 (m, 4H), 7.33
(br, IH), 7.49 (t, IH) ;
IR (KBr5 Cm-1): 3260, 2960, 1590, 1512, 1445, 1335, 1158.
Example 22: 3-[4-(t-butyl)phenyl]-N-[2-chloro-4- (methanesulfonylamino)benzyl]thiopropionamide
To a solution of 3-[4-(t-butyl)phenyl]-N-2-chloro-4-[(methanesulfonyl)amino] benzylpropionamide (70 mg, 0.16 mmol) in Toluene (5.0 ml) was added Lawesson's reagent (130 mg, 0.32 mmol) and heated to reflux for 5 hrs. The reaction was concentrated in vacuo and diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated in vacuo. Purification via flash column chromatography (EtOAc : rc-hexane = 1 : 2) of the residue was afforded 3-[4-(t- δwty/)phenyl]-iV-2-chloro-4-[(methanesulfonyl)amino]benzylthiopropionamide (64.0 mg, 91%) as a white solid.
1H-NMR (300MHz, CDCl3) : δ 1.28 (s, 9H), 2.94 (t, 2H, J = 6.9 Hz), 3.02 (s, 3H), 3.06 (t, 2H, J = 6.9 Hz), 4.80 (d, 2H, J - 5.5 Hz ), 6.87 (bs, IH), 7.01 (dd, IH J = 2.4, 8.2 Hz), 7.10 (d, 2H, J = 8.2 Hz), 7.25-7.29 (m, 4H); IR (neat) cm -1I 3433, 3218, 2957, 1608, 1525, 1373, 1318; Mass (F AB+) : 439 [M+H]+
3 - [4-(t-b w/;y/)phenyl] -N- [3 -iodo-4-(methanesulfonyl amino)benzylpropionamide (48 mg, 0.09 mmol) and Lawessons reagent (2.0eq, 0.19 mmol, 75.5 mg) were dissolved in Toluene (1.0 mL). The reaction mixture was stirred for 3hrs in reflux. The reaction mixture was purified according to similar procedure of Example 2 to obtain 3-[4-(t-&ω/>'/)phenyl]-Λ'-{3-iodo-4-[(methanesulfonyl)methyl- benzyl} -thiopropionamide (35 mg, 71%) as a white solid.
1H-NMR (300MHz, CDCl3) : δ 1.28 (s, 9H), 2.95 (t, 2H, J = 7.0 Hz), 2.98 (s, 3H), 3.08 (t, 2H, J = 7.0 Hz), 4.68 (d, 2H, J = 5.3 Hz ), 6.60 (s, IH), 7.09-7.20 (m, 4H), 7.28 (d, 2H, J = 8.2 Hz), 7.52 (d, IH, J = 8.4 Hz), 7.70 ( d, IH, J= 1.8 Hz) ; IR (neat) cm"1: 3322, 2960, 1533, 1488, 1386, 1329; Mass (F AB+): 531 [M+H]+
Example 24: 3-[4-(t-butyl)phenyl]-N-[4-(methanesuIfonylamino)-3- vinylbenzyl]thiopropionamide
3 - [4-(t-butyl)phenyl] -N- [4-(methanesulfonylamino)-3 -vinylbenzyl] - propionamide (65 mg, 0.16 mmol) and Lawessons reagent (2.0eq, 0.31 mmol, 125 mg) was dissolved in Toluene (3.0 mL). The reaction mixture was stirred for 3hr in reflux.
The 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.
1H-NMR (300MHz, CDCl3) : δ 1.27 (s, 9H)5 2.94 (t, 2H, J= 7.1 Hz), 2.98 (s, 3H), 3.08 (t, 2H, J = 7.2 Hz), 4.72 (d, 2H, J = 5.1 Hz ), 5.48 (d, IH, J = 11.7 Hz), 5.70 (d, IH, J = 18.1 Hz), 6.36 (s, IH), 6.84 (dd, IH, J = 11.0, 17.4 Hz), 7.05 (dd, IH, J = 2.0, 8.2 Hz), 7.11 ( d, 2H, J = 8.3 Hz), 7.14 (bs, IH), 7.27 (d, 2H, J = 8.3 Hz), 7.36 (d, IH, J = 2.0 Hz), 7.38 (d, IH5 J = 8.3 Hz); IR (neat) cm"1: 3299, 3020, 2962, 2920, 1497, 1397, 1326; Mass (EI): 430[M]+
Example 25: 3-[4-(t-butyl)phenyl]-N-[3-ethyl-4-
(methanesulfonylamino)benzyllthiopropionamide
3 - [4-(t-b wtj//)phenyl] -N- [3 -ethyl-4-(methanesulfonylamino)benzyl]- propionamide (75 mg, 0.18 mmol) and Lawessons reagent (2.0eq, 0.36 mmol, 145 mg) were dissolved in Toluene (3.0 niL). The reaction mixture was stirred for 3hrs in reflux. The 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.
1H-NMR (300MHz, CDCl3) : δ 1.16 (t, 3H, J = 7.5 Hz) 1.23 (s, 9H), 2.57 (q, 2H, J
= 7.5 Hz), 2.78 (t, 2H, J = 7.3 Hz), 2.94 (s, 3H), 3.03 (t, 2H, J = 7.4 Hz), 4.64 (d, 2H, J = 5.0 Hz ), 6.26 (s, IH), 6.93 (dd, IH, J = 2.0, 8.3 Hz), 7.05-7.08 (m, 4H), 7.23 (d, 2H, J = 8.2 Hz), 7.32 ( d, IH, J = 8.2 Hz) ; IR (neat) cm'1: 3301, 2962, 1504, 1397, 1323, 1153 ; Mass (FAB+): 433 [M+H]+
Example 26: 3-[4-(t-butyl)phenyl]-N-[3-(trifluoromethyl)-4-
(methanesulfonylamino)benzyl]thiopropionamide
3-[4-(t-butyl)phenyl]-iV-[3-(trifluoromethyl)-4-(methanesulfonylammo) benzyl]propionamide (23.7 mg, 0.05 mmol) and Lawessons reagent (2.0eq, O.lOmmol, 42.0mg) were dissolved in Toluene (3.0 niL). The reaction mixture was stirred for 3hrs in reflux. The 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.
1H-NMR (300MHz, CDCl3): δ 1.28 (s, 9H), 2.94-2.97 (t, 2H), 3.00 (s, 3H), 3.07-3.11 (t, 2H), 4.77 (d, 2H, J= 5.5 Hz), 6.62 (s, NH), 7.10-7.15 (m, IH), 7.24-7.37 (m, 4H), 7.52-7.77 (m, 2H) ; IR (neat) cm-1: 3317, 2961, 1650, 1510, 1400, 1323, 1270 ; Mass (FAB+) 473.0 [M+H]+
Example 27: 3-[4-(t-butyl)phenyl]-N-[2-(trifluoromethyl)-4-
(methanesulfonylamino)benzyl]thiopropionamide
3-[4-(t-butyl)phenyl]-N-[2-(trifluoromethyl)-4-(methanesulfonyl amino) benzyljpropionamide (25mg, 0.05mmol) and Lawessons reagent (2.0eq, O.lOmmol, 44.3mg) were dissolved in Toluene (3.0 mL). The reaction mixture was stirred for 3hrs in reflux. The 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.
1H-NMR (300MHz, CDCl3): δ 1.27 (s, 9H), 2.92-2.96 (t, 2H), 3.00 (s, 3H), 3.03-3.08
(t, 2H), 4.91 (d, 2H, J= 5.5 Hz), 6.87 (s, NH), 7.07-7.15(m, 2H), 7.24-7.42 (m, 4H),
7,44-7.45 (m> 2H) ;
IR (neat) cm-1: 3315, 2961, 1648, 1515, 1397, 1321, 1156;
Mass (FAB+) 473.0 [M+H]+
Example 28 : 3- [4-(t-butyl)phenyl] -N- [3,5-difluoro-4-(methanesuIfonyIammo)- benzyl]thiopropionamide
Step 1: 4-Amino-3,5-difluoro-benzonitrile To a suspension of iodine (5.59g, 22.0mmol) and AgNO2 (6.85g, 22.0mmol) in
methylene chloride was added a solution of 2,6-difluoroaniline (2.58g, 20.0mmol) in methylene chloride at O0C, and the mixture was stirred for 30min at O0C and 30min at ambient temperature. The reaction was quenched with Na2S2O3. The reaction solution was extracted with methylenechloride, washed with water and brine, dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was column-chromatographed (hexane/ethylacetate = 15/1) to yield a yellow solid (2.57mg, 51%).
A mixture of the solid and CuCN in DMF was heated with reflux for 2 days and then filtered through celite. The filtrate was dissolved in methylene chloride and water, and the aqueous phase was extracted with methylene chloride. The combined organic layer was washed with brine, dried over anhyd. MgSO4, filtered, and concentrated under reduced pressure. The crude residue was column-chromatographed (hexane/ethylacetate = 4/1) to yield a yellow solid (1.03g, 66%).
1HNMR (300MHz, CDC13): 7.15 (dd, 2H, J= 2.4 and 6.0 Hz), 4.28 (bs, 2H).
Step 2: N-(4-Cyano-2,6-difluoro-phenyl)-methanesulfonamide
To a ice-cooled solution of 4-amino-3,5-difluoro-benzonitrile (1.03g,
6.68mmol) in methylene chloride was added pyridine (1.5mL) followed by methanesulfonyl chloride (1.5mL). The mixture was warmed up to room temperature and then heated at 50 0C ovenight. The reaction was quenched with water, and the reaction solution was extracted with methylene chloride, washed with water and brine, dried over anhyd. MgSO4; filtered and concentrated under reduced pressure. The resulting residue was treated with IN NaOH/MeOH/THF (1/2/1) for 2 hrs, and then
neutralized by adding IN HCl. After evaporating methanol, water was added to the residue. The resulting mixture was extracted with EtOAc, and the combined organic layer was washed with brine, dried over anhyd. MgS 04, filtered, and concentrated under reduced pressure. The crude residue was column-chromatographed (hexane/ethylacetate = 1/1) to yield a white solid (780mg, 69%).
1HNMR (300MHz, CDC13): 7.33 (d, 2H, J = 7.2 Hz), 6.50 (bs, IH), 3.33 (s, 3H).
Step 3: N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt
N-(4-Cyano-2,6-difluoro-phenyl)-methanesulfonamide (780mg, 3.36mmol) and
Pd/C (lOOmg) were suspended in MeOH containing c-HCl, and the mixture was hydrogenated under 40 psi hydrogen pressure for 4hrs. The reaction mixture was filtered through celite, and the filtrated was concentrated under reduced pressure to yield a yellow solid (795mg, 87%).
1HNMR (300MHz, DMSO-d6 + CDC13): 8.70 (bs, 3H), 7.21 (d, 2H, J = 7.8 Hz), 3.96 (s, 2H), 3.02 (s, 3H).
Step 4: 3-(4-t-butyl-phenyl)-N-(3,5-difluoro-4-methanesulfonylamino-benzyl)- propionamide
N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, and HCl salt (lOOmg, 0.37mmol) were suspended in methylene chloride, and treated with triethylamine followed by 3-(4-t-butyl-phenyl)-acrylic acid (HOmg) and DMTMM
(141mg). The resulting mixture was stirred for 2days at ambient temperature and concentrated under reduced pressure. The crude residue was column-chromatographed (hexane/ethylacetate = 1/1) to yield a white solid (150mg, 96%). The solid and Pd/C (1 mall spetula) were suspended in MeOH containing c-HCl, and the mixture was hydrogenated under 40 psi hydrogen pressure for 4hrs. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to yield a white solid (160mg, 54%).
1HNMR (300MHz, DMSO-d6): 8.43 (t, IH, J = 6.0 Hz), 7.27 (d, 2H, J = 8.4 Hz), 7.11 (d, 2H, J= 8.1 Hz), 6.95 (d, 2H, J= 8.4 Hz), 4.24 (d, IH, J= 5.7 Hz), 3.02 (s, 3H), 2.81 (t, IH, J= 7.5 Hz), 2.45 (t, IH, J= 7.5 Hz), 1.25 (s, 9H).
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 P4S10 according to the general procedure to give 3-(4-t-butyl-phenyl)-N-(3,5-difluoro-4-methanesulfonylamino- benzyl)-thiopropionamide (35mg, 26%).
1HNMR (300MHz, DMSO-d6): 10.43 (t, IH), 9.51 (bs, IH), 7.29 (d, 2H, J =
8.1 Hz), 7.14 (d, 2H, J = 8.1 Hz), 6.99 (d, 2H, J = 8.7 Hz), 4.75 (d, IH, J = 5.4 Hz), 3.04 (s, 3H), 2.98 (m, IH), 2.89 (m, IH), 1.25 (s, 9H).
Example 29: 3-[4-(t-butyl)phenyl]-N-[3-fluoro-4-(methanesulfonylamino)-5-vinyl-
benzyl]thiopropionamide
3 - [4-(t-butyl)phenyl] -N- [3 -fluoro-4-(methanesulfonyl)amino-5-vinyl-benzyl] propionamide (48mg, O.l lmmol) and Lawessons reagent (2.0eq, 0.22mmol, 89mg) were dissolved in Toluene (3.0 mL). The reaction mixture was stirred for 3hrs in reflux. The reaction mixture was purified according to similar procedure of Example 2 to obtain 3-[4-(t-έwζμ/)phenyl]-iV-[3-fluoro-4-(methanesulfonylamino) -5-vinylbenzyl]thiopropionamide (41 mg, 83%) as a white solid.
1H-NMR (400MHz, CDCl3) : δ 1.27 (s, 9H), 2.95 (t, 2H, J = 7.3 Hz), 3.06 (s, 3H), 3.09 (t, 2H3 J- 7.4 Hz), 4.74 (d, 2H, J = 5.4 Hz ), 5.45 (d, IH, J= 11.1 Hz), 5.76 (d, IH, J= 17.5 Hz), 5.99 (s, IH), 6.89 (dd, IH, J= 6.0, 9.9 Hz), 7.07-7.16 (m, 3H), 7.26- 7.28 (m, 4H); IR (neat) cm-1 : 3305, 2961, 1578, 1533, 1445, 1398, 1326; Mass (F AB+): 449 [M+H]+
Example 30: 3-[4-(t-butyl)phenyl]-N-[3-ethynyl-5-fluoro-4-
(methanesulfonylamino)-benzyl]thiopropionamide
3-[4-(t-butyl)phenyl]-N-[3-ethynyl-5-fluoro-4-(methanesulfonylamino)benzyl] propionamide (48.8 mg, 0.11 mmol) and Lawessons reagent (2.0eq, 0.22 mmol, 91.7
mg) were dissolved in toluene (5.0 mL). The reaction mixture was stirred for 3hrs in reflux. The 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.
1H-NMR (300MHz, CDCl3) : δ 1.28 (s, 9H), 2.93-2.97 (t, 2H), 3.06-3.11 (t, 2H), 3.23 (s, 3H), 3.45(s, IH), 4.69 (d, 2H, J= 5.3 Hz), 6.41 (s, NH), 6.97-7.00 (d, IH, J= 10.6 Hz), 7.10-7.18 (m, 3H), 7.27~7.30(m, 2H); IR (neat) cm-1 : 3272, 2960, 1534, 1483, 1397, 1154; Mass (F AB+) 447 [M+H]+
Example 31: 3-[4-(t-butyl)phenyI]-N-[3-cyclopropyI-5-fluoro-4-
(methanesulfonylamino)-benzyl]thiopropionamide
3-[4-(t-butyl)phenyl]-N-[3-cyclopropyl-5-fluoro-4-(methanesulfonylamino)- benzyljpropionamide (17 mg, 0.04 mmol) and Lawessons reagent (2.0eq, 0.08 mmol, 32 mg) were dissolved in Toluene (2.0 mL). The reaction mixture was stirred for 3hrs in reflux. The reaction mixture was purified according to similar procedure of Example 2 to obtain 3-[4-(t-butyl)phenyl]-iV-[3-cyclopropyl-5-fluoro-
4-(methanesulfonylamino)benzyl]thiopropionamide (17 mg, 97%) as a colorless oil.
1H-NMR (300MHz, CDCl3) : δ 0.62-0.67 (m, 2H), 1.02-1.09 (m, 2H), 1.27 (s, 9H),
2.21 (m, IH), 2.29 (t, 2H, J = 7.2 Hz), 3.08 (t, 2H, J= 7.4 Hz), 3.15 (s, 3H), 4.66 (d, 2H, J= 5.3 Hz ), 6.09 (s, IH), 6.64 (s, IH), 6.75 (d, IH, J= 10.1 Hz ), 7.11 (d, 2H, J = 8.1 Hz), 7.17 (bs, IH), 7.28 (d, 2H, J= 8.3 Hz); IR (neat) cm"1: 3302, 2961, 1535, 1446, 1324, 1152; Mass (F AB+): 463 [M+H]+
Example 32: 3-[4-(t-butyl)phenyl]-N-[3-chloro-5-methyl-4-
(methanesulfonylammo)-benzyl]thiopropionamide
3 - [4-(t-butyl)phenyl] -N- [3 -chloro-5-methyl-4-(methanesulfonylamino)-benzyl] propionamide (11.8 mg, 0.03 mmol) and Lawessons reagent (2.0eq, 0.06 mniol, 22.0 mg) were dissolved in Toluene (3.0 mL). The reaction mixture was stirred for 3hrs in reflux. The 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.
1H-NMR (300MHz, CDCl3): δ 1.28 (s, 9H), 2.47 (s, 3H), 2.50-2.55 (t, 2H), 2.92-2.97 (t, 2H), 3.08 (s, 3H), 4.59 (d, 2H, J= 5.1 Hz), 5.28 (s, NH), 6.03 (s, NH), 7.05-7.32 (m, 6H); IR (neat) cm-1: 3247, 2960, 1650, 1536, 1395, 1323; Mass (F AB+): 453.0 [M+H]+
Example 33: 3-[4-(t-butyl)phenyl]-N-[3-cyano-4-(methanesulfonylamino)-
benzyl] thiopropionamide
3 - [4-(t-butyl)phenyl] -N- [3 -cyano-4-(methanesulfonylamino)-benzyl] propionamide (64 mg, 0.16 mmol) and Lawessons reagent (2.0eq, 0.31 mmol, 130 mg) were dissolved in Toluene (3.0 mL). The reaction mixture was stirred for 3hrs in reflux. The reaction mixture was purified according to similar procedure of Example 2 to obtain 3 - [4-(t-butyl)phenyl] -JV-3 -cyano-4-
[(methanesulfonylamino)benzyl]thiopropionamide (42mg, 65%) as a white solid.
1H NMR (300MHz, CDCl3) : δ 1.28 (s, 9H), 2.94-2.99 (m, 2H), 3.06-3.11 (m, 2H), 2.09 (s, 3H), 4.75 (d, 2H, J= 5.7 Hz ), 6.92 (s, IH), 7.11 ( d, 2H, J= 8.4 Hz), 7.20 (bs, IH), 7.29 (d, 2H, J= 8.4 Hz), 7.35 (dd, IH, J= 2.2, 8.6 Hz), 7.47 (d, IH, J= 2.2 Hz), 7.62 (d, IH, J= 8.6 Hz); IR (neat) cm -1 : 3311, 2959, 1534, 1500,1418, 1336, 1158, 1109; Mass (EI) m/e 429[M]+
Example 34: 3-(4-t-butyl-phenyI)-N-[4-(methanesulfonylamino)benzy]-2-methyl- thiopropionamide
Step 1 : 2-(4-t-butyl-benzyl)-2-methyl-malonic acid dimethyl ester
NaH (225mg, 8.9mmol) was suspended to anhydrous THF (20ml) and cooled to
0°C . Thereto 2-methyl-malonic acid dimethyl ester (Ig, 6.84mmol) dissolved in anhydrous THF (10ml) was added slowly, 4-t Butyl benzyl bromide(l .3ml, 6.84mmol)was added and stirred for 30 minutes. The reaction mixture was quenched with saturated ammonium chloride solution and diluted with 300ml of Ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous MgSO4, and filtered, concentrated in vacuo and the residue was purified by columnn chromatography (n-Hexane: Ethyl acetate=2.5:l) to yield title compound (1.85g, 93%) as colorless oil.
1H NMR (CDCl3, 300 MHz) δ 7.27 (d, J=8.43Hz, 2H), 7.02 (d, J=8.43), 3.74 (s, 6H), 3.20 (s, 2H), 1.35 (s, 3H), 1.29 (s, 9H)
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). The organic layer was washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous MgSO4, and filtered, concentrated in vacuo.The obtained residue was diluted with toluene (50ml) and refluxed for 10 hours and concentrated in vacuo to yield title compound (620 mg, 94%) as a white solid.
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) and 3-(4-t-butyl-phenyl)-2-methyl- propionic acid (HOmg, 0.5mmol) was dissolved in CH2Cl2 (3ml), and TEA (70/^6, 0.5mmol) was added and stirred for 10 mins. The 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 MgSO4 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.
1H NMR (CDCl3, 300 MHz) δ 7.14 (m, 8H), 6.47 (s, IH), 5.49 (bs, IH), 4.33 (m, 2H), 3.76 (m, 2H) 2.97 (s, 3H), 1.26 (m, 13H)
Step 4 : 3 -(4-t-butyl-phenyl)-N-(4-methanesulfonylamino-benzyl)-2-methyl- thiopropionamide
3-(4-t-butyl-phenyl)-N-(4-methanesulfonylamino-benzyl)-2-methyl- propionamide (50mg, 0.124mmol) was dissolved in dry benzene (2ml), and Lawssen's reagent (26mg, 0.064mmol) was added. The resulting mixture refluxed on Argon atmosphere for 20 minutes. The reaction mixture was concentrated in vacuo and purified by column chromatography (n-Hexane: Ethyl acetate=2:l) to yield title compound (37mg, 72%) as a white solid.
1H NMR (CDCl3, 300 MHz) δ 7.17 (m, 8H), 6.77 (s, IH), 5.35 (d, J=5.52, IH), 4.64 (d, J=5.13, 2H), 2.99 (s, 3H), 2.93 (m, 2H), 1.33 (m, 4H) 1.31 (s, 9H)
Example 35: 2-(4-t-butyl-benzyl)-N- [4-(methanesuIf onylamino)-benzyl] - thiobutyramide
NaH (146mg, 5.86mmol) was suspended to anhydrous THF (10ml) and cooled to 0°C . Thereto 2-Ethyl-malonic acid diethyl ester (0.91g, 4.83mmol) dissolved in anhydrous THF (10ml) was added slowly, 4-t-Butyl benzyl bromide (0.92ml, 4.83mmol) was added and stirred for 30 minutes. The reaction mixture was quenched with saturated ammonium chloride solution, and diluted with 300ml of Ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous MgSO4 and filtered, concentrated in vacuo. The residue was diluted with ethanol (10ml), and KOH (400mg, 7.1mmol) dissolved in ethanol (20ml) was added thereto and refluxed for 10 minutes. After completion of the reaction, the reaction mixture was concentrated in vacuo and dissolved in water (30ml) and acidified with 3N aqueous HCl to pH4, and extracted with ethyl acetate (20 ml* 5). The organic layer was washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous MgSO4 and filtered, concentrated in vacuo. The obtained residue was diluted with toluene (50ml) and refluxed for 10 hours and concentrated in vacuo to yield title compound (1.05g, 93%) as a white solid.
1H NMR (CDCl3, 300 MHz) δ 7.17 (m, 4H), 2.20 (m, IH), 131 (m, 2H), 3.23 (m, 2H),
1.28 (s, 9H) 0.92 (t, J=7.5Hz, 3H)
Step 2 : 2-(4-t-butyl-benzyl)-N-(4-methanesulfonylamino-benzyl)-butyramide
N-(4-Aminomethyl-phenyl)-methanesulfonamide(134mg, 0.67mmol), EDC
(127mg, 0.67mmol), 4-DMAP(6mg, 0.05mmol), and 3-(4-t-butyl~phenyl)-2-ethyl- propionic acid(155mg, 0.67mmol) were dissolved in CH2Cl2(SmI), and TEA (90 μi, 0.67 mmol) was added. The reaction mixture was refluxed for 10 hours. The 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 MgSO4 and filtered, concentrated in vacuo and the residue was purified with columnn chromatography (n-Hexane: Ethyl acetate=l :l) to yield title compound (100 mg, 36%) as a white solid.
1H NMR (CDCl3, 300 MHz) 57.26 (m, 2H), 7.04 (m, 6H), 6.79 (bs, IH), 5.55 (d, J=5.49Hz, IH), 4.30 (m, 2H), 2.97 (s, 3H), 2.82 (m, 2H), 2.23 (m, IH), 1.67 (m, 2H), 1.31 (s, 9H), 0.93 (t, 3H)
Step 3 : 2-(4-t-butyl-benzyl)-N-[4-(methanesulfonylamino)-benzyl]- thiobutyramide
The title compound (15mg, 48%) was synthesized by the similar procedure of Example 34 as a white solid.
1H NMR (CDCl3, 300 MHz) δ 7.28 (m, 2H), 7.11 (m, 4H), 6.99 (m, 3H), 6.61 (bs, IH), 4.64 (d, J=4.95Hz, 2H), 2.99 (s, 3H), 2.95 (m, 2H), 2.48 (m, IH), 1.32 (s, 9H), 1.26 (m, 2H), 0.90 (t, J=5.49, 3H)
Example 36: 3-(4-t-butyl-phenyl)-N-[3-fluoro-4-(methanesulfonyIamino)-benzyl]-2- methyl-thiopropionamide
3 -(4-t-butyl-phenyl)-N- [3 -fluoro-4-(methanesulfonylamino)-benzyl] -2-methyl- propionamide (57mg, 20%) as a white solid, is prepared according to similar procedure step 2 of Example 35 using 3-(4-t-butyl-phenyl)-2-methyl-propionic acid and 3-fluoro- 4-methanesulfonylaminobenzylamine hydrochloride.
1H NMR (CDCl3, 400 MHz) δ7.41(m,lH), 7.29(d, J=8.15Hz, 2H), 7.08(d, J=8.14 Hz, 2H), 6.87(m, 2H), 6.81(bs, IH), 5.79(bs, IH), 4.30(m, 2H), 2.99(s, 3H), 2.94(m, IH), 2.67(m, IH), 2.51(m, IH), 1.30(s, 9H), 1.22(d, 3H, J=6.69)
Step 2 : 3 -(4-t-butyl-phenyl)-N- [3 -fluoro-4-(methanesulfonylamino)-benzyl]-2- methyl-thiopropionamide
3-(4-t-butyl-phenyl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-2-methyl- thiopropionamide (68mg, 28%) was synthesized with the similar procedure of Step 3 of Example 35, as white solid.
1H NMR (CDCl3, 300 MHz) δ 7.48 (m, IH), 7.29 (d, J=8.22, 2H), 7.11 (d, J=8.07, 2H),
6.85 (m, 2H), 6.66 (bs, IH), 4.67 (m, 2H), 3.00 (s, 3H), 2.92 (m, 3H), 1.35 (d, J=6.39),
1.30 (s, 9H).
Example 37: 3-(4-t-butyl-phenyl)-N-[3-fluoro-4-(methanesulfonylamino)-benzyl]-2- ethyl-thiopropionamide
Step 1 : 3-(4-t-butyl-phenyl)-N-[3-fluoro-4-(methanesulfonylamino)-benzyl]-2- ethyl-propionamide
3-(4-t-butyl-phenyl)-N-[3-fluoro-4-(methanesulfonylamino)-benzyl]-2-ethyl- propionamide (33mg, 64%) as a white solid, was synthesized by the similar procedure of step 2 of Example 35 using 3-(4-t-butyl-phenyl)-2-ethyl-propionic acid and 3-fluoro- 4-methanesulfonylaminobenzylamine hydrochloride.
1H NMR (CDCl3, 300 MHz) δ 7.41 (m, IH), 7.27 (d, J=8.58,2H), 7.08 (d, J=8.4 Hz, 2H), 6.85 (m, 2H), 6.70 (bs, IH), 5.68 (bs, IH), 4.30 (m, 2H), 2.99 (s, 3H), 2.81 (m, 2H), 2.25 (m, IH), 1.67 (m, 2H), 1.30 (s, 9H), 0.93 (t, J=7.32, 3H)
Step 2 : 3 -(4-t-butyl-pheny I)-N- [3 -fluoro-4-(methanesulfonylamino)-benzyl] -2- methyl-thiopropionamide
3 -(4-t-butyl-phenyl)-N- [3 -fluoro-4-(methanesulfonylamino)-benzyl] -2-methyl- thiopropionamide (35mg, 56%) was synthesized by the similar procedure of step 3 of Example 35 as a white solid.
1H NMR (CDCl3, 300 MHz) δ 7.55 (m, IH), 7.28 (d, J=8.43 Hz, 2H), 7.11 (d, J=8.22,
2H), 6.82 (m, 2H), 6.54 (bs, IH)5 4.67 (m, 2H), 3.01 (s,3H), 2.96 (m, 2H), 2.50 (m, IH), 1.86 (m, 2H), 1.30 (s, 9H), 0.91 (t, J=7.5 Hz, 3H)
Example 38: 3-(4-t-butyI-phenyl)-N-(4-methanesuIfonylamino-3-trifluoromethoxy- benzyl)-thioacrylamide
Step 1 : N-(4-Cyano-2-trifluoromethoxy-phenyl)-methanesulfonamide To an ice-cooled solution of 4-amino-3-trofluoromethoxybenzonitrile (500mg, 2.47mmol) in methylene chloride was added pyridine (0.6OmL) followed by methanesulfonyl chloride (0.57mL). The mixture was warmed up to room temperature and then heated at 50 °C overnight. The reaction was quenched with water, and the reaction solution was extracted with methylenechloride, washed with water and brine, dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The resulting residue was treated with IN NaOH/MeOH/THF (1/2/1) for 2hrs, and then neutralized by adding IN HCl. After evaporating methanol, water was added to the residue. The resulting mixture was extracted with EtOAc, and the combined organic layer was washed with brine, dried over anhyd. MgSO4, filtered, and concentrated under reduced pressure. The crude residue was column-cliromatographed (hexane/ethylacetate = 1/1) to yield N-(4-cyano-2-trifluoromethoxy-phenyl)- methanesulfonamide (500 mg, 72%).
1HNMR (300MHz, CDCl3): 7.83 (d, IH, J= 8.7 Hz), 7.62 (m, 2H), 7.13 (bs, IH), 3.14
(s, 3H).
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) and Pd/C (30 mg) were suspended in MeOH containing c-HCl, and the mixture was hydrogenated under 40 psi hydrogen pressure for 4hrs. 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. The crude residue was column- chromatographed (hexane/ethylacetate = 1/1) to yield a white solid (190mg, 86%).
1HNMR (300MHz, CDCl3): 7.66 (d, IH, J= 15.6 Hz), 7.60 (d, IH, J= 8.7 Hz), 7.43 (d, 2H, J= 8.7 Hz), 7.37 (d, 2H, J= 8.7 Hz), 7.26 (m, 2H), 6.96 (s, IH), 6.45 (t, IH), 6.44 (d, IH, J= 15.6 Hz), 4.52 (d, 2H, J= 6.0 Hz), 3.00 (s, 3H), 1.31 (s, 9H).
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%).
1HNMR (300MHz, CDCl3): 7.87 (d, IH5 J= 15 Hz), 7.70 (d, IH5 J = 8.7 Hz)5 7.48 (d, 2H5 J= 8.1 Hz)5 7.39 (d, 2H, J= 8.1 Hz)5 7.38 (m, 2H)5 6.82 (d, IH5 J= 15 Hz)5 6.68 (s, IH), 5.02 (d, 2H5 J= 5.4 Hz)5 3.04 (s, 3H)5 1.33 (s, 9H).
Example 39: 3-[4-(t-butyl)phenyl]-N-[3-acetyI-4-(methanesulfonylamino)-5-fluoro- benzyljthiopropionamide
(methanesulfonylamino)benzyl]thiopropionamide (30 mg5 0.07 mmol) and NHMe(OMe) (9.8mg, 0.1 Ommol) in THF (2.0ml) was added 2.0M of /PrMgCl in
THF (0.14mL, 0.28mmol) at 0 °C . After the reaction mixture was stirred for 2h at same temperature, the reaction was concentrated in vacuo and diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated in vacuo.
Purification via flash column chromatography (EtOAc : 72-hexane = 3 : 2) of the residue afforded (23 mg, 72%) amide.
To a solution of above amide in THF (ImL) was added MeMgI 1.0M (0.06mL, 0.06mmol) at 0 °C and stirred for 2h. The reaction mixture was diluted with ethyl acetate, quenched by NH4Cl5 washed with water and brine, dried over MgSO4, and concentrated in vacuo. Purification via flash column chromatography (EtOAc: «-hexane = 1 : 1) of the residue afforded 6 mg (%) of a title compound.
1H-NMR (300MHz5 CDCl3) : δ 1.22 (s, 9H)5 2.58 (s, 3H), 2.94 (t, 2H, J = 7.1 Hz),
2.99 (s, 3H), 3.04 (t, 2H, J = 7.2 Hz)5 4.71 (d, 2H, J= 5.7 Hz ), 7.06 (d, 2H5 J = 8.3 Hz)5 7.24-7.26 (m, 3H)5 7.60 (d, IH5 J = 8.6 Hz)5 7.85 (d, IH5 J= 2.2 Hz) ; Mass (EI): 446[M]+
Example 40: (z)-3-[4-(t-butyl)phenyI]-2-fluoro-N-[3-fluoro-4-
(methanesuIfonyIamino)benzyl]-2-butenethioamide
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 O0C. 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. A combined organic layer was washed with H2O and Brine, dried with MgSO41 and concentrated in vacuo. A residue was purified with column chromatography (EtOAc : n- hexane = 1 : 5) to yield ethyl(z)-3-[4-(t-butyl)phenyl]-2-fluoro-2-butenoste (310mg5 98%).
1H-NMR (300MHz5 CDCl3): δ 0.97 (t, 3H5 J= 14.3 Hz)5 1.32 (s, 9H)5 2.15 (d, 3H, J = 4.4 Hz5), 4.12-4.15 (m, 2H), 7.07-7.11 (m, 2H)5 7.31-7.35 (m, 2H)
Step 2: (z)-3-[4-(t-butyl)phenyl]-2-fluoro-2-butenoic acid
Ethyl(z)-3-[4-(t-butyl)phenyl]-2-fluoro-2-butenoste (300mg5 1.13mmol) and lithium
hydroxide monohydrate (190mg, 4.54mmol) were dissolved in THF/H2O (1 :1, 14ml). The reaction mixture was stirred for 12hr at 350C. A reaction mixture was acidified with 2N HCl. A reaction mixture was poured into the EtOAc. A reaction mixture was washed with H2O and brine, dried with MgSO4, and concentrated in vacuo to yield (z)-3-[4-(t-butyl)phenyl]-2-fluoro-2-butenoic acid (252mg, 91%).
1H-NMR (400MHz, CDCl3): δ 1.30 (s, 9H), 2.14 (d, 3H, J = 4.6 Hz), 7.10-7.12 (d, 2H, J= 8.3 Hz), 7.33-7.35 (d, 2H, J= 8.3 Hz)
Step 3 : (z)-3 - [4-(t-butyl)phenyl] -2-fluoro-N- { 3 -fluoro-4- [(methanesulfonyl) aminojbenzyl} -2-butenamide
(z)-3-[4-(t-butyl)phenyl]-2-fluoro-2-butenoic acid (60mg, 0.25mmol), 4-(4,6- dimethoxy-l,3,5-triazin-2-yl)-4-methylmol phlinium chloride (DMTMM) (470 mg, 1.7 mmol) and Et3N (85 fd, O.βlmmol) were added in the THF (10 mL). The reaction mixture was stirred for 2 hr. 3-Fluoro-4-methanesulfonylbenzylamine HCl (77.6mg, 0.30 mmol) was added into the reaction mixture. The mixture was stirred for 3hr at room temperature. The reaction mixture was concentrated in vacuo. The residue was extracted with EtOAc. A combined organic layer was washed with H2O and brine, dried with MgSO4, concentrated in vacuo. The residue was purified with column chromatography (EtOAc: Tz-hexane = 1: 1) to yield (z)-3-[4-(t-έwty/)phenyl]-2-fluoro-N- {3 -fluoro-4- [(methanesulfonyl) aminojbenzyl} -2-butenamide (238 mg, 79%).
1H-NMR (300MHz, CDCl3) : δ 1.32 (s, 9H), 2.15 (d, 3H, J = 4.4 Hz,), 3.05 (s, 3H), 4.39 (d, 2H, J= 5.9 Hz)5 6.44 (s, NH), 6.81 (s, NH), 7.04 (s, IH), 6.99-7.04 (m, 2H),
7.20-7.25 (m, 2H)5 7.38-7.41 (m, 2H), 7.50-7.56 (m, IH) ; IR (neat) cm"1: 2962, 1651, 1516, 1455, 1333 ; Mass (EI+) 436.0 [M+H]+
Step 4: (z)-3-[4-(t-butyl)phenyl]-2-fluoro-N-{3-fluoro-4-
[(methanesulfonyl)methyl] - benzyl} -2-buteneamide (30.0mg, 0.07mmol) and Lawessons reagent (2.0eq, 0.14mmol, 55.6mg) were dissolved in Toluene (3.0 mL). The reaction mixture was stirred for 3hr in reflux. The reaction mixture was purified according to similar procedure to Example 1 to obtain (z)-3-[4-(t-5wty/)phenyl]-2-fluoro-N-{3-fluoiO-4-
[(methanesulfonyl)methyl] benzyl }-2-butenethioamide (16.0mg, 51%) as a white solid.
1H-NMR (300MHz, CDCl3): δ 1.29 (s, 9H), 2.09 (s, 3H), 3.01 (s, 3H), 4.49 (d, 2H, J = 5.1 Hz), 6.43 (s, NH), 6.62 (m, IH), 6.98-7.58 (m, 3H), 8.03~8.27(m, 3H) ; IR (neat) cm"1: 3271, 2962, 1596, 1509, 1453, 1334, 1266; Mass (F AB+) 453 [M+H]+.
Experimental Example: Biological potency test
1. 4S 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, 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 370C 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. 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 for 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 5Ca (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 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 and results are given as IC50.
For practical reasons, the compounds are grouped in four classes of activity as follows:
IC50=A (<or=) 0.1 μM < B (< or =) 0.5 μM < C (< or =) 1 μM< D
[Table 1 ]
Results of Calcium Influx Test
3. Analgesic activity test: Mouse writhing test by inducing with phenyl-p-quinone
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. 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-T)/C x 100), wherein C and T represent the number of writhes in control and compound-treated group, respectively (Table 2).
[Table 2]
Test result of analgesic activity for writhing by phenyl-p-quinone
Industrial applicability
As explained above, 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.
More specifically, 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.
Claims
1. A compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof :
(I)
wherein,
X represents CHR13 wherein R13 represents hydrogen, halogen, or C1-C5 alkyl;
R1 and R2 represent independently hydrogen, -SO2R16, -SOR16, 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 15 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 R16 represents
hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, trifluoromethyl, phenyl, or phenyl (C1-C3) alkyl ;
R3 represents hydrogen, hydroxy, C1-C5 alkyl, halo (C1-C5) alkyl, COOBu-t, MePhSO2-, phenyl, or phenyl (Cl -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;
R4, R5, R6, and R7 independently represent hydrogen, carboxy, C1-C5 alkyl, halogen, nitro, cyano, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkylcarbonyl, C1-C5 alkylcarbonylamino, C1-C5 alkylsulfonylamino, phenylsulfonylamino, C1-C5 alkylthio,
C1-C5 alkylsulfonyl, or C1-C5 alkoxycarbonyl; and
Rg, R9, R10, R11, and R12 independently represent hydrogen, carboxy, C1-C5 alkyl, nitro, C2-C5 alkenyl, C1-C5 alkoxy, C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, or halogen.
[Claim 2]
A compound according to claim 1,
wherein,
X represents CHR13 wherein R13 represents hydrogen, halogen, or C1-C5 alkyl;
Y represents CHR14, CHR14-CHR15, CR14=CR15, ~
HC
s wherein R14 and Ri5 independently represents hydrogen, C1-C5 alkyl, halogen, or phenyl;
Ri and R2 represent independently hydrogen, -SO2Ri6, -SOR16, 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 R16 represents hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, trifluoromethyl, phenyl, or phenyl (Cl -C3) alkyl ;
R3 represents hydrogen, hydroxy, C1-C5 alkyl, halo (C1-C5) alkyl, COOBu-t, SO2PhCH3, 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;
R4, R5, R6, and R7 independently represent hydrogen, carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkoxy, halo (C1-C5) alkyl, Cl-
C5 alkylcarbonyl, C1-C5 alkylcarbonylamino, C1-C5 alkylsulfonylamino, phenylsulfonylamino, C1-C5 alkylthio, C1-C5 alkylsulfonyl, or C1-C5 alkoxycarbonyl; and
R8, R9, R1O, R11, and R12 independently represent hydrogen, carboxy, C1-C5 alkyl, nitro, C2-C5 alkenyl, C1-C5 alkoxy, C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5
alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, or halogen.
[Claim 3]
A compound according to claims 1 or 2, an isomer thereof, or a pharmaceutically acceptable salt thereof: wherein,
X represents CHR13 wherein R13 represents hydrogen, halogen, or C1-C5 alkyl;
Y represents CH2-CH2 or CH=CH;
R1 and R2 represent independently hydrogen, -SO2R16, -SOR16, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl, phenyl, phenyl (C1-C3) alkyl, or Cl- C3 alkoxyphenyl, wherein R16 represents hydrogen, C1-C5 alkyl, C2-C5 alkenyl, trifiuoromethyl, phenyl, or benzyl;
R3, R7, and R12 represent hydrogen;
R4, R5, and R6 independently represent hydrogen, carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkoxy, halo (C1-C5) alkyl, Cl- C5 alkylcarbonyl, C1-C5 alkylcarbonylamino, C1-C5 alkylsulfonylamino, phenylsulfonylamino, or C1-C5 alkoxycarbonyl; and
R8, R9, R1O, and R11 independently represent hydrogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkylsulfonyl, or halogen.
[Claim 4]
A compound according to anyone of the preceding claims, wherein RlO is
isopropyl or tert-butyl.
[Claim 5]
A compound according to anyone of the preceding claims, an isomer thereof, or a pharmaceutically acceptable salt thereof: wherein,
Y represents CH2-CH2;
R1 represents hydrogen;
R2 represents -SO2R16 wherein R16 represents hydrogen, C1-C5 alkyl, C2-C5 alkenyl, or trifluoromethyl;
R5 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
R10 represents isopropyl or tert-butyl.
[Claim 6]
A compound according to anyone of claims 1 or 2 , an isomer thereof, or a pharmaceutically acceptable salt thereof: wherein,
R1 represents methanesulfonyl or trifluoromethanesulfonyl;
R2 and R3 represent hydrogen;
R4, R5, R6, and R7 independently represent hydrogen, methyl, ethyl, ethenyl, fluoro, chloro, bromo, nitro, carboxy, methylcarbonyl, methoxycarbonyl, methoxy, or
CF3;
R8, R9, Ru, and Rj2 independently represent hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, t-butyl, sec-butyl, methoxy, bromo, chloro, trifluoromethyl, or methoxycarbonyl; and
R10 represents isopropyl or t-butyl.
[Claim 7]
A compound according to anyone of claims 1 or 2, an isomer thereof, or a pharmaceutically acceptable salt thereof;
wherein
X represents CHR13 wherein R13 represents hydrogen or C1-C5 alkyl;
Y represents CHR14, CHR14-CHR15,
wherein R14 and R15 are independently hydrogen, C1-C5 alkyl, halogen, or phenyl;
R1 and R2 represent independently hydrogen, -SO2R16, wherein R16 represents C1-C5 alkyl;
R3 represents hydrogen;
R4, R5, R6 and R7 independently represent hydrogen, carboxy, C1-C5 alkyl, halogen, nitro, cyano, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, halo (Cl -C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkylcarbonyl, or C1-C5 alkoxycarbonyl;
R8, R9, and R11 independently represent hydrogen, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, or halogen;
R10 is C3-C5 alkyl or CF3; and
R12 represents hydrogen or fluoro.
[Claim 8]
A compound according to claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof;
wherein,
X represents CHR13 wherein R13 represents hydrogen or methyl ;
Y represents CHR14-CHR15, wherein R14 and R15 are independently hydrogen or methyl;
R1 represents hydrogen, and R2 represents -SO2R16, wherein R16 represents Cl- C3 alkyl;
R3,and R7 represent hydrogen;
R4, R5, and R6 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 ;
R8, R9, and R11 independently represent hydrogen, C1-C3 alkyl, C1-C3 alkoxy, halo (C1-C3) alkyl, or halogen;
Rio is C3-C5 alkyl or CF3; and
Ri2 represents hydrogen or fluoro.
[Claim 9]
A compound according to claim 8, an isomer thereof, or a pharmaceutically acceptable salt thereof;
wherein,
X represents CH2;
Y represents CH2CH2;
R2 represents methanesulfonyl;
R1, R3, R4, and R7, represent hydrogen;
R8, R9, R11 and R12 independently represent hydrogen or fluoro;
R5 and R6 independently represent hydrogen, C1-C3 alkyl, halogen, nitro, cyano, ethenyl, or ethynyl; and
R10 represents t-butyl .
[Claim 10]
A compound according to claim 9, wherein R5 is selected from hydrogen, methyl, fluoro, chloro, nitro, ethenyl, or ethynyl; and R6 is selected from hydrogen, fluoro, chloro, or methyl.
[Claim 11 ]
A compound according to claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 3-[4-(t-butyl)phenyl]-N-[4-(methanesulfonylamino) benzyl]thiopropionamide, 3 - [4-(t-butyl)phenyl] -N- [3 -fluoro-4-(methanesulfonylamino) benzyljthiopropionamide,
3 - [4-(t-butyl)phenyl]-N- [3 -chloro-4-(methanesulfonylamino) benzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -methyl-4-(methanesulfonylamino) benzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -methoxycarbonyl-4- (methanesulfonylamino)benzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 , 5 -dimethyl-4-(methanesulfonylamino) benzyljthiopropionamide, 3 - [4-(t-butyl)phenyl] -N- [3-carboxy-4-(methanesulfonylamino)benzyl] thiopropionamide,
3- [4-(t-butyl)phenyl] -N- [3 -nitro-4-(methanesulfonylamino) benzyljthiopropionamide,
2- [4-(t-butyl)phenyl]-N- [3 -fluoro-4-(methane sulfonylamino)benzyl] cyclopropanthiocarboxamide,
2- [4-(trifluoromethyl)phenyl] -N- [3-fluoro-4-(methanesulfonyl amino)benzyl]thiopropionamide,
(E)-3-[4-(t-butyl)phenyl]-N-[3-fluoro-4-(methanesulfonylamino)benzyl]- thioacrylamide,
(R)-3-[4-(t-butyl)phenyl]-N-[l -(4- methanesulfonylaminophenyl)ethyl]thioacrylamide,
(R)-3 -[4-(t-butyl)phenyl] -N- [ 1 -(4-methanesulfonylaminophenyl)ethyl] thiopropionamide, 3-[4-(t-butyl)phenyl]-2-fluoro-N-[4-(methanesulfonylamino)benzyl] thioacrylamide,
3 - [4-(t-butyl)phenyl] -2-fluoro-N- [4-(methanesulfonyamino)benzyl] thiopropionamide,
3 - [4-(iso-propyl)phenyl] -N- [3 -fluoro-4-(methanesulfonylamino)benzyl] thiopropionamide,
3 - [3 ,4-dimethoxyphenyl] -N- [3 -fluoro-4-(methanesulfonylamino)benzyl] thiopropionamide,
3 - [3 ,4-dimethylphenyl] -N- [3 -fluoro-4-(methanesulfonyl amino)benzyl]thiopropionamide, 3 - [4-chlorophenyl] -N- [3 -fluoro-4-(methanesulfonylamino)benzyl] - thioacrylamide,
2- [4-chlorophenyl] -N- [3 -fluoro-4-(methanesulfonylamino)benzyl] thioacetamide,
2- [4-isopropylphenyl] -N- [3 -fluoro-4-(methanesulfonyl amino)benzyl]thioacetamide,
3-[4-(t-butyl)phenyl]-N-[2-chloro-4- (methanesulfonylamino)benzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -iodo-4-(methanesulfonylamino) benzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [4-(methanesulfonylamino) -3-vinylbenzyl]thiopropionamide,
3-[4-(t-butyl)phenyl]-N-[3-ethyl-4- (methanesulfonylamino)benzyl]thiopropionamide, 3 - [4-(t-butyl)phenyl] -N-[3 -(trifluoromethyl)-4-
(methanesulfonylamino)benzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [2-(trifluoromethyl)-4- (methanesulfonylamino)benzyl]thiopropionamide,
3-[4-(t-butyl)phenyl]-N-[3,5-difluoro-4-(methanesulfonylamino)- benzyljthiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -fluoro-4-(methanesulfonylamino)-5-vinyl- benzyljthiopropionamide,
3-[4-(t-butyl)phenyl]-N-[3-ethynyl-5-fluoro-4-(methanesulfonylamino)- benzyl]thiopropionamide, 3 - [4-(t-butyl)phenyl] -N- [3 -cyclopropyl-5 -fluoro-4-(methanesulfonylamino)- benzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -chloro-5-methyl-4-(methanesulfbnylamino)- benzyljthiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3-cyano-4-(methanesulfonylamino)- benzyljthiopropionamide,
3-(4-t-butyl-phenyl)-N-(4-methanesulfonylamino-benzyl)-2-methyl- thiopropionamide,
2-(4-t-butyl-benzyl)-N-(4-methanesulfonylamino-benzyl)-thiobutyr amide,
3-(4-t-butyl-phenyl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-2-methyl-
thiopropionamide,
3-(4-t-butyl-phenyl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-2-ethyl- thiopropionamide,
3-(4-t-butyl-phenyl)-N-(4-methanesulfonylamino-3-trifluoromethoxy-benzyl)- thioacrylamide,
3 -[4-(t-butyl)phenyl] -N- [3 -acetyl-4-(methanesulfonylamino)-5 -fluoro- benzyl] thiopropionamide, and
(z)-3 - [4-(t-butyl)phenyl]-2-fluoro-N- [3 -fluoro-4- (methanesulfonylamino)benzyl]-2-butenethioamide.
[Claim 12]
A compound according to claim 9, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
3 - [4-(t-butyl)phenyl] -N- [3 -fluoro-4-(methanesulfonylamino) benzyl]thiopropionamide, 3-[4-(t-butyl)phenyl]-N-[3-chloro-4-(methanesulfonylamino) benzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -methyl-4-(methanesulfonylamino) benzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 -nitro-4-(methanesulfonylamino) benzyljthiopropionamide,
3-[4-(t-butyl)phenyl]-N-[4-(methanesulfonylamino) -3-vinylbenzyl]thiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 ,5-difluoro-4-(methanesulfonylamino)-
benzyl]thiopropionaraide,
3-[4-(t-butyl)phenyl]-N-[3-fluoro-4-(methanesulfonylamino)-5-vinyl- benzyl]thiopropionamide,
3-[4-(t-butyl)phenyl]-N-[3-ethynyl-5-fluoro-4-(methanesulfonylamino)- benzyljthiopropionamide,
3 - [4-(t-butyl)phenyl] -N- [3 ~chloro-5-methyl-4-(methanesulfonylamino)- benzyl]thiopropionamide, and
3 - [4-(t-butyl)phenyl] -N- [3 -cyano-4-(methanesulfonylamino)- benzyl]thiopropionamide.
[Claim 13]
A compound according to anyone of the preceding claims for use as a medicament.
[Claim 14]
A pharmaceutical composition comprising a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, as an active ingredient, together with a pharmaceutically acceptable carrier.
[Claim 15]
A pharmaceutical composition for preventing and treating a condition associated with the pathological stimulation and/or aberrant expression of vanilloid receptors, wherein said composition comprise a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12; and a pharmaceutically acceptable carrier thereof.
[Claim 16]
The pharmaceutical composition for treating a condition selected from pain, inflammatory disease of the joints, urinary bladder hypersensitivity including urinary incontinence, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), neurotic/allergic/inflammatory skin disease, psoriasis, asthma, chronic obstructive pulmonary disease (COPD), pruritus or prurigo comprising a compound, an isomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12; and a pharmaceutically acceptable carrier.
[Claim 17]
The pharmaceutical composition according to claim 16 wherein the pain is or is associated with a condition selected from osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches.
[Claim 18]
The pharmaceutical composition according to anyone of claims 15-17 characterized in that it is adapted for oral administration.
[Claim 19]
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, an isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12.
[Claim 20]
A method for preventing or treating a condition selected from pain,
inflammatory disease of the joints, urinary bladder hypersensitivity including urinary incontinence, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), neurotic/allergic/inflammatory skin disease, psoriasis, asthma, chronic obstructive pulmonary disease, pruritus or prurigo, which comprises administering to a mammal including a person in need thereof a therapeutically effective amount of a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12.
[Claim 21 ]
A method according to claim 20, wherein the pain is or is associated with a condition selected from osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches.
[Claim 22]
Use of a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for prevention or treatment of a condition that is associated with the aberrant expression and/or aberrant activation of a vanilloid receptor.
[Claim 23 ]
Use of a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, in preparation of a medicament for prevention or treatment of a condition that is selected from pain, inflammatory disease of the joints, urinary bladder hypersensitivity including urinary incontinence, stomach
duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), neurotic/allergic/inflammatory skin disease, psoriasis, asthma, chronic obstructive pulmonary disease, pruritus or prurigo.
[Claim 24]
Use of a compound according to claims 23, wherein the condition is pain or is associated with a condition selected from osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches.
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