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Definitions

• Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist as vanilloid receptor antagonist ; and pharmaceutical compositions containing the same
• the 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.
• vanilloid receptor Vanilloid Receptor 1 ; VR1 ; TRPV1
• neurotic/allergic/inflammatory skin disease such as psoriasis, pruritus and prurigo(Southall et al., 2003, J. Pharmacol. Exp. Then, 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, pp165-70); cardiac disease such as inotropic ischemia etc.(Scotland et al., 2004, Circ. Res. 95, pp1027-1034; Pan et al., 2004, Circulation, 110, pp1826-1831) can be enumerated.
• neurotic/allergic/inflammatory skin disease such as psoriasis, pruritus and prurigo(Southall et al., 2003, J. Pharmacol. Exp. Then,
• the vanilloid receptor (VR1) 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, pp816-824). This receptor is a non-selective cation channel composed of 6 transmembrane domains and belongs to the TRP channel family. Recently, it was named TRPV1.
• 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).
• 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, lungs, intestines 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.
• TRPV1 receptor knock-out mice exhibit a normal response to harmful physical stimuli, but show a reduction in pain responses and sensory sensitivity to thermal stimuli by vanilloid, 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, pp183-187; Karai et al., 2004, J. Clin. Invest., 113, pp1344-1352).
• vanilloid receptor may be present in the form of a heteromultimer with TRPV3, another TRP channel (Smith et al., 2002, Nature, 418, pp186-190).
• 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).
• afferent nerve cells 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, pp143-201; Mezey et al., 2000, PNAS, 97, 3655-3660).
• the vaniiloid receptor is expressed in all regions of the gastrointestinal tract, for example, ganglia of tensor, tunica muscularis, mucosa and epithelial cells. In particular, the vaniiloid receptor is highly expressed in inflammatory disorders of the colon and ileum.
• vaniiloid receptor In addition, activation of the vaniiloid 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 vaniiloid 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 , pp1313-1320. According to such references, it seems that the vaniiloid receptor antagonists will be effective for prevention or treatment of gastrointestinal diseases such as gastroesophageal reflux disease (GERD) and gastroduodenal ulcer (DU).
• GDD gastroesophageal reflux disease
• DU gastroduodenal ulcer
• Bronchial hypersensitivity is very similar to hyperalgesia, and protons and lipoxygenase products, known as endogenous ligands for the vaniiloid receptor, are well known as crucial factors responsible for development of asthma and chronic obstructive pulmonary diseases (Hwang et al., 2002, Curr. Opin. Pharm. pp235-242; Spina et al., 2002, Curr. Opin. Pharm. pp264-272).
• 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, pp1250-1252; lnoue et al., 2002, Biochem. Biophys. Res.
• the present invention provides a novel compound of the following formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition containing the same.
• R 1 is C2-C5 alkenyl, or C2-C5 alkynyl
• R 2 is hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxy, 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; R 3 is hydrogen, C1-C5 alkyl,
• R 4 , R 5 , R ⁇ , R 7> and R 8 are independently hydrogen, carboxy, C1-C5 alkyl, nitro,
• Rg and R 10 are independently hydrogen, -SO 2 Ri 3 , -SORi 3 , 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 13 is hydrogen, amino, C1 - C5 alkyl,
• One preferred aspect of the present invention is a compound of the formula (I),
• R 1 is C2-C5 alkenyl or C2-C5 alkynyl
• R 2 is hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxy, C1-C5 alkoxycarbonyl, C1-C5 alkylthio,
• phenyl or phenyl (C1-C3) alkyl, wherein, each phenyl may be unsubstituted or
• alkylthio C1-C5 alkylsulfonyl, and C1-C5 alkoxycarbonyl
• R 3 is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, or halo (C1-C5) alkyl;
• R 4 , R5, Re, R 7 , and R 8 are independently hydrogen, carboxy, C1-C5 alkyl, nitro,
• phenyl may be unsubstituted or substituted with one or more substituent
• C1-C5 alkyl C1-C5 alkylcarbonyl, C1-C5 alkylthio, C1-C5 alkylsulfonyl, and C1-C5
• 0 are independently hydrogen, -SO 2 Ri 3 , -SOR 13 , C1-C5 alkyl, C1-C5
• phenyl or phenyl (C1-C3) alkyl, wherein, each phenyl may be unsubstituted or
• R 13 is hydrogen, amino
• Another aspect of the present invention is a compound according to the above
• R 1 is ethenyl, ethynyl, propenyl, or propynyl
• R 2 is hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, propyl,
• R 3 is hydrogen, methyl, or ethyl
• R 4 , Rs, R ⁇ . R7 > and R 8 are independently hydrogen, carboxy, methyl, ethyl,
• propyl isopropyl, t-butyl, nitro, ethenyl, ethynyl, methylthio, trifluoromethyl, methoxycarbonyl, or halogen;
• R 9 and R 10 are independently hydrogen, -SO 2 Ri 3 , -SOR 13 , C1-C5 alkyl, C1-C5
• alkoxy halo (C1-C5) alkyl, C2-C5 alkenyl, phenyl, phenyl (C1-C3) alkyl, or C1-C3
• R 13 is hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl,
• R 6 is C1-C5 alkyl, halo (C1-C5) alkyl, C1-C5 alkylthio, or
• R 3 is hydrogen or C1-C5 alkyl; wherein compounds are
• R 3 is hydrogen or methyl; compounds wherein R 4 , R 5 , R 7 , and R 8 are preferably independently hydrogen,
• R 5 , R 7 , and R 8 are hydrogen
• Ri is ethenyl, ethynyl, propenyl, or propynyl, and most
• R 2 is hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano,
• R 2 is hydrogen, fluoro
• R 1 is ethenyl or ethynyl
• R 2 is hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, propyl,
• R 3 is hydrogen, methyl, or ethyl
• R 4 , R5, R7, Rs, and R 10 are hydrogen
• R 6 is chloro, isopropyl or t-butyl and particularly preferably isopropyl or tert
• R 9 is methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, or
• R 1 is ethenyl or ethynyl
• R 2 is hydrogen, fluoro, chloro, b ' romo, iodo, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, trifluoromethyl, carboxy, methoxycarbonyl,
• R 3 is hydrogen, methyl, or ethyl
• R 4 , R 5 , R 7 , and R 8 are hydrogen
• R 6 is isopropyl or t-butyl.
• R 1 is ethenyl, ethynyl, propenyl, or propynyl
• R 2 is hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, ethynyl, ethenyl, carboxy, or methoxycarbonyl;
• R 3 is hydrogen, methyl, or ethyl
• R 4 , R5, R 7 , and R 8 are independently hydrogen, fluoro, carboxy, methyl, ethyl, propyl, isopropyl, t-butyl, nitro, ethenyl, ethynyl, trifluoromethyl, methoxycarbonyl, halogen, methoxyethoxy, methoxyethoxymethyl, methylpiperazinyl, methoxyethylamino, hydroxy, methoxy, allyloxy, isohexylamino, isobutylammino, isopropylamino, morpholinyl, morpholinylethoxy, or tetrahydropyranyloxy;
• R 6 is C3-C5 alkyl or halo (C1-C3) alkyl and particularly preferably isopropyl or t-butyl;
• R 9 and Ri 0 are independently hydrogen or methanesulfonyl.
• Another preferred embodiment of the present invention are compounds of the above formula I 1 wherein,
• X is NHCH 2 , CHRi 1 CHR 12 or C ⁇ C, wherein, R 11 is hydrogen or methyl and R 12 is hydrogen;
• R-i is ethenyl or ethynyl
• R 2 is hydrogen, fluoro, methyl, or chloro
• R 3 is hydrogen or methyl
• R 4 is hydrogen, fluoro, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethylamino, allyloxy, or tetrahydropyranyloxy;
• R5, R7 and R8 are hydrogen or fluoro;
• R 6 is C3-C5 alkyl or halo (C1-C3) alkyl, and particularly preferably isopropyl or t-butyl;
• R 9 is hydrogen and R 10 represents methanesulfonyl.
• R 1 is ethenyl or ethynyl
• R 2 is hydrogen, fluoro, methyl, or chloro
• R 3 is hydrogen or methyl
• R 4 is hydrogen, fluoro, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethylamino, allyloxy, or tetrahydropyranyloxy
• R5, R7 and R8 are hydrogen or fluoro
• R 6 is C3-C5 alkyl or halo (C1-C3) alkyl and particularly preferably isopropyl or t-butyl ; and Rg is hydrogen and Ri 0 represents methanesulfonyl.
• Another preferred embodiment of the present invention are compounds of the above formula I, wherein,
• X is C ⁇ C
• R 1 is ethenyl or ethynyl
• R 2 is hydrogen, fluoro, methyl, or chloro
• R 3 is hydrogen or methyl
• R 4 is hydrogen, fluoro, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethylamino, allyloxy, or tetrahydropyranyloxy;
• R5, R7 and R8 are hydrogen or fluoro;
• R 6 is C3-C5 alkyl or halo (C1-C3) alkyl and particularly preferably isopropyl or t-butyl ;
• R 9 is hydrogen and Ri 0 represents methanesulfonyl.
• Another preferred embodiment of the present invention are compounds of the above formula I, wherein X is NHCH 2 , R 1 is ethenyl or ethynyl; R 2 is hydrogen, fluoro, methyl, or chloro; R 3 is hydrogen or methyl;
• R 4 is hydrogen, fluoro, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethylamino, allyloxy, or tetrahydropyranyloxy and particularly preferably hydrogen or fluoro;
• R5, R7 and R8 are hydrogen or fluoro;
• R 6 is C3-C5 alkyl or halo (C1-C3) alkyl and particularly preferably isopropyl or t-butyl;
• Rg is hydrogen and Ri 0 represents methanesulfonyl.
• Another preferred embodiment of the present invention are compounds of the above formula I, wherein,
• X is CHR 11 CHR 12 , wherein, R- I1 is hydrogen or methyl and R- I2 is hydrogen;
• R 1 is ethenyl or ethynyl
• R 2 is hydrogen, fluoro, methyl, or chloro;
• R 3 is hydrogen or methyl;
• R 4 is hydrogen, fluoro, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethylamino, allyloxy, or tetrahydropyranyloxy and particularly preferably hydrogen, fluoro or tetrahydropyranyloxy;
• R5, R7 and R8 are hydrogen or fluoro;
• R 6 is C3-C5 alkyl or halo (C1 -C3) alkyl and particularly preferably isopropyl or t-butyl;
• R 9 is hydrogen and R 10 represents methanesulfonyl.
• Another preferred embodiment of the present invention are compounds of the above formula I, wherein,
• X is NH
• R 1 is ethenyl or ethynyl
• R 2 is hydrogen, fluoro, methyl, or chloro
• R 3 is methyl
• R 4 is hydrogen, fluoro, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethylamino, allyloxy, or tetrahydropyranyloxy and particularly preferably hydrogen or fluoro;
• R5, R7 and R8 are hydrogen or fluoro
• R 6 is C3-C5 alkyl or halo (C1-C3) alkyl and particularly preferably isopropyl or t-butyl;
• R 9 is hydrogen and Ri 0 represents methanesulfonyl.
• One embodiment of the present invention relates to compounds of formula I as defined further above, wherein X is CHR11-CHR12. These compounds have the general formula (Ib).
• Rn and R 12 are independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, or phenyl;
• R 1 is C2-C5 alkeny! or C2-C5 alkynyl
• R 2 is hydrogen, halogen, nitro, cyano, C1-C5 alkyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxy, 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-
• R 3 is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, or halo (C1-C5) alkyl;
• R 4 , R5, Re, R7, and R 8 are independently hydrogen, carboxy, C1-C5 alkyl, nitro,
• R 9 and R 1 0 are independently hydrogen, -SO 2 Ri 3 , -SOR 13 , 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 13 is hydrogen, amino, C1 - C5 alkyl
• R 11 and Ri 2 are methyl or hydrogen
• Ri is ethenyl or ethynyl
• R 2 is hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, trifluoromethyl, carboxy, or methoxycarbonyl;
• R 3 is hydrogen, methyl, or ethyl
• R 4 , R 5 , R 7 , and R 8 are independently hydrogen, fluoro, carboxy, methyl, ethyl, propyl, isopropyl, t-butyl, nitro, ethenyl, ethynyl, trifluoromethyl, methoxycarbonyl, halogen, methoxyethoxy, methoxyethoxymethyl, methylpiperazinyl, methoxyethylamino, hydroxy, methoxy, allyloxy, isohexylamino, isobutylammino, isopropylamino, morpholinyl, morpholinylethoxy, or tetrahydropyranyloxy; and
• R 6 is isopropyl, t-butyl, or halo (C1-C3) alkyl and particularly preferably isopropyl or t-butyl.
• R 11 is hydrogen or methyl, and R 12 is hydrogen;
• Ri is ethenyl or ethynyl
• R 2 is hydrogen, fluoro, chloro, or methyl
• R 4 is hydrogen, fluoro, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethylamino, allyloxy, or tetrahydropyranyloxy
• R 5 , R 7 and R s are hydrogen or fluoro
• R 6 is tert-butyl
• R 9 is hydrogen
• R- t o represents methanesulfonyl.
• R 9 is hydrogen
• R 10 is methanesulfonyl
• R 1 is bound to the phenyl ring in ortho-position to the methansulfonylamino group.
• Those preferred compounds have the general formula (Ic).
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Rs and X have the meaning according to the various embodiments defined above, and wherein the description of the various preferred embodiments and features of the compounds of formula I and (Ib) do also apply to the compounds of formula (Ic).
• R 9 is hydrogen
• R 10 is methanesulfonyl
• R 1 and R 2 are both bound to the phenyl ring in ortho-position to the methansulfonylaminogroup.
• Those preferred compounds have the general formula (Id).
• R-i, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Rs and X have the meaning according to the various embodiments defined above, and wherein the description of the various preferred embodiments and features of the compounds of formula I and (Ib) do also apply to the compounds of formula (Id).
• R 1 is ethenyl or ethynyl;
• R 2 is hydrogen, fluoro, chloro, or methyl;
• R 3 is hydrogen or methyl;
• R 4 is hydrogen, fluoro, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxy, methoxyethylamino, allyloxy, or tetrahydropyranyloxy;
• R 5 , R 7 and R 8 are hydrogen or fluoro;
• R 6 is halo (C1-C3) alkyl, isopropyl or, preferably, tert-butyl.
• Preferred examples of compounds according to the invention are selected from the group consisting of;
• Example compounds of the present invention are shown in Table 1.
• Table 1 The compounds of formular (I) according to 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.
• R1 vinyl, or acetylenyl
• the above Scheme 1 shows a proposed process for synthesizing dibenzyl urea with vinyl or acetylene.
• substituted benzylamine is reacted with di-t- butyldicarbonate to yield benzyl carbamate in situ and to this reaction mixture is immediately added substituted benzylamine with vinyl or acetylenyl group (2) and triethylamine to yield dibenzylurea with vinyl or acetylene group (3).
• the above Scheme 2 shows various processes for synthesizing urea derivatives.
• Boc derivatives of 4-nitrobenzylamine (4) is reduced to yield the aniline compound (5).
• the iodo group is introduced to the neighboring location of amino group of the compound (5) to yield the compound (6).
• lodination of compound (5) can be achieved also at ortho position of amino by using iodine and silver sulfate at O 0 C (Synth. Commun. 1992, 22, 3215-3219).
• Vinyl stannane compound is coupled to the compound (6) to yield compound with vinyl group (7).
• the methanesulfonyl group is introduced to amino group of compound (7) to yield the compound (8).
• the protecting group(Boc) is removed using TFA(Trifluoroacetic acid) to yield the benzylamine compound (9).
• the dibenzyl urea derivatives(IO) is synthesized according to the similar procedure as described in scheme 1.
• the above Scheme 3 shows a proposed process for synthesizing urea derivatives with optical activity.
• the urea compound (17) having an optical activity is synthesized according to the above scheme 3 in which the reactant with methyl or ethyl group at R 3 position is used as a starting material.
• R1 vinyl, or acetylenyl
• the above Scheme 5 shows another process for synthesizing the acrylamide compound.
• the compound (20) is synthesized using DMTMM ⁇ 4-(4,6-dimethoxy-1 ,3,5- triazin-2-yl)-4-methylmorpholinium chloride ⁇ (Tetrahedron Lett., 1999, 40, 5327) instead of diethylcyanophosphate.
• the above Scheme 7 shows a proposed process for synthesizing the acrylamide derivatives(26).
• the fatty acid ester compound (24) having various substituents at alkene position of unsaturated fatty acid is hydrolyzed to yield the fatty acid (25).
• the compound (26) is synthesized using the unsaturated fatty acid (25) with substituent according to the same procedure as described in scheme 4.
• the above Scheme 8 shows a proposed process for synthesizing the acrylamide compound (34) with acetylene substituent group.
• iodo group is introduced at the neighboring location of amine group of aniline compound (28) to yield the compound (29).
• the iodo-compound is reduced and thereto the benzylamine is Boc-protected to yield compound (30).
• the compound (30) can be also synthesized by carrying out reduction and iodination in order.
• the amine group neighboring to benzene is treated with methanesulfonyl to yield the compound (32).
• the Boc-protecting group of the compound (32) is removed to prepare benzylamine compound (33).
• Benzylamine compound (33) having the acetylene substituent is reacted with unsaturated fatty acid to yield the acrylamide compound (34).
• R1 vinyl or acetylene
• the Scheme 12 shows a proposed process for synthesizing urea compound with the vinyl substituent (39).
• the Scheme 13 shows a proposed process for synthesizing urea compound having ethensulfonylamino group.
• Aniline compound is reacted with 2- chloroethanesulfonylchloride to yield compound (40) with ethenylsulfonylamino group.
• the compound (40) is reacted with tributyltin to yield the compound (41).
• the protecting group of compound (41) is removed to prepare benzylamine compound (42).
• Benzylamine compound (42) with ethensulfonyl amino group is reacted with 4-t- butylphenylisocyanate to yield amide compound (43).
• the Scheme 14 shows a proposed process for synthesizing urea compound having phenylacetylenyl group, lodoaniline compound is reacted with phenylacetylene via sonogashira reaction to yield compound (44).
• the compound (44) is reacted with methanesulfonyl anhydride to yieid compound (45).
• the compound (45) is treated with TFA to yield benzylamine compound (46).
• Benzylamine compound (46) is reacted with phenylisocyanate to yield urea compound (47).
• Compound (47) is reduced with lindlar catalyst to prepare urea compound (48) with phenyl ethane moiety.
• the Scheme 15 shows a proposed process for synthesizing acrylamide compound with various substituents.
• 3-t-Butylphenol is reacted with NIS to yield compound (50).
• the compound (50) is reacted with methylacrylate to give compound (51 ).
• Compound (51) is reacted with alkyl halide or alkoxylalkyl halide to yield compound (52).
• Compound (52) is hydrolyzed in basic condition.
• Compound (53) is reacted with benzylamine compound to yield the compound (55).
• the Scheme 16 shows also a proposed process for synthesizing acrylamide compound with various substituents.
• Amid compound (61) is obtained by using DEPC (diethylcyanophosphate) or DMTMM.
• the Scheme 17 shows a process for synthesizing the (R) -N-[4-(1- aminoethyl)-2-fluoro-6-vinylphenyl]methanesulfonamie (71).
• Butylvinylether is coupled to the iodoaniline (62) to yield compound (63).
• lodination of compound (62) can be achived by using NIS.
• Compound (64) is reacted with (R)-(+)- 2-methyl-2-propane-2- sulfinamide to yield 2-methylpropane-2-sulfinc acid [1-(4-amino-3-fluoro-5- iodophenyl)ethyl]amide (65).
• Compound (65) is reduced with 1 N HCI solution to yield compound (67).
• Compound (71) was synthesized according to similar procedure of the Scheme 3.
• the Scheme 17 shows a process for synthesizing a specific unsaturated amide compound (72), amide compound (73) and urea compound (74).
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic) or (Id), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
• 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, postoperative 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), (Ia), (Ib), (Ic) or (Id), 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), (Ia), (Ib), (Ic) or (Id), 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, prurigo, asthma, chronic obstructive pulmonary disease, urinary incontinence, inflammatory bowel disease, hyperacusis, tinnitus, vestibular hypersensitiveness, or inotropic ischemia.
• the present invention provides a pharmaceutical composition for treating a condition selected from pain, inflammatory disease of the joints including inflammatory 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 anyone of formula (I), (Ia), (Ib), (Ic) or (Id), as defined further above.
• 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 post-operative pain
• non-inflammatory musculoskeletal pain including fibromyalgia, myofascial pain syndrome and back pain
• migraine other types of headaches.
• 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 "inflammatory disease of the joints” includes diseases that involve to a more or less degree inflammatory processes in the joints, e.g. in knees, fingers, hips etc. An example for such a disease is osteoarthritis.
• the term "inflammatory disease of the joints” does also include diseases or conditions which may involve autoimmune processes, such as e.g. rheumatoid arthrtitis or ankylosing spondylitis.
• the inventive treatment of "inflammatory diseases of the joints” is primarily aimed at treating pain associated with these conditions but may also aim at improving the function of the affected joints, either directly or indirectly, e.g. by reducing the pain associated with the movement of said joints.
• One outcome of the administration of the compounds of the present invention to patients suffering from an inflammatory disease of the joints may thus be reducing the pain experienced by the subject suffering from said disease 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 disease of the joints, including particularly osteoarthritis, rheumatoid arthritis ankylosing spondylitis.
• the treatment may suitably result in an improved functionality of the joints, such as decreased stiffness, improved mobility.
• 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.
• 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 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.
• 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.
• 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).
• a normally non-nociceptive stimulus allodynia
• nociceptive stimuli hyperalgesia
• the treatment of non-inflammatory 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.
• 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), (Ia), (Ib), (Ic) or (Id), 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), (Ia), (Ib), (Ic) or (Id), an isomer thereof, or a pharmaceutically acceptable salt thereof.
• 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
• 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, noninflammatory 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 noninflammatory 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), (Ia), (Ib), (Ic) or (Id), 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), (Ia), (Ib), (Ic) or (Id), 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), (Ia), (Ib), (Ic) or (Id), an isomer thereof, or a pharmaceutically acceptable salt thereof, in preparation of a medicament for prevention or treatment of a condition related to vaniiloid receptor.
• the present invention relates to the use of a compound of formula (I), (Ia), (Ib), (Ic) or (Id), 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), neurotic/allergic/inflammatory skin disease, psoriasis, asthma, chronic obstructive pulmonary disease (COPD), pruritus, or prurigo.
• 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), neurotic/allergic/inflammatory skin disease, psoriasis, asthma, chronic obstructive pulmonary disease (COP
• 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), (Ia), (Ib), (Ic) or (Id), 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 intracerebroventricular 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.
• 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.
• 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, methanesulfonyl, 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-NH 2 .
• Halo'Or “halogen” refers to fluoro, chloro, bromo and iodo. Preferred halo groups are either fluoro or chloro.
• Haloalkyl includes an “alkyl” group as defined further above which is substituted with one or more halogens which may be the same, e.g. in trifluoromethyl or pentafluoroethyl, or which may be different.
• Haldroxy refers to the radical-OH.
• Niro refers to the radical-NO 2 .
• Piperidinyl(C1-C5)alkoxy refers to a piperidinyl residue that is bound to "alkoxy” as defined further above, wherein the piperidinyl is preferably bound to a C- atom of "alkoxy” via the nitrogen or via the para-C-Atom of the piperidine ring.
• Morpholinyl(C1-C5)aikyloxy refers to a morpholine residue that is bound to
• alkoxy wherein the morpholinyl ring is preferably bound to a C-Atom of "alkoxy” via the nitrogen atom of the morpholine ring.
• Tetrahydropyranyloxy refers to a tetrahydropyranyl group that is bound to an oxo (-O-) group, wherein the oxo group is preferably bound to the para C-atom of the tetrahydropyranyl group.
• Alkylpiperazinyl refers to a piperazine ring that carries an “alkyl” as substituent
• the piperazinyl ring is bound both to the “alkyl” as well as to the second attachment position via its nitrogen atoms.
• Porturedoxy refers to a piperidinyl group that is bound to an oxo (-O-) group, wherein the oxo group is preferably bound to the para C-atom of the piperidinyl group.
• “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, 2-hydroxyethanesulfonic acid, benzen
• “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.
• “treating” or “treatment” refers to delaying the onset of the disease or disorder.
• Step 1 (4-nitrobenzyl)carbamic acid t-butyl ester
• Step 2 (4-aminobenzyl)carbamic acid t-butyl ester
• Step 4 (4-amino-3-vinylbenzyl)carbamic acid t-butyl ester
• a 50 ml two-neck round bottom flask was filled with argon gas and the solution of tetrakis(triphenyl phosphine)palladium(O) (123.7 mg, 0.107 mmol, 0.06 eq.) and lithium chloride(211.9mg, 4.998 mmol, 2.8 eq.) in DMF was put into the flask.
• Step 5 (4-methanesulfonylamino-3-vinylbenzyl)carbamic acid t-butyl
• Step 1 4-aminomethyl-2-fluoro-6-iodophenylamine
• Step 2 (4-amino-3-fluoro-5-iodobenzyl)carbamic acid t-butyl ester
• Step 3 (4-amino-3-fluoro-5-vinylbenzyI)carbamic acid t-butyl ester
• a 25 ml two-neck round bottom flask was filled with argon gas and the solution of tetrakis (triphenyl phosphine) palladium(O) (18.9mg, 0.016mmol, O.O ⁇ eq.) and lithium chloride(32.4 mg, 0.765 mmol, 2.8 eq.) in DMF was put into the flask.
• Step 4 (S-fluoro ⁇ -methanesuIfonylamino-S-vinylbenzyOcarbamic acid t- butyl ester
• Step 6 N-4-[3-(4-t-butylbenzyl)ureidomethyl]-2-fluoro-6-vinylphenyl methane sulfonamide
• a 25 ml two-neck round bottom flask was filled with argon gas and the solution of 4-t-butylbenzylamine (59.3 ⁇ i, 0.338mmol, 1 eq.) in methylenechloride was put into the flask.
• 4-dimethylaminopyridine 8.3mg, 0.068mmol, 0.2eq.
• di-t-butyl dicarbonate 93.3 ⁇ 1 0.406mmol, 1.2eq.
• Step 4 N- ⁇ 4-[3-(4-t-butylbenzyl)ureidomethyll-2-ethynyl-6-fluoropheny[ ⁇ methanesulfonamide
• step 1 (4-amino-2-chloro-5-vinylbenzyl)carbamic acid t-butyl ester
• Pd(PPh3) 4 (0.06 eq, 0.01 mmol, 11.09 mg)
• LiCI 2.8 eq, 0.45 mmol, 18.99 mg
• Step 2 (2-chloro-4-methanesulfonylamino-5-vinylbenzyl)carbamic acid t- butyl ester
• a dried 25 ml two-neck round bottom flask was filled with argon gas and the solution of ⁇ -amino ⁇ -chloro- ⁇ -vinyl-benzyO-carbamic acid t-butyl ester (103.0mg, 0.37mmol) in methylenechloride was added to the flask and then cooled to O 0 C .
• the solution was stirred for 1 hr and then confirmed the completion of the reaction with TLC.
• the reaction solution was acidified by 10% HCI, extracted with ethylacetate, washed with water and brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure.
• Step 4 N- ⁇ 4-[3-(4-t-butylbenzyI)ureidomethyl]-5-chIoro-2-vinylphenyl ⁇ methanesulfonamide
• a dried 25 ml two-neck round bottom flask was filled with argon gas and the solution of 4-t-butylbenzylamine (29.38/ ⁇ l, 0.18mmol) in methylene chloride was added to the flask.
• Boc 2 O(1.5eq, 0.27mmol, 151.78/ ⁇ ) and DMAP (0.2 eq, 0.09 mmol, 10.15 mg) slowly and stirred for 5 hours.
• Stepi (4-amino-2-chloro-5-trimethylsilanylethynylbenzyl)carbamic acid t- butyl ester
• a dried 25 ml two-neck round bottom flask was filled with argon gas and the solution of (4-amino-2-chloro-5-iodo-benzyl)-carbamic acid t-butyl ester (60mg, 0.16mmol), CuI(0.05eq, O.OO ⁇ mmol, 1.52mg) and PdCI 2 (PPh3) 2 in DMF was put into the flask. The solution was stirred at room temperature for 30minut.es.
• Step 2 (2-chloro-5-ethynyl-4-methanesulfonylaminobenzyl) carbamic acid t-butyl ester
• a dried 25 ml two-neck round bottom flask was filled with argon gas.
• the solution of (4-amino-2-chloro-5-trimethylsilanylethynyl-benzyl)-carbamic acid t-butyl ester (225.3mg, 0.64mmol) in methylenechloride was put into the flask and then cooled to 0 ° C.
• reaction solution was acidified by 10% HCI, extracted with ethylacetate, washed with water and brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure.
• Step 3 N-(4-aminomethyl-5-chloro-2-ethynylphenyl)methanesulfonamide
• Step 4 N- ⁇ 4-[3-(4-t-butylbenzyI)ureidomethyl]-5-chloro-2-ethynyl phenyl ⁇ methanesulfonamide
• a dried 25 ml two-neck round bottom flask was filled with argon gas and the solution of 4-t-butyl-benzylamine (44.08 ⁇ , 0.27 mmol) in methylenechloride was put into the flask.
• Boc 2 O(1.5eq, 0.41mmol, 93.14 ⁇ ) and DMAP (0.2 eq, 0.05 mmol, 6.59 mg) slowly and stirred for 5 hours.
• Step 2 (R)-[I -(4-aminophenyl)ethyl]carbamic acid t-butyl ester
• Step 3 (R)-[I -(4-amino-3-iodophenyl)ethyl]carbamic acid t-butyl ester
• the solution of [1-(4-amino-phenyl)-ethyl]-carbamic acid t-butyl ester (141.1mg, O. ⁇ Ommol, 1eq.) in methylenechloride was put into 50 ml two-neck round bottom flask.
• iodomonochloride (106.6mg, 0.66mmol, 1.1eq.
• Step 4 (R)-[I -(4-amino-3- ethenylphenyl)ethyl]carbamic acid t-butyl ester
• a dried 25 ml two-neck round bottom flask was filled with argon gas and the solution of tetrakis(triphenyl phosphine)palladium(O) (27.9mg , 0.02mmol, 0.06 eq.) and lithium chloride(47.7mg, 1.13 mmol, 2.8 eq.) in DMF was put into the flask.
• Step 5 (R)-[I -(4-methanesulfonylamino-3-ethenylphenyl)ethyl]carbamic acid t-butyl ester
• Step 6 (R)- [1-(4-methanesulfonylamino-3- ethenylphenyl)ethyl]ammonium trifluoro-acetate
• Step 7 N-(4- ⁇ 1-(R)-[3-(4-t-butylbenzyl)ureido]ethyl ⁇ -2-v ⁇ nylphenyl) methanesulfonamide
• a 25 ml two neck round-bottom flask was filled with Ar gas and the solution of 2-fluoro-4-iodophenylamine (1500mg, 6.33mmol) in DMF, palladium ( II ) acetate (0.19mmol, 42.62mg), 1 ,3-bisdiphenyl phosphinopropane (0.06eq, 0.38mmol, 156.65mg), Thallium( I )acetate (6.96mmol, 1834.19mg), butyl vinyl ether(2eq, 12.66mmol, 1.64ml) were put into the flask. The reaction mixture was heated and stirred for 15hr.
• reaction mixture was poured into the THF soulution, and then 10% HCI was added slowly.
• the reaction mixture was extracted with ethyl acetate (300*3), washed with H 2 O and brine.
• Step 3 2-Methylpropane-2-sulfinic acid [1-(4-amino-3-fluoro-5- iodophenyl)ethyl]amide 1-(4-Amino-3-fluoro-5-iodophenyl)ethanone (0.36mmol, 100mg), Ti(OEt) 4 (0.59mmol, 122.68/ ⁇ ), (R)-(+)-2-methyl-2-propane sulfinamide(0.32mmol, 39.27mg) was added to THF solution. A reaction mixture was heated and stirred for 12 hr. After confirming the completion of the reaction with TLC, a reaction mixture was cooled down to -40 0 C.
• Step 4 4-(1-Aminoethyl)-2-fluoro-6-iodophenylamine
• Step 5 [1-(4-Amino-3-fluoro-5-iodophenyl)ethyl] carbamic acid tert-butylester
• Step 6 [1-(4-Amino-3-fluoro-5-vinylphenyl)ethyl]carbamic acid tert- butylester
• Step 7 [1-(3-Fluoro-4-methanesulfonylamino-5-vinylphenyl)ethyl] carbamic acid tert-butyl ester
• Step 8 N-[4-(1-Aminoethyl)-2-fluoro-6-vinylphenyl]methanesulfonamide [1-(3-fluoro-4-methanesulfonylamino-5-vinyl phenyl)ethyl]carbamic acid tert- butyl ester (O.O ⁇ mmol, 20.2mg) was dissolved in methylene chloride, 5-6 drops of CF 3 COOH were added. A reaction mixture was stirred for 12 hr. A toluene was added. The reaction mixture was concenctrated in vacuo to yield brownish syrup (20.8mg, 100.0%).
• Step 2 4-Amino-3-iodo-5-methylbenzonitrile 4-Amino-3-methyl-benzonitrile (786.5 ⁇ d, 5.95mmol) and ICI(L 1eq, 6.55mmol,
• Step 3 (4-Amino-3-iodo-5-methylbenzyl)carbamic acid tert-butyl ester
• Step 4 (4-Amino-3-methyl-5-vinylbenzyl)carbamic acid tert-butyl ester Pd(PPh 3 ) 4 (0.06eq, 0.017mmol, 19.41mg) and LiCI(2.8eq, 0.74mmol, 33.23mg) was dissolved in DMF. (4-Amino-3-iodo-5-methylbenzyl)carbamic acid tert-butyl ester (100mg, 0.28mmol) and Tributylvinyltin (1.5eq, 0.41mmol, 121.08/ig) were added into the reaction mixture. The reaction mixture was stirred for 12hr in reflux. The reaction mixture was purified according to a similar procedure to step 3 to obtain solid (61.8mg, 85.34%).
• Step 5 (4-Methanesulfonylamino-3-methyl-5-vinylbenzyl)carbamic acid tert-butyl ester (4-Amino-3-methyl-5-vinyl-benzyl)-carbamic acid tert-butyl ester (30.9mg,
• Step 1 4-Amino-3-chloro-5-iodobenzonitriIe
• Step 2 (4-Amino-3-chloro-5-iodobenzyl)carbamic acid tert-butyl ester
• Step 3 (4-Amino-3-chloro-5-vinylbenzyI)carbamic acid tert-butyl ester
• Step 4 (S-Chloro ⁇ -methanesulfonylamino-S-vinylbenzyOcarbamic acid
• Step 6 N- ⁇ 4-[3-(4-tert-Butylbenzyl)ureidomethyl]-2-chloro-6-vinylphenyl ⁇ methanesulfonamide
• Step 1 4-lodo-2-trifluoromethylphenylamine
• Step 4 (4-Amino-3-iodo-5-trifluoromethylbenzyl)carbamic acid tert-butyl ester 4-Amino-3-iodo-5-trifluoromethylbenzonitrile (1805.2mg, 5.19mmol) was dissolved in THF at O 0 C. After Borane-THF complex (3eq, 17.36mmol, 17.36ml) was slowly added into the reaction mixture, A reaction temperature was heated to reflux. The reaction mixture was stirred for 12hr with reflux. After confirming the completion of the reaction, MeOH was added. The mixture was stirred for 4hr. The reaction solvent was removed in vacuo.
• Step 5 (4-Amino-3-trifluoromethyl-5-vinylbenzyl)carbamic acid tert-butyl ester
• Example 8 5 of Example 8 to give a title product, yellow syrup (89.3mg, 30.21 %).
• Step 1 (4-t-butyl-phenyl)- propynoic acid methyl ester
• 4-t-butyl-benzoyl chloride 500 mg, 2.34 mmol
• To the solution was added (triphenylphoshoranylidene)acetic acid methyl ester (1.5eq, 3.52 mmol, 1178.39 mg) and refluxed at 90 ⁇ 100 ° C for 12 hours.
• Step 3 3-(4-t-butylphenyl)-N-[1-(R)-(4-methanesulfonylamino-3-vinyl phenyl)ethyl]propiolicamide
• reaction solution was extracted with methylenechloride, washed with water and brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
• the acryl amide (90 mg) was synthesized according to the same procedure as described similar procedure in Example 17.
• the acrylamide (120 mg) was synthesized according to the same procedure as described in Example 11.
• N-(4-Aminomethyl-2-methyl-6-vinylphenyl)methanesulfonamide (1 eq, 33.5mg, 0.14mmol), 3-(4-tert-butylphenyl)acrylic acid (1.2eq, 0.17mmol, 34.18mg), DEPC(1.2eq, 0.17mmol, 25.49 ⁇ ), and TEA(2eq, 0.28mmol, 39.03/ ⁇ ) were added in DMF. The mixture was stirred for 12hr. The reaction mixture was purified according to Example 17 to give a white solid (29.83 mg, 51.3%).
• N-(4-Aminomethyl-2-chloro-6-vinylphenyl)methanesulfonamide (step 5 of Ex 9, 1eq, 33.4mg, 0.09mmol), 3-(4-tert-butylphenyl)acrylic acid (1.2eq, O.Ummol, 21.87mg), DEPC (1.2eq, O.Ummol, 16.63/ ⁇ ), and TEA (2eq, 0.18mmol, 25.09/ ⁇ ) were added in DMF. The mixture was stirred for 12hr. The reaction mixture was purified according to Example17 to give a white solid (20.8mg, 51.80%).
• Step 1 3-(4-tert-Butyl-2-morpholin-4-yl-phenyl)acrylic acid ethyl ester
• Step 2 3-(4-tert-Butyl-2-morpholin-4-yl-phenyl)-N-(3-fluoro-4- methanesulfonylamino-5-vinylbenzyl)acrylamide
• Step 1 4-tert-Butyl-1-iodo-2-(2-methoxyethoxy)benzene
• Step 2 3-[4-tert-Butyl-2-(2-methoxyethoxy)phenyl]acrylJc acid methyl ester Palladium acetate(63.77mg, 0.2841 mmol, 6%moleq), and 1.1'-
• Step 3 3-(4-tert-Butyl-2-morpholie-4-yl-phenyl)-N-(3-fluoro-4- methanesulfonylamino-5-vinylbenzyl)acrylamide 3-[4-tert-Butyl-2-(2-methoxyethoxy)phenyl]acrylic acid ethyl ester(40.4mg,
• N-(4-Aminomethyl-2-trifluoromethyl-6-vinylphenyl)methanesulfonamide (step 7 in Example 10, 1eq, 44.1 mg, 0.13mmol), 3-(4-tert-Butyl-phenyl)-acrylic acid (1.1eq, 0.15mmol, 29.99mg), DEPC(1.2eq, 0.16mmol, 23.67 ⁇ ) and TEA(2eq, 0.26mmol, 20 36.24/ ⁇ 1) were added in DMF. The reaction mixture was stirred for 12hr. The reaction mixture was purified according to Example 17 to give a white solid (55.4mg, 88.75%).
• Example 25 3-[4-tert-Butyl-2-(4-methylpiperazin-1 -yl)phenyl]-N-(3-fluoro-4- methanesulfonylamino-5-vinylbenzyl)acrylamide
• Step 1 3-[4-tert-Butyl-2-(4-methylpiperazine-1-yI)phenyl]acrylic acid ethyl ester
• Step 2 3-[4-tert-Butyl-2-(4-methylpiperazin-1-yl)phenyl]-N-(3-fluoro-4- methanesuIfonylamino-5-vinylbenzyl)acrylamide 3-[4-tert-Buty!-2-(4-methylpiperazin-1-yl)phenyl]acry!ic acid ethyl ester(29.1mg, 0.092mmol, 1eq) and sodium hydroxide(36.7mg, 0.917mmole were added in methanol and H 2 O. The mixture was stirred for 12hrs. The reaction mixture acidified with 5% HCI. The reaction mixture was concentrated in vacuo to give a yellow solid (27.8mg, 100%).
• Step 1 3-[4-tert-Butyl-2-(2-piperidine-1 -yl-ethoxy)phenyl] acrylic acid ethyl ester
• Step 2 3-[4-tert-Butyl-2-(2-piperidine-1-yl-ethoxy)phenyl]-N-(3-fluoro-4- methanesulfonylamino-5-vinylbenzyl)acrylamide
• Step 1 3-[4-tert-Butyl-2-(2-methoxyethylamino)phenyl]acrylic acid methyl ester Tris(dibenzylideneacetone)-dipalladium (19.1 mg, 0.021 mmol), 1 ,1 '- bis(diphenylphosphino)-ferrocene (34.7 mg, 0.063 mmol), 2-methoxyethylamine (72.5 ⁇ l, 0.834 mmol), and 3-(4-tert-butyl-2-trifluoromethanesulfonyloxyphenyl)-acrylic acid methyl ester (152.6mg, 0.417mmol, 1eq) were added to anhydrous toluene.
• Step 2 3-[4-tert-Butyl-2-(2-methoxyethylamino)phenyl]-N-(3-fluoro-4- methanesulfonylamino-5-vinylbenzyl)acrylamide
• Step 1 3-(4-tert-Butyl-2-methoxyphenyl)acryIic acid methyl ester
• Step 2 3-(4-tert-Butyl-2-methoxyphenyl)-N-(3-fluoro-4- methanesulfonylamino-5-vinyl-benzyl)acrylamide
• Step 1 5-tert-Butyl-2 iodophenol 3-tert-Butylphenol (30mg, 0.199mmol, 1eq) and N-iodosucdnimide(44.9mg,
• Step 3 3-(4-tert-Butyl-2-hydroxyphenyl)-N-(3-fluoro-4- methanesulfonylamino-5-vinylbenzyl)acrylamide
• reaction mixture was stirred for 5 hrs.
• a reaction mixture was purified according to step 2 of Example 27 to give a solid (78.7 mg, 89.9%).
• Step 1 4-[5- tert-Butyl-2-(2-methoxycarbonylvinyl) phenoxy]piperidine -1- carboxylic acid tert-butyl ester
• Step 2 4-(5-tert-Butyl-2-[2-(3-fluoro-4-methanesulfonylamino-5- vinylbenzylcarbamoyl)vinyl]phenoxy)-piperidine-1 -carboxylic acid tert-butyl ester
• Step 1 3-(4-tert-Butyl-2-butylaminophenyl)acrylic acid methyl ester
• Step 2 3-[4-tert-butyl-2-(3-methylbutylamino)phenyI]-N-(3-fluoro-4- methanesulfonylamino- 5-vinylbenzyl)acrylamide
• Step 1 3-(4-tert-Butyl-2-isobutylaminophenyl)acrylic acid methyl ester
• Tris(dibenzylideneacetone)-dipalladium (5%, 0.04 mmol, 37.24 mmol), 1 ,1'- bis(diphenylphosphino)-ferrocene (15%, 0.12mmol, 67.36mg), isobutylamine (1.62 mmol, 160.98/ ⁇ 6), and 3-(4-tert-butyl-2-trifluoromethanesulfonyloxy-phenyl)acrylic acid methyl ester (0.81 mmol, 298mg) were added in toluene. Cesium carbonate (1.22mmol, 395.87mg) was added. The reaction mixture was stirred for 12hrs at 80 ° C . A reaction mixture was purified according to step 1 of Example 27 to give yellow syrup (22.8mg, 10%).
• Step 3 3-(4-tert-Butyl-2-isobutylaminophenyl)-N-(3-fluoro-4- methanesulfonylamino-5-vinylbenzyl)acrylamide 3-(4-tert-butyl-2-isobutylaminophenyl)acrylic acid (O.O ⁇ mmol, 22.02mg), N-(4-
• Step 1 3-(4-tert-Butyl-2-trifluoromethanesulfonyloxyphenyl) acrylic acid ethyl ester
• Step 2 3-(4-tert-Butyl-2-isopropylaminophenyl)acrylic acid methyl ester Tris(dibenzylidene acetone)dipalladium (5%, 0.04 mmol, 37.24 mmol), 1 ,1'- bis(diphenylphosphino) ferrocene (15%, 0.12mmol, 67.36mg), isopropylamine (1.62mmol, 137.98/ ⁇ 6) and 3-(4-tert-butyl-2-trifluoromethanesulfonyloxyphenyl)-acrylic acid methyl ester (0.81 mmol, 298mg) were added in toluene under argon atmosphere.
• Step 3 3-(4-tert-Butyl-2-isopropylaminophenyl)acrylic acid 3-(4-tert-butyl-2-isopr ⁇ pylaminophenyl)acrylic acid methyl ester (0.14mmol,
• N-[4-(1-Aminoethyl)-2-fluoro-6-vinylphenyl]methanesulfon amide step 5 of Example 7, O.O ⁇ mmol, 30.6mg), 3-[4-tert-butyl-2-(3-methylbutylamino) phenyl]propionic acid (O.O ⁇ mmol, 18.65), DEPC (O.IOmmol, 14.57/i ⁇ ) and TEA (0.16mmol, 22.49/ ⁇ S) were added in DMF. The reaction mixture was stirred for 12hrs. The reaction mixture was purified according to Example 21 to yield a solid (27.2mg, 67.73%). mp: 154-156 °C ;
• N-[4-(1 -Aminoethyl)-2-fluoro-6-vinylphenyl]methanesulfon amide (0.7mmol, 25.3mg), 3-[4-tert-butyl-2-(3-methylbutylamino)phenyl]acrylic acid (0.7mmol, 15.27mg), DEPC (O.O ⁇ mmol, 12.75//£), and TEA (0.14mmol, 19.51/ ⁇ ) were added in DMF. The reaction mixture was stirred for 12hrs. The reaction mixture was purified according to similar procedure of Example 21 to yield title product (36.1 mg, 100.0%).
• Step 1 3-[4-tert-Butyl-2-(2-morpholin-4-yl-ethoxy)-phenyl]acrylic acid methyl ester
• Step 2 3-[4-tert-Butyl-2-(2-morpholine-4-yl-ethoxy)phenyl]-N-(3-fluoro-4- methanesulfonylamino-5-vinylbenzyl)acrylamide
• Step 1 3-[4-tert-Butyl-2-(tetrahydropyran-4-yloxy)-phenyl]acrylic acid methyl ester
• Step 2 3-[4-tert-Butyl-2-(tetrahydropyran-4-yloxy)phenyl]-N-(3-fluoro-4- methanesulfonylamino-5-vinylbenzyl)acrylamide
• Step 1 3-[4-tert-Butyl-2-(tetrahydropyran-4-yloxy)phenyl]propionic acid methyl ester
• Step 2 3-[4-tert-Butyl-2-(tetrahydropyran-4-yloxy)phenyl]-N-(3-fluoro-4- methanesulfonylamino-5-vinylbenzyl)propionamide
• Step 1 3-(4-tert-Butylphenyl)-2-methylpropionic acid
• Step 2 3-(4-tert-Butylphenyl)-N-(3-fluoro-4-methanesulfonylamino-5- vinylbenzyl)-2-methylpropionamide
• Step 1 tert-butyl N-[4-(methanesulfonylamino)-3-vinylbenzyl]carbamate
• tert-Butyl N-[4- (methanesulfonylamino)-3-iodobenzyl]carbamate (1.0 g, 2.3 mmol) was dissolved in toluene (20 ml_).
• Tributyl vinyltin (0.8 ml_, 2.8 mmol) and Pd(PPh3) 4 140 mg, 0.12 mmol
• Step 2 N-[4-(aminomethyl)-2-vinylphenyl]methanesulfonamide tert-butyl N-[4- (methanesulfonylamino)-3-vinylbenzyl]carbamate (100 mg, 0.23 mmol) and TFA (0.4 ml) were added in methylene chloride (2 ml_). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo to yield title compound (100%).
• Step 3 3-[4-(tert-butyl)phenyI]-N-[4- (methanesuIfonylamino)-3-vinyl b enzyl] pr opion amide
• Step 1 (4-Amino-2-methoxy-benzyl)-carbamic acid tert-butyl ester 2-Methoxy-4-nitro-benzonitrile (1.78g, lOmmol) and Pd/C (4 small spetula) were suspended in MeOH containing c-HCI, 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 yellow solid (1.58g, 70%). The solid was dissolved in THF, and the solution was cooled to O 0 C. Triethylamine (1.43g, 14mmol) was added to the solution followed by BoC 2 O, and the reaction mixture was stirred overnight at ambient temperature.
• Step 2 (4-Amino-5-iodo-2-methoxy-benzyl)-carbamic acid tert-butyl ester
• Step 3 (4-Amino-2-methoxy-5-vinyl-benzyl)-carbamic acid tert-butyl ester
• Step 4 (4-Methanesulfonylamino-2-methoxy-5-vinyl-benzyl)-carbamic acid tert-butyl ester
• 4-amino-2-methoxy-5-vinyl-benzyl)-carbamic acid tert-butyl ester (220mg, 0.79mmol) in methylene chloride was added triethylamine (132).

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• 2006
  • 2006-03-15 KR KR1020077024002A patent/KR101304981B1/ko not_active Expired - Fee Related
  • 2006-03-15 JP JP2008502895A patent/JP5159604B2/ja not_active Expired - Fee Related
  • 2006-03-15 BR BRPI0608714-0A patent/BRPI0608714A2/pt not_active Application Discontinuation
  • 2006-03-15 US US11/909,136 patent/US7763657B2/en active Active
  • 2006-03-15 EA EA200702020A patent/EA200702020A1/ru unknown
  • 2006-03-15 EP EP06716379.0A patent/EP1861357B1/en not_active Expired - Lifetime
  • 2006-03-15 MX MX2007011466A patent/MX2007011466A/es not_active Application Discontinuation
  • 2006-03-15 AU AU2006225496A patent/AU2006225496A1/en not_active Abandoned
  • 2006-03-15 WO PCT/KR2006/000929 patent/WO2006101318A1/en not_active Ceased
  • 2006-03-15 CA CA002601871A patent/CA2601871A1/en not_active Abandoned
  • 2006-03-17 TW TW095109337A patent/TW200716523A/zh unknown
  • 2006-03-17 CA CA002601873A patent/CA2601873A1/en not_active Abandoned
  • 2006-03-17 WO PCT/KR2006/000988 patent/WO2006101321A1/en not_active Ceased
  • 2006-03-17 US US11/909,144 patent/US7960584B2/en active Active
  • 2006-03-17 EP EP06716438A patent/EP1861358A4/en not_active Withdrawn
  • 2006-03-17 AR ARP060101059A patent/AR053561A1/es unknown
  • 2006-03-17 KR KR1020077024004A patent/KR101304979B1/ko not_active Expired - Fee Related
  • 2006-03-17 TW TW095109137A patent/TW200716522A/zh unknown
  • 2006-03-17 MX MX2007011205A patent/MX2007011205A/es not_active Application Discontinuation
  • 2006-03-17 EA EA200702021A patent/EA200702021A1/ru unknown
  • 2006-03-17 BR BRPI0608624-1A patent/BRPI0608624A2/pt not_active Application Discontinuation
  • 2006-03-17 AU AU2006225434A patent/AU2006225434A1/en not_active Abandoned
  • 2006-03-17 JP JP2008502896A patent/JP5064374B2/ja not_active Expired - Fee Related
  • 2006-03-17 AR ARP060101058A patent/AR056943A1/es unknown
• 2007
  • 2007-09-11 IL IL185891A patent/IL185891A0/en unknown
  • 2007-09-11 IL IL185892A patent/IL185892A0/en unknown
  • 2007-10-18 NO NO20075353A patent/NO20075353L/no not_active Application Discontinuation
  • 2007-10-18 NO NO20075354A patent/NO20075354L/no not_active Application Discontinuation

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